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Project Summary Postpartum cardiomyopathy (PPCM) is a disease of unknown etiology that arises as a complication of pregnancy in women with no prior heart disease. It occurs in 1:1800 to 1:3500 births in the United States and is characterized by an acute onset of heart failure during the last month of pregnancy or within five months postpartum. PPCM is a major cause of maternal morbidity and mortality with no PPCM-specific treatment options available. During pregnancy, pregnancy-associated hypertrophy initiates the activation of cardiomyocyte protective signaling pathways that block stress-mediated apoptosis. In PPCM patients there is an increase in cardiomyocyte apoptosis that leads to irreversible dysfunction and heart failure. The cellular mechanisms driving cardiomyocyte apoptosis are not fully understood. We have identified a gene PTRH2 (also called Bit-1) that is evolutionarily conserved, mediates integrin regulated cell survival and apoptosis, and mutations in this gene promote multisystem disease in humans. We hypothesize that PTRH2 is essential for cardioprotection from peripartum stresses in the maternal heart. To study this we developed a cardiomyocyte-specific deletion of PTRH2 (CKO). CKO male and never- pregnant female mice demonstrate no heart defects and live to old age. However, 100% of CKO pregnant female mice develop PPCM in a dose-dependent manner (CKO>HET). We will use cell and molecular biology and our CKO mice to determine how PTRH2 mediates cardioprotection, test whether PTRH2 associated proteins abrogate the PPCM phenotype in CKO pregnant mice, determine whether PTRH2 expression blocks hypertrophy and examine PPCM patient heart samples for PTRH2 gene mutations. The proposed project has the potential to identify an essential survival pathway that is activated in pregnancy-associated hypertrophy, test PTRH2 directed therapeutic strategies in a preclinical mouse model of PPCM and determine whether mutations in PTRH2 promote PPCM.
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TY - RPRT
T1 - Weak looking-ahead and its application in computer-integrated process planning
T3 - Kaiserslautern ; Saarbrücken : DFKI, 1993
A1 - Meyer,Manfred A.
A1 - Müller,Jörg P.
Y1 - 2011/06/27
N2 - Constraint logic programming has been shown to be a very useful tool for knowledge representation and problem-solving in different areas. Finite Domain extensions of PROLOG together with efficient consistency techniques such as forward-checking and looking-ahead make it possible to solve many discrete combinatorial problems within a short development time. In this paper we present the weak looking-ahead strategy (WLA), a new consistency technique on finite domains combining the computational efficiency of forward-checking with the pruning power of looking-ahead. Moreover, incorporating weak looking-ahead into PROLOG's SLD resolution gives a sound and complete inference rule whereas standard looking-ahead itself has been shown to be incomplete. Finally, we will show how to use weak looking-ahead in a real-world application to obtain an early search-space pruning while avoiding the control overhead involved by standard looking-ahead.
KW - Künstliche Intelligenz
CY - Saarbrücken
PB - Saarländische Universitäts- und Landesbibliothek
AD - Postfach 151141, 66041 Saarbrücken
UR - http://scidok.sulb.uni-saarland.de/volltexte/2011/3654
ER -
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2 Comments:
Men with high mate quality (e.g. handsome, rich, etc.) tend to do less parental investment (because they have greater mating opportunity costs). Their mates put up with it, as it were, because of the trade-off for high mate quality. These men tend to have greater facial symmetry and testosterone, and women are more likely to have sex with them. The men themselves, might provide positive feedback here as well (e.g. greater testosterone leads to greater sex drive).
Its based on principles for Parentla Investment and Sexual Selection theory.
Seems like they could easily be confusing cause and correlation. Seems entirely possible to me that men that are more prone to do "womens's chores" could easily be men with lesser sexual drives--or they simply have less direct and forward mentalities so they're less likely to initiate...activities...to begin with.
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Mutual benefits. Hospital-business wellness partnerships yield.
Hospitals and employers see a strong business case for developing wellness partnerships.
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(J Am Heart Assoc. 2017;6:e007026 DOI: 10.1161/JAHA.117.007026.)29042422
Clinical PerspectiveWhat Is New?In this nonrandomized, retrospective, observational study of patients undergoing cardiac resynchronization therapy (CRT) with quadripolar (QUAD) and non‐QUAD left ventricular leads, programmed to biventricular, single‐site left ventricular pacing, QUAD was associated with a lower total mortality, cardiac mortality, and heart failure hospitalization.These benefits were observed after both CRT‐defibrillation and CRT‐pacing, after adjustment for heart failure etiology.Re‐interventions for left ventricular displacement or phrenic nerve stimulation, which were lower with QUAD, were associated with worse outcomes.What Are the Clinical Implications?The markedly better outcomes after CRT observed with QUAD supports their preferential use over non‐QUAD in clinical practice.The relative benefits of CRT‐defibrillation over CRT‐pacing requires further evaluation in the QUAD era.
Introduction {#jah32587-sec-0008}
============
Cardiac resynchronization therapy (CRT), with CRT‐defibrillation (CRT‐D) or without (CRT‐pacing \[CRT‐P\]) defibrillation, is a standard treatment for selected patients with heart failure (HF) with severe left ventricular (LV) dysfunction and a wide QRS complex.[1](#jah32587-bib-0001){ref-type="ref"} Since the first transvenous CRT implantations were undertaken in the 1990s,[2](#jah32587-bib-0002){ref-type="ref"}, [3](#jah32587-bib-0003){ref-type="ref"} improvements in delivery catheter and LV lead design, as well as implantation techniques using venoplasty and snaring, have helped to improve implantation success. Prominent among the challenges still encountered at implantation and thereafter is achieving acceptable LV pacing thresholds without phrenic nerve stimulation (PNS).[4](#jah32587-bib-0004){ref-type="ref"} Deactivation of the LV lead mainly occurs as a result of LV lead displacement which, in studies using unipolar and bipolar leads, occurs more frequently than with atrial or right ventricular leads.[5](#jah32587-bib-0005){ref-type="ref"}, [6](#jah32587-bib-0006){ref-type="ref"}, [7](#jah32587-bib-0007){ref-type="ref"}, [8](#jah32587-bib-0008){ref-type="ref"}, [9](#jah32587-bib-0009){ref-type="ref"}
Since their launch in 2010, quadripolar LV leads (QUAD) have been considered by implanters as a "game‐changer," even before robust clinical evidence emerged in their favor. Observational studies and a randomized, controlled trial[10](#jah32587-bib-0010){ref-type="ref"} have since shown that QUAD is associated with higher implant success rates and lower rates of re‐interventions for LV lead displacement or PNS.[11](#jah32587-bib-0011){ref-type="ref"}, [12](#jah32587-bib-0012){ref-type="ref"}
Some observational studies have suggested that CRT‐D using QUAD programmed to single‐site LV pacing also improves survival.[12](#jah32587-bib-0012){ref-type="ref"}, [13](#jah32587-bib-0013){ref-type="ref"}, [14](#jah32587-bib-0014){ref-type="ref"} These findings, however, are not consistent,[15](#jah32587-bib-0015){ref-type="ref"} and there is uncertainty as to whether they also apply to CRT‐P. Moreover, the possible influence of HF etiology and the effects of QUAD on HF hospitalization and mode of death remain largely unexplored.
Methods {#jah32587-sec-0009}
-------
This is a nonrandomized, retrospective, observational study comparing clinical outcomes of patients undergoing CRT‐D and CRT‐P device implantation using unipolar, bipolar, and quadripolar leads in a single center (Queen Elizabeth Hospital, Birmingham, United Kingdom) from February 2010 to January 2017. The study was approved by the Clinical Audit Department at the Queen Elizabeth Hospital, which does not require informed consent for audit of clinical care delivery. The study conforms to the Declaration of Helsinki.
Implantation {#jah32587-sec-0010}
------------
Device implantation was undertaken using standard techniques with patients under local anesthesia and intravenous sedation. Access was gained via subclavian, axillary, and cephalic veins. The LV pacing site was chosen by the implanter on the basis of lead stability, absence of PNS, and adequate pacing parameters. An implant was considered a failure in the event of failure to deploy all desired leads and device at the index procedure. The first QUAD was implanted in February 2010. The following QUAD leads were used: Quartet 1458Q (St. Jude Medical, Sylmar, CA), Attain Performa (Medtronic Inc, Minneapolis, MN), and Acuity X4 (Boston Scientific, Marlborough, MA). The choice of vector was made at implantation and was made on the basis of presence or absence of PNS.
Follow‐Up {#jah32587-sec-0011}
---------
Patients were followed up in dedicated device therapy clinics. Before 2013, patients underwent systematic echocardiographic optimization. To this end, patients in sinus rhythm underwent transmitral Doppler‐directed optimization of atrioventricular delay using an iterative technique before discharge and at every scheduled visit thereafter. In patients with sinus rhythm, atrial pacing was set at 60 beats/min, and the pacing mode was set to DDDR with an interventricular delay of 0 to 4 ms, according to the manufacturer. In patients with permanent atrial fibrillation, right ventricular and LV leads were implanted and a CRT generator was used, plugging the atrial port and programming the generator to a ventricular triggered mode. In patients with uncontrolled atrial fibrillation despite medical therapy with suboptimal biventricular pacing capture (\<98%), atrioventricular junction ablation was undertaken, according to the individual clinician\'s decision. After 2013, echocardiographic optimization was only undertaken in symptomatic nonresponders.
End Points {#jah32587-sec-0012}
----------
The primary end point was total mortality, which included cardiac transplantation. Secondary end points included cardiac mortality and unplanned HF hospitalization. The first event was included in the analysis. With respect to mode of death, sudden cardiac death was defined as a "natural, unexpected death due to cardiac causes, heralded by an abrupt loss of consciousness within 1 hour of the onset of acute symptoms,"[16](#jah32587-bib-0016){ref-type="ref"} whereas death from pump failure was defined as "death after a period of clinical deterioration in signs and symptoms of heart failure despite medical treatment"[17](#jah32587-bib-0017){ref-type="ref"} or cardiac transplantation. Mortality data were collected through medical records every 3 months by investigators who were blinded to all other patient data. Mortality and event data were collected by separate investigators who were blinded to all other data, except patient identifiers.
Statistical Analysis {#jah32587-sec-0013}
--------------------
In preliminary analyses, no differences in outcomes emerged between unipolar and bipolar LV leads (data not shown). On this basis, the latter were classified as "non‐QUAD" in statistical analyses. Normality was tested using the Shapiro--Wilk test. Continuous variables are expressed as mean (±SD) and compared using the Student *t* test. Categorical variables were compared using the χ^2^ tests. Kaplan--Meier curves and the log‐rank tests were used to assess observed cumulative survival and to test for differences in survival, respectively. Cox proportional hazard models were used to compare hazard rates of subgroups. Variables reaching a *P*\<0.10 on univariable analyses were entered in multivariable models, and further backward elimination was applied for the final multivariable models. Confounders included in final models were the following: quadripolar lead, sex (male), age at implantation, New York Heart Association (NYHA) class, creatinine, QRS duration, and medication of angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers. Proportionality hypotheses were verified by visual examination of log (survival) graphs to ensure parallel slopes, and by examining Schoenfeld residuals. Statistical analyses were undertaken using Stata 14 (StataCorp, Houston, TX). A 2‐sided *P*≤0.05 was considered statistically significant.
Results {#jah32587-sec-0014}
=======
Baseline Characteristics {#jah32587-sec-0015}
------------------------
Over the study period of 6.9 years, 847 patients underwent CRT (CRT‐D: 436 \[51.5%\]; CRT‐P: 411 \[48.5%\]), using QUAD (287 \[33.9%\]), unipolar (63 \[7.43%\]), or bipolar (497 \[58.7%\]) leads. Implantations using unipolar and bipolar leads were classified as non‐QUAD. As shown in Table [1](#jah32587-tbl-0001){ref-type="table"}, the groups were well matched for age, sex, cause of cardiomyopathy, comorbidities, proportion of upgrades from pacemaker, atrial rhythm (sinus rhythm or atrial fibrillation), QRS morphology, QRS duration, and left ventricular ejection fraction. Compared with the non‐QUAD group, QUAD were more likely to be in NYHA class I and II (*P*\<0.001) and to undergo CRT‐D (62.0% versus 46.1%, *P*\<0.001). In addition, QUAD had a lower uptake of loop diuretics (*P*=0.003) and a higher uptake of β‐blockers (*P*=0.004).
######
Characteristics of the Study Group
QUAD Non‐QUAD *P* Value[a](#jah32587-note-0002){ref-type="fn"}
------------------------------------------------------------------- --------------- --------------- --------------------------------------------------
N 287 560
Sex (male), n (%) 209 (72.8) 398 (71.1) 0.592
Age, y 72.5±12.2 73.2±11.3 0.517
NYHA class, n (%)
I 40 (14.3) 32 (5.8) \<0.001
II 87 (31.1) 66 (11.9)
III 148 (52.9) 419 (75.5)
IV 5 (1.79) 38 (6.9)
Cause of cardiomyopathy, n (%)
Ischemic 151 (52.6) 279 (49.8) 0.442
Nonischemic 136 (47.4) 281 (50.2)
Device type, n (%)
CRT‐D 178 (62.0) 258 (46.1) \<0.001
CRT‐P 109 (38.0) 302 (53.9)
Comorbidities, n (%)
Diabetes mellitus 80 (28.1) 127 (22.9) 0.099
Hypertension 87 (30.5) 165 (29.7) 0.811
CABG 48 (16.7) 102 (18.2) 0.591
Upgrade from pacemaker 56 (19.5) 119 (21.6) 0.554
ECG variables
Sinus rhythm, n (%) 195 (67.9) 356 (63.6) 0.206
Atrial fibrillation, n (%)[b](#jah32587-note-0003){ref-type="fn"} 92 (32.1) 204 (36.4)
QRS morphology (LBBB), n (%) 228 (79.4) 438 (78.2) 0.680
QRS duration, ms[c](#jah32587-note-0004){ref-type="fn"} 152.6±24.0 152.4±25.0 0.896
Medication, n (%)
Loop diuretics 274 (95.5) 553 (98.8) 0.003
ACEIs/ARA 257 (89.6) 489 (87.3) 0.344
β‐Blockers 227 (79.1) 391 (69.2) 0.004
MRA 124 (43.2) 244 (43.6) 0.919
LVEF, % 24.9±9.1 25.8±11.2 0.249
Creatinine, μmol/L[d](#jah32587-note-0005){ref-type="fn"} 106 (89--129) 104 (87--132) 0.727
Variables are expressed as mean±SD, unless indicated otherwise. ACEI indicates angiotensin‐converting enzyme inhibitors; ARA, angiotensin receptor blockers; CABG, coronary artery bypass grafting; CRT‐D, cardiac resynchronization therapy‐defibrillation; CRT‐P, cardiac resynchronization therapy‐pacing; LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonists; NYHA, New York Heart Association; QUAD, quadripolar left ventricular lead.
Refers to differences between the groups from ANOVA for continuous variables and from χ^2^ tests for categorical variables.
Includes permanent, persistent, and paroxysmal atrial fibrillation.
Excludes upgrades to pacemaker.
Log‐transformed for statistical analyses.
Total Mortality {#jah32587-sec-0016}
---------------
Over a follow‐up period of 3.2 years (median \[interquartile range,1.90 to 5.0; 1.8 years \[interquartile range, 1.0--2.6\] for QUAD; 4.7 years \[interquartile range, 3.4--5.7\] for non‐QUAD), QUAD was associated with a lower total mortality in Kaplan--Meier survival analyses (log rank *P*\<0.001, Figure [1](#jah32587-fig-0001){ref-type="fig"}). The annualized total mortality rate was 3.6% (n=19) for QUAD and 10.9% (n=218) for non‐QUAD. Event rates are shown in Table [2](#jah32587-tbl-0002){ref-type="table"}. Univariable Cox proportional hazards analyses are shown in Table [3](#jah32587-tbl-0003){ref-type="table"}. In multivariable analyses (Table [4](#jah32587-tbl-0004){ref-type="table"}), QUAD was associated with a lower mortality (adjusted hazard ratio \[aHR\]: 0.32, 95% confidence interval \[CI\], 0.20--0.52), after adjustment for age, sex, NYHA class, and creatinine. Other confounders failed to reach significance in multivariable models. In order to exclude a possible time‐related bias, we explored whether date of implant emerged as a predictor of total mortality. In multivariable Cox proportional hazards analysis, date of implant did not predict total mortality (HR: 1.46, 95% CI, 0.95--2.26).
{#jah32587-fig-0001}
######
Event Rates According to Lead Type
QUAD (n=287) Non‐QUAD (n=560)
------------------------- -------------- ------------------ ----- ------
Total mortality 19 3.6 218 10.9
Cardiac mortality 13 2.4 136 6.0
HF hospitalization 22 4.4 104 5.6
Death from pump failure 11 2.1 122 5.4
SCD 2 0.4 13 0.6
HF indicates heart failure; QUAD, quadripolar left ventricular lead; SCD, sudden cardiac death.
Data are expressed in terms of annualized event rates.
######
Univariable Cox Proportional Hazards Analyses of Baseline Variables in Relation to Clinical Outcomes
Total Mortality Cardiac Mortality HF Hospitalization
------------------------ ----------------- ------------------- -------------------- --------- ------ ------ ------- --------- ------ ------ ------ ---------
Lead type (QUAD) 0.31 0.19 0.49 \<0.001 0.35 0.20 0.63 \<0.001 0.60 0.37 0.95 0.030
Sex (male) 1.76 1.28 2.42 0.001 1.99 1.30 3.04 0.001 1.23 0.82 1.84 0.309
Age 1.04 1.02 1.05 \<0.001 1.02 1.00 1.03 0.029 1.03 1.01 1.04 0.004
NYHA class
III 1.50 1.04 2.18 0.031 1.41 0.90 2.21 0.138 1.25 0.80 1.94 0.329
IV 3.74 2.25 6.21 \<0.001 2.40 1.25 4.61 0.009 1.24 0.51 3.03 0.634
Cause (ischemic) 1.23 0.95 1.59 0.112 1.21 0.88 1.67 0.249 1.31 0.92 1.87 0.130
Device type (CRT‐D) 0.81 0.63 1.04 0.100 0.96 0.70 1.33 0.810 0.98 0.69 1.39 0.922
Comorbidities
Diabetes mellitus 1.33 1.00 1.77 0.050 1.57 1.11 2.22 0.010 1.48 1.02 2.16 0.042
Hypertension 1.10 0.83 1.45 0.509 0.91 0.63 1.31 0.620 0.96 0.65 1.41 0.820
CABG 1.16 0.85 1.60 0.352 1.05 0.70 1.59 0.801 1.04 0.66 1.63 0.872
ECG variables
Atrial fibrillation 1.36 1.05 1.76 0.019 1.26 0.91 1.74 0.171 0.94 0.65 1.36 0.741
QRS morphology (LBBB) 0.81 0.60 1.09 0.161 0.71 0.50 1.02 0.064 0.57 0.39 0.84 0.004
QRS duration, ms 1.00 0.99 1.00 0.115 0.99 0.99 1.00 0.041 0.99 0.98 0.99 \<0.001
Medication
Loop diuretics 1.38 0.44 4.32 0.578 2.73 0.38 19.51 0.317
ACEIs/ARA 0.54 0.39 0.76 \<0.001 0.52 0.35 0.79 0.002 1.28 0.69 2.39 0.428
β‐Blockers 0.87 0.66 1.14 0.309 0.81 0.57 1.13 0.215 0.91 0.62 1.33 0.612
MRA 0.90 0.69 1.16 0.410 1.01 0.73 1.40 0.949 1.25 0.88 1.77 0.210
LVEF, % 1.00 0.98 1.01 0.462 0.99 0.97 1.01 0.211 1.01 0.99 1.02 0.404
Creatinine, log μmol/L 2.20 1.72 2.82 \<0.001 1.92 1.38 2.67 \<0.001 1.93 1.34 2.76 \<0.001
ACEIs indicates angiotensin‐converting enzyme inhibitors; ARA, angiotensin receptor blockers; CABG, coronary artery bypass grafting; CRT‐D, cardiac resynchronization therapy‐defibrillation; HF, heart failure; LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonists; NYHA, New York Heart Association; QUAD, quadripolar left ventricular lead.
Results are expressed as hazard ratios and 95% confidence intervals (CI) from Cox proportional hazards analyses.
######
Multivariable Analyses of Baseline Variables in Relation to Clinical Outcomes
Total Mortality Cardiac Mortality HF Hospitalization
------------------------ ----------------- ------------------- -------------------- --------- ------ ------ ------ ------- ------ ------ ------ ---------
Lead type (QUAD) 0.32 0.20 0.52 \<0.001 0.36 0.20 0.65 0.001 0.62 0.39 0.99 0.047
Sex, male 1.65 1.18 2.31 0.003 1.74 1.13 2.70 0.013 ··· ··· ··· ···
Age, y 1.03 1.02 1.05 \<0.001 1.02 1.00 1.03 0.043 1.03 1.01 1.05 0.001
NYHA class (IV) 1.89 1.25 2.86 0.003 ··· ··· ··· ··· ··· ··· ··· ···
QRS duration, ms ··· ··· ··· ··· 0.99 0.99 1.00 0.019 0.99 0.98 0.99 \<0.001
ACEIs/ARAs ··· ··· ··· ··· 0.64 0.42 0.99 0.044 ··· ··· ··· ···
Creatinine, log μmol/L 1.68 1.25 2.25 0.001 1.50 1.04 2.16 0.030 1.91 1.30 2.80 0.001
Only variables with *P*\<0.10 on univariable analyses were included in multivariable models. ACEI, angiotensin‐converting enzyme inhibitors; ARA, angiotensin receptor blockers; HF, heart failure; NYHA, New York Heart Association; QUAD, quadripolar left ventricular lead.
Results are expressed as hazard ratios and 95% confidence intervals (CI) from Cox proportional hazards analyses.
Cardiac Mortality {#jah32587-sec-0017}
-----------------
The annualized cardiac mortality rate was 2.40% (n=13) for QUAD and 6.0% (n=136) for non‐QUAD (Table [2](#jah32587-tbl-0002){ref-type="table"}). In Kaplan--Meier survival analyses, QUAD was associated with a lower cardiac mortality (log rank *P*\<0.001, Figure [1](#jah32587-fig-0001){ref-type="fig"}). In multivariable analyses (Table [4](#jah32587-tbl-0004){ref-type="table"}), QUAD was associated with a lower cardiac mortality (aHR: 0.36, 95% CI, 0.20--0.65), after adjustment for known confounders.
HF Hospitalization {#jah32587-sec-0018}
------------------
The annualized HF hospitalization rate was 4.40% for QUAD (n=22) and 5.6% (n=104) for non‐QUAD (Table [2](#jah32587-tbl-0002){ref-type="table"}). In Kaplan--Meier survival analyses, QUAD was associated with a lower risk of HF hospitalization (log rank *P*=0.028, Figure [1](#jah32587-fig-0001){ref-type="fig"}). In multivariable analyses (Table [4](#jah32587-tbl-0004){ref-type="table"}), QUAD was associated with a lower risk of HF hospitalization (aHR: 0.62, 95% CI, 0.39--0.99), after adjustment for potential confounders.
QUAD and Device Type {#jah32587-sec-0019}
--------------------
In univariable (Table [3](#jah32587-tbl-0003){ref-type="table"}) and mutivariable (Table [4](#jah32587-tbl-0004){ref-type="table"}) analyses, CRT‐D did not emerge as a predictor of any end point. Separate analyses according to device type were also undertaken. As shown in Figure [2](#jah32587-fig-0002){ref-type="fig"}, QUAD was superior to non‐QUAD with respect to all end points in Kaplan--Meier survival analyses. In univariable analyses including CRT‐D patients only, QUAD was superior to non‐QUAD with respect to total mortality (HR: 0.44, 95% CI, 0.25--0.76) and cardiac mortality (HR: 0.43, 95% CI, 0.22--0.85). A lower, albeit nonsignificant reduction with QUAD was observed in HF hospitalization (HR: 0.54, 95% CI, 0.29--1.01). In univariable analyses including CRT‐P patients only, QUAD was superior to non‐QUAD with respect to total mortality (HR: 0.16, 95% CI, 0.06--0.45) and cardiac mortality (HR: 0.23, 95% CI, 0.07--0.73), but no differences emerged in HF hospitalization (HR: 0.67, 95% CI, 0.32--1.37).
{#jah32587-fig-0002}
Mode of Death {#jah32587-sec-0020}
-------------
Over the follow‐up period, there were 11/287 (3.83%) deaths because of pump failure with QUAD and 122/558 (21.8%) with non‐QUAD. There were 2/287 (0.70%) sudden cardiac deaths with QUAD and 13/560 (2.32%) with non‐QUAD. Noncardiac deaths accounted for 3/287 (1.04%) deaths with QUAD and 42/560 (7.5%) deaths with non‐QUAD. The cause and mode of death was unknown in 3 (1.04%) patients with QUAD and in 40 (7.14%) patients with non‐QUAD. Excluding these patients, QUAD was associated with a lower mortality from pump failure (log rank *P*\<0.001; aHR: 0.33; 95% CI, 0.18--0.62), but no differences emerged with respect to sudden cardiac death (aHR: 0.58; 95% CI, 0.13--2.68, Figure [3](#jah32587-fig-0003){ref-type="fig"}).
{#jah32587-fig-0003}
Implantation {#jah32587-sec-0021}
------------
There were 856 first attempts at CRT device implantation, 833 (97.3%) of which were successful at the first attempt and 847 (98.9%) after ≥1 attempts. Re‐interventions for LV displacement or PNS were lower with QUAD than with non‐QUAD (Table [5](#jah32587-tbl-0005){ref-type="table"}, Figure [4](#jah32587-fig-0004){ref-type="fig"}). In univariable analyses, re‐interventions for LV displacement or PNS predicted total mortality (aHR: 1.68, 95% CI, 1.11--2.54), cardiac mortality (aHR: 2.61, 95% CI, 1.66--4.11), and HF hospitalization (aHR: 2.09, 95% CI, 1.22--3.58).
######
Implant‐Related Complications and Re‐Interventions
All QUAD Non‐QUAD *P* Value[a](#jah32587-note-0013){ref-type="fn"}
------------------------------------------------------------------ ----------- ----------- ----------- --------------------------------------------------
Implant‐related complications, n (%)
Hematoma treated conservatively 23 (2.72) 10 (3.48) 14 (2.50) 0.390
Hematoma requiring evacuation 4 (0.47) 0 4 (0.71)
Pneumothorax treated conservatively 5 (0.59) 2 (0.70) 3 (0.54)
Pneumothorax requiring drainage 1 (0.12) 0 1 (0.18)
Perforation by RV lead 2 (0.24) 1 (0.35) 1 (0.18)
Coronary sinus dissection[b](#jah32587-note-0014){ref-type="fn"} 5 (0.59) 4 (1.39) 3 (0.54)
Subclavian artery aneurysm 1 (0.12) 1 (0.35) 0
Arrhythmia requiring cardioversion 1 (0.12) 1 (0.35) 0
Anemia postprocedure 1 (0.12) 0 1 (0.18)
Pulmonary edema 1 (0.12) 0 1 (0.18)
Total, n (%) 44 (5.19) 19 (6.62) 28 (5.00)
Extractions for infection
Within 1 y 8 (1.43) 3 (1.05) 5 (0.89) 0.297
After 1 y 3 (0.53) 0 3 (0.54)
Total, n (%) 11 (1.96) 3 (1.05) 8 (1.43)
LV lead re‐interventions
LV lead displacement 34 (4.01) 6 (2.09) 28 (5.0) 0.007
Phrenic nerve stimulation 19 (2.24) 3 (1.05) 16 (2.86)
Total 53 (6.26) 9 (3.14) 44 (7.86)
RV indicates right ventricular.
Refers to χ^2^ tests of quadripolar (QUAD) compared with non‐QUAD left ventricular (LV) leads.
No coronary sinus dissections required re‐interventions.
{#jah32587-fig-0004}
Other Complications {#jah32587-sec-0022}
-------------------
As shown in Table [5](#jah32587-tbl-0005){ref-type="table"}, implant‐related complications were similar for QUAD and non‐QUAD (odds ratio: 1.30, 95% CI, 0.71--2.36). A total of 8 extractions for system infection were undertaken within 1 year of implantation (QUAD: 3 (1.05%); non‐QUAD: 5 (0.90%; *P*=0.828) and 3 after 1 year (QUAD: 0); non‐QUAD: 3 (0.54%; *P*=0.214). No device‐related infection or subsequent extraction led to death.
Lead Design {#jah32587-sec-0023}
-----------
Three LV lead families from 3 manufacturers were used, namely, Quartet (n=189, St. Jude Medical, Sylmar, CA), Attain Performa (n=87, Medtronic Inc, Minneapolis, MN), and Acuity X4 (n=11, Boston Scientific, Marlborough, MA). Compared with non‐QUAD leads, Quartet leads (aHR: 0.36, 95% CI, 0.21--0.6; sample size: 560 non‐QUAD and 189 Quartet leads) as well as the Attain Performa leads (aHR: 0.11, 95% CI, 0.03--0.45; sample size: 560 non‐QUAD and 87 Attain Performa) were associated with lower total mortality. Comparison of Quartet (n=189) with Attain Performa (n=87) revealed no difference in total mortality (Quartet HR: 3.06, 95% CI, 0.70--13.38). Boston Scientific Acuity X4 leads were excluded from these analysis because of the small numbers involved (n=11).
Discussion {#jah32587-sec-0024}
==========
In this study, we have compared clinical outcomes after CRT using QUAD and non‐QUAD, programmed to biventricular, single‐site LV pacing. Several findings have emerged. First, QUAD was associated with a 68% lower total mortality. Second, QUAD was associated with a marked reduction in cardiac mortality (by 64%) and in HF hospitalization (by 38%). Third, QUAD was associated with a lower mortality from pump failure, while no differences emerged in sudden cardiac death. Fourth, HF cause did not impact on the superior outcomes of QUAD over non‐QUAD. Fifth, QUAD was superior to non‐QUAD after both CRT‐D and CRT‐P. Sixth, no group differences emerged in implant complications, but QUAD was associated with fewer re‐interventions for LV lead displacement or PNS. Seventh, re‐interventions for LV displacement or PNS predicted total mortality, cardiac mortality, and HF hospitalization.
Mortality {#jah32587-sec-0025}
---------
A recent retrospective study comparing QUAD with bipolar leads showed no difference in survival at 12 months (mean follow‐up 256 days for QUAD).[15](#jah32587-bib-0015){ref-type="ref"} In contrast, a US‐wide study based on data from device implant records and telemonitoring showed that CRT‐D using QUAD was associated with a better survival than CRT‐D using bipolar leads.[13](#jah32587-bib-0013){ref-type="ref"} Observational data from 3 centers in the United Kingdom showed similar findings.[12](#jah32587-bib-0012){ref-type="ref"}
Our annualized total mortality rate for non‐QUAD (10.9%) is comparable to that found in randomized, controlled trials using non‐QUAD, which amounted to 9.7% in CARE‐HF (Cardiac Resynchronization Heart Failure)[18](#jah32587-bib-0018){ref-type="ref"} and 15% in COMPANION (Comparison of Medical Therapy, Pacing and Defibrillation in heart failure)[19](#jah32587-bib-0019){ref-type="ref"}, [20](#jah32587-bib-0020){ref-type="ref"} after CRT‐P. In the CRT‐D arm of COMPANION, the annualized total mortality rate was 12%.[20](#jah32587-bib-0020){ref-type="ref"} In contrast, the annualized total mortality rate in the present study was 3.6% with QUAD.
HF Hospitalization {#jah32587-sec-0026}
------------------
This is the first study to explore HF hospitalization after CRT using QUAD. Survival free from cardiovascular hospitalization at 1 and 2 years with QUAD was 94% and 91%, respectively. Among the few studies to address the long‐term effects of CRT on HF hospitalizations in the non‐QUAD LV lead era, van Bommel et al found survival free from cardiovascular hospitalization at 1 and 2 years was 80% and 70%, respectively.[21](#jah32587-bib-0021){ref-type="ref"}
The reasons for reduced HF hospitalizations with QUAD are not entirely clear. Several cofounders, however, could potentially explain our findings. In the telemonitoring study of Turakhia et al, potential confounders for a benefit of QUAD was limited to age, sex, remote monitoring enrollment, and socioeconomic status.[13](#jah32587-bib-0013){ref-type="ref"} Behar et al did not adjust for NYHA class, QRS duration, left ventricular ejection fraction, HF medication, or comorbidities.[12](#jah32587-bib-0012){ref-type="ref"} In the present study, which comprises a longer follow‐up period, the survival advantage of QUAD versus bipolar LV leads was observed after adjustment for age, sex, device type (CRT‐P or CRT‐D), NYHA class, QRS duration, QRS morphology, left ventricular ejection fraction, HF cause, medication, or history of hypertension, coronary artery bypass grafting, or diabetes mellitus.
Lower rates of LV lead re‐interventions may also be relevant. In this respect, we observed that no LV lead revision led to death and that LV lead re‐interventions were lower for QUAD than for non‐QUAD. On the other hand, LV lead re‐interventions were associated with an increased risk of total mortality, cardiac mortality, and HF hospitalization. These findings suggest that LV lead deactivation and the associated re‐intervention contributed to a higher risk of HF hospitalization. This, however, does not explain the lower risk of total mortality observed with QUAD. It would appear that the survival benefit of QUAD relates to the lead itself.
CRT‐D and CRT‐P {#jah32587-sec-0027}
---------------
Previous studies on QUAD[12](#jah32587-bib-0012){ref-type="ref"}, [13](#jah32587-bib-0013){ref-type="ref"} have exclusively focused on CRT‐D. We have shown better outcomes for QUAD after both CRT‐D and CRT‐P. In fact, the magnitude of the survival benefit of QUAD over non‐QUAD after CRT‐P (by 84%) was higher than after CRT‐D (by 56%). While we should be careful with overinterpreting the results of a retrospective study, such marked differences raise the possibility that the benefit of QUAD is proportionally higher after CRT‐P than after CRT‐D. If that is the case, we should reconsider the findings of COMPANION, which was underpowered to compare CRT‐D and CRT‐P. At the low event rates observed in the present study, proof of superiority of CRT‐D over CRT‐P may require much higher numbers of patients than those included in COMPANION. Meta‐analyses of CRT‐D versus CRT‐P may need to be revisited in the QUAD era.
LV Lead Re‐Interventions {#jah32587-sec-0028}
------------------------
In the MORE‐CRT (More Options Available With a Quadripolar LV Lead Provide In‐Clinic Solutions to CRT Challenges) trial, 1074 patients undergoing CRT‐D were randomized in 1:2 ratio to bipolar leads or QUAD. Freedom from the composite end point of intraoperative and postoperative LV lead--related events at 6 months was greater with QUAD than with bipolar leads (83.0% versus 74.4%, *P*=0.0002), but this was because of differences in the intraoperative rather than postoperative events.[10](#jah32587-bib-0010){ref-type="ref"} In the present study, which involved a longer follow‐up period, QUAD was associated with a lower incidence of PNS and LV lead displacement. This might be expected in view of the fact that vector optimization almost invariably eliminates PNS in patients who initially have PNS with QUAD.[12](#jah32587-bib-0012){ref-type="ref"}
HF Cause {#jah32587-sec-0029}
--------
In the QUAD era, Forleo et al[22](#jah32587-bib-0022){ref-type="ref"} showed that the cause of cardiomyopathy did not influence the LV reverse remodeling response to CRT‐D using QUAD. Similarly, Behar et al found no interaction between HF cause and the survival benefit of CRT‐D using QUAD, compared with bipolar leads.[12](#jah32587-bib-0012){ref-type="ref"} We have also found that HF cause has no bearing on survival benefit of QUAD over non‐QUAD. Importantly, however, the event rate with QUAD is much lower than with non‐QUAD. It is possible that with QUAD, higher numbers of patients are needed to show a HF cause‐specific difference in outcomes after CRT.
Single‐Site and Multipoint Pacing {#jah32587-sec-0030}
---------------------------------
In this study, multipoint pacing was not activated in any patient, suggesting that the survival advantage of QUAD is simply because of lead design or availability of multiple pacing vector configurations. We should also consider that electrical stimulation over a dipole in a QUAD could depolarize the myocardium at the anodal pole if this has a comparatively low threshold.[23](#jah32587-bib-0023){ref-type="ref"} We cannot determine whether anodal capture (and effectively multipoint pacing) could account for some of the observed effects of QUAD. These questions could not be addressed in the present study.
Limitations {#jah32587-sec-0031}
-----------
This study has the typical limitations of a single‐center, nonrandomized, retrospective study and therefore we cannot discount the possible influence of unobserved variables. While we adjusted for potential confounders, only randomization could fully correct for their biological effects. In particular, we should stress that, despite covariate adjustment, the better outcomes observed with QUAD might be because, at least in part, of different patient characteristics towards the end of the recruitment period, rather than primarily or uniquely to the utilization of QUAD. The greater proportion of patients in NYHA class I and II and in sinus rhythm as well as higher uptake of angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers and β‐blockers may still contribute to better outcomes with QUAD. Moreover, we cannot exclude the possibility that the time interval from actual LV lead displacement (deactivation) to re‐intervention may have adversely influenced outcomes. As we did not use telemonitoring, we cannot quantify the duration of LV lead deactivation before re‐intervention. A further possibility is that allowing programming over a wider range of vectors, QUAD could have converted nonresponders to responders.[24](#jah32587-bib-0024){ref-type="ref"} Unfortunately, the present study does not address vector locations or how vector configurations changed during follow‐up. It is hoped that ongoing prospective studies[25](#jah32587-bib-0025){ref-type="ref"} may shed further light on this issue. We did not collect data as on Q‐LV as an aid for targeting LV lead positions, but it is possible that this approach could influence outcomes.
Conclusions {#jah32587-sec-0032}
===========
In this study of real‐world clinical practice, we have shown that CRT using QUAD, programmed to biventricular, single‐site LV pacing, was associated with a dramatic reduction in total mortality, cardiac mortality, and HF hospitalization, compared with non‐QUAD. These findings emerged after both CRT‐D and CRT‐P, after adjustment for HF etiology and other potential confounders. The remarkably low event rate observed with QUAD in this study has implications for clinical practice and the design of future CRT trials.
Disclosures {#jah32587-sec-0033}
===========
Leyva is a consultant and has received research support from Medtronic Inc, St Jude Medical, Boston Scientific, and LivaNova. Marshall is a consultant for Spectranetics. The other authors report no conflicts of interest.
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Carlo Buscaglia
Carlo Buscaglia (9 February 1909 – 15 August 1981) was an Italian footballer from Bastia di Balocco in the Province of Vercelli who played as a midfielder.
Career
Buscaglia played club football most notably for Napoli. He spent a decade at Napoli, also serving as the team's captain, and wrote himself into the appearance records books at the club; today he is sixth in the club's all-time appearance records for the league.
After leaving Napoli in 1938, he spent two year spells at Juventus and Savona.
References
Category:1909 births
Category:1981 deaths
Category:Italian footballers
Category:Serie A players
Category:Casale F.B.C. players
Category:Juventus F.C. players
Category:S.S.C. Napoli players
Category:Savona F.B.C. players
Category:Sportspeople from Turin
Category:Association football midfielders
Category:People from the Province of Vercelli
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1. Field
The present disclosure is directed to a method and apparatus for distinguishing cells with the same physical cell identifier. More particularly, the present disclosure is directed to distinguishing cells with the same physical cell identifier by using a radio frame timing offset.
2. Introduction
Presently, in a cellular network, cells use physical cell identifiers to distinguish themselves from each other. An operator ensures that a physical cell identifier unambiguously identifies a base station. However, Closed Subscriber Group (CSG) base stations, such as access points, may use the same physical cell identifiers, which can result in physical cell identifier confusion. For example, CSG cells can be a collection of cells used for deployment in a campus or can be individual cells used for deployment in users' homes. The CSG cells co-exist with macro cells on the same carrier frequency. CSG cells have a smaller coverage area than macro cells. Unlike macro cells, the CSG cells are un-planned, in that the operator has much less control over their placement and configuration than with macro cells. Thus, two CSG cells that are located within the coverage of the same macro cell can use the same physical cell identifiers. Unfortunately, this results in physical cell identifier confusion.
To elaborate, a mobile station uses physical cell identifiers (PCID) during synchronization and during cell ranking. The mobile station ranks cells by measuring the received signal strength and then uses the ranking to facilitate handover and reselection. If a PCID is not guaranteed to be unique within a macro cell, then PCIDs cannot be used for reselection and handover. If PCIDs cannot be used for reselection and handover, a mobile terminal would need to read system information of the target cell and acquire the cell global identity to determine if it is allowed to access the cell. Unfortunately, this requires considerable additional battery usage in idle mode and can seriously impact battery life. Another problem with using the same PCIDs is that mobile station cell handover will fail when there is more than one cell with the same PCID and a network cannot determine which cell is the right one for handover.
A range of PCIDs can be reserved for CSG cells. Also, a mobile terminal can have a list of CSG PCIDs, such as a CSG white-list of cells that it is allowed to access. These restrictions limit the problem in the reselection case to when the target cell is a CSG cell in the CSG white-list. However, PCID confusion can still frequently occur in metropolitan areas where more CSG cells are deployed. Even in cases where the spatial likelihood of PCID confusion is low, when confusion occurs, it affects the same mobile terminal repeatedly. For example, if two homes within the coverage of the same macro cell use CSG cells with the same PCID, the corresponding users will experience handover failures when entering their homes and they will have substantially higher battery drain.
In order to resolve the PCID confusion, a mobile terminal could read additional system information of a cell, which contains a unique cell identifier, which the mobile terminal could rely on to determine if the cell is suitable. Unfortunately, reading the additional system information in connected mode would cause substantial delay which negatively impacts handover performance. Also, a mobile terminal would have to read the additional system information every time it encounters a CSG PCID, because different encounters with the same PCID could correspond to different cells. Furthermore, the mobile terminal would lose data being sent through the serving cell as a result of reading the additional system information because the mobile terminal would have to synchronize to the target cell.
It is also possible to ignore a cell based on the PCID if it has been found to be unsuitable after previously reading additional system information. However, this would not resolve the PCID confusion problem because a cell encountered later may be suitable to the mobile terminal but would be ignored if it has same PCID as a previously unsuitable cell. Furthermore, in connected mode, a mobile terminal would not measure and report the ignored PCIDs and the network would not know when interference from the PCID is significant and would not be able to take measures to prevent disruption of service.
Thus, there is a need for a method and apparatus for distinguishing cells with the same physical cell identifier.
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package com.tencent.mm.ui.chatting;
import android.view.View;
import android.view.ViewStub;
import android.view.animation.AnimationUtils;
import android.widget.ListView;
import com.tencent.mm.e.a.nq;
import com.tencent.mm.plugin.sight.encode.ui.ChattingSightContainerView.a;
import com.tencent.mm.sdk.c.a;
import com.tencent.mm.sdk.platformtools.ac;
import com.tencent.mm.ui.j;
import com.tencent.mm.ui.o;
final class ChattingUI$a$84$2
implements ChattingSightContainerView.a
{
View lBB = null;
ChattingUI$a$84$2(ChattingUI.a.84 param84) {}
public final void azd()
{
nq localnq = new nq();
avS.type = 6;
a.kug.y(localnq);
lBA.lAY.setRequestedOrientation(1);
lBA.lAY.Xk();
lBA.lAY.bkT();
lBA.lAY.blj();
if (lBB == null) {
lBB = ((ViewStub)lBA.lAY.findViewById(2131755932)).inflate();
}
lBB.setVisibility(0);
lBB.startAnimation(AnimationUtils.loadAnimation(lBA.lAY.kNN.kOg, 2130968612));
}
public final void onHide()
{
lBA.lAY.setRequestedOrientation(-1);
lBA.lAY.bkT();
if ((lBB != null) && (lBB.getVisibility() == 0))
{
lBB.setVisibility(8);
lBB.startAnimation(AnimationUtils.loadAnimation(lBA.lAY.kNN.kOg, 2130968613));
}
new ac().post(new Runnable()
{
public final void run()
{
nq localnq = new nq();
avS.type = 7;
avS.avT = ChattingUI.a.e(lBA.lAY).getFirstVisiblePosition();
avS.avU = ChattingUI.a.e(lBA.lAY).getLastVisiblePosition();
avS.avV = ChattingUI.a.e(lBA.lAY).getHeaderViewsCount();
a.kug.y(localnq);
}
});
}
}
/* Location:
* Qualified Name: com.tencent.mm.ui.chatting.ChattingUI.a.84.2
* Java Class Version: 6 (50.0)
* JD-Core Version: 0.7.1
*/
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Neural crest cells (NCCs) are pluripotent cells that migrate from the developing neural tube to populate various tissues including craniofacial structures, neurons and glia of the peripheral nervous system, and pigment cells. Improper migration and development of NCCs can lead to a variety of birth defects collectively termed neurocristopathies. To become migratory, NCCs undergo epithelial to mesenchymal transition (EMT). EMTs at the wrong place and time are associated with cancer progression, invasion, and metastasis among other pathological events. Thus, it is critically important to have a complete understanding of the biology of EMT. While some work has focused on identifying signals that induce EMT, much of it was done in cells outside of their natural environment, which has a great effect on cell signaling and behavior. I have focused on the physical behaviors NCCs use to carry out EMT in vivo and this proposal will test how specific molecules, namely the GTPase Rho and Cadherin-6, control these behaviors. My specific aims are to 1.) Image the distribution and level of active Rho during NCC EMT 2.) Determine the effects of Rho manipulation on dynamic cell behavior and F-actin. 3.) Determine whether Rho and Cad-6 cooperate to promote NCC EMT. These experiments will begin to define molecular pathways that control EMT in vivo and have the potential inform therapies for treatment of pathologies involving abnormal cell migration and EMT. PUBLIC HEALTH RELEVANCE: Improper development of neural crest cell (NCC) derived structures, including craniofacial bone and cartilage, leads to a class of birth defects called neurocristopathies. To populate their targets NCCs must become migratory, which involves undergoing epithelial to mesenchymal transition (EMT). EMTs are important events in development that also drive pathologies such as fibrosis, chronic inflammation, and cancer metastasis. The experiments proposed here have the potential to explain how specific molecules control these critical events and inform therapies in diseases involving EMT and abnormal cell migration.
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Copy the link below
At Sunday night’s (August 7) Teen Choice Awards in Los Angeles, it was the battle of the bespectacled boy wizard vs. the vampire, and to our enjoyment, it was Harry Potter and the Deathly Hallows that came out on top over Twilight: Eclipse. Part One picked up the Choice Sci-Fi/Fantasy gong, while its finale was crowned Choice Summer Movie. Daniel Radcliffe and Emma Watson picked up a couple of awards, including one for Choice Movie Liplock, while handsome Tom Felton was hailed Choice Movie Villian. (via The Guardian)
• John Barrowman recently revealed to The Daily Mirror that legions of female admirers go to great lengths when professing their fan devotion. “Sometimes I get sent knickers and occasionally I get requests to send some of my own underwear back,” the Torchwood: Miracle Day star said. “I always politely decline. It’s not going to happen. I get sent some seriously raunchy photographs too. They really don’t hold back, some of these women. The photographs are filthy but they’re not really my thing to be honest. All I’ll say is I appreciate the loyalty. So thank you.”
• Boy George has been describing his reception when he arrived in prison in 2009, ready to start a four month sentence. It seems (and this may shock some of you) that the introduction of a gay pop star to a tense environment did not bring out the best in some of his fellow inmates. (via Pink News)
• This probably won’t come as a surprise, but when Dionne Bromfield, Amy Winehouse‘s goddaughter, attempted to pay tribute by singing the most devastating song in her godmum’s catalogue – “Love Is a Losing Game” – at The Big Chill on Saturday (August 6), well, she could barely sing for crying. And you can imagine what kind of effect that had on her audience… (via Marie Claire UK)
• Ever the gentleman, Simon Cowell is now attempting to fall on his sword, saying he probably shouldn’t have sacked Cheryl Cole, or try to move her back across to the UK version of The X Factor, but he’s sure their friendship will survive. (via Evening Echo)
• But should he even be talking about Cheryl at all? I mean, we’ve all experienced a few pangs of outright disinterest since this story first started to play out, and now even Hollywood’s paparazzi, a gang who surely must be able to swallow down their boredom with whomsoever in the public eye they’ve got their lenses pointed at, have decided Cheryl’s too boring to bother with. She’s in L.A. right now, and apparently all she does is eat oatmeal and go to the gym. (via Heat)
• Come hell or high water, Cowell was going to have Adele involved with the UK X Factor this season. And after trying to get the best-selling songstress to appear as a guest judge, he’s apparently landed her for the show’s finale at Wembley. It’ll be epic, no doubt. (via Daily Star)
• Geri Halliwell (Ginger Spice) and her boyfriend of two and a half years, Henry Beckwith, have called it quits. (via The Sun)
• In better Spice Girls news, Melanie Brown a.k.a. Sporty Spice is prepping for the arrival of her first child with Stephen Belafonte. But coaching her at her beside may be her two daughters, Phoenix and Angel, as her hubby might be passed out on the floor from all the excitement. (via Hello!)
• Suede‘s Brett Anderson has fourth solo LP coming this fall. Black Rainbows, which he says is “restless, noisy and dynamic,” will be released September 26 in the UK. Fingers crossed that the U.S. gets it the very next day! (via Digital Spy)
• Pirates of the Caribbean star Naomie Harris — who is thought to be bringing M’s secretary, Miss Moneypenny, to life in Bond 23 — has some friendly words of advice for aspiring actors: a “steely determination” is a definite must and expect to deal with “plenty of knocks along the way.” Oh and one more thing: “never take no for an answer.” (via The Daily Telegraph)
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Pulsatile luteinizing hormone secretion in hypothalamic amenorrhea, anorexia nervosa, and polycystic ovarian disease during naltrexone treatment.
To determine if chronic treatment with the long-acting oral opioid antagonist naltrexone can increase luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion in women with secondary amenorrhea. Prospective. Large reproductive endocrinology unit of an academic hospital. Three groups of women with oligomenorrhea or amenorrhea: (1) hypothalamic amenorrhea; (2) anorexia nervosa; and (3) polycystic ovarian disease (PCOD). Naltrexone 50 mg every day for 4 days. Luteinizing hormone pulse pattern, frequency and amplitude, mean LH and FSH levels, measured by serial blood sampling over a 6-hour period before and after naltrexone. Naltrexone caused a significant increase (P less than 0.05) of the LH pulse frequency in patients with hypothalamic amenorrhea and in PCOD but not in anorexia nervosa. The mean levels of LH and FSH and LH pulse amplitudes were not significantly changed by naltrexone. The naltrexone nonresponders were underweight either because of simple weight loss or anorexia nervosa and had low levels of estradiol and an LH pulse pattern similar to the luteal one. The luteal LH pulse pattern in weight loss-related amenorrhea is caused by a nonopioid, undernutrition-linked factor.
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Inhibition of retroviral pathogenesis by RNA interference.
RNA interference (RNAi) is a newly discovered cellular defense system that is known to suppress replication of genomic parasites in model organisms. It has been widely conjectured that RNAi may also serve as an antiviral system in vertebrates. Retroviral infection could be initiated by electroporation of cloned Rous sarcoma virus (RSV) proviral DNA into the developing chick neural tube. Coelectroporation of proviral DNA and short double-stranded RNAs matching sequences of avain retroviruses, which were designed to induce RNAi against RSV, inhibited viral replication. Replication of RSV after electroporation resulted in disruption of embryonic development and early death, but this, too, could be suppressed by RNAi against the RSV genome. RNAi could also inhibit the growth of RSV and HIV in cell culture. Analysis of the step of the retroviral life cycle that is inhibited by RNAi revealed that it primarily prevented accumulation of the viral RNAs synthesized late during infection. RNA genomes introduced in viral particles early during infection were less sensitive. RNAi can block retroviral infection in vertebrates. The tissue electroporation method described here should allow RNAi to be used widely to study gene function and control of infection in vertebrate animals.
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Rationalization of the selection of tracheal tubes.
The problems of selection of tracheal tubes, and the need for a rationale, are outlined. Tracheal tubes of 7.5 mm and 8.5 mm i.d. are recommended for female and male patients, respectively. Tracheal size was determined using high pressure-low volume cuffs as measuring devices. The average diameter of the cuff at seal point was 16.2 mm (SD 1.2 mm) for female, and 20.8 mm (SD 2.3 mm) for male patients. To provide a seal with low pressure-high volume cuffed tubes, cuff sizes of 20.5 mm and 27.5 mm are recommended for female and male patients, respectively. The mechanism of sealing with low pressure-high volume cuffs is reviewed.
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Rh-Catalyzed Cyclization of 3-Aryloxycarbonyldiazonaphthoquinones for the Synthesis of β-Phenylnaphthalene Lactones and Formal Synthesis of Pradimicinone.
In this study, we developed a novel method for the synthesis of β-phenylnaphthalene lactones. The diazo-transfer reactions of 2-azido-1,3-dimethylimidazolinium chlorides to 3-aryloxycarbonyl-1-naphthols proceeded smoothly to give corresponding 3-aryloxycarbonyldiazonaphthoquinones in high yields. These intermediates were further transformed to β-phenylnaphthalene lactones through a Rh-catalyzed intramolecular formal C-H insertion reaction. This method of lactone formation was efficiently applied to the formal total synthesis of pradimicinone.
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The collective hysteria over fake news, Russia’s alleged role in the DNC hack, and the unsubstantiated kompramat that supposedly links Donald Trump to Vladimir Putin has reached a fever pitch. But mainstream cable news and the Washington intelligentsia have somehow neglected to connect it to a crucial piece of the US history: its long-standing tradition, euphemistically known as the Truman Doctrine, of intervening in democratic elections abroad to promote its commercial and ideological interests.
Truman’s doctrine would “support free peoples,” he proclaimed in March 1947, “who are resisting attempted subjugation by armed minorities or by outside pressures.” Indeed, he and his successors would go to great lengths to keep this promise during the Cold War. American presidents repeatedly directed the CIA to overthrow freely elected leaders in Iran, Guatemala, the Congo, and Chile because they nationalized industries, threatened corporate interests, and obstructed the United States’ imperial ambitions. American officials falsely branded these leaders as Communists, framed them as threats to national security, and authorized covert operations to replace them with dictators who would serve US interests.
Omission of this history from today’s discourse on Russia and our adversaries prevents our leaders, and especially the American public, from realizing the same tools the United States used to interfere in others’ affairs are now being used against us.
Shielded by this ignorance, it is easy for US officials to portray us as the victims of attacks rather than the inventors of the weapons. When Senator John McCain, for example, says, “If you’re able to change the results of an election, then you have undermined the very fundamentals of democracy,” he forgets to mention this is precisely what the United States did in Iran, Guatemala, the Congo, and Chile when they were just beginning to experience democracy.
In 1953, a US-backed military coup overthrew Iran’s first democratically elected leader, Prime Minister Mohammad Mossadegh, in response to his decision to nationalize the highly lucrative oil industry, cutting off the gravy train the Anglo-Iranian Oil Company had been riding since 1909.
Time had honored the Western-educated leader the year before the coup as its man of the year, hailing him as “the most world-renowned man his ancient race had produced for centuries.” Suddenly, because he wanted to use Iran’s oil wealth to benefit his country, he was deemed a pinko.
Using American tax dollars to develop a network of Iranian agents and to bribe the regime’s opponents, the CIA launched political warfare against Mossadegh. It distributed fake news via posters and newspapers that called him corrupt, anti-Islam, and the Soviet Union’s ally, it encouraged religious leaders to criticize the prime minister from inside their mosques, and it enlisted street mobs to incite riots across Tehran.
Success finally came on August 19. Paid infiltrators played both sides: some posed as Tudeh party members attempting to foment revolution while others convinced the citizens to rise up against this threat. Eventually, amid growing anarchy, General Fazlollah Zahedi, paid off by the CIA, ordered his bribed military units to seize government facilities and Radio Tehran. He proclaimed himself “the lawful prime minister by the Shah’s orders” and collected $1 million in cash from the CIA.
Soon after, the Shah — Washington’s chosen dictator — assumed the throne, American oil companies moved in, and US-Iranian relations quickly warmed as the new regime squashed dissent, imprisoned opponents, and received unprecedented US arms shipments, American assistance to create the Monarchy’s secret police, and US support to develop Iran’s civilian nuclear program.
The American recipe for overthrow continued to evolve. Guatemala’s freely elected president Jacobo Arbenz became the next target when his New Deal-style programs threatened the interests of American corporations. The powerful United Fruit Company, whose executives were in bed with a number of influential American officials — some of whom were former employees and some of whom had financial interests in the corporation — found Arbenz’s policies especially worrying.
The Agrarian Reform Law of 1952 authorized the Guatemalan government to seize vast tracts of United Fruit’s uncultivated acres. The next December, the CIA’s Operation SUCCESS set in motion a six-month coup. CIA agents used Voice of Liberation radio to broadcast fake news describing an impending communist takeover and civilian uprisings, recruited a rebel army to sow unrest, distributed religious leaflets calling Catholics to revolt, and coordinated air raids that dropped bombs on military installations and other targets across Guatemala City.
These efforts turned popular and military support against Arbenz, forcing his resignation and paving the way for Castillo Armas — the United States’ handpicked dictator — to become president. This established a long line of dictators, death squads, oppression, and near-genocide that wreaked havoc across Guatemala for the next four decades.
In 1960, American meddling escalated. President Eisenhower decided to skip the coup and go straight to assassination. He ordered — once again using the false pretense of an impending communist threat — the CIA to assassinate Congo’s democratically elected prime minister Patrice Lumumba, the young nationalist who ended seven decades of brutal Belgian rule and promised Congolese citizens a better future with greater control over the country’s natural resources.
When the plot to poison Lumumba failed, the CIA outsourced the job to Congolese accomplices and Belgian officers. With the help of Joseph Mobutu, the repressive military dictator installed by the United States who would rule for three decades, they eventually captured him and handed him over to his enemies. They tortured Lumumba, then murdered him by firing squad on January 17, 1961 — just three days before John F. Kennedy was inaugurated as the freely elected president of the United States.
During the early 1970s, commercial interests once again required CIA assistance. When Chile elected Salvador Allende, the anti-imperialist, working-class champion, he nationalized profitable American-dominated industries such as communications and copper, the resource gem for which Chile was the world’s leading supplier.
President Nixon, who believed the false reports of Soviet influence he received from American and Chilean industrial titans, authorized the CIA to overthrow Allende, setting in motion a ferocious propaganda campaign that included distributing fake news, strangling economic development, conspiring with disgruntled Chilean officers, indirectly assassinating a senior military leader, and staging anti-government protests.
On the climactic day of the coup, September 11, 1973, Allende gave his last words over the radio while barricaded inside the presidential palace. He indicted foreign capital and imperialism as the causes that “created the climate for the Army to break with their tradition” by carrying out American covert action. Moments before he died, he proclaimed, “Long live Chile! Long live the people! Long live the workers!”
It is slightly ironic, given the country’s record of international meddling, that American officials are whining about the “tradition in Russia of interfering in elections,” as Director of National Intelligence James Clapper recently said. Or to hear McCain say Russia’s actions are “the sign of a possible unraveling of the world order that was established after World War II… one of the most peaceful periods in the history of the world” — the same period when the United States intervened in Iran, Guatemala, the Congo, and Chile. Or to hear Representative Elijah Cummings say, “Russia’s attacks on our election are an attempt to degrade our democracy and should chill every American.”
Our electoral integrity is a legitimate concern, and American officials should express outrage at Russia’s alleged actions (should they turn out to be true). But every American should feel equally chilled by our history of undemocratic electoral interference around the world. Millions of Iranians, Guatemalans, Congolese, and Chileans suffered under the iron grips of unelected dictators the United States installed.
Hundreds of thousands died in the aftermath of these coups, countries split into civil wars, untold natural riches were stolen, and countless others endured unspeakable trauma and loss. Unforeseen blowback in response to these actions will likely continue in the years ahead.
Whether it was Russian spies or American couch potatoes who convinced Podesta to give up his password, the United States has not suffered the way other countries have — at least not yet. As the tools of American power proliferate and fall into the hands of our supposed adversaries — arms, nuclear weapons, coups, drones, and cyber-warfare — we must confront the reality that as long as the United States continues its habit of meddling abroad, other countries will be tempted to use these and other forms of covert action against us.
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Well, I'm Tony. I live in Taichung, Taiwan, but I come from Nova Scotia, Canada. Like most expatriates here, I teach English to pay the bills. I'm married to a Taiwanese woman and plan on staying here.
I started gaming around the time the Wilderness Survival Guide was released. As a player, my most fondly remembered game is a very competitive Dark Sun one shot throne war. As a GM, I ran what still looks to me like a very narrativist Vampire game for two years. I still haven't had a chance to play any of the games from this circle, although I've read a few.
My current gaming group is also doing a rotating GMing thing with Warhammer Fantasy Roleplay. I've been trying to do it thematically and with real player control and despite some system troubles it's working quite well.
I stumbled on the Indie RPG movement after a very frustrating experience with another group here - the theory really helped me understand what was going wrong and what I needed to do about it. It's still an ongoing process.
Beyond that, I'm very interested in the application of RPGs and game mechanics to other fields such as ESL and business consulting.
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Stuck with You (Zones song)
"Stuck With You" is the debut disc and 7" single of punk band Zones, released by Zoom Records on February 17, 1978.
It contained its eponymous song, "Stuck With You", which was backed with "No Angels"; both songs were a combination of punk rock and power pop, although more punk than the group's subsequent singles and the album, which were more new wave-oriented.
The single was played a lot by DJ John Peel, who shortly afterwards recorded and broadcast sessions with the band, and garnered the attention of Arista Records, who signed the group.
The band comprised vocalist and guitarist Willie Gardner (previously in Hot Valves), and ex-PVC2 members, bassist Russell Webb, keyboardist Billy McIsaac and drummer Kenny Hyslop. Their next single, "Sign of the Times" was released shortly afterwards in Arista Records.
Track list
Side A: "Stuck With You"
Side B: "No Angels"
Personnel
Willie Gardner: lead vocals, lead guitar.
Russell Webb: bass guitar.
Billy McIsaac: keyboards.
Kenny Hyslop: drums.
References
Category:1978 singles
Category:Zones (band) songs
Category:Debut singles
Category:1978 songs
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Computer systems typically comprise a combination of hardware, such as semiconductors, transistors, chips, and circuit boards, and computer programs. As increasing numbers of smaller and faster transistors can be integrated on a single chip, new processors are designed to use these transistors effectively to increase performance. Currently, many computer designers opt to use the increasing transistor budget to build ever bigger and more complex uni-processors. Alternatively, multiple smaller processor cores can be placed on a single chip, which is beneficial because a single, simple processor core is less complex to design and verify. This results in a less costly and complex verification process, as a once verified module, the processor, is repeated multiple times on a chip.
Techniques known as multiple logical partitions take advantage of multi-processors. A logically partitioned computer comprises multiple logical partitions that implement virtual computers, which execute in separate memory spaces, may execute separate operating systems, and may use shared resources. Examples of shared resources are processors, memory, co-processors, network bandwidth, or secondary storage. Partitions are often implemented on computer systems that include multiple processors and/or on multiple computer systems (often called compute nodes or simply nodes) that comprise processors, which run the multiple partitions to accomplish tasks.
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/* -*- Mode: C++; tab-width: 4; indent-tabs-mode: nil; c-basic-offset: 4 -*-
* vim: set ts=4 sw=4 et tw=99:
*
* ***** BEGIN LICENSE BLOCK *****
* Version: MPL 1.1/GPL 2.0/LGPL 2.1
*
* The contents of this file are subject to the Mozilla Public License Version
* 1.1 (the "License"); you may not use this file except in compliance with
* the License. You may obtain a copy of the License at
* http://www.mozilla.org/MPL/
*
* Software distributed under the License is distributed on an "AS IS" basis,
* WITHOUT WARRANTY OF ANY KIND, either express or implied. See the License
* for the specific language governing rights and limitations under the
* License.
*
* The Original Code is Mozilla SpiderMonkey JavaScript 1.9 code, released
* May 28, 2008.
*
* The Initial Developer of the Original Code is
* Brendan Eich <[email protected]>
*
* Contributor(s):
* David Anderson <[email protected]>
* David Mandelin <[email protected]>
*
* Alternatively, the contents of this file may be used under the terms of
* either of the GNU General Public License Version 2 or later (the "GPL"),
* or the GNU Lesser General Public License Version 2.1 or later (the "LGPL"),
* in which case the provisions of the GPL or the LGPL are applicable instead
* of those above. If you wish to allow use of your version of this file only
* under the terms of either the GPL or the LGPL, and not to allow others to
* use your version of this file under the terms of the MPL, indicate your
* decision by deleting the provisions above and replace them with the notice
* and other provisions required by the GPL or the LGPL. If you do not delete
* the provisions above, a recipient may use your version of this file under
* the terms of any one of the MPL, the GPL or the LGPL.
*
* ***** END LICENSE BLOCK ***** */
#if !defined jsjaeger_methodjit_inl_h__ && defined JS_METHODJIT
#define jsjaeger_methodjit_inl_h__
namespace js {
namespace mjit {
enum CompileRequest
{
CompileRequest_Interpreter,
CompileRequest_JIT
};
/* Number of times a script must be called before we run it in the methodjit. */
static const size_t CALLS_BEFORE_COMPILE = 16;
/* Number of loop back-edges we execute in the interpreter before methodjitting. */
static const size_t BACKEDGES_BEFORE_COMPILE = 16;
static inline CompileStatus
CanMethodJIT(JSContext *cx, JSScript *script, JSStackFrame *fp, CompileRequest request)
{
if (!cx->methodJitEnabled)
return Compile_Abort;
JITScriptStatus status = script->getJITStatus(fp->isConstructing());
if (status == JITScript_Invalid)
return Compile_Abort;
if (request == CompileRequest_Interpreter &&
status == JITScript_None &&
!cx->hasRunOption(JSOPTION_METHODJIT_ALWAYS) &&
script->incCallCount() <= CALLS_BEFORE_COMPILE)
{
return Compile_Skipped;
}
if (status == JITScript_None)
return TryCompile(cx, fp);
return Compile_Okay;
}
/*
* Called from a backedge in the interpreter to decide if we should transition to the
* methodjit. If so, we compile the given function.
*/
static inline CompileStatus
CanMethodJITAtBranch(JSContext *cx, JSScript *script, JSStackFrame *fp, jsbytecode *pc)
{
if (!cx->methodJitEnabled)
return Compile_Abort;
JITScriptStatus status = script->getJITStatus(fp->isConstructing());
if (status == JITScript_Invalid)
return Compile_Abort;
if (status == JITScript_None &&
!cx->hasRunOption(JSOPTION_METHODJIT_ALWAYS) &&
cx->compartment->incBackEdgeCount(pc) <= BACKEDGES_BEFORE_COMPILE)
{
return Compile_Skipped;
}
if (status == JITScript_None)
return TryCompile(cx, fp);
return Compile_Okay;
}
}
}
#endif
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Use of the radial maze in studies of phencyclidine and other drugs of abuse.
Effects of drugs known to disrupt performance in an 8-arm radial maze are reported in terms of changes caused in the pattern of arm entry. Phencyclidine (PCP) and N-allyl-N-normetazocine (SKF-10,047) alter the pattern of arm entry in a way which distinguishes their actions from those of scopolamine and certain serotonergic agonists. The apparent rank order of potencies for causing this effect is (+)SKF-10,047 greater than PCP greater than (-)SKF-10,047. Results of previous radial maze studies evaluating the interactions of clonidine and verapamil with PCP are summarized. Data are reported which indicate that the ability of verapamil to potentiate PCP's behavioral effects stems from an alteration of the pharmacokinetics of PCP; when verapamil (20 mg/kg, IP) was administered 15 minutes before [3H]PCP (40 microCi/kg, IP), brain levels of tritium were increased by 154 to 225 percent. Finally, possible advantages of using a 4-arm radial maze in studies of PCP and related drugs are discussed.
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Background
==========
Diamond holds a variety of extraordinary physical and chemical properties, facilitating its possible applications in novel functional devices \[[@B1]-[@B7]\]. As a semiconductor with a wide bandgap of 5.47 eV, it is a promising candidate for short-wavelength optoelectronic devices such as ultraviolet light-emitting diodes. The extreme mechanical hardness of diamond endows it with potential applications in nanomechanical devices. When doped with boron, it was found to display superconductivity around liquid helium temperature. To utilize the qualities of diamond, it is imperative to grow high-quality materials. Chemical vapor deposition is an efficient and versatile technique for the growth of diamond. A large body of experiments and theories are dedicated to understanding the growth process \[[@B8]\]. Graphitic-like surface reconstructions on stepped C(111) surfaces are predicated by first-principles calculations \[[@B9]\]. Surface graphitization of diamond nanoparticles is investigated from an experimental viewpoint \[[@B10]\]. A unique character of diamond growth is the existence of *sp*^2^-hybridized bonds in the graphitic-like layer of diamond surfaces, in contrast to other group IV element semiconductors (Si and Ge), which do not exhibit energetically favorable *sp*^2^ bonding configurations. This may account for different surface reconstructions on Si and diamond surfaces \[[@B11]\]. Besides low-index surfaces, high-index Si surfaces are extensively investigated to unveil their atomic and electronic structures \[[@B12],[@B13]\], whereas less attention has been paid to the study of high-index diamond surfaces. The graphite-like *sp*^2^ bonding is expected to give rise to the significant difference between high-index diamond and Si surfaces.
Graphene, a two-dimensional atomic crystal with graphite-like *sp*^2^ bonding, has attracted considerable interests due to its novel physical and chemical properties and its potential applications in nanoelectronics and optoelectronics \[[@B14]\]. Large-scale graphenes are grown on metal substrates \[[@B15]\]. Here, we explore the formation of graphene-like stripes on a reconstructed high-index diamond C(331) surface using first-principles density functional theory (DFT) calculations. During the structural relaxation of the bulk-terminated surface, the terrace C atoms in the first layer delaminate from the second layer, leading to local *sp*^3^ to *sp*^2^ rehybridization and the formation of graphene-like stripes on the surface. The driving force for the graphitic-like reconstruction is the presence of high-density dangling bonds on the surface, which gives rise to the rebonding of top-layer atoms. The comparison of the calculated absolute surface energies of C(331), C(111), and C(110) demonstrates the relative stability of the C(331) surface with the graphitic-like reconstruction. Local density of electronic states (LDOS) analysis reveals the occurrence of localized electronic states near the Fermi level (FL), which may play an essential role in determining the surface conductivity \[[@B16],[@B17]\].
Methods
=======
The calculations are conducted in the framework of the DFT method by DMol^3^ codes \[[@B18]\]. We use the Perdew-Burke-Ernzerhof generalized gradient approximation \[[@B19]\]. A double numeric basis set including *d*-polarization function, all electron treatment, and an 8 × 2 × 1 Monkhorst-Pack *k-*point mesh for the Brillouin zone sampling \[[@B20]\] are employed to carry out geometry optimization and electronic band structure calculations. Spin-unpolarized self-consistent field calculations are performed with a convergence criterion of 2.0 × 10^−5^ hartree (1 hartree = 27.2114 eV) for total energies. The maximum force tolerance is 0.004 hartree Å^−1^, and the maximum displacement tolerance is 0.005 Å.
The periodically repeated slabs separated by approximately 10 Å of vacuum are used to represent the surface structures. Each slab of C(331) surface is composed of 11 atomic layers with 40 C atoms and 6 H atoms per unit cell. The H atoms are used to passivate the surface C atoms at the bottom of the slabs to make the calculation more efficient. The dashed lines in Figure [1](#F1){ref-type="fig"}a and the dashed box in Figure [1](#F1){ref-type="fig"}b indicate the supercell used for the calculation. Each slab of H-passivated C(331) surface is composed of 12 atomic layers with 40 C atoms and 12 H atoms per unit cell. The dashed lines in Figure [2](#F2){ref-type="fig"} indicate the supercell used for the calculations.
![**Calculated atomic structure of diamond C(331) surface with graphene-like stripes.** (**a**) The dashed lines indicate the supercell viewed from the $\left\lbrack {0\overline{1}1} \right\rbrack$ direction. The large circles denote the C atoms, and the small circles denote the H atoms. (**b**) The dashed box indicates the supercell viewed from the \[331\] direction, and the bottom is viewed from the $\left\lbrack {0\overline{1}1} \right\rbrack$ direction. The large circles denote the C atoms of the graphitic layer, and the smaller circles indicate the *sp*^3^-bonded C atoms in the outmost surface. The other C and H atoms are represented by the smallest circles.](1556-276X-7-460-1){#F1}
{#F2}
Results and discussion
======================
Figure [1](#F1){ref-type="fig"} shows the atomic structure of the graphene-like stripes formed on the reconstructed diamond C(331) surface calculated after the structural relaxation of the bulk-terminated surface. We allow this surface to relax using a steepest descent algorithm. The top-layer C atoms exhibit the *sp*^2^ bonding configuration in the graphene-like structure, as shown in Figure [1](#F1){ref-type="fig"}b. Upon structural relaxation, the terrace C atoms (see 4 and 10 C atoms in Figure [3](#F3){ref-type="fig"}) delaminate from the subsurface diamond and form the graphene-like stripes along the $\left\lbrack {0\overline{1}1} \right\rbrack$ direction. The energetically favorable hexagonal rings are found to emerge in the graphitic layer on the reconstructed surface. The driving force for the graphitic-like reconstruction on the surface is the presence of high-density dangling bonds which have unpaired electrons. This situation is similar to the reconstruction of the C(111) surface, where the top-layer C atoms are rearranged to make the dangling bonds become the nearest neighbors and form the π bonding \[[@B21]\]. For the C(331) surface, the delamination of the terrace C atoms can lead to the formation of graphite-like *sp*^2^ bonds, thereby reducing the energetically unfavorable dangling bonds.
{#F3}
The representative C-C bond lengths for the graphitic-like reconstructed C(331) surface are shown in Figure [3](#F3){ref-type="fig"}. The distance between the delaminated C atom and the subsurface C atom increases to approximately 2.51 Å, much larger than the bond length of diamond (1.54 Å). The bond lengths for the C atoms in the graphitic structure decrease to 1.44 and 1.46 Å. These values are quite close to the bond length of graphite (1.42 Å), whereas much smaller than that of diamond. The C atoms with the unsatu-rated dangling bonds at the subsurface positions remain *sp*^3^-hybridized in character, although they have stretched by almost 34%. The C-C bonds are stretched to 1.62 and 1.57 Å for the outmost C atoms attached to the second-layer C atoms. The severe subsurface rebonding increases the elastic strain, which is energetically unfavorable. The competition between the favorable *sp*^2^ bonding in the graphitic layer and the unfavorable strain energy leads to the graphitic-like reconstruction of the C(331) surface.
The energetic stability of the C(331) surface is studied by comparing its absolute surface energy (ASE) with those of low-index diamond C(111) and C(110) surfaces \[[@B21]-[@B23]\]. In the centrosymmetric slab used for computing the ASE, the top and bottom surfaces are physically equivalent. After full structural relaxation, the same *n* × *m* surface reconstruction is observed to occur on both sides of the slab. Therefore, it allows calculating directly the ASE. For the slab with *N* atoms at the atomic configuration $\left\{ R_{i} \right\}$, the surface energy per 1 × 1 surface cell, $E_{\text{surf}}^{n \times m}$, can be calculated from the total energy $E_{\text{tot}}\left( {N,\left\{ R_{i} \right\}} \right)$ of the slab subtracted by *N* times the bulk diamond energy μ per atom. The surface energy is expressed as
$$E_{\text{surf}}^{n \times m} = \frac{1}{2nm}\left\{ {E_{\text{tot}}\left( {N,\left\{ R_{i} \right\}} \right) - N\mu} \right\}\text{.}$$
Since two equivalent surfaces are involved in the calculations for a slab, a prefactor, $\frac{1}{2}$, is added in Equation 1. For the *n* × *m* surface reconstruction, the *nm* gives the number of the 1 × 1 surface cell. The surface energy per unit area is as follows:
$$\gamma^{n \times m} = \frac{E_{\text{surf}}^{n \times m}}{A}\text{,}$$
where *A* is the area of a 1 × 1 surface cell for a given surface orientation *n*. For the H-covered C(331) surface, the surface energy per 1 × 1 surface cell is given by
$$E_{\text{surf}}^{\text{H}} = \frac{1}{2}\left\{ {E_{\text{tot}}\left( {N,N_{\text{H}},\left\{ R_{i} \right\}} \right) - N\mu - N_{H}\mu_{H}} \right\},$$
where $E_{\text{tot}}\left( {N,N_{\text{H}},\left\{ R_{i} \right\}} \right)$ is the total energy of the slab, N~H~ is the number of H atoms, and μ~H~ is the chemical potential of the H atom in the reservoir that is defined in \[[@B21]\]. Table [1](#T1){ref-type="table"} collected the surface energies $E_{\text{surf}}^{n \times m}$, $\gamma^{n \times m}$, and $E_{\text{surf}}^{H}$ for various orientations and reconstructions. The computed energies for low-index C(111) and C(110) surfaces agree well with the previous investigation \[[@B21]\]. The graphitic-like reconstructed C(331) surface is found to have lower $\gamma^{n \times m}$ than low-index C(111) and C(110) surfaces, indicating that the C(331) surface is one of the stable crystalline diamond surfaces.
######
**Absolute surface energies**$\mathbf{E}_{\textbf{surf}}^{\mathbf{n} \times \mathbf{m}}$**and**$\mathbf{\gamma}^{\mathbf{n} \times \mathbf{m}}$**for various orientations and reconstructions**
**Orientation** **Reconstruction** ***E***~**surf**~**(eV/1 × 1 cell)** ***γ*(J/m**^**2**^**)**
----------------- -------------------- -------------------------------------- -------------------------
\(111\) 2 × 1 0.993 2.91
(1.369) (4.06)
H-covered −1.903 −5.57
(−2.760) (−8.19)
\(110\) 1 × 1 relaxed 1.824 3.27
(3.264) (5.93)
H-covered −4.971 −8.91
(−5.496) (−9.99)
\(331\) 1 × 1 graphitic 2.040 2.31
H-covered −5.808 −6.58
The values in parentheses from \[[@B21]\] are listed for comparison.
The H adsorption on the graphitic-like reconstructed C(331) surface is found to give rise to the reversion of *sp*^2^ hybridization back to *sp*^3^ hybridization. Figure [2](#F2){ref-type="fig"} shows the calculated atomic structure of the H-covered C(331) (1 × 1) surface. The top-layer C atoms display *sp*^3^ bonding configuration. Thus, the H atoms can give rise to the dereconstruction of the graphitic-like C(331) surface.
Figure [4](#F4){ref-type="fig"}a shows the LDOS of the H-passivated diamond (331) surface. The zero energy corresponds to the FL which is at the position of the top valence band. An energy bandgap of 4.2 eV is obtained from the calculated electronic band structure. Figure [4](#F4){ref-type="fig"}b shows the LDOS of the reconstructed C(331) surface with the graphene-like stripes. The zero energy corresponds to the FL, which lifts up to a position in the bulk bandgap. The peak near the FL in the LDOS curve is attributed to the localized electronic states at the graphitic surface and subsurface regions, which may give rise to the semimetallic or metallic conduction along the surface. Further partial electronic density of states (PDOS) analysis reveals that the localized electronic states near the FL is predominant with the *p* character for the graphitic-like reconstructed C(331) surface.
{#F4}
Conclusions
===========
We carry out first-principles DFT calculations to study the spontaneous formation of graphene-like stripes on the reconstructed diamond C(331) surface. The *sp*^2^-hybridized bonding in the graphitic layer on the surface plays a central role in reducing the energetically unfavorable dangling bonds on the bulk-terminated surface, thereby lowering the surface free energy. A sharp peak is found to occur near the FL in the LDOS curve, which arises from the localized electronic states at the surface and subsurface regions. These states may have a significant impact on the surface conductivity. The graphene-like stripes directly formed on a semiconductor surface may be used for nanoelectronic and optoelectronic devices.
Abbreviations
=============
ASE: absolute surface energy; DFT: density functional theory; FL: Fermi level; LDOS: local density of electronic states; PDOS: partial electronic density of states.
Competing interests
===================
The authors declare that they have no competing interests.
Authors' contributions
======================
MJX did the calculations and wrote the manuscript. YFZ conceived and suggested the calculations. YZZ, JZ, BJQ, JYL, DJL, LW, XSC, and HS discussed about the calculations and revised the final manuscript. All authors read and approved the final manuscript.
Authors' information
====================
Dr. MJX obtained his Ph.D. from University of Tsukuba, Japan, and is currently working with Prof. YFZ as postdoctoral research fellow in Shanghai Jiao Tong University, China. Mr. YZZ, Ms. JZ, Mr. BJQ, Mr. JYL, and Mr. DJL are currently postgraduate students in Shanghai Jiao Tong University. Dr. YFZ obtained his Ph.D. from Lanzhou University, China, and is currently working as a professor in Shanghai Jiao Tong University. Dr. LW obtained his Ph.D. from Shanghai Institute of Technical Physics, Chinese Academy of Sciences, China, and is working with Prof. YFZ as postdoctoral research fellow. Dr. XSC obtained his Ph.D. from Nanjing University, China, and is currently working as a professor in Shanghai Institute of Technical Physics, Chinese Academy of Sciences, China. Dr. HS obtained his Ph.D. from Tokyo University, Japan, and is currently working as a professor in University of Tsukuba, Japan.
Acknowledgments
===============
This work is supported by the National High-Tech R&D Program (863 Program) of China under contract no. 2011AA050504, the National Natural Science Foundation of China (grant no. 61006002), the U-M/SJTU Collaborative Research Program and the Analytical and Testing Center of SJTU.
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Initiating the T Cell Response to Liver-Stage Malaria.
Kurup et al. (Cell Host Microbe 2019;25:565-577.e6) define the liver-based antigen-presenting cell driving CD8 T cell responses to mosquito transmission of Plasmodium spp., and show direct interaction of CD11c+ cells with infected hepatocytes. We discuss this work in context, highlighting gaps and new approaches suggested by the work to target liver-stage vaccine antigens.
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1. Introduction {#sec1}
===============
Nuclear magnetic resonance spectroscopy (NMR, or MRS) has enormous potential for the study of biochemical and physiological changes in cancer tissues, due to its noninvasive nature and the large quantity of specific molecular information it can generate. Despite the sensitivity limitations of the technique, the inherent complexity of the spectra, and inevitable presence of overlapping resonances, there have been several successful NMR-metabonomics studies of cell tissue culture and culture extracts. The focus has been on elucidating the physiopathology of tumors and tumor cells, their drug toxicology and drug resistance, often with a view to identifying diagnostic markers \[[@B1]--[@B8]\]. A further significant complication in such studies arises from variability in the metabolite profile from sample to sample. This reflects many factors \[[@B9]\] including minor variations in growing conditions, the biochemical heterogeneity of the growing cells, the effect of different batches of sera (if used), and variations in cell and sample preparation. These additional factors may mask the inherent metabolite distribution, which may be diagnostic of the pathophysiological state of interest.
Experimental complications and difficulties also compromise the extraction of critical information from *in vivo* MRS experiments. In this case, the problems arise from the use of different MR-protocols, which affect the quality of the water suppression, differences in echo time and in the baseline, and so forth. While the causes are different in origin, they have a similar effect on the application. For both forms of magnetic resonance, many of these issues can, in principle, be addressed by improved experimental design, however, it is common for additional sources of variance to be identifiable only after extensive experimentation. In addition to technical issues are the natural physiological variability and the individual treatment history of the subject. As a result, there is an ongoing requirement for the development of magnetic resonance-based diagnostics using advanced statistical-, or other data-, analysis techniques which can reduce or compensate for additional sources of variability.
^1^H NMR spectra of intact tissues or whole-cell samples are inherently complex due to the large number of contributing species which results in significantly overlapping resonance signals. Cell membranes also produce magnetic field inhomogeneity, further broadening the spectra \[[@B10]\]. In the case of cancer cells, a significant proportion of the lipids reside in a fluid environment and hence appear in the liquid-state ^1^H spectra as strong "mobile-lipid" resonances \[[@B7], [@B8], [@B11]\]. Although the identification of the major resonances in ^1^H NMR spectra can be used to characterise the metabolite profile, the complexity of the data sets usually necessitates the use of data reduction and pattern recognition techniques. These can provide information on the biochemical and physiological changes in cancer tissues, related to their physiopathology, drug toxicology, and drug resistance \[[@B12], [@B13]\]. Prominent amongst such techniques is principal component analysis (PCA), \[[@B14], [@B15]\] which involves diagonalisation of the spectral correlation or covariance matrix to identify independent sources of variance (principal components) across the set of spectra, and ranking of the components by their contribution to the overall variance. Thus, PCA is an unsupervised approach to data reprojection that can reveal the presence of classes, it has been applied to a variety of problems in biological science \[[@B16], [@B17]\].
Artificial Neural Networks (ANNs) belong to the so-called Artificial Intelligence group of methods, which were inspired by neurobiology and by the architecture of the human brain \[[@B18]\]. In recent times, these approaches have found applications in many branches of science. For example, they have been used in chemotaxonomy to classify limpets \[[@B19]\] from HPLC mass spectrometric data and in the identification of insect species from morphological measurements \[[@B20]\]. ANNs can be used to model data where the relations, or functions, are not known.
There have been some reports of the use of artificial intelligence and network methods in medical diagnostics which have involved analysis of magnetic resonance spectroscopic data. El-Deredy et al. \[[@B21]\] used ANNs to achieve reasonable prediction of the measured *in vitro* chemotherapeutic response from ^1^H NMR of glioma biopsy extracts. More recently, Suna et al. \[[@B22]\] demonstrated the diagnostic potential of unsupervised approaches to classification by successfully analysing simulated ^1^H NMR spectra using self-organising maps. This approach allowed the identification of stages along a metabolic pathway ranging from "normolipidaemic" to "metabolic syndrome". Tate and coworkers \[[@B23]\] reported the trial of an automated decision support system for classification of brain tumors from *in vivo* MRS, which showed a small but significant improvement in diagnostic accuracy over spectroscopy used and interpreted on its own.
In recent work \[[@B24]\], we reported PCA of ^1^H NMR spectra recorded for a group of human lung carcinoma cell lines in culture and ^1^H NMR analysis of extracts from the same samples. The samples studied were cells of lung tumor origin with differing chemotherapy drug resistance patterns. For whole-cell samples, it was found that the statistically significant causes of spectral variation were an increase in the choline and a decrease in the methylene and mobile lipid ^1^H resonance intensities, which were correlated with our knowledge of the level of resistance displayed by the different cell lines. In this paper, we investigate the use of artificial neural network (ANN), a supervised method, to classify lung carcinoma. Two sets of whole-cell ^1^H NMR spectra will be examined. These were recorded for two groups of human lung carcinoma cell lines, these were grown in culture and characterised over two different periods by two different groups of researchers (each consisting of a biologist and a spectroscopist), who both adhered to the same experimental protocol and used the same spectrometer. The cell lines studied include (i) the parent cell line DLKP, a human squamous nonsmall cell lung carcinoma; (ii) DLKP-A; (iii) DLKP-A5F, two resistant daughter lines; (iv) A549, a human lung adenocarcinoma cell line. The study also examines the capability of supervised techniques to compensate for experimental sources of variance, which may include operator bias and the cell culture growth process and in particular provide a test case for the application of ANN architectures in the identification and monitoring of resistance states in cancer tissue by MRS.
2. Experimental {#sec2}
===============
2.1. Cell Samples {#sec2.1}
-----------------
The cell lines DLKP \[[@B25], [@B26]\], DLKP-A \[[@B27]\], DLKP-A5F \[[@B28]\], and A549 were grown in culture to approximately 70--80% confluency in 175 cm^2^ tissue culture flasks. Culture conditions were as follows: DLKP, DLKP-A, and DLKP-A5F and were cultured in minimal essential medium/Hams F12 (1 : 1, v/v) supplemented with 5% fetal calf serum and 2 mM L-glutamine. A549 was cultured in Dulbecco\'s modified Eagle\'s medium/Hams F12 (1 : 1, v/v) supplemented with 5% fetal calf serum. Cells were cultured as monolayers in tissue culture flasks and incubated at 37°C. A cell count was performed and c. 5 × 10^7^ cells were separated and pelleted. These were then resuspended in deuterated PBS buffer and were kept in a container at 37°C before the start of the NMR measurements. The methods used were described in detail previously \[[@B24]\]. DLKP cells express a small amount of the multidrug resistance protein-1 (MRP-1) MDR drug efflux pump \[[@B25], [@B26]\]. DLKP-A \[[@B27]\] is a highly resistant clone of DLKP, which overexpresses the P-gp drug efflux pump. DLKP-A5F \[[@B28]\] was derived from DLKP by a different drug exposure profile, it is also highly drug resistant. A549 is an unrelated human lung adenocarcinoma cell line which was obtained from the American Type Culture Collection.
The first group of 13 samples, G1_13_21, were grown by a biologist during a six-month period, they were analysed by a first NMR spectroscopist. G1_13_21 contained 21 spectra and so was relatively sparse, it comprised DLKP \[4 samples, 6 spectra\], DLKP-A \[[@B4], [@B6]\], DLKP-A5F \[[@B3], [@B5]\], and A549 \[[@B2], [@B4]\]. The second group of 17 samples, G2_17_33, was grown independently, by a second biologist during a later six-month period and was analysed by a second spectroscopist \[[@B24]\]. G2_17_33 contained 33 spectra, it comprised DLKP \[[@B3], [@B6]\], DLKP-A \[[@B5], [@B10]\], DLKP-A5F \[[@B5], [@B9]\], and A549 \[[@B4], [@B8]\]. Thus for the integrated study presented here, a total of 30 samples were prepared and 54 ^1^H spectra was recorded. The same protocols and methods were used by all the researchers for cell growth and NMR spectroscopy. The biologist and spectroscopist who produced G1_13_21 will be collectively referred to as R1, and the biologist and spectroscopist who produced G2_17_33 will be referred to as R2. Due to the significant work involved in producing the large number of cells required for each spectrum, the number of samples in the study is inevitably somewhat limited. However, the total data set is larger than those usually reported in the analysis of NMR data by pattern recognition methods \[[@B16], [@B17], [@B29]\].
2.2. ^1^H NMR Spectroscopy of Intact Cells {#sec2.2}
------------------------------------------
NMR spectra of the intact cell samples were recorded in deuterated PBS buffer on a Bruker DPX 400 spectrometer operating at 400.13 MHz for ^1^H. Before all NMR experiments, the sample temperature was calibrated and controlled at 36.4 ± 0.2°C using an internal ethylene glycol thermometer (80% solution of ethane-1,2-diol in dimethyl sulfoxide-d^6^). ^1^H NMR spectra were acquired, without spinning, using WET \[[@B30]\] solvent suppression, with two Carr-Purcell-Meiboom-Gill (CPMG) echoes appended, using an echo delay of 1 ms \[[@B10]\]. Chemical shifts were referenced to an external 0.1% solution of sodium trimethylsilyl-\[2,2,3,3-d~4~\]-propionate (TSP) in D~2~O. All experiments were performed with a spectral width of 5200 Hz, an acquisition time of 3.15 s, and relaxation delay of 2 s. Three acquisition schemes were used to record the one-dimensional ^1^H NMR spectra, all amounting to 128 scans. The first scheme (I) employed cycles of 16 dummy scans followed by four acquisition scans, (16,4)~32~, giving an acquisition time of 3/4 hour. In the second scheme (II), 16 dummy scans were applied once prior to acquisition 16((0,16)~8~), giving an acquisition time of 13 minutes. In the third scheme (III), 16 dummy scans and 128 acquisition scans were collected into 32 K data points, giving an acquisition time of 15 minutes. The time taken from resuspension to the start of data acquisition was typically less than 3/4 hour, and never more than 1 hour. All the data presented were recorded within 1 hour.
For the first group of 13 samples (G1_13_21) in the study, the acquisition schemes (I) and (II) were used for each sample. For the second group of 17 samples (G2_17_33), all three schemes were tested for each sample. Hence, the greater number of repeat spectra is for the second group. The inclusion of multiple spectra in the analysis from the same sample tests the stability of the samples over the time of the analysis. The insensitivity of the spectra to the sampling scheme used demonstrates that the samples do not change, for example, due to sedimentation, over the timescale that a single spectrum is acquired.
2.3. PCA Analysis {#sec2.3}
-----------------
In the spectral region from 1.08 to 1.20 ppm, ethanol was observed, which was probably the result of endogenous processes. However, its intensity was highly variable, even within the same cell line, so this region was excluded from the analysis. The region containing the residual water resonance signal (3.56--6.05 ppm) was also excluded. The region above 6.05 ppm contained no features of sufficient intensity for reliable quantification, given the linewidth. For this study, we chose, as descriptors, the integrals over chemical shift regions (bins) of size 0.04 ppm \[[@B12]\] which was found to produce the clearest separation of the cell types in the scores plots and the least noise in the corresponding loadings plots. Thus, the NMR spectra were reduced to 71 descriptors, with bin centres in the range 0.60--1.04, 1.24--3.56 ppm. We adopted the conventional approach \[[@B31]\] of normalisation relative to the total sum of the bin intensities in the region of interest. All the measures were implemented through writing an MATLAB (version 6.5.1, The Mathworks Inc.) code making use of the built in eigensolver.
2.4. ANN Analysis {#sec2.4}
-----------------
ANNs are a sophisticated computational modelling tool, which can be used to solve a wide variety of complex problems. The attractiveness of ANNs comes from their capability to "learn" and/or model very complex systems and from the possibility of using them in classification. An ANN is a computational model formed from a certain number of single units, artificial neurons, or nodes, connected with coefficients (weights), *w*~*ij*~, which constitute the neural structure. Many different neural network architectures can be used. One of the most common is the feed forward neural network of multilayer perceptions. The network is conventionally constructed with three or more layers, that is, input, output, and hidden layers, [Figure 1](#fig1){ref-type="fig"}.
Each layer has a different number of nodes. The input layer receives the information about the system (the nodes of this layer are simple distributive nodes, which do not alter the input value at all). The hidden layer processes the information initiated at the input, while the output layer is the observable response or behaviour. The inputs, input~i~, multiplied by connection weights *w*~*ij*~ are first summed and then passed through a transfer function to produce the output, out~i~. The determination of the appropriate number of hidden layers and number of hidden nodes in each layer is one of the most critical tasks in ANN design. Unlike the input and output layers, one starts with no prior knowledge of the number and size of hidden layers.
The use of ANN consists of two steps: "*Training*" and "Prediction". The "*Training*" consists first of selecting input and output data for the network. This data is referred to as the training set. In the training phase, where actual data must be used, the optimum structure, weight coefficients and biases of the network are identified. Training is considered complete when the neural networks achieve the desired statistical accuracy, that is, when they produce the required outputs for a given sequence of inputs. A good criterion to find the correct network structure and therefore to stop the learning process is to minimise the root mean square (RMS) error as follows: $$\text{RMS} = \sqrt{\frac{\sum_{i = 1}^{N}{\sum_{j - 1}^{M}\left( {y_{ij} - \text{out}_{ij}} \right)^{2}}}{N \times M}},$$ where *y*~*ij*~ is the element of the matrix (*N* × *M*) for the training set or test set, and out~*ij*~ is the element of the output matrix (*N* × *M*) of the neural network, where *N* is the number of variables in the pattern, and *M* is the number of samples. RMS gives a single number, which summarises the overall error.
After a supervised network performs well on training data, it is important to check its performance with data that has not been used in training. This process is called *verification*. This testing is critical to insure that the network has not simply memorised the training set but has learned the general patterns involved within an application. At this stage, other input data are submitted to the network in order to evaluate if it can predict the outputs. In this case, the outputs are already known, but they are not shown to the network. The predicted value is compared to the experimental one to see how well the network is performing. If the system does not give reasonable outputs for this test set, the training period is not over or the network is able to model the data but cannot predict them.
In this work, ANN was used as a supervised method where a training data set was created from the library of NMR spectra, and the lung carcinoma classification of this training data set was known. The backpropagation method was used throughout. Firstly, the optimal ANN architecture was searched for and when the correct classification in the training phase was obtained, the usefulness of the created database and the prediction power of the networks were validated using an independent verification set. For the ANN analysis, we used 72 inputs; the 71 binned NMR intensities and the identity of the pairs of researchers (R1 and R2) as numbers 1 and 2. For output 4, nominal values were used, these identify the four cell lines, DLKP, DLKPA, DLKP-A5F, and A549, for which there were 12, 16, 14, and 12 spectra, respectively. All calculations were performed using the software Trajan Neural Network Simulator, Release 3.0 D. (Trajan Software Ltd 1996--1998, UK), on a standard PC computer running Microsoft Windows Professional XP 2000.
3. Results {#sec3}
==========
3.1. ^1^H NMR Spectroscopy of Whole Cells {#sec3.1}
-----------------------------------------
A typical ^1^H NMR spectrum of intact DLKP cells is shown in [Figure 2](#fig2){ref-type="fig"}. The appearance of the spectra and the assignment suggested below are broadly similar for all the cell samples analysed. A tentative assignment which is consistent with the literature \[[@B2], [@B4], [@B32], [@B33]\] is included in the figure \[[@B24]\]. Direct quantitative analysis of the whole-cell spectra is hampered by the potential multiple contributions from different metabolites to any given resonance line by the nonlorentzian lineshapes and by the broadness of the resonance lines. The resonances in the downfield region arise from species that are at low concentration, so quantification is precluded by the sensitivity limitations of the NMR measurement.
3.2. PCA Visualization of Whole-Cell Spectra {#sec3.2}
--------------------------------------------
The binned NMR spectra of the intact cells were analysed using PCA. The scores plots are shown in [Figure 3](#fig3){ref-type="fig"}. Separation of the four cell types, within each of the two data sets, is apparent using the first two PCs, demonstrating that resistance type can be classified by PCA. It also demonstrates that the samples were stable over the course of the experiment and that the spectra are insensitive to the NMR sampling scheme. Loadings analysis shows that, for each data set, the spectral regions that contribute significantly to the first two principal components are from 1.24 to 1.50 ppm, corresponding to overlapped resonances from lipid methylenes and lactate methyls, and from 2.90 to 3.40 ppm, corresponding to overlapped resonances from N-methyl signals in the choline moieties of phosphatidylcholine, phosphocholine, and glycerophosphocholine. The contribution from other spectral regions to these two principal components is marginal.
Despite the fact that the same spectral regions allow separation within each data set, separation using PCA fails when the two sets of spectra are combined into one; see Supplementary Material available at doi:10.1155/2011/158094. It is apparent that, in addition to the metabolite differences of biological interest, there are subtle differences between G1_13_21 and G2_17_33 in the distribution of metabolites, which prevent classification of the entire (54 spectra) data set. The loadings analysis indicates contributions from across the spectral range, which may suggest variations in more than one metabolite. These spectral differences arise despite stringent efforts of the second group of researchers to adhere to the original experimental protocols and are reflected in the fact that there is not a simple correspondence between the orientation of the first two principal components between the two sets of spectra, [Figure 3](#fig3){ref-type="fig"}.
3.3. ANN Analysis of Whole-Cell Spectra {#sec3.3}
---------------------------------------
ANN analysis consists of separate training and verification steps. For this study, we adopted the strategy of choosing multiple verification sets of spectra at random from the 54 spectra available. In training, the first aim is to find an optimal ANN architecture to enable classification of the training data set. Several architectures of three up to four layered structures were examined for this purpose.
3.4. 3-Layers Architecture {#sec3.4}
--------------------------
Initially we adopted the simplest 3 layers architecture, in which case the search of the optimal architecture consists of optimising the number of nodes in the single hidden layer, effectively determining the corresponding weights, *w*~*ij*~, to minimize the RMS (root mean square error) value according to ([1](#EEq1){ref-type="disp-formula"}). For our analysis, the RMS value ceases to decrease significantly above 5 to 6 nodes, [Figure 4](#fig4){ref-type="fig"}, we therefore used networks with 6 hidden nodes for verification. This optimal architecture will be labelled (72, 6, 4), with it we obtained an RMS = 1.38 × 10^−3^. [Figure 4](#fig4){ref-type="fig"}illustrates the process of searching for the optimal network architecture.
In spite of the fact that very low values for the residual mean squares were achieved using the (72, 6, 4) architecture, the appropriateness of the architecture and of the training set was then tested with various verification sets, that is, a "cross-validation" procedure was undertaken. Initially, five spectra were randomly chosen and excluded from the training set and used then as the verification set. From 10 combinations and 10 independent networks trained, in only two cases were any of the 5 spectra classified as unknown, [Table 1](#tab1){ref-type="table"}. These results are encouraging; two cases represent \~4% of the total, so for (72, 6, 4) the classification was verified as 96% successful. The failures may have arisen due to an insufficient number of spectra in the training set or because networks with three layers have insufficient complexity for 100% prediction accuracy, in this case.
3.5. 4-Layers Architecture {#sec3.5}
--------------------------
We then examined networks with four layers (2 hidden). From several cases examined, it was found that four-layer ANN architectures performed similarly to simpler three layers architectures. Networks of the form (72, 4, 3, 4) or (72, 5, 4, 4) were investigated, note that the numbers in brackets refer to the number of inputs, the number of nodes in the first and in the second hidden layers, and the number of outputs. Acceptable RMS values, of 1.22 × 10^−3^ and 1.41 × 10^−3^ were obtained for (72, 4, 3, 4) and (72, 5, 4, 4), respectively, which are similar to the values obtained using the optimal three-layer architecture. Networks with the architecture (72, 4, 3, 4) performed very similarly to (72, 5, 4, 4) and require fewer unknowns (or weights, *w*~*ij*~), 312 as opposed to 396. As a result, (72, 4, 3, 4) was found to converge faster and to be less sensitive to the number of spectra excluded from training to form the verification set. In fact, we found that 5 to 10 samples could be used for verification with 100% correct classification of the spectra, see [Table 1](#tab1){ref-type="table"}. So in summary, the optimal 3- and 4-layer architectures were found to be (72, 6, 4) and (72, 4, 3, 4), respectively, [Figure 5](#fig5){ref-type="fig"}.
4. Discussion {#sec4}
=============
The ^1^H NMR spectra of intact cells for both G1_13_21 and G2_17_33 have similar general appearance with severe signal overlap and line broadening. Reprojection of either data set, using PCA, demonstrates that separation by cell types is possible due to systematic differences in the lipid methylene and lactate methyl resonances and the overlapped N-methyl ^1^H nuclei of the choline-containing species \[[@B24]\]. Alterations in signal intensity and chemical shift from such cellular metabolites and biochemical intermediates have been described by other researchers in the area \[[@B6], [@B11]\]. However, because of the complex biochemical role played by these substances, we cannot ascribe a particular functional role to the findings, what is more the alterations appear to correlate and associate with particular phenotypic changes, for example, drug resistance. On the basis of the principal component analysis of either group, one could speculate that metabolite profiling by *in vivo* MRS has potential applications in monitoring the development of resistance in a given cancerous tissue. However, for the full data set such a possibility is effectively prevented by other influences on the metabolite distribution, which are comparable to, and nonorthogonal with, the "relevant" biochemical variation. We have shown that this significant obstacle can be eliminated, at least for *in vitro* studies of cell culture, by using a suitable ANN architecture. The most successful network was a four-layer structure with two hidden layers. After appropriate training, the (72, 4, 3, 4) architecture enabled 100% successful classification. Our approach may, in time, be expanded to the classification of larger data sets of spectra which have been recorded with less stringent control over sources of variance unrelated to the classification of interest. This result is encouraging and it is, to our knowledge, the first reported application of the use of ANNs specifically to correctly classify ^1^H NMR spectra in a data set when additional "nonrelevant" sources of variance are included.
Other related examples of the combination of supervised and unsupervised methods include a report by Griffiths and coworkers \[[@B34]\], who obtained 85% accurate classification of meningiomas from nonmeningiomas, by initially using PCA to reduce the dimensionality of ^1^H NMR spectra recorded for tumor biopsy extracts. The first thirty PCs from this first stage of analysis were then classified using a network. More recently, the performance of lineshape fitting and quantitative ANN analyses were compared by Hiltunen et al. \[[@B35]\] for both *in vivo* and simulated ^1^H spectra. The good correlation obtained with these two approaches, for simulated data at least, suggested that ANNs have potential for quantification of *in vivo* MRS long echo time spectra. A further advantage of ANNs in the development of analysis methods for *in vivo* MRS is that they require less processing time than line fitting or other computational approaches \[[@B36]\]. Thus, our study adds to the growing number of applications of supervised techniques for exploiting the diagnostic potential of ^1^H NMR spectra for biomedical purposes.
5. Conclusions {#sec5}
==============
We have found that NMR data recorded for human lung carcinoma whole-cell culture samples can be used for analysis and classification. When sources of variation not directly related to the biological state of interest (drug resistance) are minimised or kept constant, visual separation of the cell type can be achieved using unsupervised pattern recognition techniques, such as PCA. On the other hand, when this condition is not met, in our case when different researchers were responsible for cell culture and spectroscopy, successful classification of the cell type could be achieved using artificial neural networks. The experimental and ANN methodology developed are a step towards the goal of robust and reliable diagnostics based on magnetic resonance spectral data. Furthermore, as similar experimental problems may be encountered in metabolomics applications using other spectroscopic techniques, biological classification using ANNs of data sets that include "nonbiological" sources of variance may be generally possible.
Supplementary Material {#supplementary-material-sec}
======================
######
Supplementary figure 1: Scores plot for the entire data set; group 1 solid markers, group 2 open markers.
######
Click here for additional data file.
The authors acknowledge the support of the Higher Education Authority of Ireland, under the Programme for Research in Third Level Institutions (PRTLI3). D. Brougham, M. Gottschalk, and G. Ivanova acknowledge the financial support of the National Institute for Cellular Biotechnology, at DCU. They would like to thank the School of Chemical Sciences for its provision of spectrometer time. J. Havel would like to acknowledge the support of the EU Erasmus/Socrates exchange program between DCU and Masaryk University and to thank the Ministry of Education and Sports of the Czech Republic, Project LC 0635.
{#fig1}
{#fig2}
![PCA scores plots for A549, DLKP, DLKPA, and DLKP-A5F, whole-cell data. Analysis is shown for G1_13_21 (a), G2_17_33 (b). The right hand panel is reproduced from \[[@B24]\] with permission.](JBB2011-158094.003){#fig3}
{#fig4}
{#fig5}
######
Results of cross-validation verification process for the three- and four-layer ANN networks.
Architecture (72, 6, 4)\*
---------------------------- --------------------------------------- --------------------------------
1 2, 13, 17, 27, 38 all correct
2 21, 24, 31, 35, 51 all correct
3 4, 12, 22, 35, 44 spec. 35 classified as unknown
4 16, 17, 22, 25, 52 all correct
5 15, 16, 17, 23, 54 all correct
6 9, 15, 20, 24, 43 spec. 9 classified as unknown
7 3, 12, 15, 25, 51 all correct
8 19, 21, 43, 47, 54 all correct
9 16, 36, 37, 47, 48 all correct
10 12, 42, 44, 48, 50 all correct
Architecture (72, 4, 3, 4)
1 5, 13, 20, 21, 22, 23, 24, 31, 51, 54 all correct
2 5, 8, 12, 15, 16, 29, 35, 36, 42, 49 all correct
3 8, 10, 13, 18, 23, 28, 33, 39, 40, 53 all correct
4 3, 5, 7, 9, 17, 27, 41, 45, 50, 52 all correct
5 5, 11, 16, 14, 20, 22, 24, 26, 44, 50 all correct
\*where (72, 6, 4) refers to (the no. of inputs, the number of nodes in the hidden layer(s), the number of outputs).
[^1]: Academic Editor: Mika Ala-Korpela
|
|
---
abstract: |
Flexible and performant Persistency Service is a necessary component of any HEP Software Framework. The building of a modular, non-intrusive and performant persistency component have been shown to be very difficult task. In the past, it was very often necessary to sacrifice modularity to achieve acceptable performance. This resulted in the strong dependency of the overall Frameworks on their Persistency subsystems.
Recent development in software technology has made possible to build a Persistency Service which can be transparently used from other Frameworks. Such Service doesn’t force a strong architectural constraints on the overall Framework Architecture, while satisfying high performance requirements. Java Data Object standard (JDO) has been already implemented for almost all major databases. It provides truly transparent persistency for any Java object (both internal and external). Objects in other languages can be handled via transparent proxies. Being only a thin layer on top of a used database, JDO doesn’t introduce any significant performance degradation. Also Aspect-Oriented Programming (AOP) makes possible to treat persistency as an orthogonal Aspect of the Application Framework, without polluting it with persistence-specific concepts.
All these techniques have been developed primarily (or only) for the Java environment. It is, however, possible to interface them transparently to Frameworks built in other languages, like for example C++.
Fully functional prototypes of flexible and non-intrusive persistency modules have been build for several other packages, as for example FreeHEP AIDA and LCG Pool AttributeSet (package Indicium).
author:
- Julius Hřivnáč
title: Transparent Persistence with Java Data Objects
---
JDO
===
Requirements on Transparent Persistence
---------------------------------------
The Java Data Object (JDO) [@JDO1],[@JDO2],[@Standard],[@Portal] standard has been created to satisfy several requirements on the object persistence in Java:
- [**Object Model independence on persistency**]{}:
- Java types are automatically mapped to native storage types.
- 3rd party objects can be persistified (even when their source is not available).
- The source of the persistent class is the same as the source of the transient class. No additional code is needed to make a class persistent.
- All classes can be made persistent (if it has a sense).
- [**Illusion of in-memory access to data**]{}:
- Dirty instances (i.e. objects which have been changed after they have been read) are implicitly updated in the database.
- Catching, synchronization, retrieval and lazy loading are done automatically.
- All objects, referenced from a persistent object, are automatically persistent ([*Persistence by reachability*]{}).
- [**Portability across technologies**]{}:
- A wide range of storage technologies (relational databases, object-oriented databases, files,…) can be transparently used.
- All JDO implementations are exchangeable.
- [**Portability across platforms**]{} is automatically available in Java.
- [**No need for a different language**]{} (DDL, SQL,…) to handle persistency (incl. queries).
- [**Interoperability with Application Servers**]{} (EJB [@EJB],…).
Architecture of Java Data Objects
---------------------------------
The Java Data Objects standard (Java Community Process Open Standard JSR-12) [@Standard] has been created to satisfy the requirements listed in the previous paragraph.
{width="135mm"}
The persistence capability is added to a class by the Enhancer (as shown in Figure \[Enhancement\]):
- Enhancer makes a transient class PersistenceCapable by adding it all data and methods needed to provide the persistence functionality. After enhancement, the class implements PersistenceCapable interface (as shown in Figure \[PersistenceCapable\]).
- Enhancer is generally applied to a class-file, but it can be also part of a compiler or a loader.
- Enhancing effects can be modified via Persistence Descriptor (XML file).
- All enhancers are compatible. Classes enhanced with one JDO implementation will work automatically with all other implementations.
![Enhancer makes any class PersistenceCapable.[]{data-label="PersistenceCapable"}](PersistenceCapable.eps){width="80mm"}
The main object, a user interacts with, is the PersistenceManager. It mediates all interactions with the database, it manages instances lifecycle and it serves as a factory for Transactions, Queries and Extents (as described in Figure \[PersistenceManager\]).
![All interactions with JDO are mediated by PersistenceManager.[]{data-label="PersistenceManager"}](PersistenceManager.eps){width="80mm"}
Available Implementations
-------------------------
After about a year since the JDO standardization, there are already many implementations available supporting all existing storage technologies.
JDO Implementations
-------------------
### Commercial JDO Implementations
Following commercial implementations of JDO standard exist:
enJin(Versant), FastObjects(Poet), FrontierSuit(ObjectFrontier), IntelliBO (Signsoft), JDOGenie(Hemisphere), JRelay(Object Industries), KODO(SolarMetric), LiDO(LIBeLIS), OpenFusion(Prism), Orient(Orient), PE:J(HYWY), …
These implementation often have a free community license available.
### Open JDO Implementations
There are already several open JDO implementations available:
- [**JDORI**]{} [@JDORI] (Sun) is the reference and standard implementation. It currently only works with the FOStore files. Support for a relational database via JDBC implementation is under development. It is the most standard, but not the most performant implementation.
- [**TJDO**]{} [@TJDO] (SourceForge) is a high quality implementation originally written by the TreeActive company, later put on the GPL license. It supports all important relational databases. It supports an automatic creation of the database schema. It implements full JDO standard.
- [**XORM**]{} [@XORM] (SourceForge) does not yet support full JDO standard. It does not automatically generate a database schema, on the other hand, it allows a reuse of existing schemas.
- [**JORM**]{} [@JORM] (JOnAS/ObjectWeb) has a fully functional object-relational mapping, the full JDO implementation is under development.
- [**OJB**]{} [@OJB] (Apache) has a mature object-relational engine. Full JDO interface is not yet provided.
Supported Databases
-------------------
All widely used databases are already supported either by their provider or by a third party:
- [**RDBS and ODBS**]{}: Oracle, MS SQL Server, DB2, PointBase, Cloudscape, MS Access, JDBC/ODBC Bridge, Sybase, Interbase, InstantDB, Informix, SAPDB, Postgress, MySQL, Hypersonic SQL, Versant,…
- [**Files**]{}: XML, FOSTORE, flat, C-ISAM,…
The performance of JDO implementations is determined by the native performance of a database. JDO itself introduces a very small overhead.
HEP Applications using JDO
==========================
Trivial Application
-------------------
A simple application using JDO to write and read data is shown in Listing \[Trivial\].
[|l|]{} $//\ Initialization$\
$PersistenceManagerFactory\ pmf = JDOHelper.getPersistenceManagerFactory(properties);$\
$PersistenceManager\ pm = pmf.getPersistenceManager();$\
$Transaction\ tx = pm.currentTransaction();$\
\
$//\ Writing$\
$tx.begin();$\
$\dots$\
$Event\ event = \dots;$\
$pm.makePersistent(event);$\
$\dots$\
$tx.commit();$\
\
$//\ Searching\ using\ Java-like\ query\ language\ translated\ internally\ to\ DB\ native\ query\ language$\
$//\ (SQL\ available\ too\ for\ RDBS)$\
$tx.begin();$\
$Extent\ extent = pm.getExtent(Track.class, true);$\
$String\ filter = "pt > 20.0";$\
$Query\ query = pm.newQuery(extent, filter);$\
$Collection\ results = query.execute();$\
$\dots$\
$tx.commit();$\
Indicium
--------
Indicium [@Indicium] has been created to satisfy the LCG [@LCG] Pool [@Pool] requirements on the Metadata management: “To define, accumulate, search, filter and manage Attributes (Metadata) external/additional to existing (Event) data.” Those metadata are a generalization of the traditional Paw ntuple concept. They are used in the first phase of the analysis process to make a pre-selection of Event for further processing. They should be efficient. They are apparently closely related to Collections (of Events).
The Indicium package provides an implementation of the AttributeSet (Event Metadata, Tags) for the LCG/Pool project in Java and C++ (with the same API). The core of Indicium is implemented in Java.
All expressed requirements can only be well satisfied by the system which allows in principle any object to act as an AttributeSet. Such system can be easily built when we realize that mentioned requirements are satisfied by JDO:
- [**AttributeSet**]{} is simply any Object with a reference to another (Event) Object.
- [**Explicit Collection**]{} is just any standard Java Collection.
- [**Implicit Collection**]{} (i.e. all objects of some type T within a Database) is directly the JDO Extent.
Indicium works with any JDO/DB implementation. As all the requirements are directly satisfied by the JDO itself, the Indicium only implements a simple wrapper and a code for database management (database creation, opening, …). That is in fact the only database-specific code.
It is easy to switch between various JDO/DB implementations via a simple properties file. The default Indicium implementation contains configuration for JDORI with FOStore file format and TJDO with Cloudscape or MySQL databases, others are simple to add.
The data stored by Indicium are accessible also via native database protocols (like JDBC or SQL) and tools using them.
As it has been already mentioned, Indicium provides just a simple convenience layer on top of JDO trying to capture standard AttributeSet usage patterns. There are four ways how AttributeSet can be defined:
- [**Assembled**]{} AttributeSet is fully constructed at run-time in a way similar to classical Paw ntuples.
- [**Generated**]{} AttributeSet class is generated from a simple XML specification.
- [**Implementing**]{} AttributeSet can be written by hand to implement the standard AttributeSet Interface.
- [**FreeStyle**]{} AttributeSet can be just about any class. It can be managed by the Indicium infrastructure, only some convenience functionality may be lost.
To satisfy also the requirements of C++ users, the C++ interface of Indicium has been created in the form of JACE [@JACE] proxies. This way, C++ users can directly use Indicium Java classes from a C++ program. CIndicium Architecture is shown in Figure \[AttributeSet\], an example of its use is shown in Listing \[CIndicium\].
{width="135mm"}
[|l|]{} $//\ Construct\ Signature$\
$Signature\ signature("AssembledClass");$\
$signature.add("j", "int", "Some Integer Number");$\
$signature.add("y", "double", "Some Double Number");$\
$signature.add("s", "String", "Some String");$\
\
$//\ Obtain\ Accessor\ to\ database$\
$Accessor\ accessor = AccessorFactory::createAccessor("MyDB.properties");$\
\
$//\ Create\ Collection$\
$accessor.createCollection("MyCollection", signature, true);$\
\
$//\ Write\ AttributeSets\ into\ database$\
$AssembledAttributeSet*\ as;$\
$for (int\ i = 0; i < 100; i++) \{$\
$\ \ as = new\ AssembledAttributeSet(signature);$\
$\ \ as->set("j", ...);$\
$\ \ as->set("y", ...);$\
$\ \ as->set("s", ...);$\
$\ \ accessor.write(*as);$\
$\ \ \}$\
\
$//\ Search\ database$\
$std::string\ filter = "y > 0.5";$\
$Query\ query = accessor.newQuery(filter);$\
$Collection\ collection = query.execute();$\
$std::cout << "First: " << collection.toArray()[0].toString() << std::endl;$\
AIDA Persistence
----------------
JDO has been used to provide a basic persistency service for the FreeHEP [@FreeHEP] reference implementation of AIDA [@AIDA]. Three kinds of extension to the existing implementation have been required:
- Implementation of the IStore interface as AidaJDOStore.
- Creation of the XML description for each AIDA class (for example see Listing \[AIDA\]).
- Several small changes to exiting classes, like creation of wrappers around arrays of primitive types, etc.
------------------------------------------------------------------------------------
$<jdo>$
$\ \ <package\ name="hep.aida.ref.histogram">$
$\ \ \ \ <class\ name="Histogram2D"$
$\ \ \ \ \ \ \ persistence-capable-superclass="hep.aida.ref.histogram.Histogram">$
$\ \ \ \ \ \ \ </class>$
$\ \ \ \ </package>$
$\ \ </jdo>$
------------------------------------------------------------------------------------
It has become clear, that the AIDA persistence API is not sufficient and it has to be made richer to allow more control over persistent objects, better searching capabilities, etc.
Minerva
-------
Minerva [@Minerva] is a lightweight Java Framework which implements main Architectural principles of the ATLAS C++ Framework Athena [@Athena]:
- [**Algorithm - Data Separation**]{}: Algorithmic code is separated from the data on which it operates. Algorithms can be explicitly called and don’t a have persistent state (except for parameters). Data are potentially persistent and processed by Algorithms.
- [**Persistent - Transient Separation**]{}: The Persistency mechanism is implemented by specified components and have no impact on the definition of the transient Interfaces. Low-level Persistence technologies can be replaced without changing the other Framework components (except for possible configuration). A specific definition of Transient-Persistent mapping is possible, but is not required.
- [**Implementation Independence**]{}: There are no implementation-specific constructs in the definition of the interfaces. In particular, all Interfaces are defined in an implementation independent way. Also all public objects (i.e. all objects which are exchanged between components and which subsequently appear in the Interface’ definitions) are identifiable by implementation independent Identifiers.
- [**Modularity**]{}: All components are explicitly designed with interchangeability in mind. This implies that the main deliverables are simple and precisely defined general interfaces and existing implementation of various modules serves mainly as a Reference implementation.
Minerva scheduling is based on InfoBus \[InfoBus\] Architecture:
- Algorithms are [*Data Producers*]{} or [*Data Consumers*]{} (or both).
- Algorithm declare their supported I/O types.
- Scheduling is done implicitly. An Algorithm runs when it has all its inputs ready.
- Both Algorithms and Services run as (static or dynamic) Servers.
- The environment is naturally multi-threaded.
Overview of the Minerva Architecture is shown in Figure \[InfoBus\].
{width="135mm"}
It is very easy to configure and run Minerva. For example, one can create a Minerva run with 5 parallel Servers. Two of them are reading Events from two independent databases, one is processing each Event and two last write new processed Events on two new databases depending on the Event characteristics. (See Figure \[Minerva\] for a schema of such run and Listing \[MinervaScript\] for its steering script.)
![Example of a Minerva run.[]{data-label="Minerva"}](Minerva.eps){width="80mm"}
---------------------------------------------------
$new\ Algorithm(<Algorithm\ properties>);$
$new\ ObjectOutput(<db3>, <Event\ properties1>);$
$new\ ObjectOutput(<db4>, <Event\ properties2>);$
$new\ ObjectInput(<db1>);$
$new\ ObjectInput(<db2>);$
---------------------------------------------------
: Example of steering script for a Minerva run.[]{data-label="MinervaScript"}
Minerva has also simple but powerful modular Graphical User Interface which allows to plug in easily other components as the BeanShell [@BeanShell] command-line interface, the JAS [@JAS] histogramming, the ObjectBrowser [@ObjectBrowser], etc. Figure \[GUI\] and Figure \[ObjectBrowser\] show examples of running Minerva with various interactive plugins loaded.
{width="135mm"}
{width="135mm"}
Prototypes using JDO
====================
Object Evolution
----------------
It is often necessary to change object’ shape while keeping its content and identity. This functionality is especially needed in the persistency domain to satisfy [*Schema Evolution*]{} (Versioning) or [*Object Mapping*]{} (DB Projection), i.e. retrieving an Object of type A dressed as an Object of another type B. This functionality is not addressed by JDO. In practice, it is handled either on the lower lever (in a database) or on the higher level (in the overall framework, for example EJB).
It is, however, possible to implement an Object Evolution for JDO with the help of Dynamic Proxies and Aspects.
Let’s suppose that a user wants to read an Object of a type A (of an Interface IA) dressed as an Object of another Interface IB. To enable that, four components should co-operate (as shown in Fig \[Evolution\]):
- JDO Enhancer enhances class A so it is PersistenceCapable and it is managed by JDO PersistenceManager.
- AspectJ [@AspectJ] adds read-callback with the mapping A $\rightarrow$ IB. This is called automatically when JDO reads an object A.
- A simple database of mappers provides a suitable mapping between A and IB.
- DynamicProxy delivers the content of the Object A with the interfaces IB:\
$IB\ b = (IB)DynamicProxy.newInstance(A, IB);$.
All those manipulations are of course hidden from the End User.
![Support for Object Evolution.[]{data-label="Evolution"}](Evolution.eps){width="80mm"}
Foreign References
------------------
HEP data are often stored in sets of independent databases, each one managed independently. This architectures do not directly support references between objects from different databases (while references inside one database are managed directly by the JDO support for Persistence by Reachability). As in the case of the Object Evolution, foreign references are usually resolved either on the lower level (i.e. all databases are managed by one storage manager and JDO operates on top) or on the higher level (for example by the EJB framework).
Another possibility is to use a similar Architecture as in the case of Object Evolution with Dynamic Proxy delivering foreign Objects.
Let’s suppose, that a User reads an object A, which contains a reference to another object B, which is actually stored in a different database (and thus managed by a different PersistenceManager). The database with the object A doesn’t in fact in this case contain an object B, but a DynamicProxy object. The object B can be transparently retrieved using three co-operating components (as shown on Fig \[References\]):
- When reference from an object A to an object B is requested, JDO delivers DynamicProxy instead.
- The DynamicProxy asks PersistenceManagerFactory for a PersistenceManager which handles the object B. It then uses that PersistenceManager to get the object B and casts itself into it.
- PersistenceManagerFactory gives this information by interrogating DBcatalog (possibly a Grid Service).
All those manipulations are of course hidden from the End User.
![Support for Foreign References.[]{data-label="References"}](References.eps){width="80mm"}
Summary
=======
It has been shown that JDO standard provides suitable foundation of the persistence service for HEP applications.
Two major characteristics of persistence solutions based on JDO are:
- Not intrusiveness.
- Wide range of available JDO implementations, both commercial and free, giving access to all major databases.
JDO profits from the native databases functionality and performance (SQL queries,...), but presents it to users in a native Java API.
[99]{}
More details talk about JDO:\
[http://hrivnac.home.cern.ch/hrivnac/Activities/2002/June/JDO]{}
More details talk about JDO:\
[http://hrivnac.home.cern.ch/hrivnac/Activities/2002/November/Indicium]{}
Java Data Objects Standard:\
[http://java.sun.com/products/jdo]{}
Java Data Objects Portal:\
[http://www.jdocentral.com]{}
JDO Reference Implementation (JDORI):\
[http://access1.sun.com/jdo]{}
TJDO:\
[http://tjdo.sourceforge.net]{}
XORM:\
[http://xorm.sourceforge.net]{}
JORM:\
[http://jorm.objectweb.org]{}
OJB:\
[http://db.apache.org/ojb/]{}
Indicium:\
[http://hrivnac.home.cern.ch/hrivnac/Activities/Packages/Indicium]{}
AIDA:\
[http://aida.freehep.org]{}
FreeHEP Library:\
[http://java.freehep.org]{}
Minerva:\
[http://hrivnac.home.cern.ch/hrivnac/Activities/Packages/Minerva]{}
JACE:\
[http://reyelts.dyndns.org:8080/jace/release/docs/index.html]{}
Lightweight Scripting for Java (BeanShell):\
[http://www.beanshell.org]{}
InfoBus:\
[http://java.sun.com/products/javabeans/infobus/]{}
Java Analysis Studio (JAS):\
[http://jas.freehep.org]{}
Object Browser:\
[http://hrivnac.home.cern.ch/hrivnac/Activities/Packages/ObjectBrowser/]{}
AspectJ:\
[http://www.eclipse.org/aspectj/]{}
Enterprise Java Beans (EJB):\
[http://java.sun.com/products/ejb]{}
ATLAS C++ Framework (Athena):\
[http://atlas.web.cern.ch/ATLAS/GROUPS/SOFTWARE/OO/architecture/General/index.html]{}
LCG Computing Grid Project (LCG):\
[http://wenaus.home.cern.ch/wenaus/peb-app]{}
LCG Persistency Framework (Pool):\
[http://lcgapp.cern.ch/project/persist]{}
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Assisted and unassisted suicide in men and women: longitudinal study of the Swiss population.
In Switzerland assisted suicide is legal if no self-interest is involved. To compare the strength and direction of associations with sociodemographic factors between assisted and unassisted suicides. We calculated rates and used Cox and logistic regression models in a longitudinal study of the Swiss population. Analyses were based on 5 004 403 people, 1301 assisted and 5708 unassisted suicides from 2003 to 2008. The rate of unassisted suicides was higher in men than in women, rates of assisted suicides were similar in men and women. Higher education was positively associated with assisted suicide, but negatively with unassisted. Living alone, having no children and no religious affiliation were associated with higher rates of both. Some situations that indicate greater vulnerability such as living alone were associated with both assisted and unassisted suicide. Among the terminally ill, women were more likely to choose assisted suicide, whereas men died more often by unassisted suicide.
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Politics
FILE PHOTO. President Donald Trump's tweets calling for a probe of widespread voter fraud but providing no evidence that it actually took place have rankled California elections officials.
Pool/Getty Images
In the wake of President Donald Trump's call Wednesday for an investigation into widespread voter fraud, a claim widely seen as without merit, California's Secretary of State Alex Padilla pushed back sharply, calling the contention "a flat-out lie."
Trump repeated his previous criticism of the voting process on Twitter saying he may move to strengthen voting procedures depending on the investigation's results.
I will be asking for a major investigation into VOTER FRAUD, including those registered to vote in two states, those who are illegal and....
Padilla said officials have been hearing for several months about Trump's allegations of rampant voter fraud across the country, especially in California, which voted overwhelmingly for Democrat Hillary Clinton in the presidential election.
"But despite our request for any information he may have, they have yet to provide any evidence, any proof to back up their claims," Padilla said. "It's frankly dangerous to people's faith in our democratic system."
Trump's insistence that there was massive voter fraud has confounded political observers who say he may be undermining his own election and that of other Republicans on 2016 voter ballots.
Trump's yet unsubstantiated claim was also dismissed by Democrats and some Republicans.
House Speaker Paul D. Ryan (R-Wis.) said Tuesday that he has “seen no evidence to that effect.” House Minority Leader Nancy Pelosi (D-Calif.) said at a news conference Wednesday that she cannot understand why the newly installed president is “so insecure.”
“To suggest and to undermine the integrity of our voter system is really strange,” Pelosi said. “... On top of it, he wants to investigate something that can clearly be proven to be false, but he resists investigations of a Russian disruption of our election and any connection to his campaign. All we want is the truth for the American people.”
On Tuesday, White House press secretary Sean Spicer fielded questions during a press briefing about President Trump's views on voter fraud. Spicer did not provide specifics on what evidence the president based his statements on.
"I think he stated his concerns of voter fraud and people voting illegally during the campaign and he continues to maintain that belief based on studies and evidence that people have presented to him," Spicer said.
Los Angeles County Registrar Dean Logan said he is concerned about the impression that Trump's tweets are sending to voters.
"What I think is important is that we don't send a message to our electorate that their vote is in question or that their vote doesn't have value," he said.
Logan acknowledged that in Los Angeles County duplicate registrations do occur, usually when voters move addresses. Logan also said sometimes people who have died are still on the voter rolls after their death. But he said there's no evidence that those situations have led to incorrect votes.
"The voter registration list is a fluid list," he said. "There is going to be a timing issue."
Logan said voters should be confident in the system.
"I believe that there are safeguards in place to ensure the integrity of the election," Logan said.
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Serum alpha-tocopherol, lipids, potassium, and creatine phosphokinase in normal and malabsorption patients.
Serum alpha-tocopherol, lipids, potassium, and creatine phosphokinase levels were measured in 20 adult male control patients and eight malabsorption patients. The malabsorption group had significantly lower serum alpha-tocopherol levels than the control group. This change was independent of serum total lipid levels that were not significantly different among the two groups. Serum potassium and creatine phosphokinase levels that are normally used to assess muscle pathology in man did not correlate with serum alpha-tocopherol levels in either the control of the malabsorption groups. Body mass indices that are directly related to adiposity of the individuals were calculated. Among the control patients, there was a significant increase in serum alpha-tocopherol and serum total lipids with increase in body mass index. Similar correlations did not exist in the malabsorption group. In the latter group serum alpha-tocopherol levels may have reached low enough levels to be independent of factors such as adiposity and serum total lipids.
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Unihemispheric slow-wave sleep in the Amazonian dolphin, Inia geoffrensis.
An electroencephalographic study of sleep in Amazonian dolphins, Inia geoffrensis, revealed that unihemispheric slow-wave sleep is the dominant sleep type in this species, as in the other two dolphin species that were studied earlier.
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// Code generated by go-swagger; DO NOT EDIT.
package models
// This file was generated by the swagger tool.
// Editing this file might prove futile when you re-run the swagger generate command
import (
"github.com/go-openapi/errors"
"github.com/go-openapi/strfmt"
"github.com/go-openapi/swag"
"github.com/go-openapi/validate"
)
// RegistrationViaAPIResponse The Response for Registration Flows via API
//
// swagger:model registrationViaApiResponse
type RegistrationViaAPIResponse struct {
// identity
// Required: true
Identity *Identity `json:"identity"`
// session
Session *Session `json:"session,omitempty"`
// The Session Token
//
// This field is only set when the session hook is configured as a post-registration hook.
//
// A session token is equivalent to a session cookie, but it can be sent in the HTTP Authorization
// Header:
//
// Authorization: bearer ${session-token}
//
// The session token is only issued for API flows, not for Browser flows!
// Required: true
SessionToken *string `json:"session_token"`
}
// Validate validates this registration via Api response
func (m *RegistrationViaAPIResponse) Validate(formats strfmt.Registry) error {
var res []error
if err := m.validateIdentity(formats); err != nil {
res = append(res, err)
}
if err := m.validateSession(formats); err != nil {
res = append(res, err)
}
if err := m.validateSessionToken(formats); err != nil {
res = append(res, err)
}
if len(res) > 0 {
return errors.CompositeValidationError(res...)
}
return nil
}
func (m *RegistrationViaAPIResponse) validateIdentity(formats strfmt.Registry) error {
if err := validate.Required("identity", "body", m.Identity); err != nil {
return err
}
if m.Identity != nil {
if err := m.Identity.Validate(formats); err != nil {
if ve, ok := err.(*errors.Validation); ok {
return ve.ValidateName("identity")
}
return err
}
}
return nil
}
func (m *RegistrationViaAPIResponse) validateSession(formats strfmt.Registry) error {
if swag.IsZero(m.Session) { // not required
return nil
}
if m.Session != nil {
if err := m.Session.Validate(formats); err != nil {
if ve, ok := err.(*errors.Validation); ok {
return ve.ValidateName("session")
}
return err
}
}
return nil
}
func (m *RegistrationViaAPIResponse) validateSessionToken(formats strfmt.Registry) error {
if err := validate.Required("session_token", "body", m.SessionToken); err != nil {
return err
}
return nil
}
// MarshalBinary interface implementation
func (m *RegistrationViaAPIResponse) MarshalBinary() ([]byte, error) {
if m == nil {
return nil, nil
}
return swag.WriteJSON(m)
}
// UnmarshalBinary interface implementation
func (m *RegistrationViaAPIResponse) UnmarshalBinary(b []byte) error {
var res RegistrationViaAPIResponse
if err := swag.ReadJSON(b, &res); err != nil {
return err
}
*m = res
return nil
}
|
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Menu
SELECT HowTo FROM WriteSQLSyntax Part 1 : DML
In my years working in BPM, SQL syntax has played a part in almost every peice of work. The ‘long running’ characteristic of BPM requires that process and state data be persisted to a long term data store because this will ultimatley outlast the hosting server in terms of lenth of operation (some processes could go on for years). As well as using databases for peristing BPM state, almost every application that exists these days, including applications or systems that utilise BPM have a data store of some kind that will need to be queried for user or process data. It’s a given that you know SQL in this day and age.
For the experienced developer, this article is not for you.
SQL is a standard that allows for the general interaction with database data. We have the commands that manipulation existing data and the commands that build the structure of the data (tables, schemas etc). Microsoft have a flavour of standard SQL-92 that they name Transact-SQL and split this language into 2 main categories. DML (data manipulation language) are the statements used to manipulate your data using common statements such as SELECT and UPDATE. DDL (Data Definition Language) represents the TSQL statements that assist the management and maintenance of your database objects (ALTER PROCEDURE, DROP TABLE etc).
SQL skills are seen as a basic essential requirement these days in the fields of software development, BPM, EAI, web site design and even scripting and so having a this under your belt is a must. I’ve tried to create a ‘cheat sheet’ of sorts for the DML side of the TSQL language which can be used as a quick reference, starting with the basics :
SELECT (* means ALL columns)
SELECT * FROM POItems | SELECT POL_RowID, POL_OrderNo FROM POItems
DISTINCT(Unique values, non duplicates returned)
SELECT DISTINCT POL_InvApproverName FROM POItems
SELECT INTO (selects from one table and inserts into the other)
SELECT * INTO NewPOItems FROM POItems SELECT POL_OrderNo, POL_Description INTO NewPOItems FROM POItems
|
|
s [ ]
w [a-z0-9A-Z]
W [^a-z0-9A-Z]
d [0-9]
%%
((MERGE.*USING{s}*\()|(EXECUTE{s}*IMMEDIATE{s}*\")|({W}+{d}{s}+HAVING{s}+{d})|(MATCH{s}*[a-zA-Z\\(\\),+\-]+{s}*AGAINST{s}*\()) printf('attack detected');
%%
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|
Derek Duncan
Derek Henry Junior Duncan (born 23 April 1987) is an English footballer who plays as a winger or as a left back for VCD Athletic .
Career
Duncan was signed by Grays Athletic on a one-year contract on 25 May 2007, following his release by Leyton Orient. The left-winger left Grays Athletic by mutual consent, just a month after he signed, after his agent offered him to other Football League clubs.
Duncan was signed by Paul Lambert in the summer of 2007 and joined Wycombe Wanderers, where he failed to make a league appearance before having his contract terminated by mutual consent in January 2009.
On the same day it was announced that he had left Wycombe Wanderers, it was announced that the winger had signed for Ebbsfleet United until the end of the 2008–09 season. The following day Duncan made his debut for Ebbsfleet in their 1–0 home league win over Rushden & Diamonds.
Duncan signed for AFC Wimbledon on 15 June 2009, but after one season at Kingsmeadow he signed for former club Ebbsfleet, on 6 July 2010.
On 29 July 2011, it was announced he had signed for Conference South side Woking.
At the start of 2012–13 season he signed for Conference South side Maidenhead United.
Isthmian League side VCD Athletic recruited Duncan for the 2016-17 season. He featured throughout the first part of the season, before picking up a straight-red card sending off on 1 January 2017 versus local rivals Phoenix Sports.
References
External links
Category:1987 births
Category:Living people
Category:English footballers
Category:Association football wingers
Category:Leyton Orient F.C. players
Category:Lewes F.C. players
Category:Grays Athletic F.C. players
Category:Wycombe Wanderers F.C. players
Category:Ebbsfleet United F.C. players
Category:AFC Wimbledon players
Category:Woking F.C. players
Category:Maidenhead United F.C. players
Category:Thamesmead Town F.C. players
Category:English Football League players
Category:National League (English football) players
Category:Isthmian League players
Category:Footballers from Upton Park, London
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Comparative recovery of 50-Hz and 100-Hz posttetanic twitch following profound neuromuscular block.
To determine if posttetanic twitch following 100-Hz tetanic stimulation enables titration of a nondepolarizing relaxant infusion to a greater depth of block than that achieved with posttetanic twitch following 50 Hz. Prospective, observational study. Operating rooms of a university tertiary care center. 10 ASA physical status II and III patients free of known neuromuscular disease and undergoing general endotracheal anesthesia for routine elective surgery. Following induction of general anesthesia, neuromuscular block was maintained with a continuous intravenous vecuronium infusion. Depth of neuromuscular block was assessed by tactile evaluation of the evoked responses of the adductor pollicis muscle following supramaximal stimulation of the ulnar nerve via surface electrodes. The vecuronium infusion was titrated to loss of posttetanic twitch following 100-Hz tetanic stimulation, at which point the infusion was discontinued. 100-Hz tetanic stimulation was repeated every two minutes until recovery of the first posttetanic twitch, at which point 50-Hz tetanic stimulation was repeated every two minutes until recovery of the first posttetanic twitch. The median time (interquartile range) from discontinuation of the vecuronium infusion to recovery of the first posttetanic twitch following 100-Hz tetanic stimulation was 27% faster than the corresponding time to recovery of the first posttetanic twitch following 50-Hz tetanic stimulation [19 (10 to 24) min and 26 (20 to 30) min respectively, p < 0.002]. Posttetanic twitch following 100-Hz tetanic stimulation enables titration of a vecuronium infusion to a greater depth of block than posttetanic twitch following 50-Hz tetanic stimulation. The present findings should enable more effective titration of this relaxant, thereby reducing the likelihood of unwanted patient movement or unduly prolonged recovery due to relaxant overdosing.
|
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Guy Fouché
Guy Fouché (17 June 1921 – 28 May 1998) was a French operatic tenor.
Life
Born in Bordeaux, Fouché graduated from the Conservatoire de Bordeaux with the First Prize in Opera and opéra comique. He began his career at the Grand Théâtre de Bordeaux in 1942 in Bizet's Les Pêcheurs de perles.
He also obtained a second prize at the Conservatoire de Paris in 1943. From 1945 to 1953, he performed in French opera houses, including those of Toulouse, Marseille, Lyon, Lille, Nantes, Rennes and Bordeaux.
In 1953, he was in Oran. From 1954 to 1956, he was part of the troupe of the Opéra Royal de Wallonie in Liège before being, for six seasons, the first tenor at La Monnaie in Brussels.
Back in Oran, he sang the title role of Faust. In 1961, he moved to Toulon where he ended his career two years later.
Quotes
Discography
Complete
Berlioz's La Damnation de Faust (Faust)
with Ninon Vallin - Pléiade P3082 (33 rpm)
with Régine Crespin, Michel Roux, Peter Van Der Bilt - BellaVoce BLV107.202 (CD)
Donizetti's La Favorite (Fernand), with Simone Couderc, Charles Cambon, choir and Pasdeloup Orchestra, Jean Allain (dir.) - Pléiade P3071 / Vega 28000 - recorded in 1962
Massenet's Hérodiade (Jean), with Andréa Guiot, Mimi Aarden, Charles Cambon, Germain Guislain, Jos Burcksen, Corneluis Kalkman - Malibran CDRG 191 (CD).
Meyerbeer's Les Huguenots (Raoul de Nangis), with Renée Doria, Jeanne Rinella, Henri Médus, Adrien Legros, Académie chorale de Paris, Pasdeloup Orchestra, Jean Allain (dir.) - Pléiade P3085/86 (33 rpm) - recorded in 1953 at the Théâtre de l'Apollo reissued CD Accord 204592
Verdi's Rigoletto (Duke of Mantoue), with Renée Doria, Ernest Blanc, Denise Scharley, Gérard Bourreli, Maria Valetti, Maurice Faure, André Dumas, Pierre Cruchon director - Pléiade P3076 (33 rpm) - French version
Extracts
Puccini's La Bohème, aria of Rodolphe Que cette main est froide (act I) - Pléiade P45152 (Extended play) - French version
Verdi's Rigoletto, arias of the Duke of Mantoue Qu'une belle (act I) and Comme la plume au vent (act III) - Pléiade P45152 (45 rpm) - French version
References
External links
Guy Fouché on Forgotten opera singer
Les Huguenots, Acte II, Scène 1: Ô ciel, où suis-je ? Beauté divine et enchanteresse (YouTube)
Category:1921 births
Category:1998 deaths
Category:People from Bordeaux
Category:Conservatoire de Paris alumni
Category:French operatic tenors
Category:20th-century French singers
Category:20th-century male singers
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This invention relates generally to carbon-to-liquids systems, and more specifically to methods and systems for minimizing liquid product variation from a reactor portion of a system.
The terms C5+ and “liquid hydrocarbons” are used synonymously to refer to hydrocarbons or oxygenated compounds having five (5) or greater number of carbons, including for example pentane, hexane, heptane, pentanol, pentene, and which are liquid at normal atmospheric conditions. The terms C4− and “gaseous hydrocarbons” are used synonymously to refer to hydrocarbons or oxygenated compounds having four (4) or fewer number of carbons, including for example methane, ethane, propane, butane, butanol, butene, propene, and which are gaseous at normal atmospheric conditions.
At least some known Fischer-Tropsch (FT) units have been optimized to produce synthesis gas (syngas) from natural gas, also known as Gas-to-Liquids process (GTL). Typically, syngas refers to a mixture of H2, CO and some CO2 at various proportions. To improve C5+ selectivity and minimize selectivity to C4−, i.e. natural gas and liquefied petroleum gas (LPG) production in known units, a FT reactor is operated with relatively high residence times, with relatively high per pass conversion, and with hydrogen to carbon monoxide (H2/CO) ratios below the consumption ratio. The remote location of most carbon-to-liquids plants makes natural gas and LPG co-production economically unattractive because of the relatively high transportation costs.
Minimizing natural gas and LPG production generally results in a significant fraction (30-40%) of the FT liquids being over-converted to wax. The wax formed must then be converted back to a diesel range, typically C10-C20 hydrocarbons, using a separate hydrocracking reactor. Also, the relatively high per pass conversion that is used to increase C5+ production generally adversely limits the pressure of the FT reactor, and the byproduct water partial pressure increases with conversion and total pressure. As the water partial pressure is increased the catalyst can be generally deactivated through oxidation of the active catalyst sites. Low water partial pressure may cause competitive adsorption of water, CO, and H2 molecules on the catalyst active site, thus reducing syngas conversion. Iron-based FT catalysts in particular can be greatly affected by water. Cobalt-based FT catalysts are generally more resistant to oxidation by water. Other carbonaceous fuels may also be used to provide the syngas input to the FT process. However, undesirable product variations may be caused by the operating characteristics of the known FT gas-to-liquids systems described above.
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Buy Nureflex (ibuprofen) 600mg Cheapest Price Online
When is nureflex used?
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Ocular melanoma.
Intraocular melanoma of the ciliary body and choroid is the most common primary ocular malignant tumor in adults and the most common noncutaneous melanoma. To describe the most salient clinical features, histopathologic findings, and treatment modalities of intraocular melanoma, as well as the novel therapies currently being tested. Clinically, it is important to determine which lesions carry a worse prognosis so as to offer patients the best treatment modalities available. Tumor location, size, histopathology, cytogenetic abnormalities, and tumor profiling are all used in determining the risk of death from metastatic disease of uveal melanocytic lesions. Despite successful local tumor control, up to 50% of patients have metastatic disease within 15 years of diagnosis; there is no effective treatment for metastatic disease. Pathologists should be aware of the importance of tumor gross description, cellular histopathology classification, the use of fine-needle aspiration biopsy coupled with cytogenetics, and the new classification of uveal malignant melanomas that is based on chromosome 3 status.
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Achilles tendinitis as a rare extraintestinal manifestation of ulcerative colitis.
Patients with inflammatory bowel disease often have extraintestinal manifestations (EIMs) involving almost all organ systems, but little has been reported on Achilles tendinitis. Herein, we present a unique case of Achilles tendinitis, which manifested shortly after initiation of mesalazine therapy for ulcerative colitis. A 26-year-old Japanese woman with bloody diarrhea and abdominal cramps lasting for 7 days was referred to our hospital. The Lichtiger clinical activity index (CAI) score was 9 at the first visit. Based on the clinical symptoms and examination results, she was diagnosed with ulcerative pancolitis in the active phase, and treatment with mesalazine (2.4 g/day) and probiotics was initiated. Her symptoms resolved within 7 days of treatment (CAI 3). However, she then developed bilateral Achilles tendinitis without any apparent cause. The Achilles tendinitis subsided with conservative management within 2 weeks, despite continuation of mesalazine therapy. This case instructively suggests that Achilles tendinitis should be noted as an EIM of ulcerative colitis.
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Massive immune hemolysis due to minor ABO incompatibility is an underappreciated, potentially fatal complication of allogeneic hematopoietic transplantation. The increased lymphoid content and rapid engraftment seen with peripheral blood stem cell (PBSC) transplants may increase the frequency and severity of this event. In addition, nonmyeloablative conditioning regimens favor rapid and vigorous donor-type immune reconstitution, relying on donor lymphocytes to mediate both an anti-tumor effect and durable myeloid engraftment. To further the graft versus tumor effect, antiproliferative agents such as methotrexate are frequently omitted from posttransplant anti-GVHD regimens. We observed abrupt, catastrophic hemolysis in the first NIH patient to receive a nonmyeloablative PBSC transplant involving minor ABO incompatibility. We established a protocol for close clinical and laboratory monitoring of the next nine consecutive minor ABO-incompatible, nonmyeloablative PBSC transplants performed on NHLBI and NCI services. Cyclosporine alone was employed to prevent GVHD in all nine cases. Two additional cases of massive immune hemolysis were detected. Hemolysis began 7 to 11 days following stem cell infusion. Both cases responded rapidly to vigorous hydration and prompt donor-compatible red cell transfusions, without adverse clinical consequences. All patients with hemolysis demonstrated a positive direct antiglobulin test (DAT), with eluate reactivity against the relevant recipient blood group (anti-A in two cases, anti-B in one). However, neither the intensity of the DAT nor the donor isohemagglutinin titer distinguished cases with from those without hemolysis. These results demonstrate that isohemagglutinins produced by donor passenger B lymphocytes in minor ABO incompatible, PBSC transplants utilizing cyclosporine alone for GVHD prophylaxis can mediate massive immune hemolysis in a considerable proportion of subjects at risk. In view of this high risk, anti-GVHD regimens in NHLBI protocols were changed to include mycophenolate mofetil (MMF), an antiproliferative agent. None of the next 10 consecutive minor ABO incompatible nonmyeloablative stem cell transplants was accompanied by significant immune hemolysis, although serologic abnormalities were seen. GVHD regimens continue to be modified to maximize graft anti-tumor immune effects while minimizing other immune complications of transplant, and MMF doses are being reduced in an effort to increase complete remission rates posttransplant. We continue to monitor daily blood counts and red cell serologic studies (DAT, IAT) during the period at risk (day 6 to 11 posttransplant) and to promptly administer donor-compatible red cell transfusions in these cases. Improved awareness can avert serious complications due to minor ABO incompatibility following stem cell transplant and should be practiced in all such cases.
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4?
False
Is -0.1 equal to 0.234?
False
Is -1/155 != 14?
True
Which is smaller: 0.8 or -0.17?
-0.17
Is 14 at most as big as 615/49?
False
Which is bigger: 1031 or 1034?
1034
Which is smaller: 107 or 79?
79
Which is smaller: 73 or 0.2?
0.2
Is -4 != -1/6?
True
Which is smaller: 0 or -3/295?
-3/295
Is 4329 greater than 4329?
False
Is -28/2889 < 0?
True
Is 1026 greater than or equal to 1024?
True
Which is smaller: -37 or 1?
-37
Is -108 <= -109?
False
Which is bigger: -2 or 1105?
1105
Is 0 != 15/11?
True
Is 6092 less than or equal to 2?
False
Which is smaller: -193 or -187?
-193
Is -4/243 at least -1?
True
Which is bigger: 2/199 or -1?
2/199
Is 0 equal to -1/1667?
False
Is -1/49 greater than -1/54?
False
Which is smaller: 121 or 133?
121
Are -3/229 and -1/4 nonequal?
True
Is 43 < 75?
True
Does 24 = 25?
False
Is 88 at least as big as -2/63?
True
Is 2375 > 2374?
True
Is -62 not equal to -13?
True
Which is bigger: -263 or -284?
-263
Which is bigger: -424 or -412?
-412
Is -1.82 smaller than 1?
True
Which is bigger: -0.1 or -4522?
-0.1
Which is bigger: 58/11 or 6?
6
Which is greater: -13/6 or -6?
-13/6
Do 1/126 and 1 have the same value?
False
Which is smaller: -2/3 or 639/7?
-2/3
Is -8/3 > 36?
False
Is -1529 bigger than -1529?
False
Are 0.846 and 1/4 nonequal?
True
Is 16/911 greater than 1?
False
Is 3 at most as big as 4?
True
Which is smaller: -74/245 or -0.1?
-74/245
Which is bigger: 8 or -722?
8
Is 327 greater than or equal to -4?
True
Is -295 greater than or equal to -288?
False
Is -1 smaller than 2/3783?
True
Which is greater: 39 or 35?
39
Do 2395 and 2394 have the same value?
False
Is -8 smaller than -31/4?
True
Do 63 and 65 have the same value?
False
Which is bigger: -102 or -103?
-102
Which is smaller: 21/547 or -1?
-1
Does 277 = 104?
False
Which is greater: -36 or -56?
-36
Are 207 and 2 unequal?
True
Which is greater: 5/2 or 0.081?
5/2
Is -264 smaller than -266?
False
Which is bigger: 1/2 or 63?
63
Which is smaller: 23 or 112/5?
112/5
Which is smaller: 471/38 or 12?
12
Do 807 and 804 have the same value?
False
Which is greater: 1 or -2/16961?
1
Which is smaller: -19 or -0.2?
-19
Is 0 not equal to 0.12367?
True
Which is bigger: 615/68 or 9?
615/68
Is 1165 < 1163?
False
Is -0.2 != -9/74?
True
Is 206 at most 206?
True
Which is smaller: -1/4 or -37846?
-37846
Is -1/3 < -105?
False
Are -146 and -3 unequal?
True
Which is greater: -93 or -92?
-92
Is -338 < -342?
False
Are -1 and -8/977 equal?
False
Is -5/3358 greater than or equal to 0?
False
Do -113/52 and -1 have the same value?
False
Which is smaller: 0.2 or -6/37?
-6/37
Is -0.08647 greater than -2/7?
True
Which is smaller: 919 or 8?
8
Do -870 and -907 have the same value?
False
Which is greater: 4 or 11/8?
4
Is -42 greater than or equal to -38?
False
Which is smaller: -192 or -191?
-192
Does 0 = 2/13587?
False
Does -4872 = -4871?
False
Which is bigger: 105.7 or 1/4?
105.7
Which is smaller: 48 or -3?
-3
Which is bigger: -2824 or -2823?
-2823
Is 291 <= 291?
True
Are 79 and 2877/37 unequal?
True
Which is bigger: 80 or 68?
80
Are -129 and -133 unequal?
True
Is 112 at most 335/3?
False
Do 0 and -9/10 have different values?
True
Which is smaller: -1.7 or 24?
-1.7
Is -138 at least -137?
False
Is -3.16 <= 2?
True
Which is bigger: 1 or 5/292?
1
Which is greater: -451 or -458?
-451
Which is smaller: -7706 or 0.1?
-7706
Which is greater: -1 or -5/99?
-5/99
Are -1702 and -1703 nonequal?
True
Is -13 at most as big as -66/5?
False
Which is greater: 89 or 703/8?
89
Is -54 at least as big as -63?
True
Which is smaller: -0.16 or -0.4?
-0.4
Which is greater: -37272 or -37273?
-37272
Which is smaller: 10/1533 or -1?
-1
Which is smaller: 232 or -1?
-1
Which is smaller: 0 or -213/164?
-213/164
Which is greater: 2520 or 2521?
2521
Do 134 and 133 have the same value?
False
Which is smaller: 2/4959 or 0?
0
Which is bigger: -2 or -2324?
-2
Is -8834 > -1?
False
Which is smaller: -3/13 or -1/487?
-3/13
Is 399 at least as big as 397?
True
Is 2995 greater than -2/7?
True
Which is bigger: 2/5 or -97?
2/5
Do 1/12 and -2/61 have the same value?
False
Which is greater: 0.07 or 1?
1
Which is bigger: 368 or -48?
368
Which is bigger: 29 or 100?
100
Which is greater: -8/51 or -1?
-8/51
Is -2/7 < 18/17?
True
Do -28/1091 and 1 have the same value?
False
Is 4 <= -0.066?
False
Do -46/13 and -5 have different values?
True
Is -1/5069 <= 0?
True
Is 49/16 at most 3?
False
Is 9985 at least as big as 9986?
False
Is 47 greater than or equal to 93/2?
True
Which is smaller: -266 or -2?
-266
Is 5496 < 5497?
True
Which is smaller: 49/32 or 3?
49/32
Is 6 equal to -6?
False
Which is smaller: 32 or 617?
32
Is 234 greater than or equal to 41?
True
Which is bigger: -59 or -17?
-17
Which is bigger: -6.6 or -2/211?
-2/211
Which is smaller: -945 or -956?
-956
Is 51 less than 72?
True
Which is greater: -1/11231 or 1?
1
Which is greater: 1 or -22/5591?
1
Which is smaller: -92 or -185/2?
-185/2
Which is greater: 71 or 58?
71
Which is bigger: 9/203 or 0?
9/203
Which is bigger: 0 or -1/97?
0
Is -1093 < -6559/6?
False
Which is smaller: 3/202 or 0?
0
Which is greater: 5/12199 or 1?
1
Which is greater: -1 or 1/292?
1/292
Is -71 greater than -1?
False
Is -26/109 greater than or equal to 0?
False
Do -241 and -242 have different values?
True
Which is smaller: 0.09 or 7?
0.09
Is 794 equal to 3177/4?
False
Which is smaller: 0.135 or -2?
-2
Do 4/7 and 1 have different values?
True
Which is smaller: -106 or -952/9?
-106
Is 1.085 != 1?
True
Which is smaller: 51 or 24?
24
Which is bigger: -4/523 or 1?
1
Is 142 at most as big as 712/5?
True
Which is greater: 0.18 or 68.4?
68.4
Is -293 > -293?
False
Which is smaller: 4/1127 or 0?
0
Which is smaller: -822 or -820?
-822
Which is smaller: -1330 or -6651/5?
-6651/5
Which is greater: -3405 or -10219/3?
-3405
Do -344 and -343 have the same value?
False
Which is smaller: -82 or 0.04?
-82
Are 0.24 and 6 equal?
False
Is -3 < -0.089?
True
Which is greater: -1 or -6/2297?
-6/2297
Which is bigger: -1.18 or -14/9?
-1.18
Which is smaller: -7 or -6?
-7
Which is greater: 0 or -2/561?
0
Which is smaller: 2/117405 or 0?
0
Which is bigger: -866/3 or -289?
-866/3
Is -21 greater than or equal to -21?
True
Which is greater: 73485 or 73484?
73485
Do 339 and 5/2 have different values?
True
Is -1465 at least as big as -1465?
True
Which is smaller: -290 or -42?
-290
Are 22 and 178 nonequal?
True
Which is smaller: -259 or -260?
-260
Which is greater: -16/241 or 0?
0
Is -186 >= 0?
False
Does 55/8 = 8?
False
Which is greater: 0 or -3/16?
0
Is -6 bigger than -110/21?
False
Which is smaller: -2348/33 or -71?
-2348/33
Is 0 at most as big as -1/7143?
False
Which is smaller: 537 or 536?
536
Is 137/3 at most -0.1?
False
Are 38128 and 38128 non-equal?
False
Does -3 = -24?
False
Which is smaller: -10/791 or 0?
-10/791
Which is bigger: 164 or 163?
164
Is 818 greater than 2455/3?
False
Is 7/713 not equal to -1?
True
Which is greater: 3801/29 or 131?
3801/29
Is 2678 at most 2680?
True
Which is smaller: 12 or 100/9?
100/9
Is -0.3 bigger than -0.02?
False
Which is smaller: 0 or 3/637?
0
Which is smaller: -1248 or -2/25?
-1248
Which is greater: -21/8 or 0.02?
0.02
Which is bigger: -132 or -0.17?
-0.17
Do 38 and 25 have the same value?
False
Is -5 smaller than -114/23?
True
Which is greater: -22 or -50?
-22
Is 1 less than or equal to -3/56?
False
Is 1/4 >= -0.022?
True
Which is smaller: -1136 or 3?
-1136
Is -172 greater than -165?
False
Which is greater: -1565 or -1564?
-1564
Which is greater: -64 or -70?
-64
Which is bigger: 13 or 25?
25
Which is bigger: -37 or -20?
-20
Is -1/13 less than -1?
False
Which is smaller: -0.099 or 15/7?
-0.099
Is 3215 > 3217?
False
Is 4066 less than 4066?
False
Is -65/622 < 1?
True
Are 819 and 813 unequal?
True
Is 10 at least as big as 54/5?
False
Which is smaller: 18749 or 18751?
18749
Is 1 < 42/25?
True
Is 7609 greater than or equal to 7613?
False
Which is bigger: -131 or -129?
-129
Which is bigger: -2/11 or -58?
-2/11
Which is smaller: -0.3 or -696?
-696
Is -233 smaller than -232?
True
Which is smaller: -0.4 or 7194?
-0.4
Is 1 less than -18/529?
False
Which is smaller: 1 or -4/30331?
-4/30331
Which is bigger: 675 or 682?
682
Is 1 at least 1/4110?
True
Which is bigger: 2054 or 2053?
2054
Does -1 = 44/413?
False
Which is greater: -3
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Waste heat recovery in various types of combustion engines is a way to improve the overall efficiency of these systems. Waste heat recovery systems range from power plants that have bottoming cycles, to thermoelectric systems that generate electricity. Power plants that have bottoming cycles utilize the excess heat in the low pressure exhaust gases from the primary work generating cycle. Thermoelectric systems utilize similar waste heat sources.
On piston engines, waste heat recovery systems can consist of a closed loop Rankine Cycle. A Rankine Cycle uses the heat from the exhaust to power the cycle. These systems typically have a separate, dedicated, expander that extracts power from the working fluid and is connected to the crankshaft of the engine.
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Monday, August 2, 2010
'AuGusT Has comE..But my MinD sEt Still'
Ive intended to post this in the murnin...but it seems im not feeling that well before lunch hehe..gediks kan...after LUNCH i was simply FINE!!! I guess im pretty hungry ek today..huhu...for sure its sounds crazy for me or what...but i just want to admit that todays MOnDay it seems HAPPY+EXCITING for me..(sambil wat Mexican wave uol!!!) coz ive really HATE my Monday's usually..but today it turns out OK!!! as ive come early in the office + seeing my clinical trial patient in the ICU (his conditions turns out okay!!!) and after that back to the office and manage the time to just blogwalking on some of the B2B blogs (before doing my analysis + database update)...it makes u enjoy and do feel the excitement like they do...when some of them share their stories on preparations + theme+door gifts etc2...as im also busy with in that kind of state their goin through!!!huhu...its just that ive did'nt know how to start sometimes in talking about what i did for my weddings prep...heheh...coz there's lot of things that i just want to blurp it out...without stopping...i guess i'll be doin a full post of the vendors after the wedding itself i guess...mcm to lagi thrill la kot...heheh...as for now myb..akan post some of it..tapi tak byk sgtla..(sorry la yerk kwn2..kadang2 takder idea)..anyway some update's..last week when with my 2 besties(Syaz and Mirah) to "Pameran Pengantin KL 2010" at AEON Setiawangsa..what do we manage to find??tadaa...at last we ended up booking a Studio Photoshoot with Creative LiteBoxfor only RM140 for about 1hour and half!!! as we got 30% off.Thanks to Syaz as she mention that she visited their website and also their FB(kalo tak dier bagi 10% diskaun ajer)..tup tap tup tap..dpt harga mcmtu..best2..so as for now..we are thinking of a concept to do that day as the photoshoot will be on the 14/8/2010 at 11.30am(until now still thinking)...consist of me,Mr R (pun join heheh),Syaz and Mirah.Gambar dierong shot mcm best...coz we love it for the 1st sight we ended up want to try it for ourselves...kalo korang nak try tgk..pg kat blog dieorng,www.creativelitebox.blogspot.com ofis dieorng kat Bangi dkt ajer=) meanwhile this Thursday kiterong akan pagi memanjakan diri di TAJIRI spa(after magrib)...heheh...and not to forget this week 7/8/2010 we will be goin to Wani and Son wedding (majlis bertandang) yeahhh will be seeing Cammy to...ok back to work mode uols...XOXO
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Phullu
Phullu is a 2017 Indian drama film directed by Abhishek Saxena. Produced by Pushpa Chaudhary, Dr. Anmol Kapoor, Kshitij Chaudhary & Raman Kapoor under the Kapoor Film Inc Kc Production Pvt.Ltd banner. The film was released worldwide on June 16, 2017. The film stars Sharib Hashmi, Jyotii Sethi, and Nutan Surya which is inspired from the life of Arunachalam Muruganantham, a social activist from Tamil Nadu.
Phullu is about Phullu, an errand boy who eventually makes low-cost menstruation pads.
Plot
Phullu the titular character (portrayed by Sharib Hashmi) that's the typical good guy. Phullu's mother sells quilts because he doesn't have a job. He helps out his mom by procuring all the raw material for the quilts from the nearby town. In addition, he also picks up all the other stuff the women in his village may need from there.
When Phullu gets married, he realises that his wife keeps taking away pieces of red cloth from the material he gathers for the quilts. He wonders about it, but doesn't connect the dots as he knows nothing about menstruation. Neither his wife or mother explain the concept to him.
The women in his life also want Phullu to move to a big city and find work. But he's adamant about staying back in the village.
Finally, a turning point in Phullu's life comes when he finds out about menstruation through a female doctor at a chemist's shop on one of his city visits. He finally begins to understand why his wife needs the cloth, and why she suffers from itching every night.
He then takes rather drastic step of using all the money reserved for the last installment payment for his sister's jewellery to get a whole lot of sanitary pads. His furious mother kicks him out of the house, saying that he's wasted the money she earned with so much difficulty. When he tries to protest that the sanitary napkins are more important, his mother says her grandmother used wood to get rid of the itching and went on to live for 102 years, so pads are irrelevant.
Phullu goes to the city, where he gets in touch with the doctor who'd educated him about menstruation. He manages to create a sanitary napkin of his own. However, his mother and sister refuse to test it, as do the other women in the village for whom he used to run errands in the city. His wife is pregnant at this time, so she can't help him out either but is in how supportive Phullu's wife is, of his endeavour to manufacture low-cost sanitary napkins.
See also
Pad Man
Period. End of Sentence.
References
External links
Category:Indian drama films
Category:2017 films
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The subject matter disclosed herein generally relates to an aircraft deicing system, and more particularly, to a deicing system for a rotor blade of a rotary wing aircraft.
Rotary wing aircrafts may encounter atmospheric conditions that cause the formation of ice on rotor blades and other surfaces of the aircraft. Accumulated ice, if not removed can add weight to the aircraft and may alter the airfoil configuration, causing undesirable flying characteristics.
A common approach to ice management is thermal deicing. Thermal deicing includes heating portions of the rotor blades, such as the leading edge for example, to loosen accumulated ice. Centrifugal forces acting on the rotor blades, and the airstream passing there over, remove the loosened ice from the rotor blades. Desired portions of the rotor blades are typically heated using electro thermal heating elements arranged at the leading edges of the airfoils, in direct contact with the blade spar. As a result of this direct contact, a malfunction of the electro thermal heating elements, such as by overheating or shorting for example, may damage the spar thereby affecting the structural stability and/or the airfoil of the rotor blade.
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Investigation on the heavy metal content of zinc-carbon and alkaline manganese dry cells.
The objective of this work was to test the compliance of commercially available batteries with the German Battery Ordinance, a project of the German government that was initiated by the Federal Environment Agency. Different types of commercially available dry cells were analysed for their cadmium, lead and mercury contents. The dry cells underwent mechanical pre-treatment, separation of the different components and microwave-assisted digestion before determination of the heavy metals. Mercury is sometimes added to prevent the generation of gaseous hydrogen from the electrochemical process. Lead could be present since it is sometimes used as an alloying element of zinc. Cadmium has no technical importance and is an undesirable impurity. None of the batteries contained higher heavy metal mass fractions than the permissible limits.
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Dog the Bounty Hunter hunts down incredible ratings
Meagan Morris is an entertainment and lifestyle journalist living in New York City. In addition to SheKnows, Morris contributes to many publications including The New York Times, Yahoo! News, PopEater, NBC New York and Spinner. Follow he...
Dog and family dealing with personal issues
Dog the Bounty Hunter is back for 2012! Find out what sort of shenanigans brought in millions of viewers during its Wednesday night debut.
Duane "Dog" Chapman and his family of bounty hunters snagged nearly 2.9 million viewers for the first episode of Dog the Bounty Hunter for the new season, according to the network.
"The eighth season premiere was cable's most-watched entertainment show in the 10 p.m. hour last night and A&E became the number one entertainment cable network in primetime among adults 25-54 and 18-49 for the night," the network said in a statement.
This season is poised to explore some family problems within the large Chapman family — daughter "Baby" Lyssa Chapman's March arrest will air on an episode, as will tensions between Chapman and his oldest son, Duane Lee.
"I love you, dad. This is Travis. I want to go home. I don't like it here," the boy told his father also named Travis. They gained custody after an audio recording surfaced that allegedly showed the father beating the child with a belt.
"I've told (my grandson) that daddy is not gone forever. Daddy has to go to school and you know what he told me, 'will they really tell him not to hit me anymore?' I said yes they won't just tell him they'll make sure, and he goes (big sigh) 'good,'" Dog said.
It sounds like they'll be dealing more with family drama than criminal drama this season.
Image courtesy Michael Wright/WENN.com
Did you watch Dog the Bounty Hunter Wednesday night? What are your thoughts on the new season?
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Off The Wire
Goldcorp says protest could halt production at Mexico gold mine
MEXICO CITY (Reuters) - Canada’s Goldcorp said on Monday an ongoing protest blocking entry to its Penasquito mine, one of Mexico’s biggest gold producers, could force the company to halt output.
The mine, in northern Zacatecas state, produced 476,000 ounces of gold last year, comprising 18 percent of Goldcorp’s total production and generating more than 33 percent of its revenue.
The demonstration began on June 1, led by local truck-drivers who say the company reneged on promises to hire locally.
Local residents also blocked access at the mine last year, protesting for more than a week over a water dispute. The company later said it was able to resume normal operations without a hit to production.
Michael Harvey, Goldcorp’s director of corporate affairs, said the current blockade was illegal and had prevented the flow of workers and supplies.
“We are still working, but if we can’t let supplies in, at some point we will stop producing,” he said.
Ascension Carrillo, one of the protest leaders, said the goal was to get Goldcorp to fulfill its hiring promises.
“The only thing we want is the work that was promised to us ... we’re fighting to feed our families,” Carrillo said.
Disclaimer: The views expressed in this article are those of the author and may not reflect those of Kitco Metals Inc. The author has made every effort to ensure accuracy of information provided; however, neither Kitco Metals Inc. nor the author can guarantee such accuracy. This article is strictly for informational purposes only. It is not a solicitation to make any exchange in commodities, securities or other financial instruments. Kitco Metals Inc. and the author of this article do not accept culpability for losses and/ or damages arising from the use of this publication.
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[The assessment of 99mTc-HMPAO tumor scintigraphy using VX-2 tumors in rabbits].
Tumor scintigraphy using 99mTc-hexamethyl-propyleneamine oxime (99mTc-HMPAO) was performed in VX-2 tumors implanted in the muscles of the lower limbs of rabbits to evaluate the possibility that this agent could be used to estimate the blood perfusion of the tumor. The distribution of 99mTc-HMPAO in the tumor immediately after the intravenous injection of this radiopharmaceutical exhibited almost the same distribution on the static image 1 hour after administration. Tumor time-activity curve for 99mTc-HMPAO revealed initial peak after the injection followed by fading of 99mTc-HMPAO activity and subsequent gradual decrease in activity over the next 1 hour. The ratio of 99mTc-HMPAO activity in the tumor to that in normal muscle tissue during this next 1 hour was high and independent of time. These findings indicate that static 99mTc-HMPAO scintigraphy can provide qualitative but not quantitative data useful in the estimation of tumor blood perfusion. Moreover, comparison of distribution of 99mTc-HMPAO on the static images and angiographic, histological findings also suggest that static 99mTc-HMPAO images accurately reflect tumor blood perfusion.
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Revision gastric bypass after laparoscopic adjustable gastric band: a 10-year experience at a public teaching hospital.
In Australia, there is limited access to public revisional bariatric procedures. However, the need for such procedures is rising. We investigated the safety and efficacy of band-to-bypass procedures in our experience at a public teaching hospital over a period of 10 years. Using a prospectively maintained bariatric surgical database, we analysed 91 consecutive planned band-to-bypass procedures from 2007 to November 2016. All patients had prior laparoscopic adjustable gastric bands removed and formation of Roux-en-Y gastric bypass, in one or two stages. Primary outcomes were 30-day complication rate and excess weight loss from 12 months. The impact of fellows as primary operators on these outcomes was assessed. Eighty-two patients met the inclusion criteria. Seventy-one (84.5%) were females. Mean age was 48.8 years (SD: 8.85). Immediate post-operative complications included six (7.3%) patients with gastrojejunostomy leak, three of whom required conversion to laparotomy, with one mortality (1.22%). Fifty-two patients had follow-up of 1 year or more (median: 2.36, range: 1-9.24). Mean excess weight loss at the end of follow-up was 52.79% (SD: 46.46). Twenty-eight (34.14%) cases were performed primarily by a fellow under the guidance of an experienced bariatric surgeon, with equivalent results. Revisional band-to-bypass in the public setting is an effective but complex procedure associated with morbidity. Some risk may be ameliorated by development of selection criteria to exclude certain high-risk groups. We hope discussion amongst other bariatric groups will further refine this approach.
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Dave Davis (bowler)
Dave Davis (born April 28, 1942) is a former American professional ten-pin bowler and former member of the Professional Bowlers Association (PBA). He grew up in Sweet Valley, Pennsylvania, and now resides in Lake Placid, Florida.
Beginning his PBA career in 1964, the left-hander won 18 PBA Tour titles, including four majors. He was inducted into the PBA Hall of Fame in 1978. Davis won multiple titles in a season four times, including six titles in the 1967 season alone. The 1967 season would see him win the PBA National Championship on his way to Player of the Year honors. He also won the PBA National Championship in 1965, plus two PBA Tournament of Champions titles (1968 and 1975). As a PBA Senior Tour bowler, Davis won back-to-back titles in the USBC Senior Masters (1995 and 1996).
In addition, Davis served the PBA in various positions on the Executive Board and Tournament Committee. He was ranked #19 on the PBA's 2008 list of "50 Greatest Players of the Last 50 Years."
For a brief period, Davis spent time in the TV broadcast booth, alongside play-by-play announcer Chris Schenkel. After the death of Schenkel's long-time broadcast partner, Billy Welu, in 1974, Davis and Dick Weber shared analyst duties on ABC-TV's Professional Bowlers Tour until Nelson Burton Jr. was hired as a full-time replacement in 1975.
Davis also appeared regularly on the 1970s version of Celebrity Bowling as an analyst and cohost.
References
Category:1942 births
Category:Living people
Category:American ten-pin bowling players
Category:Sportspeople from Hackensack, New Jersey
Category:Bowling broadcasters
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Python swarm
Just found out about PyObjC. Talked earlier this week with Corinne Coen, over in the School of Management, who has done some work with Swarm. I played with Swarm a bit while at Santa Fe, and would love to do more work with it, but I fear that writing objects for simulation in Objective C could be a stumbling point for some of our grad students. It seems that there are other efforts under way to simplify the process, but since I am planning on teaching an intro to “Programming for Informaticists” in Python next year, it might be worth looking into how to integrate python objects into Swarm.
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Introduction
Replace the Oil with Unsweetened Applesauce to make these Waffles perfect in taste as well as Calories and Fat.
Replace the Oil with Unsweetened Applesauce to make these Waffles perfect in taste as well as Calories and Fat.
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1. Technical Field
Embodiments of the present invention relate generally to providing an on-board diagnostic port connector in an automobile with a lockable connection, and specifically to a lockable connection that is discreet and easy to operate.
2. Background of Related Art
On-board diagnostic regulations require passenger cars and trucks to be equipped with a standardized connector to provide access to the vehicles diagnostic information. Since 1996, the standard required has been one published in Society of Automotive Engineers paper SAE J1962, known as OBD-II (or OBD2). This standard specifies the signal and message protocols, the pinout of the connector, and the details of the connector itself.
This standard connector is the access point for the diagnostic and operational information about the vehicle. The OBD-II port is crucial in such tasks as checking and clearing diagnostic trouble codes, allowing for governmental vehicle inspection, and driver provided supplemental instrumentation and telematics. These applications generally involve temporary, and voluntary, connections to the car's OBD-II port, commonly referred to as plug and remove.
In the car rental and fleet vehicle industries, there is often a desire to have a device connected to the vehicle's diagnostics. These devices can be hard-wired into the vehicle's electronics, or they can be plugged into the vehicle's OBD-II port. Each of these options has its own advantages and disadvantages.
Devices that are hard-wired into the vehicle's electronics provide the most secure and least intrusive option. Such devices connect directly to the vehicle control unit or are spliced into the wiring harness of the vehicle. If done properly, these connections will be semi-permanent and very reliable. These devices also allow the OBD-II port to be unobstructed and be available for other devices to connect. Furthermore, since they are made in the vehicles wiring, they are rarely visible or otherwise evident without removing dashboard panels or looking in the engine bay. In a rental or fleet situation, the user not being aware of the device can be helpful to prevent tampering or removal.
Though these hard-wired devices offer several advantages, their main drawback is the cost of time and labor associated with their proper installation. Proper installation of a hard-wired device requires a trained technician to first remove interior panels to access the wiring necessary. Once the technician has access to the wiring of the vehicle, great care must be taken to properly tap into the necessary inputs without doing permanent damage to the vehicle. This process can take anywhere from a few hours to a few days per vehicle. Additionally, mistakes made during this installation can cost thousands of dollars to repair. Once the vehicles are no longer to be used in the fleet, uninstalling them to be installed in other fleet vehicles (or to provide for the sale of the decommissioned vehicle) is an equally labor intensive process.
The alternative to such laborious installation procedures is an OBD-II port connected device. These devices have the advantage of taking only minutes or hours to install and secure in the dash area of the vehicle. Similarly, they are easily uninstalled at the end of a vehicle's service time.
Because they are so easily installed and uninstalled, their downside is that they are often disconnected before it is desired by the fleet owner. This could be from vibrations gradually loosening the connection, an operator accidentally knocking the plug out, or a driver intentionally unplugging a device. The standard for OBD-II requires that the port be located within reach of the steering wheel, which typically results in the port being located in or around the foot well of a passenger vehicle. As such, a driver may accidentally contact the plug, loosening or disconnecting the device from the vehicle. Furthermore, potential operators may seek to intentionally remove the devices, either to prevent the collection of vehicle data, or to steal the device.
What is needed, therefore, is an OBD-II compliant connector that is easy for a technician to install and uninstall, but difficult for an operator to knock loose or remove without permission. It is to such systems and methods that embodiments of the present invention are primarily directed.
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Same-sex marriage legalized in Australia by overwhelmingly public vote
Australians at home and abroad are rejoicing because their fellow countrymen & women have made sure their voices are heard regarding same-sex marriage — and they are all unanimously in favor of it!
According to the results of a groundbreaking national postal survey that was carried out by the Australian Bureau of Statistics (ABS), close to 62 percent of Australians who voted said YES to legalize same-sex marriage with a clear majority in every single state and territory demanding they get marriage equality. The overall turnout of eligible voters nationwide was close to 76 percent.
The government, which chose to survey the people instead of conventional methods, will present the results before the parliament to pass the verdict on the issue.
Its expected that a bill for the same will pass, with many opponents of same-sex marriage in their parliament surprisingly promising to respect the result and provisions for amendments. Labor MPs are unanimously in favor of the bill along with a large section of cross-benchers expected to support the bill.
Australian Prime Minister Malcolm Turnbull (who voted yes), has already pledged to follow through with the popular vote. “We must respect the voice of our people. We asked them for their opinion and they have clearly given it to us. It is overwhelming,” he said at a press conference. The Prime Minister said a decision vote will come sometime before Christmas.
The Opposition Labor Party’s leader, Bill Shorten, at a rally in Melbourne, said: “What a fabulous time to be an Australian – because in this survey the Australian population has stated that Australia is absolutely ready for wholesome marriage equality.
With this, Australia is en route to become the 25th country in the world to legalize same-sex marriage (in at least some jurisdictions and provinces).
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Liestal, Switzerland, September 28, 2016 - Santhera Pharmaceuticals (SIX: SANN) announces that the first patient has been enrolled at the University of Kansas Medical Center (KUMC), Department of Neurology, Kansas (USA) in Santhera's randomized, double-blind, placebo-controlled phase III (SIDEROS) trial. The trial will assess the efficacy of Raxone in slowing the rate of respiratory function decline in Duchenne muscular dystrophy (DMD) patients receiving concomitant glucocorticoids.
"We first observed the efficacy of Raxone in slowing the rate of respiratory function decline in DMD patients in both glucocorticoid-using and non-using patients in the phase II DELPHI study," commented
Thomas Meier
, PhD, CEO of Santhera. "The successful Phase III DELOS trial which enrolled glucocorticoid non-using patients then confirmed a clinically relevant and statistically significant benefit of Raxone treatment on pulmonary function. The now initiated Phase III SIDEROS trial is designed to confirm the efficacy of Raxone in patients experiencing respiratory function decline that are currently taking glucocorticoids. If successful, this study will provide data that support use of Raxone in all DMD patients experiencing respiratory decline irrespective of their glucocorticoid use. The high level of interest from investigators and the patient community should allow us to recruit this study quickly."
"We are hopeful that this phase III trial is the final step in the development program with Raxone in DMD," said
Gunnar Buyse
, MD, PhD, Professor of Child Neurology at the University Hospitals Leuven (Belgium) and SIDEROS PI and Lead Investigator for Europe. "Following the exploratory phase II program and the successful phase III DELOS trial, I am grateful that Santhera is committed in exploring the full therapeutic potential of Raxone for patients with DMD."
"Maintaining pulmonary function in patients with DMD has only recently become a prominent therapeutic objective in DMD, particularly in non-ambulatory patients," added
Oscar Henry Mayer
, MD, Medical Director of the Pulmonary Function Testing Laboratory at the Children's Hospital of Philadelphia and Lead Investigator for US. "A patient and caregiver survey conducted by Parent Project Muscular Dystrophy clearly demonstrated that the DMD community highly values treatment options for pulmonary complications."
About the SIDEROS Trial
SIDEROS is a phase III, double-blind, randomized, placebo-controlled trial with Raxone in approximately 260 DMD patients receiving concomitant glucocorticoids. Patients with declining respiratory function on any stable glucocorticoid treatment scheme and irrespective of the underlying dystrophin mutation or ambulatory status will be eligible. Study participants will receive either Raxone (900 mg/day; given as 2 tablets 3 times a day with meals) or placebo for 78 weeks (18 months). The primary endpoint of the trial is change from baseline to week 78 in forced vital capacity % predicted (FVC%p). Secondary endpoints include changes from baseline in % predicted peak expiratory flow (PEF%p), time to first 10% decline in FVC and change from baseline in inspiratory flow reserve. Patients completing the trial will be offered the opportunity to enroll in an open label extension study where all patients receive Raxone. The study will be conducted at about 50 centers in the United States and Europe. Patients wishing to enroll in the study should contact their neuromuscular clinic physician. Further information about the study is available under
www.clinicaltrials.gov
.
About Raxone
®
(Idebenone) in Duchenne Muscular Dystrophy and Regulatory Status
Duchenne muscular dystrophy (DMD) is one of the most common and devastating types of muscle degeneration and results in rapidly progressive muscle weakness. DMD is characterized by a loss of the protein dystrophin, leading to cell damage, impaired calcium homeostasis, elevated oxidative stress and reduced energy production in muscle cells. This results in progressive muscle weakness and wasting and early morbidity and mortality due to respiratory failure.
Idebenone is a synthetic short-chain benzoquinone and a cofactor for the enzyme NAD(P)H:quinone oxidoreductase (NQO1) capable of stimulating mitochondrial electron transport, reducing and scavenging reactive oxygen species (ROS) and supplementing cellular energy levels.
The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) is currently assessing a Marketing Authorization Application (MAA) for Raxone in DMD patients with respiratory function decline who are not taking concomitant glucocorticoids. The indication would include patients who previously were treated with glucocorticoids or in whom glucocorticoid treatment is not desired, not tolerated or is contraindicated. The MAA was submitted as a Type II variation of the company's existing marketing authorization for Raxone for the treatment of visual impairment in patients with Leber's hereditary optic neuropathy (LHON).
About Santhera
Santhera Pharmaceuticals (SIX: SANN) is a Swiss specialty pharmaceutical company focused on the development and commercialization of innovative pharmaceutical products for the treatment of orphan mitochondrial and neuromuscular diseases. Santhera's lead product Raxone is authorized in the European Union, Norway, Iceland and Liechtenstein for the treatment of Leber's hereditary optic neuropathy (LHON). For Duchenne muscular dystrophy (DMD), the second indication for Raxone, Santhera has filed a Marketing Authorization Application (MAA) in the European Union. In collaboration with the US National Institute of Neurological Disorders and Stroke (NINDS) Santhera is developing Raxone in a third indication, primary progressive multiple sclerosis (PPMS), and omigapil for congenital muscular dystrophy (CMD), all areas of high unmet medical need. For further information, please visit the Company's website
www.santhera.com
.
Disclaimer / Forward-looking statements
This communication does not constitute an offer or invitation to subscribe for or purchase any securities of Santhera Pharmaceuticals Holding AG. This publication may contain certain forward-looking statements concerning the Company and its business. Such statements involve certain risks, uncertainties and other factors which could cause the actual results, financial condition, performance or achievements of the Company to be materially different from those expressed or implied by such statements. Readers should therefore not place undue reliance on these statements, particularly not in connection with any contract or investment decision. The Company disclaims any obligation to update these forward-looking statements.
PharmiWeb.com is Europe's leading industry-sponsored portal for the Pharmaceutical sector, providing the latest jobs, news, features and events listings.
The information provided on PharmiWeb.com is designed to support, not replace, the relationship that exists between a patient/site visitor and his/her
physician.
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The new documentary Beyond Elections: Redefining Democracy in the Americas proves that democracy can and should be more than casting a ballot every four years. This empowering film gives hopeful and concrete examples from around the Americas of people taking back the reigns of power and governing their own communities. Beyond Elections is a road map for social change, drawing from communal councils in Venezuela and social movements in Bolivia to participatory budgeting in Brazil and worker cooperatives in Argentina. The film gracefully succeeds in demonstrating that these grassroots examples of people’s power can be applied anywhere. Particularly as activists in the US face the challenges of an Obama administration and an economic crisis, this timely documentary shows that the revolution can start today right in your own living room or neighborhood.
In this interview, Michael Fox, Co-Producer of Beyond Elections, talks about how the film was created, what its aims were, and what impact the film has had among viewers in the US.
Benjamin Dangl: How did you decide on the focus and message of Beyond Elections?
Michael Fox: I’ve been living and working in Latin America for many years, studying and reporting on, above all else, the experiences in participatory democracy — cooperatives, communal councils, participatory budgeting, social movements, community radio, etc. . . . Sílvia (my wife, who grew up in Southern Brazil, and who is also Co-director of the film) and I were living in Venezuela in 2006 when the communal councils law was passed, and local communities all across the country began to come together and take on this new form of organizing. You could see how it was empowering people on an individual and local level.
In March of 2007, Sílvia and I found ourselves in Porto Alegre, Brazil — where we now live — at the same time that the 2007 Participatory Budgeting cycle was about to begin. We realized that although there have been many local videos on the experiences of participatory budgeting, cooperatives, social movements and even some on the recently-formed communal councils, there was no documentary film that tried to give both the big and local picture of these new participatory concepts of democracy across the hemisphere.
This concept is almost completely absent in the United States, and yet, it is absolutely necessarily for people to understand what is going on across Latin America, and also extremely important for activists and people in the United States to understand the failures of our own system and the lack of participation and input from everyday citizens.
We originally planned the film to focus only on participatory democracy, but quickly realized that the only people who would want to see it would be activists that are already doing this type of work. We needed to open it up to the very concept of democracy itself.
This was important to us, because time and again in the United States, pundits, elected officials, everyday folks, and even journalists use the word “democracy” as an excuse to de-legitimize extremely democratic groups and governments. They say, “Venezuela is threatening democracy in the region,” and yet depending on your definition, Venezuela is perhaps the most democratic country in the region — much more so than the United States. But these realities are very subtle, and if you have never been to Venezuela, or Brazil, or Bolivia, or Ecuador (or if you go and only stay at the resorts and the upper-class part of town), then you’re never going to know what to believe because the mainstream media is quick to repeat the manipulations.
There are some mainstream media that actually call Venezuelan President Hugo Chavez a dictator, despite the fact that during his ten years in office there have been more than a dozen free and fair elections in Venezuela legitimately recognized by international observers from around the world, and that he has always respected the Venezuelan Constitution and the laws. He may be a very charismatic, domineering, and powerful figure, but he’s not a dictator.
Then the real question is, “What is democracy?” And that’s where we wanted to focus our attention — giving people the space to tell their stories across the Hemisphere.
As the Portuguese Sociologist Boaventura de Sousa Santos says, (and you can find the link to more of his work on our website, www.beyondelections.com), the United States has created a monopoly on the definition of democracy — U.S. style hegemonic representative politics.
But Sousa Santos points out that, in reality, democracy is a work in progress. As he says, “democracy without end.”
His colleague, Leonardo Avritzer, professor from Brazilian Federal University of Minas Gerais, points out in our film, “What we’ve tried to stress is the idea that democracy is an open concept and the frontiers of democracy are always imprecise. For instance, in the 19th century you could say that it’s democratic to expand suffrage. And that’s true. It was democratic at the end of the 19th century to expand suffrage to women. Or at the beginning of the 20th century it could appear democratic to expand democracy to the countries of the global South. So the question today in the Southern countries is how to think about the democratization of things like the budget, health policies, education policies, urban policies, the democratization of life where you live.”
Of course, it’s not always easy. Especially when you are trying to make a film for not one audience, but audiences in various languages all across the Hemisphere. But that’s what we set out to do, and I think we succeeded.
BD: Could you talk a bit about the process of making your documentary?
MF: This is very important, because we wanted the making of the film to reflect as much as possible the “democracy” that we are trying to portray. We used very little narration — only about two and a half minutes worth — because we wanted people to tell the stories in their own words. We tried not to change the scenery where we were filming. We only used music from local musicians, and tried to only use it when it was part of the scene. It is also a testament to what two people can do without any external resources or really expensive equipment.
The entire budget came out of our own pockets and Silvia and I filmed nearly the entire film with our Panasonic 3CCD handycam, and edited it all on our aging G4 Powerbook.
Of course, we had more than a half a dozen individuals and groups that supported with b-roll, and either shot for us, or allowed us to use footage they had already filmed in areas that we couldn’t make it to like Ecuador, Bolivia, and the Bay Area.
The SF-based musician and sound editor, Ben Bernstein, donated his time to post-produce our audio, which came out great. The Venezuela-based film group, Panafilms was a huge support, as were hundreds of folks all across the region.
BD: What was the response among viewers during your tour in the US?
MF: We did our tour last fall from mid September straight through till two days before the 2008 Presidential elections. We drove from the East Coast to the West Coast and back, covering our costs with donations from the nearly two-dozen showings all across the U.S. It was an amazing experience. Of course, we were organizing the tour ourselves, so our audiences varied from a couple hundred people at some Universities all the way down to a living room showing with a few people in Oklahoma City. But really, the response was the best we could have hoped for, and both Silvia and I were impressed with the diversity of opinions. Some viewers were struck by the amount of local democracy and participation in Venezuela specifically, especially with the negative press that it gets in the United States. Many viewers were impressed with the democratic experiences, and the fact that people all across the region are all participating in similar ways. Others were shocked because so little of this is happening in the U.S. Others felt the movie really put things into a perspective that they had rarely seen or heard of before. This was the case of one gentleman in the Lower 9th Ward in New Orleans where we showed Beyond Elections with a projector on the side of a building. He said, “Wow, I’ve always known all of this, but I had never understood that everything was connected. I feel like I have a new perspective on things.”
Without a doubt, the biggest and only major critique was that it was, and remains, a long documentary — just under two hours, which we’ll keep in mind for our next documentary. The DVD version of the movie is divided into chapters, which can each stand alone, so it can easily be used in university and high school classrooms according to theme. The right hand side of the website www.beyondelections.com has dozens of links to additional information, all also sorted according to the chapter and the theme.
We tried to build the film in order to give people an understanding of the realities, and also leave them with a sense of hope. Because these experiences anywhere, be it in Latin America or the United States, in the local government, the community, the office, the school, or the home can only happen if we take the steps to open the democratic spaces of participation. This is the exciting thing about the film and I believe that people could feel it. The film gave people an idea about some of the things that are being done, and some of the things that they can also do. As Sílvia often said in our after-film discussions, “The best thing you can do to support these democratic experiences abroad is to make change in your own communities, attempt to open democracy in your own community.” As a Brazilian, she knows the effect that this can have.
In our discussions after nearly all of our showings, we tried to stress this point: how we can open up these democratic experiences in our own lives. After numerous requests, we actually developed a “Beyond Elections Democracy Discussion Guide,” which attempts to help people to do just that, Bring Democracy Home. It is also available to download halfway down the right-hand side of our website, under “Beyond Elections Materials.”
Monthly Review Essays
Historically, capitalism develops institutions and ideologies that justify surplus extraction and capital accumulation. In the last decades of the twentieth century, the financialization of capitalism initiated a new era of accumulation which is known in academic contexts as finance-capital-driven neoliberalism.
Both Sweezy and Dimitrov agree that fascism arises in the middle class and becomes a threat when the bourgeoisie embraces it, but Sweezy’s unique contribution is to demonstrate fascism’s relationship to the postwar transitional period of class equilibrium.
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Marie phoned me to request that I send to Lindsay Hamilton, St.Johnstone, 1 pair 036 size 9 and they were sent (No.97).
28th November 1991 10.20
Marie also asked me to send to Nicky Hammond, Swindon, 1 pair 036 size 7.5, and they were sent (No.98).
28th November 1991 11.45
Marie phoned to say that she had forgotten to ask if the 2 pairs of gloves ordered earlier today could be sent today. I told her that they had already been packed.
28th November 1991 2.50
John Burridge, Hibernian, phoned to order some goods and 2 pairs 036 size 9.5 were sent to him (No.99) along with an uhlsport catalogue. He wanted the phone number in Germany which I gave him and he also asked what was new. I told him that Line 7 had seen the new range but that I had not yet seen any of it. I asked him what had happened about the signed gloves and newspaper competitions to win them, and he told me that he had sent off the gloves but had not seen or heard anymore about the competitions. I said that I would try to find out more information.
2nd December 1991 10.25
Marie phoned and asked me to send to Gerry Gallagher of Eurone Management 1 pair 036 size 8.5, 1 pair 040 size 8.5 for Paul Mathers, Dundee, and 1 pair 036 size 8.5, 1 pair 040 size 8.5 for Andy Murdoch. Partick, and they were sent (No.1). I asked Marie if David Spensley was yet available as I had left a message on Thursday, again on Friday, for him to phone me, but had not yet heard from him. She said he was on the phone but would ask him to phone me.
2nd December 1991 4.45
David Spensley called and I asked him about the competitions with John Burridge gloves. He said that he did not think anything had happened yet but Chris Jones was dealing with it. He suggested that if John Burridge really wanted to know he should contact Chris Jones. I asked if he was ready yet to take over promotion goods and he said no, although goods had been ordered from Germany. We then discussed matters in general.
3rd December 1991
Having received a delivery I sent to Theo Snelders, Aberdeen, 1 pair 566 XL (No.2).
3rd December 1991
Having received a delivery I sent to Ludek Miklosko, West Ham, 2 pairs 636 elbow pads Large, 2 pairs 638 knee pads Large (No.3).
3rd December 1991 11.35
John Lukic, Leeds, phoned to see if I could do him a favour. Theo Foley, the manager at Northampton, had asked John for some gloves as Northampton have no money and cannot afford to buy them. I said that this time I would send 2 pairs 073 size 9.5, 1 pair 040 size 9.5 to Theo Foley (No.4) along with details of the special prices scheme. John Lukic was grateful as it enabled him to help his old Arsenal coach Theo Foley.
I saw Phil Parkes, coach at QPR, and asked him why Tony Roberts, who had been given uhlsport gloves, wore Reusch in the Zenith Cup match v Crystal Palace. He told me that it was because he had had the uhlsport gloves stolen from the kit room at the ground and only had old Reusch gloves. I said that if he wanted more gloves I needed back the signed 2 year goods only contract, and Phil told me that he would pass it on to Tony Roberts.
10th December 1991 10.15
Pat Jennings, ex Northern Ireland goalkeeper, who still wears uhlsport in the charity matches he plays arouind the world, phoned to ask about gloves for his son. He said that he would pay but I said that I would send them free of charge, and 1 pair 019 size 8, 1 only 010 glove bag were sent to him (No.6).
11th December 1991 4.00
Jochen phoned to ask me what "SHUT OUTS" mean as he had rceived a contract offer from Line 7 regarding Andy Goram, Rangers. I said that it was when he did not concede a goal in a game. He then asked me in general about Andy Goram and I said that he was very much the first choice for Scotland and he had played in every qualifying game for the European Championships in Sweden, and seemed likely to be first choice for Scotland in Sweden. However, I pointed out that he had previously been under contract with uhlsport, arranged by Readers, and there was a problem about the length of his contract. The contract he signed was dated 5th November 1986 and valid for 3 years meaning that it expired in November 1989, was later claimed by Goram to have been signed over a year earlier than it was dated, and in 1988 he changed to Sondico although the written evidence showed he was still under contract to uhlsport. The contract was for £xx , paid in full when the contract was dated and signed. Jochen said that the contract offer was complicated and I warned him to be very careful as playing for Glasgow Rangers, Scotland's most successfull club, they were likely to win most competitions they entered, meaning that uhlsport may have to pay out a lot in bonus's the way the contract is set out. I said that I would do some research and let him know the details.
12th December 1991 9.00-9.05
I phoned Jochen to give him details on Andy Goram including that at the half way stage of this season, 22 League games, he had conceeded 18 goals and had kept 11 "SHUT OUTS". I said that I would put down the information in writing and send it to him with the magazines.
12th December 1991
I bought and sent to Jochen this weeks issues of "Shoot" and "Match".
12th December 1991 1.00
Alan Knight, Portsmouth, phoned for some goods and 2 pairs 036 size 9.5, 2 pairs 040 size 9.5 were sent to him (No.7)
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George Vierra Winemaking
Monday, June 27, 2011
Get out of the Office and Into the Street
When Multicultural is the Culture
June 23, 2011
The 2010 Census confirmed something Nielsen has been noting for some time: multicultural consumers are rapidly becoming the majority in the United States and their buying power is significant. Understanding their purchasing and media habits is the next big challenge/opportunity facing marketers and brands today. Taking a deep dive into data and trends within the African American, Asian American and Hispanic communities, Nielsen’s Claudia Pardo laid out compelling statistics and a demographic framework shaping the future. It’s clear that marketers and brands will be forced to rethink their perspective — and their share of spend — when it comes to multicultural groups.
“Can anyone in the room honestly say they’re doing everything they can to satisfy the consumption needs of this population?” Pardo asked attendees. “The demographic growth of these groups is simply becoming too great to ignore.” The good news, noted Pardo, is that multicultural groups are actually more loyal to brands and there’s an opportunity to win a consumer for life.
In the past multiculturalism was talked about as a melting pot, but it’s really more like a salad bowl where each group stands out and is different in the way they value their culture and traditions. Pardo offered examples of notable distinctions in the way these diverse groups shop and consume media.
BUYINGHispanics
Spend the most per trip and annually
Shop less often, usually with family
Blacks/African Americans
Shop more frequently than any other ethnicity
The most brand loyal; fewer purchases of private label
Asian Americans
Most likely group to compare prices and shop online
Frequent fewer super centers, dollar stores or convenience stores
WATCHING
Daily Total household TV usage by Race and Origin
Hispanics: 4hrs 35min
Blacks/African Americans: 7hrs 12min
Asian Americans: 3hrs 14min
National Average: 5hrs 11min
Pardo noted that understanding these and other details (such as understanding that multicultural consumers are actually ahead of the curve when it comes to mobile phone adoption, understanding their different TV viewing and online browsing habits, or ensuring that ethnicities are portrayed more often and more appropriately in ads) is key to seizing the massive market opportunity ahead.
“The story here is that within the next five years, multicultural clients will drive 86 percent of the total growth on spending in retail,” Pardo highlighted. “If you look at growth without these groups, you are only addressing 10 percent of the growth.”
Pardo suggested a number of key questions organizations should ask before embarking on an effective multi-cultural strategy:
What is your share of the multi-cultural market?
Do you know this consumer better than your peers?
Are you fishing where the fish are?
Do you have the depth of consumer insight to ensure you deploy the most effective marketing mix?
Is your advertising culturally relevant?
Is your organization ready?
Are you investing in the right structures and incentives to ensure multi-culturalism remains top of mind?
A panel discussion with Roberto Ruiz of Univision, Idaliz Chacon of Procter & Gamble, Angela Joyner of ConAgra Foods and Bill Imada of IW Group followed the presentation and generated the following guidance for organizations looking to engage in effective multicultural strategies:
Create Internal Champions: From creating a Center of Excellence for multicultural marketing, through tracking success via executive scorecards, all panelists agreed that a multi-cultural approach must be a top-down business imperative to avoid a transient, “flavor of the month” approach to engagement.
Scale Your Investment: Bill Imada advised participants to “start small, get some wings, build confidence and go from there.” He maintained that many companies do not exploit what they already know and have in their historic “corporate inventory.” He advised participants to find which current product lines make the most sense in multi-cultural markets, to pick just one of the population segments with the biggest opportunity and build as much cultural learning and competency as possible before roll-out to other populations as part of an organic growth strategy. Idaliz Chacon said it was important to understand the “size of the prize” to build product category and right-size the investment. To close share gaps faster, she indicated that companies should “invest to win,” even disproportionately if necessary. This view was shared by Angela Joyner who stated that trying to drive brand penetration into new markets would potentially require substantial investment as part of a five year strategy to build brand presence and advocacy.
Don’t over-segment: For an effective segmentation strategy, all panelists agreed that it was more important to look for similarities than differences among the focus population and that over-segmentation would decrease the opportunity. Roberto Ruiz stated that the key to effective segmentation is “actionability” and that the nuance of “bi-culturalism” of individuals, for instance being “dominant Hispanic,” while “fascinating,” was completely “worthless” as a segmentation consideration on the basis that people tend to be entirely immersed in both aspects of their culture.
Get out of the Office and Into the Street: “Consumer immersion” was considered the most powerful way to energize a company’s multi-cultural strategy and summarized as “the power of being there and seeing what’s going on.” Leveraging employee ethnic groups within organizations was viewed as a unique asset companies could deploy to generate proprietary insight and delight and win with diverse consumers.
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PREFIX dc: <http://purl.org/dc/elements/1.1/>
PREFIX ns: <http://example.org/ns#>
SELECT ?title ?price
{ ?x ns:price ?p .
?x ns:discount ?discount
BIND (?p*(1-?discount) AS ?price)
FILTER(?price < 20)
?x dc:title ?title .
}
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As Seen in Vanity Fair's August 2006 Issue!
As Seen in US News & World Report's September 11 Fifth Anniversary Issue!
As Seen in Time Magazine's September 11, 2006 Issue!
As Seen in Phoenix New Times' August 9, 2007 Issue!
Yet another poor "reaching" post. I'm beginning to thing you guys can't actually understand what you read taking quotes and ideas out of context like that. No wonder you think Osama pulled this thing off. You're brain has been turd to mush by the Zionist propaganda mainstream mechanism.
Beleiving in Israel is like beleiving in a chair. It's there, it exists, what more is there to say? Why exactly do you feel a need to assign them a name? What's next, calling people who beleive in America "Americanists"? What would you call people who beleive in Palestine? Palestinianists? It wouldn't surprise me at all if there were more christian "zionists" than jewish "zionists". there's certainly more christians in the world than there are jews, and the majority of those christians are reasonable people. They're not going to deny the existance of a country which has been around since the 1940's.
That you are a Zionist or have been conned to accept that satanic movement.
Satanic? Are we getting religious now?
ISRAEL EXISTS AS A COUNTRY. There's no ifs, ands, or buts about it. Jews bought the land, and eventually a narrow strip was given to them by the UN. The land had been abandoned and nobody wanted it till those damn JOOOS came.
Last Saturday morning there was a C-span call-in with an Israeli journalist and a Palestinian journalist. The Palestinian journalist stated this and the Israeli journalist made no attempt to object or correct:
When the UN partitioned Palestine in 1948, it gave 55% of the land to the Jewish state and 45% of the land to the Arabs, even though, at the time, Jews owned only 10% of the land.
So he didn't object, so what? It certainly doesn't make it true. When Israel was created, there was no such thing as Palestine. In addition to that, something like 90% of the land falling under the Brittish mandate went into creating trans-Jordan, which was specificaly intended as an Arab homeland. I don't see you complaining about all the Jews who were displaced from that area. Finaly, the question of land ownership is irrelevant. The UN mandate was passed by some 33 nations. It became binding at that point. Even if it didn't not have the authority of the UN behind it, the Arabs gave up whatever claims they may have made when they attempted to anhilliate Israel militarily. If they had continued to neogtiate diplomaticaly, perhaps they could claim the moral high ground. As it is, they tried to kill off the Jews, they got their asses kicked, and they lost whatever moral superiority they may have had.
If the UN came in here and partitioned off 55% (or even 5%) of our country to give it to some ethnic group, I would hope there'd be some Americans who'd stand up and fight.
The British were a colonial power ruling over land they had no right to. The proof is in the pudding and the indigenous people have suffered greatly from the League of Nations giving a "mandate" over Palestine to the British.
They scrambled planes over New York too. They just got there about 10 minutes too late to do anything.
Even if they did get there before impact, what could they have done? Does ANYONE really think that even after the first impact, the Air Force would shoot down commercial airlners over populated areas? Seriously?
Could you imagine what the CTers would be doing with that if say after the first hit, the remaining 3 planes were shot down? They'd be screaming that the planes weren't even hijacked and the government shot down planes that posed no threat... Oh, wait, nevermind.
If the UN came in here and partitioned off 55% (or even 5%) of our country to give it to some ethnic group, I would hope there'd be some Americans who'd stand up and fight.
That's not exactly how it happened little girl...
You see, before we even had that tragedy called the Holocaust, Jewish folks had been buying up land in a pretty much useless, abadoned strip of land. When the UN created Israel it didn't suddenly take away Palestinian land (as there were no "Palestinians" at the time), it just gave sovereignty to the area that had been bought up and no one wanted but the Jews. Arabs started moving back after infrastructure had been built up.
The British were a colonial power ruling over land they had no right to.
The Ottomans lost a war and European powers took control of the area.
The proof is in the pudding and the indigenous people have suffered greatly from the League of Nations giving a "mandate" over Palestine to the British.
The indigenous people were called Jews (but I digress). I assume you mean the occupants just before Israel was created. Well, as I stated before, the "Palestinians" kept their land (Egypt gobbled up a bit, Jordan some, and Syria the rest). Technically speaking, the creation of Jordan was the creation of the Arab Palestinian nation.
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The Hottest NBA Trade Rumors provided daily
Blazers preparing offer for Utah's Paul Millsap
After a series of trades fell through this week, the Trail Blazers have settled on their next target: Utah power forward Paul Millsap.
Although Millsap is a restricted free agent, meaning the Jazz can match any offer, the Blazers are preparing what one source called a "toxic" offer designed to exterminate interest from other teams.
Millsap, 24, is a bruising and active player who excels at rebounding. Despite being only 6-foot-8, Millsap last season used his 250-pound frame to average 13.5 points and 8.6 rebounds in 30.1 minutes per game. His 3.3 offensive rebounds per game ranked fourth in the NBA and his 251 offensive rebounds ranked sixth.
If Millsap signs an offer sheet accepting the Blazers’ deal, Utah will have seven days to match the offer. The Jazz is already facing the luxury tax next season with a team salary of more than $73 million. Their finances, and prospects of competing with a lucrative offer to Millsap, took a hit last week when Carlos Boozer ($12.6 million), Mehmet Okur ($9 million) and Kyle Korver ($5.1 million) all exercised options to stay in Utah.
The Blazers figure to exhaust nearly all of their cap space to lock up Millsap. They are $7.7 million under the cap, but can gain an additional $1.65 million by renouncing the rights to Petteri Koponen and Joel Freeland. However, in the process, the Blazers would be assessed with a roughly $450,000 cap hold for having less than 11 players, thus giving them $8.9 million in cap space.
“2015-04-01_19-33-57_ILCE-6000_5372_DxO” (CC BY-SA 2.0) by miguel.discart The Los Angeles Lakers are in a spot of bother: Iconic shooting guard Kobe Bryant, who played for the Lakers for the entirety of Read More »
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package volumes
var _ ResizeService = (*LinuxResizeService)(nil)
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Meade incinerator plan criticized
Officials decry environmental impact of sewage-burning plant
February 07, 2007|By Phillip McGowan | Phillip McGowan,sun reporter
Fort Meade is proposing to build a sewage sludge incinerator, a prospect that has drawn outrage among western Anne Arundel County civic leaders and criticism from the county's top health official about the potential environmental and health impacts.
The Maryland Department of the Environment is holding a public hearing tonight in Odenton to discuss plans by a Tennessee contractor, Ameresco Federal Solutions, to build the incinerator near the Army post's sewage plant adjacent to the intersection of Routes 32 and 198.
The incinerator would run 24 hours a day on weekdays, disposing of hundreds of tons of sewage a year more cheaply than by trucking the waste away, county and Fort Meade officials said.
MDE spokesman Robert Ballinger declined to disclose details about the incinerator and did not return a phone call yesterday seeking comment. Ameresco Federal Solutions did not reply to an e-mail request for information.
County health officials said that MDE has issued a tentative approval for the incinerator, but a Fort Meade spokeswoman, Summer Barkley, said yesterday in an e-mail that the post will not make a decision about the project for at least six months. She said a series of improvements being made at the post's sewage treatment plant might reduce the volume of sludge.
Civic leaders from Russett, Maryland City and Odenton said they learned of the scheduled public hearing Monday. Members of the Restoration Advisory Board, a group of residents and regulators overseeing Fort Meade's Superfund environmental cleanup, learned of the proposal when contacted yesterday by The Sun.
"I thought we were past the point of the base trying to sneak things through," said Zoe B. Draughon, co-chairwoman of the Restoration Advisory Board. "I am obviously mistaken."
Barkley referred questions about the timing of the public hearing to MDE.
There are about 170 sewage sludge incinerators in the United States, according to the Environmental Protection Agency. The facilities heat the waste to more than 1,500 degrees, turning solid waste into ash, and producing electricity.
The Sun reported last summer that the demand for electricity to operate expanding intelligence systems at the National Security Agency, which has its headquarters at Fort Meade, has left the high-tech eavesdropping agency on the verge of exceeding its power supply.
Activists questioned the placement of an incinerator at the nexus of impending growth expected to sweep over western Anne Arundel. An estimated 20,000 defense workers are expected to settle at Fort Meade over the next four years, a movement that will spawn billions of dollars of residential and office development from Hanover to Laurel and Odenton.
"This is ridiculous," said Ray Smallwood, president of the Maryland City Civic Association. "This is something that needs a lot of study. Haven't they thought about the environmental impact?" Smallwood added: "I can't believe they had the audacity to do this."
Several activists called on MDE to schedule a second hearing to allow for broader public comment. According to an advance copy of county Health Officer Frances B. Phillips's testimony to be read tonight, she criticizes MDE for not adequately advertising the hearing on the proposed incinerator.
Phillips also raises concerns that an incinerator -- which would emit mercury sulfur, nitrogen oxide, carbon monoxide and lead -- could lead to declining air quality and pollute groundwater.
She also points out that there are six public schools on the base, with a combined enrollment of more than 2,000. At least 169 students are known to have asthma, she says.
County Councilman G. James "Jamie" Benoit, a Piney Orchard Democrat, decried the incinerator's potential health effect on those children. He is delivering a letter to MDE to voice his displeasure with the project.
David A. Tibbetts, vice president of the Greater Odenton Improvement Association and the organization's environmental chairman, said the county has one of the highest ozone levels in the country. "And now we are going to add another source of ozone" Tibbetts said. "It just doesn't make any sense."
Phillips in her testimony questions assertions by MDE that incinerator emissions would not exceed air-quality standards set by the EPA. County officials note that MDE does not monitor air quality at Fort Meade.
She also noted that at a meeting at MDE headquarters Jan. 31, state officials said that "the combustion process itself generally does not produce odors, but that stored sludge awaiting burning is often a source of noxious odor."
[email protected]
The hearing is to begin at 7 p.m. at the West County Area Library, 1325 Annapolis Road.
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Details
The new Gameness Flex Board Shorts are the next generation of fight short that combines the comfort of a board short and the toughness of an MMA short. Each pair of shorts is constructed with an advanced 4-Way HyperFlex fabric that makes these shorts ultra-light and moisture wicking.
The Gameness Flex Board Shorts feature a 4” side slit for increased mobility, and an MMA inspired Hook & Loop closure with a draw string to ensure the perfect fit.
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Graduate of Virginia School of Massage - 637 hour professional course. Skilled in orthopedic massage testing of patients to a ccess and treat with the intent to return them to daily function. Specialize in treating injures and pain...
Welcome to my Website! If you’re looking for a professional clinical orthopedic massage therapist, you’ve come to the right place.
Hi, my name is Peter Juergensen, NCLMT, CKTP and my goal is to return the client to their fully functional life in the shortest amount of time. I’ m a Nationally Certified State Licensed massage therapist serving Berkeley, Jefferson, and Morgan Counties of West Virginia. I’m licensed in the states of West Virginia and Virginia, and have an office location at 295 Rock Cliff Drive, Martinsburg West Virginia, 25401-2835.
Request an appointment with me today by clicking on the "Request a Session" page. I will call you to confirm the details of your appointment, and also answer any questions you might have.
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/*
* TupleTypeUtil.java
*
* This source file is part of the FoundationDB open source project
*
* Copyright 2015-2019 Apple Inc. and the FoundationDB project authors
*
* Licensed under the Apache License, Version 2.0 (the "License");
* you may not use this file except in compliance with the License.
* You may obtain a copy of the License at
*
* http://www.apache.org/licenses/LICENSE-2.0
*
* Unless required by applicable law or agreed to in writing, software
* distributed under the License is distributed on an "AS IS" BASIS,
* WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
* See the License for the specific language governing permissions and
* limitations under the License.
*/
package com.apple.foundationdb.record.metadata;
import com.apple.foundationdb.record.provider.foundationdb.FDBRecordVersion;
import com.apple.foundationdb.tuple.Tuple;
import com.google.protobuf.ByteString;
import com.google.protobuf.Descriptors;
import com.google.protobuf.ProtocolMessageEnum;
import javax.annotation.Nonnull;
import javax.annotation.Nullable;
import java.math.BigInteger;
import java.util.ArrayList;
import java.util.List;
/**
* Utility class for dealing with {@link Tuple} types. In theory, these methods should live in
* {@link com.apple.foundationdb.tuple.TupleHelpers TupleHelpers} except that they use some Protobuf specific things
* like the {@link ByteString} class, and {@code TupleHelpers} is defined in the
* <a href="https://javadoc.io/doc/org.foundationdb/fdb-extensions/">fdb-extensions</a> sub-project
* which does not (and probably should not) take Protobuf as a dependency.
*/
class TupleTypeUtil {
@Nonnull
private static final BigInteger BIG_INT_MAX_LONG = BigInteger.valueOf(Long.MAX_VALUE);
@Nonnull
private static final BigInteger BIG_INT_MIN_LONG = BigInteger.valueOf(Long.MIN_VALUE);
/**
* Normalize a list of values so that it can be checked for equality with other lists sharing
* the same {@link Tuple} representation. In other words, it should be the case that:
*
* <pre> {@code
* toTupleEquivalentValue(list1).equals(toTupleEquivalentValue)
* == Arrays.equals(Tuple.fromList(toTupleAppropriateList(list1)).pack(), Tuple.fromList(toTupleAppropriateList(list2)).pack())
* }</pre>
*
* <p>
* for any two lists {@code list1} and {@code list2}.
* </p>
*
* @param values the list of values to normalized
* @return a new list containing the normalized elements of {@code values}
*/
@Nonnull
static List<Object> toTupleEquivalentList(@Nonnull List<?> values) {
List<Object> tupleEquivalentList = new ArrayList<>(values.size());
for (Object o : values) {
tupleEquivalentList.add(toTupleEquivalentValue(o));
}
return tupleEquivalentList;
}
/**
* Normalize a value so that it compares equal to anything with the same {@link Tuple} representation.
* The value that is returned cannot necessarily be packed by a {@code Tuple} (for example,
* a <code>byte[]</code> is returned as a {@link ByteString}), but it does implement {@link Object#equals(Object)}
* and {@link Object#hashCode()}, so the value can be used in hash-based data structures like
* {@link java.util.HashSet HashSet}s and {@link java.util.HashMap HashMap}s. In other words, it should
* bethe case that:
*
* <pre> {@code
* Objects.equals(toTupleEquivalentValue(value1), toTupleEquivalentValue(value2))
* == Arrays.equals(Tuple.from(value1).pack(), Tuple.from(value2).pack())
* }</pre>
*
* <p>
* for any two values {@code value1} and {@code value2}.
* </p>
*
* <p>
* This will only return {@code null} if {@link #toTupleAppropriateValue(Object)} would return {@code null}
* on the same input. If the object is already in
* </p>
*
* @param obj the value to normalize
* @return a value that has the same representation when {@link Tuple}-encoded
*/
@Nullable
static Object toTupleEquivalentValue(@Nullable Object obj) {
if (obj == null || obj instanceof Key.Evaluated.NullStandin) {
return null;
} else if (obj instanceof List<?>) {
List<?> list = (List<?>)obj;
return toTupleEquivalentList(list);
} else if (obj instanceof Tuple) {
return toTupleEquivalentList(((Tuple)obj).getItems());
} else if (obj instanceof byte[]) {
return ByteString.copyFrom((byte[]) obj);
} else if ((obj instanceof Byte) || (obj instanceof Short) || (obj instanceof Integer)) {
return ((Number)obj).longValue();
} else if (obj instanceof BigInteger) {
BigInteger bigInt = (BigInteger)obj;
if (bigInt.compareTo(BIG_INT_MIN_LONG) > 0 && bigInt.compareTo(BIG_INT_MAX_LONG) < 0) {
return bigInt.longValue();
} else {
return bigInt;
}
} else if (obj instanceof ProtocolMessageEnum) {
return (long)((ProtocolMessageEnum)obj).getNumber();
} else if (obj instanceof Descriptors.EnumValueDescriptor) {
return (long)((Descriptors.EnumValueDescriptor)obj).getNumber();
} else if (obj instanceof FDBRecordVersion) {
return ((FDBRecordVersion)obj).toVersionstamp(false);
} else {
return obj;
}
}
/**
* Convert a list of values into items that can all be stored within a {@link Tuple}.
*
* @param values a list of values
* @return a new list with {@link Tuple}-encodable versions of the elements of {@code values}
*/
@Nonnull
static List<Object> toTupleAppropriateList(@Nonnull List<?> values) {
List<Object> tupleAppropriateList = new ArrayList<>(values.size());
for (Object o : values) {
tupleAppropriateList.add(toTupleAppropriateValue(o));
}
return tupleAppropriateList;
}
/**
* Convert a value into a type that can be stored within a {@link Tuple}.
*
* @param obj the value to convert
* @return the value converted to some {@link Tuple}-encodable type
*/
@Nullable
static Object toTupleAppropriateValue(@Nullable Object obj) {
if (obj instanceof Key.Evaluated.NullStandin) {
return null;
} else if (obj instanceof ByteString) {
return ((ByteString) obj).toByteArray();
} else if (obj instanceof List) {
return toTupleAppropriateList((List<?>) obj);
// Following two are both Internal.EnumLite, so could use that, too.
} else if (obj instanceof ProtocolMessageEnum) {
return ((ProtocolMessageEnum) obj).getNumber();
} else if (obj instanceof Descriptors.EnumValueDescriptor) {
return ((Descriptors.EnumValueDescriptor) obj).getNumber();
} else if (obj instanceof FDBRecordVersion) {
return ((FDBRecordVersion) obj).toVersionstamp(false);
} else {
return obj;
}
}
private TupleTypeUtil() {
}
}
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If, like many of the Badger team, you first discovered F1 during the nineties, the entry list for this year’s Le Mans 24 Hours makes rather nostalgic reading. Consider names like Jean Christophe Bullion, who enjoyed a brief and unspectacular 11 race stint at Sauber in 1995; the entirely forgetable Shinji Nakano; and Christophe Bouchet, a man confirmed as an F1 driver who never got the chance to start a grand prix. They’re names you’d forgotten, careers you thought had ended but continue in the sportscar world.
Add to that list a pair of grand prix winners, a Champ Car title-winner turned F1 flop and BBC Radio 5Live’s diminutive driver-cum-commentator and you’ve got a pretty interesting list of former F1 men on the entry list for this year’s enduro classic, and here we’re naming the whole bunch.
The #7 Peugeot – probably the favourite to claim outright victory – is made up entirely of former F1 drivers, so what better place to start than with the French marque’s entry. Alright, they’re weren’t particularly successful F1 drivers, but they were grand prix driver none the less.
Two-time F1 podium finisher Alex Wurz is effectively leader of the three man squad, the cheery Austrian combining his sportscar commitments with an increasingly prominent role at the FIA (he’ll be president one day and you heard it on Badger first). Alex is joined by former Minardi and Williams man Marc Gene and one-time Super Aguri racer Anthony Davidson in the #7 machine. Nothing less than the win will do for these boys.
In the #8 Peugeot we have another ex-grand prix driver Stephane Sarazzin. Don’t remember the lad? We wouldn’t blame you: he started just one race, in a Minardi, at the Brazilian Grand Prix of 1999. Then seen as an F1 racer of the future, Sarazzin was subbing for the injured Luca Badoer at Interlagos, and actually qualified rather well, taking 17th on the grid and thus out-doing his team-mate – which, funnily enough, was the aforementioned Gene. However Sarazzin would exit his one and only race in spectacular fashion – see the video below for proof.
http://www.youtube.com/watch?v=xKkwT_4TMVg
Spinning Steph is joined by Franck Montagny, who ran seven races for Super Aguri in 2006 after they’d fired the slow-and-dangerous Yuji Ide but before they’d hired the just-plain-slow Sakon Yamamoto. Franck was better than both but, unfortunately, he isn’t Japanese. A talented all-rounder, he has raced Champ Cars, Indycar, Superleague and sportscars since his brief F1 stint. Former F3000 front-runner Nicolas Minassian completes the line-up
There are two more ex-F1 drivers in the #9 Peugeot, with Le Mans native Sebastien Bourdais and Pedro Lamy – who had stints with Team Lotus and Minardi in the mid-nineties – completing the French marque’s factory effort.
On to the Audi team, who have just one former F1 man in their ranks: Scotsman Allan McNish. Nishy is a two-time Le Mans winner, having triumphed aboard a Porsche in 1998 and then in an Audi ten years later, and will likely be in the running again this year. The fact he shares his #3 machine with eight-time Le Mans winner and all-round endurance racing god Tom Kristensen should help.
We’ve a pair of Frenchmen to tell you about now. First up is Olivier Panis, who (effectively) leads the #10 Oreca car’s line-up. The 1996 Monaco Grand Prix winner making his fourth appearance at Le Circuit de Sarthe in 2011 and will look to better his best finish of fifth, achieved in 2009. Jean-Christophe Bullion meanwhile will drive the #13 Rebellion Racing entry. The Frenchman drove the majority of the 1995 season for Sauber, scoring a best finish of fifth in Germany, before handing his seat back to Karl Wendlinger, whose place he had taken following the Austrian’s severe injuries at the previous year’s Monaco Grand Prix. Bullion never returned to F1.
He’s not quite French, but Olivier Beretta is near enough that we’ve lumped him in with Panis and Bullion. In fact Olivier was the third (and to date last) Monaco-born F1 driver, contesting the first ten races of the 1994 campaign for French squad Larrousse before getting le boot. Veteran Jan Lammers meanwhile will participate in the #5 Hope Racing entry. Competing in F1 mainly between 1979 and 1982, the Dutchman holds the record for the longest gap between starting two grand prix, having been absent from the sport for a full decade before contesting the final two races of the 1992 campaign for the ailing March team. Ultimately he never scored a point and failed to qualify on 18 occasions. Still, there’s always Hope (get it?)
Christian Klien is the most recent F1 departee contesting Le Mans this year, having raced sporadically for Hispania last season and now competing for Aston Martin at the Circuit de la Sarthe. The 28-year-old Austrian will be behind the wheel of the British marque’s #007 machine, teamed with Brit Darren Turner and Germany’s Stefan Mucke.
Thiago Monteiro is one of the men set to pilot the #15 OAK LMP1 machine. Monteiro drove for Jordan in 2005, landing a podium at the infamous U.S Grand Prix that year, and stayed on as the team became Midland in ’06. He has since raced in the World Touring Car Championship, part-owns the Ocean GP2 team and oversees the career of young countryman Antonio Felix ad Costa. The #49 OAK LMP2 entry meanwhile counts former Prost and Minardi rent-a-driver Shinji Nakano among its pilots.
And here’s one for you geeks: Christophe Bouchet, one of the drivers set to run in the #33 Level Five Motorsport entry, never started a grand prix, But, he was named at French minnows Larrouse for the ’95 campaign, only for the team to fold before he’d had a chance to even qualify. You have been hit with the stick of knowledge.
The most successful F1 driver in the field is Giancarlo Fisichella, three times a race winner for Jordan and Renault. The Italian will compete in the #51 AF Corse Ferrari, the favourite to win the GT class. Victory at last month’s 1000km of Spa cemented that tag, and Fisi’s pursuit of victory is aided no end by another F1 driver – and GT specialist – in the shape of Gianmaria Bruni. The Italian drove for Minardi during the 2004 campaign, taking a best result of 14th at the Malaysian, European and Hungarian Grand Prix. His post-F1 record is far better: three times a GP2 race winner between 2005 and 2006, he has since finished as runner-up in the 2007 FIA World GT championship and won the GT class at Le Mans in 2008.
Finally we’ve got Jan Magnussen, who also competes in the GT class. The Dane ran one race for McLaren in 1995 before landing a full-time ride with Stewart Grand Prix in 1997. His time there was no happy however, and he was given the boot mid-way through 1998 – the same weekend he scored his maiden F1 points. Jan will drive the #74 Corvette at the Circuit de la Sarthe.
Reasons to like… Le Mans
A Guide to life at Le Mans
BadgerGP.com is not affiliated with Formula 1, Formula One Management (FOM), Formula One Administration (FOA), or any other subsidiary associated with the official Formula One governing organisations or their shareholders. Efforts have been made to acknowledge credits wherever necessary, however, if you are the copyright holder and believe your material has been used unfairly, please contact us
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Kralingse Zoom metro station
Kralingse Zoom is a subway station on lines A, B, and C of the Rotterdam Metro, in the Kralingen neighbourhood of eastern Rotterdam. The station is located just west of the A16 motorway on the east side of Kralingse Zoom, the road it is named after. At Kralingse Zoom station, transfer is available to several bus lines, as well as to the ParkShuttle, a people mover to a nearby business district.
Kralingse Zoom is an above-ground station and is located just to the east of the metro tunnel in which the trains cross the city center. The station has two centre platforms, each with two tracks running alongside them. For most of the day, only the inner two tracks are used.
Kralingse Zoom is the metro stop to get to the Erasmus University and to the University of Applied Sciences (Economic Studies).
References
External links
www.eur.nl
www.hr.nl
Category:Rotterdam Metro
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Javier Hernández Carrera
Javier "Javi" Hernández Carrera (born 2 May 1998) is a Spanish footballer who plays for Real Madrid Castilla as either a central defender or a left back.
Club career
Born in Jerez de la Frontera, Cádiz, Andalusia, Hernández joined Real Madrid's youth setup in 2013, from Sevilla FC. On 17 July 2017, after finishing his formation, he was loaned to Segunda División B side CD El Ejido, for one year.
Hernández made his senior debut on 27 August 2017, starting and scoring his team's first in a 3–3 home draw against FC Cartagena. He finished the campaign as an undisputed starter, contributing with two goals in 33 matches.
On 13 July 2018, Hernández was loaned to Real Oviedo Vetusta also in the third division, until the end of the season. He made his first-team debut on 11 September, starting in a 0–1 away loss against RCD Mallorca for the season's Copa del Rey.
Hernández scored his first professional goal on 7 January 2019, netting the opener in a 3–2 away win against CD Numancia for the Segunda División championship.
References
External links
Real Madrid profile
Category:1998 births
Category:Living people
Category:Sportspeople from Jerez de la Frontera
Category:Spanish footballers
Category:Andalusian footballers
Category:Association football defenders
Category:Segunda División players
Category:Segunda División B players
Category:Real Madrid Castilla footballers
Category:Real Oviedo Vetusta players
Category:Real Oviedo players
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About the Program
Faculty (including research faculty) participating in the program receive 40 percent salary support from the VPR Office and are released from all teaching obligations during the term of the appointment. Departments/Schools retain the released salary to provide resources to cover the Fellow’s teaching load during the term of the appointment. Appointments are for one year with the possibility of renewal for a second year pending Department/School approval.
Areas of Appointment
For the 2015–2016 academic year (beginning Fall 2015), there are four possible Fellow appointment areas:
How to Apply
Faculty (including research faculty) wishing to be considered should submit a one-to-two-page letter of interest to the Dave Reed by February 19, 2015. Letters should specify one of the four possible areas of appointment, particular project ideas (actual assignments will be developed through discussion with VPR and appropriate administrative units), relevance of the Fellow appointment to the individual’s career goals, and any other relevant information. Relevant Department Chair or School Dean letters of support should also be attached.
How to Reapply
For Faculty Fellows considering a second year Fellowship, a short [2-3 page] description of a specific project idea that would both deepen the value of the experience to the Fellow and address an institutional issue identified during the first Fellowship year should be submitted by the same deadline date for first-year Fellowship applicants. Project ideas can be developed in cooperation with relevant administrative units. This application should be accompanied by a letter of support from the relevant Chair or School Dean. Second year Fellowships will be awarded based on the availability of funds and the project idea submitted.
One or two appointments will be offered by March 16, 2015, with an anticipated Fall 2015 start date.
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Diet is believed to be the single most important contributor to colonic carcinogenesis ([Tomatis *et al*, 1990](#bib25){ref-type="other"}). Experimental data have shown that saturated fatty acids (SFAs) and n-6 polyunsaturated fatty acids (PUFAs) have tumour-enhancing properties in the colon ([Reddy and Maeura, 1984](#bib18){ref-type="other"}; [Zhao *et al*, 1991](#bib28){ref-type="other"}, [Woutersen *et al*, 1999](#bib26){ref-type="other"}). Epidemiological data suggest that increased consumption of all meat or red meat, which contains high levels of SFAs, is strongly associated with colorectal cancer ([Giovannucci and Goldin, 1997](#bib10){ref-type="other"}; [Sandhu *et al*, 2001](#bib19){ref-type="other"}), but there is only limited evidence on the role of dietary n-6 PUFAs ([Zock and Katan, 1998](#bib29){ref-type="other"}; [Flood *et al*, 2003](#bib9){ref-type="other"}).
The putative mechanism through which dietary n-6 PUFAs may enhance colonic carcinogenesis is the increased formation of prostaglandins, with the rate-limiting and committal step being mediated by the cyclooxygenase (COX)-2 enzyme ([Dubois *et al*, 1998](#bib7){ref-type="other"}). Prostaglandins possess a wide spectrum of procarcinogenic properties ([Handler *et al*, 1990](#bib11){ref-type="other"}; [Cowlen and Eling, 1993](#bib5){ref-type="other"}; [Coffey *et al*, 1997](#bib4){ref-type="other"}; [Dermott *et al*, 1999](#bib6){ref-type="other"}). We therefore hypothesised that functional *COX-2* gene polymorphisms may impact on the conversion of n-6 PUFAs into prostaglandins, with consequent change in level of cancer risk. A single nucleotide polymorphism (−*765G*\>*C)* in the promoter region of the *COX-2* gene was recently described ([Papafili *et al*, 2002](#bib16){ref-type="other"}). We therefore investigated whether this *COX-2* gene polymorphism was related to colorectal cancer risk within a population-based, prospective cohort of middle-aged and older Chinese men and women in Singapore.
MATERIALS AND METHODS
=====================
Study subjects
--------------
The study design and subject recruitment of the Singapore Chinese Health Study have been described ([Hankin *et al*, 2001](#bib12){ref-type="other"}). Briefly, 63 257 Chinese women and men aged 45--74 years belonging to the Hokkien or Cantonese dialect group were enrolled in the study between April 1993 and December 1998. At recruitment, information on lifestyle factors and usual diet over the last year was obtained through in-person interviews. The dietary component of the questionnaire was validated through a series of 24-h food recalls ([Hankin *et al*, 2001](#bib12){ref-type="other"}). Respondents were asked to choose from predefined frequency and portion size categories for each of the 165 listed food/beverage items that he/she consumed during the past 12 months. We used the Singapore Food Composition Table to estimate average daily intake of 96 nutrient and non-nutrient compounds for each study subject ([Hankin *et al*, 2001](#bib12){ref-type="other"}). The Institutional Review Boards at the University of Southern California and the National University of Singapore had approved this study.
We identified incident colorectal cancer cases through the population-based cancer registry in Singapore ([Chia *et al*, 2000](#bib3){ref-type="other"}). As of 30 April 2002, 592 colorectal cancer cases had occurred among cohort participants. All cases (including one carcinoid tumour and two *in situ* cancers) were histologically confirmed except three (ascertained by death records and clinical evidence). Details of the biospecimen collection, processing and storage procedures have been described ([Koh *et al*, 2003](#bib14){ref-type="other"}). Briefly, we attempted to collect blood and single-void urine specimens from a random 3% sample of cohort enrollees. If the subject refused to donate blood, he/she was asked to donate buccal cells. We collected blood/buccal cell samples from 1194 subjects during April 1994--July 1999. Of these subjects, 13 developed colorectal cancer by 30 April 2002, and the remaining 1181 subjects constituted the referent group for the present study. We also attempted to collect blood/buccal cell and urine samples from all incident colorectal cancer cases. Of the 592 colorectal cancer cases, 312 (53%) donated blood/buccal cell samples.
COX-2 genotyping
----------------
Genomic DNA was extracted from buffy coats (228 cases and 895 controls) and buccal cell samples (84 cases and 286 controls) using a QIAamp 96 DNA Blood Kit (Qiagen, Valencia, CA, USA). A TaqMan assay for the −*765G*\>*C COX-2* polymorphism was developed using a TaqMan PCR Core Reagent kit (Applied Biosystems Inc., Foster City, CA, USA). The oligonucleotide primers for amplification of the polymorphic region of *COX-2* were GC093 for (5′-CATTAACTATTTACAGGGTAACTGCTTAGG-3′) and GC093rev (5′-CCCCCTCCTTGTTTCTTGGA-3′). In addition, the fluorogenic oligonucleotide probes (TaqMan MGB Probes; ABI) used to detect each of the alleles were GC093F (5′-CTTTCCCGCCTCTCT-3′) labelled with 6-FAM to detect the *G* allele and GC093V (5′-CTTTCCCCCCTCTCT-3′) labelled with VIC to detect the *C* allele. Experimental samples were compared to 12 controls to identify the three genotypes at each locus (*GG, GC, CC*). All samples were processed without knowledge of their case/control status. Any samples that were outside the parameters defined by the controls were identified as noninformative and were retested. Four controls and two cases had noninformative *COX-2* genotypes and were excluded from the present analysis.
Statistical analysis
--------------------
Data were analysed by standard methods for unmatched case--control studies ([Breslow and Day, 1980](#bib1){ref-type="other"}). Unconditional logistic regression models were used to examine the associations between *COX-2* genotypes and risk of colorectal cancer, and their possible modification by n-6 PUFA intake. The associations were measured by odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) and *P*-values (two-sided). Limited by the very low frequency of the *CC* genotype (0.003), the *GC* and *CC* genotypes were combined when compared with the *GG* genotype. All ORs were adjusted for age (year) at recruitment, year of recruitment, gender, dialect group (Cantonese, Hokkien), level of education (no formal schooling, primary school, secondary school and higher), body mass index (\<20, 20 to \<24, 24 to \<28, 28+ kg m^−2^), smoking status (never, exsmoker, current smoker), frequency of alcohol consumption (nondrinker, monthly drinker, weekly drinker, daily drinker), and familial history of colorectal cancer (yes, no).
RESULTS
=======
Of the 592 incident colorectal cancer cases, 282 were excluded from the present analysis due to unavailable blood/buccal cell samples (*n*=280) or noninformative *COX-2* genotype (*n*=2). Cases included in the present study (*n*=310) were comparable to those excluded in terms of age (mean: 65.4 *vs* 66.1 years), but slightly different in gender (57 *vs* 49% male), dialect group (45 *vs* 37% Cantonese) and level of education (69 *vs* 60% attaining primary school education or higher).
In total, 180 (58%) cases had colon cancer, and the remaining cases had either rectal or rectosigmoid cancers. [Table 1](#tbl1){ref-type="table"} Table 1Selected characteristics of colorectal cancer cases and controls, the Singapore Chinese Health Study**CharacteristicsControls (*n*=1177)Cases (*n*=310)*P*-value^a^** Mean age±s.d.^b^ (years)56.5±8.161.3±7.5\<0.001 Number (%) *Sex* Males509 (43.2)178 (57.4)\<0.001 Females668 (56.8)132 (42.6) *Dialect group* Cantonese571 (48.5)138 (44.5)0.23 Hokkien606 (51.5)172 (55.5) *Level of education* No formal schooling318 (27.0)95 (30.6)0.01 Primary school504 (42.8)151 (48.7) Secondary school288 (24.5)54 (17.4) A level/university67 (5.7)10 (3.2) *Body mass index* (*kg* *m*^−*2*^) ⩽20187 (15.9)46 (14.8)0.04 20−\<24659 (56.0)151 (48.7) 24−\<28267 (22.7)92 (29.7) 28+64 (5.4)21 (6.8) *Cigarette smoking* Never smokers853 (72.5)184 (59.4)\<0.001 Former smokers131 (11.1)52 (16.8) Current smokers193 (16.4)74 (23.9) *Frequency of alcohol consumption* Nondrinkers964 (81.9)243 (78.4)0.14 Monthly85 (7.2)21 (6.8) Weekly93 (7.9)29 (9.4) Daily35 (3.0)17 (5.5) *Familial history of colorectal cancer* No1149 (97.6)297 (95.8)0.12 Yes^c^28 (2.4)13 (4.2) *Median (5th percentile, 95th percentile)*Total calories (kcal day^−1^)1483.5 (829.9, 2477.5)1494.0 (819.3, 2589.2)0.54Total fat (g day^−1^)40.5 (19.6, 81.7)39.8 (19.0, 77.1)0.66SFAs (g day^−1^)14.0 (5.9, 30.0)13.7 (5.8, 29.2)0.62MUFAs (g day^−1^)13.6 (6.3, 28.0)13.4 (6.1, 26.5)0.88PUFAs (g day^−1^)8.1 (3.3, 18.6)7.9 (3.4, 16.5)0.74N-3 PUFAs (g day^−1^)0.8 (0.4, 1.7)0.8 (0.4, 1.7)0.94N-6 PUFAs (g day^−1^)7.2 (2.9, 16.8)7.0 (3.0, 14.9)0.75Fiber (g day^−1^)12.2 (5.0, 23.1)11.9 (4.3, 22.5)0.83Calcium (mg day^−1^)373.5 (156.7, 853.5)363.4 (158.8, 773.6)0.56Folate (*μ*g day^−1^)146.0 (64.1, 277.7)147.1 (57.9, 286.9)0.65[^1][^2][^3] shows the distributions of selected characteristics of colorectal cases and controls. Cases were older, less educated, more obese and more likely to smoke cigarettes than controls. Intakes of total calories, total fat, SFAs, monounsaturated fatty acids (MUFAs), PUFAs, n-3 PUFAs, n-6 PUFAs, fibre, calcium or folate were comparable between cases and controls.
Among control subjects, the *G* and *C* allele frequencies of the *COX-2* genotype were 0.952 and 0.048, respectively, and the *GG*, *GC* and *CC* genotype frequencies were 0.907, 0.090 and 0.003, respectively. These genotypic distributions were in Hardy--Weinberg equilibrium (*P*=0.43). Overall, there was no association between colorectal cancer risk and *COX-2* −*765G*\>*C* genotype or n-6 PUFA intake ([Table 2](#tbl2){ref-type="table"} Table 2*COX-2* −*765G*\>*C* genotype and dietary intake of n-6 PUFAs in relation to risk of colorectal cancer, the Singapore Chinese Health Study **Colorectal cancerColon cancerRectal cancer** **Controls**align=\"center\"**CasesOR (95% CI)^a^CasesOR (95% CI)^a^CasesOR (95% CI)^a^***COX-2 genotype* GG10672731.001551.001181.00 GC/CC110371.18 (0.77--1.79)251.50 (0.92--2.47)120.87 (0.45--1.66) *Dietary n-6 PUFAs in quartile*^b^ 1st (low)260701.00421.00281.00 2nd297831.08 (0.72--1.60)481.15 (0.70--1.87)350.97 (0.55--1.71) 3rd312721.00 (0.65--1.53)451.09 (0.64--1.83)270.82 (0.44--1.54) 4th (high)308851.04 (0.63--1.70)451.04 (0.56--1.92)400.99 (0.49--1.99)[^4][^5]). When subjects were stratified into high (above median) *vs* low (below median) intake levels of n-6 PUFAs, a borderline statistically significant association between genotype and risk was observed among high consumers of n-6 PUFAs (OR=1.65, 95% CI=0.95--2.87), which was mainly confined to colon cancer (OR=2.38, 95% CI=1.23--4.59) ([Table 3](#tbl3){ref-type="table"} Table 3*COX-2* −*765G*\>*C* genotype in relation to risk of colorectal cancer stratified by level of dietary n-6 PUFAs, the Singapore Chinese Health Study **Colorectal cancerColon cancerRectal cancer** **ControlsCasesOR (95% CI)^a^CasesOR (95% CI)^a^CasesOR (95% CI)^a^***Low dietary n-6 PUFAs*^b^ GG5081391.00811.00581.00 GC/CC49140.82 (0.42--1.59)90.95 (0.43--2.09)50.68 (0.25--1.89) *High dietary n-6 PUFAs*^b^ GG5591341.00741.00601.00 GC/CC61231.65 (0.95--2.87)162.38 (1.23--4.59)71.09 (0.46--2.59)[^6][^7]). There was no association between genotype and rectal cancer risk regardless of dietary n-6 PUFA intake levels. There was indication of an interaction effect between *COX-2* genotype and dietary n-6 PUFAs in colon cancer (*P*=0.07), which was absent in rectal cancer (*P*=0.51). The corresponding *P*-value for the gene--diet interaction effect in colorectal cancer combined was 0.10.
DISCUSSION
==========
In this cohort of Singapore Chinese, we reported a statistically significant effect of the *COX-2* −*765G*\>*C* gene polymorphism on colon cancer risk among subjects with high intake of dietary n-6 PUFAs. Our data support the hypothesis that COX-2 exerts its effects on colon carcinogenesis through its influence on prostaglandin synthesis from n-6 PUFAs.
The current study has several strengths. (1) Our prospective study design precludes the possibility of recall bias. Furthermore, reliable dietary nutrient estimates including n-6 PUFAs were assessed using a validated food frequency questionnaire. (2) The nationwide cancer registry has been in place in Singapore since 1968 ([Parkin *et al*, 2002](#bib17){ref-type="other"}), and migration out of Singapore has been negligible since inception of the study. This relatively complete ascertainment of cancer and death outcomes eliminates a concern for potential selection bias. (3) Study subjects originated from two contiguous regions in Southern China, resulting in a genetically homogeneous study population that facilitated the investigation of gene--disease associations. (4) Exposure information on other known/suspected risk factors for colorectal cancer was collected and accounted for in all analyses of gene--diet--cancer risk associations.
The chief limitation of our study is the lack of information on use of COX-2 inhibitors, which may bias the effect of *COX-2* genotype on risk. However, if use of COX-2 inhibitors were to exert a confounding effect on the observed COX-2 genotype/colon cancer association, our inability to control for such confounding is likely to lead to an underestimation, rather than an overestimation, of the risk associated with the putative high-activity genotype. This is because use of COX-2 inhibitors is likely to be more common among subjects with more severe symptoms of inflammation, possibly due to the possession of the high activity *COX-2* genotype. Another weakness of the present study is our relatively small number of cancer cases, which may result in less precise estimation of risk factor--disease associations.
The major n-6 PUFA in most diet is linoleic acid, the precursor of arachidonic acid. The latter is consequently converted to various prostaglandins, and COX is the crucial and rate-limiting enzyme for this conversion. There is compelling evidence that prostaglandins play important roles in colorectal carcinogenesis by enhancing cell proliferation and growth, promoting angiogenesis and inhibiting apoptosis ([Cao and Prescott, 2002](#bib2){ref-type="other"}; [Stoehlmacher and Lenz, 2003](#bib23){ref-type="other"}). *COX-2* gene expression and its mRNA and protein levels were markedly elevated in most human colorectal cancers relative to adjacent normal mucosa ([Kargman *et al*, 1995](#bib13){ref-type="other"}; [Sano *et al*, 1995](#bib20){ref-type="other"}). It is hypothesised that the COX-2-associated effect on colorectal carcinogenesis is due to the increased production of prostaglandins from dietary n-6 PUFAs ([Eberhart and Dubois, 1995](#bib8){ref-type="other"}). In support of this hypothesis, high dietary n-6 PUFAs has been shown to promote colon tumorigenesis by upregulating COX-2 expression in animal studies ([Singh *et al*, 1997](#bib22){ref-type="other"}).
The human *COX-2* gene is mapped to chromosome 1q25.2--q25.3 and spans about 8.3 kb pairs with 10 exons ([Kosaka *et al*, 1994](#bib15){ref-type="other"}). Previous studies on the 5′ flanking region of the human *COX-2* gene show that this region contains a canonical TATA box as well as several putative factor elements that are critical in inducing *COX-2* gene transcription, such as Sp1, NF-*κ*B, GRE (glucocorticoid) and IRE (insulin) elements ([Tazawa *et al*, 1994](#bib24){ref-type="other"}; [Yang *et al*, 1997](#bib27){ref-type="other"}). The region from nucleotide −827 to −454 has been described as a negative region since deletion of this region led to increased luciferase activity in reporter expression studies. The −*765G*\>*C* mutation lies within this region, and is also within one of the five putative Sp1 elements ([Yang *et al*, 1997](#bib27){ref-type="other"}). At present, data on the functionality of the −*765G*\>*C* polymorphism and the direction/magnitude of change in protein expression/activity between the *C* and *G* alleles are limited and mixed ([Papafili *et al*, 2002](#bib16){ref-type="other"}; [Schneider *et al*, 2003](#bib21){ref-type="other"}).
In summary, the present study provides the first epidemiological evidence for a possible cause-and-effect connection between the production of prostaglandins from n-6 PUFAs through the enzymatic activity of COX-2, and increased risk of tumour development in the colon. Our novel findings require confirmation in larger studies with varying levels of substrate intake and genotype frequency.
We thank Ms Siew-Hong Low of the National University of Singapore for supervising the field work of the Singapore Chinese Health Study, and Ms Kazuko Arakawa of the University of Southern California for the development and management of the cohort study database. The Singapore Chinese Health Study has been supported by Grants R01 CA55069, R35 CA53890 and R01 CA80205 from the National Cancer Institute, Bethesda, MD.
[^1]: Two-sided *P*-values derived from *t*-test (for age), *χ*^2^ test (for categorical variables) or Wilcoxon rank sum test (for nutrient intakes).
[^2]: Mean age at recruitment into the cohort, s.d.=standard deviation.
[^3]: Any of first-degree relatives had colorectal cancer.
[^4]: ORs were adjusted for age at recruitment, year of recruitment, gender, dialect group, level of education, body mass index, smoking status, frequency of alcohol consumption, and familial history of colorectal cancer; CI=confidence interval.
[^5]: In addition to all variables listed above, OR were adjusted for total energy intake.
[^6]: ORs were adjusted for age at recruitment, year of recruitment, gender, dialect group, level of education, body mass index, smoking status, frequency of alcohol consumption, and familial history of colorectal cancer; CI=confidence interval.
[^7]: Defined as less than or equal to the median ('low') and greater than the median ('high') intake level (6.96 g day^−1^) of dietary n-6 PUFAs among all cohort members.
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1. Introduction {#sec1}
===============
Stroke is the second most common cause of death in developed countries and thus is a major health problem \[[@B1]\]. According to the 2009 Annual Public Health Report by the Korean National Statistical Office, cerebrovascular disease, or stroke, was the second-leading cause of disease-related deaths in Korea, after cancer \[[@B2]\]. In Korea, many stroke patients receive traditional medical care because the country has its own system of traditional alternative medicine called Traditional korean medicine (TKM), the role of which has been emphasized in stroke management \[[@B3]\].
The Korean medical diagnosis system has unique characteristics similar to the traditional Chinese medical diagnosis system. One such feature is pattern identification (PI), which is based on information obtained from four diagnostic processes including inspection, listening and smelling, inquiry, and palpation \[[@B4]\]. PI is a diagnostic system that entails a comprehensive analysis of symptoms and signs, with implications for determining the cause, nature, and location of the illness, the patient\'s physical condition, and the patient\'s treatment \[[@B3], [@B5]\]. The inspection process involves the examination of the patient\'s symptoms or disease by observing his or her shape, expression, and tongue \[[@B6]\], among others. Observation of the tongue, also known as tongue diagnosis, is an important procedure in diagnosis by inspection in TKM. The status of the tongue is an important indicator in the diagnosis of one\'s condition, including the physiological and clinicopathological changes of internal organs in the body \[[@B7]\]. A number of studies have shown that tongue diagnosis plays an important role in clinical prognosis and treatment \[[@B8]--[@B15]\], specifically in patients with a history of stroke. However, the clinical competence of tongue diagnosis was determined by the experience and knowledge of the clinicians who used tongue diagnosis. Environmental factors, such as differences between light sources and levels of brightness also had significant influences on clinicians and their diagnostic decisions using the tongue. Unfortunately, much of the experiences in traditional tongue diagnosis have not been verified scientifically or quantitatively. Therefore, it is necessary to build an objective diagnostic standard for tongue diagnosis \[[@B7]\]. We investigated the reliability of TKM tongue diagnosis in stroke patients by evaluating interobserver reliability regarding tongue indicators as achieved by TKM practitioners.
2. Methods {#sec2}
==========
2.1. Study Subjects {#sec2.1}
-------------------
The data for this analysis were collected as part of the project named the Fundamental Study for the Standardization and Objectification of Pattern Identification in TKM for Stroke (SOPI-Stroke). Stroke patients admitted to the following oriental medical university hospitals, Kyung Hee Oriental Medical Center (Seoul), Kyung Hee East-West Neo Medical Center (Seoul), Dong Guk International Hospital (Kyunggi-do), Kyung Won Oriental Medical Hospital (Incheon), Dae Jeon Oriental Medical Hospital (Daejeon), Dong Sin Oriental Medical Hospital (Gwangju), Won Kwang Oriental Medical Hospital (Jeollabuk-do), Dae Gu Hanny University Medical Center (Daegu), and Sang Ji Oriental Medical Hospital (Gangwon-do), participated in this study between February 2010 and December 2010 ([Figure 1](#fig1){ref-type="fig"}). All patients provided written informed consent under procedures approved by institutional review boards (IRB). Eligibility inclusion criteria were that participants had to be enrolled within 30 days of the onset of their symptoms as confirmed by imaging diagnosis, such as computerized tomography (CT) or magnetic resonance imaging (MRI). Exclusion criteria were traumatic stroke patients, such as those with subarachnoid, subdural, or epidural hemorrhage.
2.2. Data Processing and Analysis {#sec2.2}
---------------------------------
All patients were seen by two experts from the same department in each site, who were well trained in standard operation procedures (SOPs) \[Appendix\] and were subjected to an examination of the status of the tongue, tongue color (pale, red, and bluish purple), fur color (white fur, yellow fur), fur quality (thick fur, thin fur, moist fur, and dry fur), and special tongue appearance (teeth marked, enlarged, mirror, and spotted). The examination parameters were extracted from parts of a case report form (CRF) for the standardization of stroke diagnosis that had been developed by an expert committee organized by the Korean Institute of Oriental Medicine (KIOM). These assessments were given individually without discussions among the clinicians. Descriptions of the grading severity for each variable were scored as the following: 1 = very much so, 2 = Much so, and 3 = Not so much. In particular, the clinicians had to measure the stroke PI of each patient following the fire-heat pattern, the phlegm-dampness pattern, the blood stasis pattern, the qi deficiency pattern, and the Yin deficiency pattern, as suggested by the KIOM \[[@B3], [@B16]--[@B18]\].
Interobserver reliability was measured in three ways, using simple percentage agreements, Cohen\'s kappa coefficient and Gwet\'s AC~1~ statistic, as well as via the corresponding confidence intervals (CI). Kappa, the preferred measure of rater reliability for nominal data, measures the reliability of agreement between two or more independent raters using a rating scheme with mutually exclusive categories. In general, definitive kappa interpretations have been proposed \[[@B19]--[@B24]\]. For most purposes, however, values ≤0.40 represent poor agreement, values between 0.40 and 0.75 represent moderate to good agreement, and values ≥0.75 indicate excellent agreement \[[@B24]\]. The AC~1~ statistic is not vulnerable to the well-known paradoxes that make Kappa appear ineffective \[[@B25]--[@B27]\]. First, interobserver reliability for the tongue indicator among all subjects was calculated via simple percentage agreements, Cohen\'s kappa coefficient, and Gwet\'s AC~1~ statistic. Later, interobserver reliability regarding PI with same opinions between the raters was calculated in the same way. The blood stasis pattern was omitted because the sample size was too small (*n* = 1). The data were statistically analyzed with SAS software, version 9.1.3 (SAS Institute Inc., Cary, NC).
2.3. Ethical Approval {#sec2.3}
---------------------
This study was approved by institutional review board of the KIOM and by each of the oriental medical university hospitals.
3. Results {#sec3}
==========
A total of 658 stroke patients were enrolled in the study. Thirty patients were excluded from analysis due to PI omitted by any one of 2 TKM clinicians. The interobserver reliability results regarding tongue indicators for all subjects (*n* = 628) are shown in [Table 1](#tab1){ref-type="table"}. The kappa measure of agreement between the two experts was generally moderate to good for the tongue indicators, ranging from 0.42 to 0.69, except for moist fur (*κ* = 0.29) and spotted (*κ* = 0.37). Moreover, the AC~1~ measure of agreement between the two experts was generally high for the tongue indicators, ranging from "moderate" (AC~1~ = 0.43) to "excellent" (AC~1~ = 0.97). Agreement, as assessed by the kappa values, was considerably lower than the AC~1~ values in most cases.
The results of interobserver reliability for subjects of PI with the same opinion between the raters are shown in [Table 2](#tab2){ref-type="table"}. A total of 451 stroke patients received PI with the following same resulting opinions by the raters: Fire-Heat Pattern (*n* = 147), Phlegm-Dampness Pattern (*n* = 158), Yin Deficiency Pattern (*n* = 80), and Qi Deficiency Pattern (*n* = 66). The blood stasis pattern was excluded because the sample size was too small (*n* = 1).
The kappa measure of agreement for the subjects of PI was generally moderate to good for the tongue indicators, ranging from 0.40 to 0.72, except for moist fur (*κ* = 0.31). Moreover, the AC~1~ measure of agreement between the two experts was generally high for the tongue indicators, ranging from "moderate" (AC~1~ = 0.5) to "excellent" (AC~1~ = 0.98) ([Table 2](#tab2){ref-type="table"}).
4. Discussion {#sec4}
=============
Inspection of the tongue in TKM diagnosis, as well as in western medicine \[[@B28]\], is one of the most important approaches for obtaining significant evidence in diagnosing the patient\'s health conditions \[[@B7]\]. It is used to observe the color, coating, and body of the tongue, among other features, in rendering a disease diagnosis.
Also, as tongue diagnosis has played a prominent role in the diagnosis and subsequent treatment of stroke patients, it has attracted an increasing amount of attention in oriental medicine \[[@B8]--[@B15]\]. Park et al. \[[@B12]\] analyzed markers that classified tongue body color, fur, fur quality, dryness, and shape to standardize tongue diagnosis and PI for stroke patients. Choi et al. \[[@B14]\], to assess the usefulness of tongue diagnosis in evaluating PI, observed the coating of the tongue and compared it with PI in acute stroke stage patients within 72 hours from the onset of stroke. In his study, a red tongue was significantly related to the fire-heat pattern and the yin deficiency pattern, while a faint white tongue was related to the phlegm-dampness pattern. Thin fur was related to the Wind and fire-heat pattern, and thick fur was related to the phlegm-dampness and blood stasis patterns. Another study \[[@B15]\] by the same author found that a stroke patient\'s motor recovery might be related to tongue diagnosis. In Kim et al.\'s recent study \[[@B3]\], the authors attempted to standardize the oriental medical PI for stroke patients using logistic regressions. An interesting finding was that all of the patterns in their study basically included tongue and pulse diagnoses in their final equations. This result shows that TKM clinicians tongue and pulse diagnosis are seriously considered in their patient management.
However, traditional tongue diagnosis does have its inevitable limitations because the clinical skill involved in tongue diagnosis depends on the clinician\'s experience and knowledge as well as on environmental factors that can exert a significant influence on the diagnostic results. Therefore, it is necessary to build an objective diagnostic standard for tongue diagnosis. To date, only a few studies have reached wide consensus among TKM clinicians, while many studies have investigated agreement measures for western medical diagnosis \[[@B29]\].
An evaluation of interobserver reliability is important when one is interested in the "true" differences among observers that often report different values for the same quantity. In other words, interobserver reliability, rather than the total observer reliability, should be used to explore the causes of the disagreements among observers. The total observer reliability masks these sources of disagreement because it contains both interobserver reliability (true differences) and intraobserver reliability (random error among the observations) made by the same observer for the same subject \[[@B30]\]. Li et al. \[[@B32]\] used the kappa value to evaluate the consistency of tongue and pulse signs for 55 patients as observed by traditional Chinese medicine (TCM) clinicians. Zhang et al. \[[@B33]\] analyzed the effect of training on improved agreement in TCM diagnosis among its practitioners based on a sample of 42 patients with rheumatoid arthritis (RA). Mist et al. \[[@B34]\], using interrater correlations and kappa values, assessed whether a training process that focused on a questionnaire-based diagnosis would improve agreement in traditional Chinese medicine TCM diagnosis. Finally, Kim et al. \[[@B35]\] examined the reliability of TCM tongue inspection by evaluating inter- and intrapractitioner agreement levels for specific tongue characteristics.
The data for this analysis were collected as parts of a multicenter study of standardization of stroke diagnosis in Korea. In this study, the evaluation of interobserver reliability in tongue status in stroke patients, as achieved by TKM clinicians, as well as interobserver reliability in all subjects (or subjects of PI with same the opinions between the raters), was calculated as simple percentage agreements, kappa values and AC~1~ measures. When investigating agreement between observers, clinicians have long used kappa and other chance-adjusted measures. A commonly used scale used to interpret kappa derives from the work of Landis and Koch in 1977 \[[@B20]\]. However, the appropriateness of kappa as a measure of agreement has recently been debated \[[@B26], [@B27]\]. A relatively new statistic, the AC~1~, has been suggested by Gwet to adjust for chance in agreement studies \[[@B25], [@B31]\].
According to our results, interobserver agreement in tongue diagnosis between the raters was generally moderate to good. The AC~1~ measure of agreement between the two experts was generally moderate to good for the tongue indicators, ranging from 0.43 to 0.97.
In particular, the AC~1~ measure of agreement was nearly perfect in mirror, spotted, and bluish purple tongue. These tongue indicators are certain signs of special tongue appearance. Mirror tongue means that the surface of tongue is smooth and shiny like a mirror, without fur. Spotted tongue means that there are purple spots on the whole tongue and bluish purple tongue means that the color of tongue body is bluish purple, or bluish purple spots appear on the surface of the tongue. It is thought that a description of these indicators is relatively objective, that agreement is very high. Whereas the AC~1~ of pale, thin fur, moist fur is lower than 0.5. The reason why the AC~1~ of these indicators is low is that perception of quality and color of tongue vary markedly from person to person. Therefore, it is necessary to improve the validity and reliability of tongue diagnosis through the development of detail-oriented criteria and enhanced training of clinicians.
One limitation of our study is the fact that we did not analyze the impact of the each site participated in this study. All patients were allocated into two experts among the eighteen clinicians in each site. While the large number of clinicians who participated in the study increased the generalizability of the results, it is possible that the variety of experiences offered by these clinicians was another limitation to the study. All clinicians who had at least more than three years of clinical experience in the field took regular SOPs training twice a year, therefore we assumed all clinicians have equal ability to take information from the patients. But, in reality it is certain that this assumption is not true. We will consider the subject carefully in the future work. Furthermore, this study has a limitation in that the actual diagnosis process in TKM is carried out not only through tongue diagnosis but also through other three diagnostic processes. Further studies may be necessary to conduct a comprehensive analysis considering all the four diagnostic processes.
Tongue diagnosis is a very important diagnostic procedure in TKM, despite its inevitable limitations associated with clinician experience and knowledge. However, this study shows that interobserver reliability in tongue status in stroke patients between the raters was considerably high. This may help to alleviate the lack of objectivity and reproducibility in tongue diagnosis in TKM. We expect that future studies will help to further establish tongue diagnosis as a useful oriental medicine diagnostic tool in the clinical management of stroke patients.
M. M. Ko, and J. A. Lee contributed equally to this work.
This research was supported by a Grant from the Korea Institute of Oriental Medicine (K11131).
{#fig1}
######
Agreement between raters for all subjects.
Variables \% Agreement Kappa (*κ*) CI of *κ* AC~1~ CI of AC~1~
---------------------------- -------------- ------------- -------------- ------- --------------
Tongue color:
Pale 71.38 0.42 (0.35, 0.49) 0.43 (0.36, 0.51)
Red 75.84 0.51 (0.44, 0.58) 0.52 (0.45, 0.59)
Bluish purple 91.99 0.42 (0.35, 0.49) 0.9 (0.87, 0.93)
Fur color:
White fur 75.17 0.49 (0.42, 0.56) 0.51 (0.44, 0.59)
Yellow fur 85.29 0.69 (0.63, 0.75) 0.71 (0.66, 0.78)
Fur quality:
Thick fur 81.15 0.60 (0.54, 0.67) 0.63 (0.57, 0.70)
Thin fur 74.61 0.49 (0.41, 0.56) 0.49 (0.42, 0.57)
Moist fur 70.27 0.29 (0.21, 0.37) 0.49 (0.42, 0.57)
Dry fur 80.5 0.48 (0.40, 0.56) 0.68 (0.63, 0.75)
Special tongue appearance:
Teeth marked 87.68 0.46 (0.36, 0.56) 0.84 (0.80, 0.88)
Enlarged 89.63 0.51 (0.41, 0.61) 0.86 (0.83, 0.90)
Mirror 97.44 0.60 (0.42, 0.78) 0.97 (0.95, 0.99)
Spotted 96.96 0.37 (0.15, 0.59) 0.96 (0.95, 0.98)
CI: confidence interval.
######
Agreement measures in PI with the same opinions between the raters.
Variables \% Agreement Kappa (*κ*) CI of *κ* AC~1~ CI of AC~1~
---------------------------- -------------- ------------- -------------- ------- --------------
Tongue color:
Pale 75.00 0.49 (0.41, 0.58) 0.51 (0.42, 0.59)
Red 76.67 0.53 (0.45, 0.61) 0.54 (0.46, 0.62)
bluish purple 94.09 0.57 (0.42, 0.72) 0.93 (0.90, 0.96)
Fur color:
White fur 77.05 0.52 (0.44, 0.60) 0.56 (0.48, 0.64)
Yellow fur 86.37 0.71 (0.64, 0.78) 0.74 (0.68, 0.81)
Fur quality:
Thick fur 83.25 0.65 (0.58, 0.73) 0.68 (0.61, 0.75)
Thin fur 75.18 0.50 (0.42, 0.58) 0.51 (0.42, 0.59)
Moist fur 70.53 0.31 (0.22, 0.40) 0.5 (0.41, 0.58)
Dry fur 82.46 0.52 (0.42, 0.61) 0.72 (0.66, 0.79)
Special tongue appearance:
Teeth marked 89.06 0.53 (0.42, 0.64) 0.86 (0.82, 0.90)
Enlarged 90.67 0.57 (0.46, 0.69) 0.88 (0.84, 0.92)
Mirror 97.99 0.72 (0.54, 0.89) 0.98 (0.96, 0.99)
Spotted 96.88 0.40 (0.15, 0.65) 0.97 (0.95, 0.99)
PI: pattern identification; CI: confidence interval.
[^1]: Academic Editor: Wolfgang Weidenhammer
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News
Auburn Public Theater will welcome a pair of high-profile musicians within a week of each other.
Performing first at the downtown theater will be John Waite at 8 p.m. Saturday, Sept. 30. On his 40th anniversary tour, the Lancaster, England-born rocker reached No. 1 on Billboard’s Hot 100 Singles chart with “Missing You” in 1984, and revisited the spot with supergroup Bad English in 1989 with the song “When I See You Smile.” Waite resumed his solo career in 1995, adding six albums since then to his millions-selling, Grammy-nominated catalogue.
Singer-songwriter Jason Sinay will open the show. Tickets are $45-$50.
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Correlation of clinical and pathologic evaluation of scarring alopecia.
Differentiating scarring and nonscarring alopecia poses a diagnostic dilemma for clinicians, with histopathology used to distinguish. The extent to which dermatologists are able to clinically classify alopecia has not been evaluated. A retrospective study of pathology reports on 458 patients was used to calculate a kappa coefficient to correlate clinical presence of scarring or nonscarring alopecia to histopathologic presence of scarring or nonscarring. A multivariate analysis was performed to assess for associations with scarring. The kappa correlation coefficient was 0.59 (P < 0.0001), indicating moderate agreement and varied by race and sex. There were 15 times higher odds of making the clinical diagnosis of scarring alopecia (OR 14.64 95% CI [8.64-24.18]; P < 0.001), and this increased with age. These results suggest that clinical exam is moderately reliable in distinguishing between scarring and nonscarring alopecia. Our results highlight the need for education and diagnostic schemata for evaluation of alopecia based on gender and in skin of color.
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Radiation Dosimetry for Ureteroscopy Patients: A Phantom Study Comparing the Standard and Obese Patient Models.
To determine the effect of obesity on radiation exposure during simulated ureteroscopy. A validated anthropomorphic adult male phantom with a body mass index (BMI) of approximately 24 kg/m(2), was positioned to simulate ureteroscopy. Padding with radiographic characteristics of human fat was placed around the phantom to create an obese model with BMI of 30 kg/m(2). Metal oxide semiconductor field effect transistor (MOSFET) dosimeters were placed at 20 organ locations in both models to measure organ dosages. A portable C-arm was used to provide fluoroscopic x-ray radiation to simulate ureteroscopy. Organ dose rates were calculated by dividing organ dose by fluoroscopy time. Effective dose rate (EDR, mSv/sec) was calculated as the sum of organ dose rates multiplied by corresponding ICRP 103 tissue weighting factors. The mean EDR was significantly increased during left ureteroscopy in the obese model at 0.0092 ± 0.0004 mSv/sec compared with 0.0041 ± 0.0003 mSv/sec in the nonobese model (P < 0.01), as well as during right ureteroscopy at 0.0061 ± 0.0002 and 0.0036 ± 0.0007 mSv/sec in the obese and nonobese model, respectively (P < 0.01). EDR during left ureteroscopy was significantly greater than right ureteroscopy in the obese model (P = 0.02). Fluoroscopy during ureteroscopy contributes to the overall radiation dose for patients being treated for nephrolithiasis. Obese patients are at even higher risk because of increased exposure rates during fluoroscopy. Every effort should be made to minimize the amount of fluoroscopy used during ureteroscopy, especially with obese patients.
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(SportsNetwork.com) - Bruce Arians was a candidate for the vacant Philadelphia
Eagles job, but the powers that be decided Chip Kelly, with no professional
experience, was better equipped.
It didn't take long for Arians to find a job, however, and he will lead the
Arizona Cardinals into the Philadelphia Sunday to battle the Eagles.
Arians, who gained notoriety by filling in for an ill Chuck Pagano with the
Indianapolis Colts last season, has guided the Cardinals to a surprising 7-4
start and has them on the brink of ending a three-year postseason layoff. The
Cardinals are currently in the hunt for a wild card spot since it appears the
Seattle Seahawks will take home the NFC West title.
The Eagles are also flirting with the idea of making a playoff run in Kelly's
first season at the helm and are even with the Dallas Cowboys for first place
in the NFC East. The Cowboys own the tiebreaker after beating the Eagles a few
weeks back at Lincoln Financial Field, where the Cardinals hope to find
similar success.
Arizona has won four in a row, including three straight after the bye, and
hammered the Colts, 40-11, on Sunday in the desert. A 26-yard touchdown
reception by Larry Fitzgerald and a 22-yard interception return for a score by
Karlos Dansby highlighted a 20-point second quarter for the Cardinals, who
racked up 410 yards of offense and hope to gain some more attention in the
competitive NFC.
"I think this was a respect game," said Cardinals quarterback Carson Palmer,
who threw for 314 yards with a pair of TD passes to Fitzgerald. "I don't think
we are well respected throughout the league, and that's not anybody's fault
but our own. But I think we are better than people think."
The Cardinals deserve a lot of credit with wins over Detroit, Carolina and
Indianapolis. Still, veteran defensive lineman Darnell Dockett feels Arizona
is slighted each week.
"You know what's funny?" Dockett said. "Whenever the Cardinals win it's always
what the other team didn't do. It's never what we forced other teams to do. We
understand that. Everyone says, 'They didn't beat nobody, they didn't beat
nobody."
Well, the Colts aren't nobodies. They, too, are in the mix for a playoff spot
and just got waxed by their former assistant coach in Arians, whose squad last
won four in a row to start the 2012 season and hasn't prevailed in five
straight games since the St. Louis Cardinals won six in a row during the 1977
campaign under head coach Don Coryell.
The Cardinals hope to keep the momentum going and keep pressing for a chance
at reaching the playoffs.
"We are in the hunt," Arizona cornerback Jerraud Powers said. "That's all you
can ask for. It seems like everyone is believing in one another."
Meanwhile, the Eagles are feeling just as confident with three straight wins
and last won four in a row to close out the 2011 campaign at 8-8. Eagles
quarterback Nick Foles was still slinging the ball for the University of
Arizona and completed 387-of-560 passes for 4,334 yards and 28 touchdowns for
the Wildcats.
The second-year pro, who was recently crowned the starter, is now lighting up
opposing defenses at a rapid rate and is building confidence in himself, with
the coaches and his teammates.
"He has the utmost confidence in himself," said Eagles wide receiver Riley
Cooper. "He is a great quarterback and he should. He is the general out there.
We are all listening to him. He does a great job."
Cooper has been the beneficiary of Foles' resurgence and is second on the
Eagles with 592 yards on 31 catches. His seven touchdown receptions is tied
with DeSean Jackson. Foles, though, is the reason for the success and has
1,554 yards with 16 TD passes and no interceptions for a 128.0 rating. His
rating ranks first in the NFL and has six games this season with a rating of
100 or better.
During the Eagles' winning streak, Foles' QB rating is 152.8. He has thrown
199 consecutive passes without an interception and his 9.6 yards per attempt
is first in the league. Foles has the Eagles flying high and helped them halt
a 10-game home losing streak with last week's 24-16 win over the Washington
Redskins. He threw for 298 yards and did not have a touchdown pass. He didn't
need to because LeSean McCoy ran for 77 yards and a pair of touchdowns.
"I feel like we've put ourselves in a good position," Foles said. "That's all
you can ask for, especially heading into the bye week. Especially with winning
our last game at home, (we're) moving in the right direction and just
continuing to change the atmosphere here. The coaches here are doing a great
job and the players are doing a great job of buying in, so I think that we
have to keep going in that direction and keep leaning on each other, and we'll
see what happens."
The New York Giants did no favors by losing to the Cowboys on Sunday, so it's
a tight rope to walk in the division.
Speaking of walking the line, Michael Vick said Foles deserves to remain the
start for how well he's played. Vick is no fool and believes in the idiom if
it's not broke, don't fix it.
"In all honesty, in all fairness, how can you take a guy out of the game who's
been playing so well?" Vick said. "I've been in this stage before, and I know
what it's like. I understand the position that this team is in, and the one
thing I never want to do is be a distraction or put our team or our coaches in
a position where they feel like they're not doing the right thing or I feel
like they're not doing the right thing."
Philadelphia has been doing the right thing offensively and is averaging 33.3
points and 453 yards during the winning streak.
Jackson, Cooper and McCoy have been Philly's big three in recent weeks, while
Jackson is 15 yards shy of the third 1,000-yard season of his career. AFter
three straight weeks of rushing for no more than 55 yards, McCoy had 155 yards
on 25 carries at Green Bay, then ran for 77 yards on 20 carries versus the
Redskins to surpass running backs coach Duce Staley for third on the team's
all-time rushing list with 4,875 yards.
McCoy also reached the 1,000-mark for the third time in his career and didn't
know it until it was brought up to him.
"I did know this though, I had 10 yards to pass Duce," McCoy said. "So I knew
that was going to happen."
The shifty back averages about half of 10 yards (4.7 ypg) for an Eagles squad
looking for revenge versus the Cardinals after last season's 27-6 loss on
Sept. 23 at University of Phoenix Stadium. Philadelphia's most recent victory
in the series was a 48-20 home rout on Thanksgiving Night of 2008, and the
Eagles have taken five of the last nine regular-season bouts since 2000 with
their former division rivals.
Including the 2008 NFC Championship, which the Cardinals won by a 32-25 count
to advance to their only Super Bowl, Arizona has won three in a row against
the Eagles.
WHAT TO WATCH FOR
The Eagles give up a league-worst 300.1 passing yards per game and are 31st in
total yards allowed (417.9). So what can they expect from Fitzgerald, one of
the top wide receivers in the game?
Fitzgerald caught nine passes for 114 yards and a touchdown in the last
meeting with the Eagles and has played them four times in his career, posting
26 catches for 418 yards and six TDs. No matter who is covering Fitzgerald,
whether it's Cary Williams, Brandon Boykin or Bradley Fletcher, who is
bothered by a pectoral muscle and is questionable Sunday, the Eagles will
experience some trouble.
Palmer gave some insight on what it's like to cover Fitzgerald, who eclipsed
the 11,000-yard mark in his career. He is the youngest to reach that mark.
"Any time you have Larry 1-on-1 down in the red zone, it's not a good matchup
for the other team," Palmer said.
Floyd can be an issue, too, so it's important for an improved Eagles defense
to force Palmer into making mistakes. Palmer's known for erratic play at
times, but the former Heisman Trophy winner can also shred defenses. Just ask
the Colts, who failed to pick off a pass.
Williams, though, is impressed with how well the unit is playing.
"We're getting there and I also think we all understand that a lot of work is
ahead to get to where we need to be," said Williams. "The play up front has
improved, which impacts everyone. I think that confidence is the big reason.
Everybody understands what the coaches are looking for and we've all worked
hard studying that. You see the results. We all feel like it's improving."
Speaking of play up front, give credit to big men Vinny Curry, Fletcher Cox
and Cedric Thornton. They have combined for eight sacks, while Curry and
linebacker Connor Barwin have four apiece. LB Trent Cole and Cox each have
posted three sacks.
The Cardinals have some muscle of their own on defense and sack master John
Abraham has seven so far. Defensive end Calais Campbell has 5 1/2 sacks and
Dockett owns 4 1/2, while veteran linebacker Karlos Dansby leads the Cardinals
with 88 tackles.
Dansby registered five stops against Indianapolis and an interception. Look
for him to disrupt Philadelphia's run game by shooting the gaps. Colts
quarterback Andrew Luck was rattled often in Sunday's game.
"They created a bit of a hornet's nest," Luck said of the defensive pressure.
Don't sleep on Arizona's secondary either with rookie Tyrann Mathieu, stud
Patrick Peterson, Powers and Yeremiah Bell. They, too, will have their hands
full with Jackson, Cooper and tight end Brent Celek. Celek hasn't been much of
a factor lately, which is why he could be a pest Sunday.
OVERALL ANALYSIS
The Cardinals seem to give the Eagles fits lately and will do so again at the
Linc. The Nick Foles show has to have some sort of commercial break and it
will be good to get that out of the way now instead of later. A loss won't
impact much in the NFC East because it's still wide open.
Arizona is fighting with the Eagles and many other teams in a push toward the
postseason and it will be up to Palmer and the defense to make that happen.
The Eagles do have some nice weapons, but the Cardinals can counter that with
their impressive defense.
Cardinals defensive coordinator Todd Bowles performed the same role in a
limited capacity for Philadelphia last season, so expect his familiarity with
the opponent to come in handy.
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Himashree Roy
Himashree Roy is a female Indian Athlete who won a bronze medal in the 100 meters women's relay race along with Merlin K Joseph, Srabani Nanda and Dutee Chand in the 22nd Asian Athletics Championships which concluded on July 9, 2017. She was born in Kolkata, West Bengal on 15 March 1995.
Career
She won the silver medal in women's 4x100m relay race along with N. Shardha, Sonal Chawla and Priyanka in the National Open athletics championships 2018 where they represented the Indian Railways.
Himashree Roy timed 11.60 seconds to set a record in women's 100 metres on 5 August 2018 in the 68th State Athletics Championships, at the Salt Lake Stadium while representing the Eastern Railway Sports Association (ERSA). She won the bronze medal in women's 100m final in 84th All India Railway Athletics Championship, 2017.
Himashree Roy, MG Padmini, Srabani Nanda and Gayathri Govindaraj won the bronze medal for women's 4x100m relay race in the second leg of the 2015 Asian Grand Prix Games, held in Thailand. She also won the gold medal in the women's 4×100 metre relay with teammates Dutee Chand, Srabani Nanda and Merlin K Joseph while representing the Indian Railways in the 55th National Open Athletic Championship, 2015.
References
Category:1995 births
Category:Sportswomen from West Bengal
Category:Indian female sprinters
Category:21st-century Indian women
Category:Living people
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Club night 7:30pm Prevention Of Obesity Club. Every Wednesday Onwards and then 8:00pm Back to School. Drag out you plimmos, school tie and shorts, for a trip back in time to your school days and dancing until 11:00pm.
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Half-Quantum Vortices in an Antiferromagnetic Spinor Bose-Einstein Condensate.
We report on the observation of half-quantum vortices (HQVs) in the easy-plane polar phase of an antiferromagnetic spinor Bose-Einstein condensate. Using in situ magnetization-sensitive imaging, we observe that pairs of HQVs with opposite core magnetization are generated when singly charged quantum vortices are injected into the condensate. The dynamics of HQV pair formation is characterized by measuring the temporal evolutions of the pair separation distance and the core magnetization, which reveals the short-range nature of the repulsive interactions between the HQVs. We find that spin fluctuations arising from thermal population of transverse magnon excitations do not significantly affect the HQV pair formation dynamics. Our results demonstrate the instability of a singly charged vortex in the antiferromagnetic spinor condensate.
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# coding=utf-8
import typing
from pyramid.config import Configurator
import transaction
from tracim_backend.app_models.contents import FOLDER_TYPE
from tracim_backend.app_models.contents import content_type_list
from tracim_backend.config import CFG
from tracim_backend.exceptions import ContentFilenameAlreadyUsedInFolder
from tracim_backend.exceptions import EmptyLabelNotAllowed
from tracim_backend.extensions import hapic
from tracim_backend.lib.core.content import ContentApi
from tracim_backend.lib.utils.authorization import ContentTypeChecker
from tracim_backend.lib.utils.authorization import check_right
from tracim_backend.lib.utils.authorization import is_contributor
from tracim_backend.lib.utils.authorization import is_reader
from tracim_backend.lib.utils.request import TracimRequest
from tracim_backend.lib.utils.utils import generate_documentation_swagger_tag
from tracim_backend.models.context_models import ContentInContext
from tracim_backend.models.context_models import RevisionInContext
from tracim_backend.models.revision_protection import new_revision
from tracim_backend.views.controllers import Controller
from tracim_backend.views.core_api.schemas import FolderContentModifySchema
from tracim_backend.views.core_api.schemas import NoContentSchema
from tracim_backend.views.core_api.schemas import SetContentStatusSchema
from tracim_backend.views.core_api.schemas import TextBasedContentSchema
from tracim_backend.views.core_api.schemas import TextBasedRevisionSchema
from tracim_backend.views.core_api.schemas import WorkspaceAndContentIdPathSchema
from tracim_backend.views.swagger_generic_section import SWAGGER_TAG__CONTENT_ENDPOINTS
try: # Python 3.5+
from http import HTTPStatus
except ImportError:
from http import client as HTTPStatus
SWAGGER_TAG__CONTENT_FOLDER_SECTION = "Folders"
SWAGGER_TAG__CONTENT_FOLDER_ENDPOINTS = generate_documentation_swagger_tag(
SWAGGER_TAG__CONTENT_ENDPOINTS, SWAGGER_TAG__CONTENT_FOLDER_SECTION
)
is_folder_content = ContentTypeChecker([FOLDER_TYPE])
class FolderController(Controller):
@hapic.with_api_doc(tags=[SWAGGER_TAG__CONTENT_FOLDER_ENDPOINTS])
@check_right(is_reader)
@check_right(is_folder_content)
@hapic.input_path(WorkspaceAndContentIdPathSchema())
@hapic.output_body(TextBasedContentSchema())
def get_folder(self, context, request: TracimRequest, hapic_data=None) -> ContentInContext:
"""
Get folder info
"""
app_config = request.registry.settings["CFG"] # type: CFG
api = ContentApi(
show_archived=True,
show_deleted=True,
current_user=request.current_user,
session=request.dbsession,
config=app_config,
)
content = api.get_one(hapic_data.path.content_id, content_type=content_type_list.Any_SLUG)
return api.get_content_in_context(content)
@hapic.with_api_doc(tags=[SWAGGER_TAG__CONTENT_FOLDER_ENDPOINTS])
@hapic.handle_exception(EmptyLabelNotAllowed, HTTPStatus.BAD_REQUEST)
@hapic.handle_exception(ContentFilenameAlreadyUsedInFolder, HTTPStatus.BAD_REQUEST)
@check_right(is_contributor)
@check_right(is_folder_content)
@hapic.input_path(WorkspaceAndContentIdPathSchema())
@hapic.input_body(FolderContentModifySchema())
@hapic.output_body(TextBasedContentSchema())
def update_folder(self, context, request: TracimRequest, hapic_data=None) -> ContentInContext:
"""
update folder
"""
app_config = request.registry.settings["CFG"] # type: CFG
api = ContentApi(
show_archived=True,
show_deleted=True,
current_user=request.current_user,
session=request.dbsession,
config=app_config,
)
content = api.get_one(hapic_data.path.content_id, content_type=content_type_list.Any_SLUG)
with new_revision(session=request.dbsession, tm=transaction.manager, content=content):
api.update_container_content(
item=content,
new_label=hapic_data.body.label,
new_content=hapic_data.body.raw_content,
allowed_content_type_slug_list=hapic_data.body.sub_content_types,
)
api.save(content)
api.execute_update_content_actions(content)
return api.get_content_in_context(content)
@hapic.with_api_doc(tags=[SWAGGER_TAG__CONTENT_FOLDER_ENDPOINTS])
@check_right(is_reader)
@check_right(is_folder_content)
@hapic.input_path(WorkspaceAndContentIdPathSchema())
@hapic.output_body(TextBasedRevisionSchema(many=True))
def get_folder_revisions(
self, context, request: TracimRequest, hapic_data=None
) -> typing.List[RevisionInContext]:
"""
get folder revisions
"""
app_config = request.registry.settings["CFG"] # type: CFG
api = ContentApi(
show_archived=True,
show_deleted=True,
current_user=request.current_user,
session=request.dbsession,
config=app_config,
)
content = api.get_one(hapic_data.path.content_id, content_type=content_type_list.Any_SLUG)
revisions = content.revisions
return [api.get_revision_in_context(revision) for revision in revisions]
@hapic.with_api_doc(tags=[SWAGGER_TAG__CONTENT_FOLDER_ENDPOINTS])
@check_right(is_contributor)
@check_right(is_folder_content)
@hapic.input_path(WorkspaceAndContentIdPathSchema())
@hapic.input_body(SetContentStatusSchema())
@hapic.output_body(NoContentSchema(), default_http_code=HTTPStatus.NO_CONTENT)
def set_folder_status(self, context, request: TracimRequest, hapic_data=None) -> None:
"""
set folder status
"""
app_config = request.registry.settings["CFG"] # type: CFG
api = ContentApi(
show_archived=True,
show_deleted=True,
current_user=request.current_user,
session=request.dbsession,
config=app_config,
)
content = api.get_one(hapic_data.path.content_id, content_type=content_type_list.Any_SLUG)
with new_revision(session=request.dbsession, tm=transaction.manager, content=content):
api.set_status(content, hapic_data.body.status)
api.save(content)
api.execute_update_content_actions(content)
return
def bind(self, configurator: Configurator) -> None:
# Get folder
configurator.add_route(
"folder", "/workspaces/{workspace_id}/folders/{content_id}", request_method="GET"
)
configurator.add_view(self.get_folder, route_name="folder")
# update folder
configurator.add_route(
"update_folder", "/workspaces/{workspace_id}/folders/{content_id}", request_method="PUT"
)
configurator.add_view(self.update_folder, route_name="update_folder")
# get folder revisions
configurator.add_route(
"folder_revisions",
"/workspaces/{workspace_id}/folders/{content_id}/revisions",
request_method="GET",
)
configurator.add_view(self.get_folder_revisions, route_name="folder_revisions")
# get folder revisions
configurator.add_route(
"set_folder_status",
"/workspaces/{workspace_id}/folders/{content_id}/status",
request_method="PUT",
)
configurator.add_view(self.set_folder_status, route_name="set_folder_status")
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Abschicken
Flow straightener
Combined processing of PBT and LSR
The combination of different materials to create multi-functional components in a single production step is one of the domains of plastics processing. Flow straighteners in shower heads are a good example: thanks to the elastic LSR nozzles integrated in the solid PBT main body, scale can be removed with ease.
Flow straighteners for shower heads are produced, inspected and packaged fully automatically in a production cell built around an electric two-component injection moulding machine from the ALLDRIVE series. This enables efficient high-volume production of this complex hard/soft combination.
Basic specifications
Technology
MachineFlow straighteners for shower heads are produced from PBT and LSR on an electric two-component ALLROUNDER 570 A, which is equipped with two size 170 injection units. Two pre-moulded parts and two finished components are produced in a cycle time of 40 s in a consistently high part quality.to electric machines
Robotic systemTransfer technology is the ideal answer for hard/soft combinations such as the flow straightener. The vertical MULTILIFT V robotic system turns the pre-moulded parts over in the mould. In addition, it removes the finished parts and transfers them first to a cooling station with integrated visual inspection, then on to a packaging system.to linear robotic systems
Process
Multi-component injection mouldingFor the combined processing of thermoplastics and liquid silicone in a single mould, the necessary thermal separation presents a challenge: while the PBT needs to be cooled, the LSR cross-links at high temperatures. For a fully automated process, transfer technology offers the ideal solution.to the process
Liquid silicone injection moulding (LSR)For sprueless part production, both the PBT main body and the LSR nozzles of the flow straightener are directly injected using hot and cold-runner technology. As a result, no non-recyclable waste is generated. Efficient use of materials is also ensured by an optimised emptying system for the LSR dosing unit.to the process
Industry
Technical injection mouldingIn technical injection moulding, high-precision components can be produced for a wide variety of applications. The production of flow straighteners is an example of how sophisticated mould technology and complex workflows can be comprehensively automated.to the industry
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Changes in axonal physiology and morphology after chronic compressive injury of the rat thoracic spinal cord.
The spinal cord is rarely transected after spinal cord injury. Dysfunction of surviving axons, which traverse the site of spinal cord injury, appears to contribute to post-traumatic neurological deficits, although the underlying mechanisms remain unclear. The subpial rim frequently contains thinly myelinated axons which appear to conduct signals abnormally, although it is uncertain whether this truly reflects maladaptive alterations in conduction properties of injured axons during the chronic phase of spinal cord injury or whether this is merely the result of the selective survival of a subpopulation of axons. In the present study, we examined the changes in axonal conduction properties after chronic clip compression injury of the rat thoracic spinal cord, using the sucrose gap technique and quantitatively examined changes in the morphological and ultrastructural features of injured axonal fibers in order to clarify these issues. Chronically injured dorsal columns had a markedly reduced compound action potential amplitude (8.3% of control) and exhibited significantly reduced excitability. Other dysfunctional conduction properties of injured axons included a slower population conduction velocity, a longer refractory period and a greater degree of high-frequency conduction block at 200 Hz. Light microscopic and ultrastructural analysis showed numerous axons with abnormally thin myelin sheaths as well as unmyelinated axons in the injured spinal cord. The ventral column showed a reduced median axonal diameter and the lateral and dorsal columns showed increased median diameters, with evidence of abnormally large swollen axons. Plots of axonal diameter versus myelination ratio showed that post-injury, dorsal column axons of all diameters had thinner myelin sheaths. Noninjured dorsal column axons had a median myelination ratio (1.56) which was within the optimal range (1.43-1.67) for axonal conduction, whereas injured dorsal column axons had a median myelination ratio (1.33) below the optimal value. These data suggest that maladaptive alterations occur postinjury to myelin sheath thickness which reduce the efficiency of axonal signal transmission.In conclusion, chronically injured dorsal column axons show physiological evidence of dysfunction and morphological changes in axonal diameter and reduced myelination ratio. These maladaptive alterations to injured axons, including decrease in myelin thickness and the appearance of axonal swellings, contribute to the decreased excitability of chronically injured axons. These results further clarify the mechanisms underlying neurological dysfunction after chronic neurotrauma and have significant implications regarding approaches to augment neural repair and regeneration.
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Introduction {#Sec1}
============
Small heat-shock proteins (sHSPs) are a diverse family of proteins that share a conserved ≈ 90-residue α-crystallin domain (ACD) that is flanked by variable N- and C-terminal regions (Basha et al. [@CR3]; Hilton et al. [@CR17]; McHaourab et al. [@CR28]). Although sHSPs are relatively small as monomers (12 to 42 kDa), the majority assemble into large oligomers. These range in size from 12 to \> 40 subunits, with some family members being monodisperse and others forming polydisperse ensembles (Basha et al. [@CR3]; Hilton et al. [@CR17]; McHaourab et al. [@CR28]). Found in all kingdoms of life, many sHSPs have been demonstrated in vitro to act as ATP-independent molecular chaperones with the ability to capture denaturing proteins in a partially unfolded form such that they can be reactivated by the cell's ATP-dependent chaperones. Recent reviews have described models for this canonical mechanism of sHSP chaperone action; however, details are derived primarily from in vitro studies with recombinant proteins and model interactors from non-homologous organisms (Haslbeck and Vierling [@CR16]; Treweek et al. [@CR40]). Thus, a major gap in our understanding of sHSP mechanism is the considerable lack of information about which substrates they protect in the cell.
In order to investigate the properties of proteins that are sHSP interactors, we identified HSP16.6 from the single-celled cyanobacterium *Synechocystis* sp. PCC 6803 (hereafter *Synechocystis*) as an ideal system to interrogate. HSP16.6 is the only sHSP in *Synechocystis* (Giese and Vierling [@CR12]; Lee et al. [@CR25]). It is strongly induced at high temperature, and cells deleted for HSP16.6 (Δ16.6) grow normally at optimal growth temperature but are sensitive to heat stress (Giese and Vierling [@CR12], [@CR13]). The temperature-sensitivity phenotype of Δ16.6 cells has enabled studies of sHSP properties required for activity in vivo in a homologous system. Crucially, point mutations in the N-terminal domain were found to decrease heat tolerance in vivo, but to have no effect on the efficiency of chaperone function in assays with model substrates in vitro (Giese et al. [@CR14]). This observation emphasizes the need to identify native interactors of sHSPs and renders *Synechocystis* an excellent system with which to do so.
We previously used immunoprecipitation and mass spectrometry (MS)-based proteomics to identify 13 proteins associated in vivo with HSP16.6 from *Synechocystis* cells that had been heat-stressed prior to cell lysis (Basha et al. [@CR2]). Notably, these 13 proteins were not detected in equivalent pull-downs from cells that had not been heat-stressed, or when recombinant HSP16.6 was added to heat-stressed Δ16.6 cells before lysis (to control for sHSP-protein interactions that might occur in the lysate, as opposed to during heat stress in vivo). Although these proteins were associated with the sHSP in the soluble cell fraction, they were also found in the insoluble cell fraction after heat stress (Basha et al. [@CR2]). All of these proteins, whose functions span a variety of cellular processes, including translation, transcription, secondary metabolism, and cell signaling, could be released from the immunoprecipitate by addition of DnaK, co-chaperones, and ATP (Basha et al. [@CR2]). In addition, one of these interactors, a serine esterase, when purified, was shown to be heat sensitive and to associate with HSP16.6 and thereby be protected from insolubilization (Basha et al. [@CR2]). While these data identified 13 proteins as potential interactors for canonical sHSP chaperone function, their relatively small number meant it was not possible to derive any common protein features that might dictate interaction with the sHSP.
Here, we have extended the identification of HSP16.6-interactors to a total of 83 proteins by performing an affinity pull-down from heat-stressed *Synechocystis*. By performing rigorous bioinformatic analyses, we provide new insights into the primary and secondary structural properties of proteins that interact with sHSPs in the soluble cell fraction during stress. We also catalogue the functions of the interactors and compare these to sHSP interactors previously identified in two other prokaryotes, *Escherichia coli* and *Deinococcus radiodurans* (Bepperling et al. [@CR4]; Fu et al. [@CR10]). Our combined results indicate that sHSPs protect a specific yet diverse set of proteins from aggregation in the cell.
Methods {#Sec2}
=======
Affinity isolation of HSP16.6-interacting proteins {#Sec3}
--------------------------------------------------
Isogenic *Synechocystis* strains were used in which the wild-type HSP16.6 gene had been replaced with a spectinomycin resistance gene (*aadA* gene) (ΔHSP16.6 strain) or with the spectinomycin gene and HSP16.6 carrying a Strep-tag II affinity tag (WSHPQFEK) on the C-terminus (HSP16.6-Strep strain) (Basha et al. [@CR2]). This HSP16.6-Strep strain had been shown previously to behave like wild type in assays of heat tolerance (Basha et al. [@CR2]), and recombinant HSP16.6-strep protein was equivalent to untagged protein in assays of chaperone activity in vitro (Friedrich et al. [@CR9]).
Cells were grown in 50-mL cultures at 30 °C as described previously to *A*~730~ ≈ 0.2 (Basha et al. [@CR2]) and then subjected to treatment at 42 °C for 2 h followed by 1 h recovery at 30 °C, to allow accumulation of HSP16.6-Strep protein. Control samples were prepared directly after this treatment, while heat-stressed samples were treated for an additional 30 min at 46 °C. To control for interaction of HSP16.6-Strep protein during sample processing, recombinant HSP16.6-Strep protein was added to heat-stressed samples of the ΔHSP16.6 strain directly after heat treatment at a concentration matching that in heat-stressed cells. Cells were harvested, suspended in 1.5 mL lysis buffer (25 mM HEPES-KOH, 0.2 M NaCl, 0.5% Triton X-100, 5 mM ϵ-aminocaproic acid, 1 mM benzamidine, 1 μg mL^−1^ leupeptin, and 1 mM EDTA, pH 7.5), and opened as described previously (Basha et al. [@CR2]). The soluble fraction was mixed with 30 μL of Strep-Tactin resin (Sigma) at 4 °C for 2 h. Resin was washed six times in lysis buffer, and bound proteins were eluted using either sample buffer (for SDS-PAGE) or isoelectric focusing (IEF) rehydration buffer (for 2D gels) (7.0 M urea, 2.5 M thiourea, 2% CHAPS, 2% IPG buffer pH 3--10 NL (Amersham Biotech), and 3 mg mL^−1^ dithiothreitol).
For 2D gel analysis, pH 3--10 NL first dimension strips (18 cm; Amersham Biotech) were rehydrated overnight at room temperature using 600 μL of sample in IEF rehydration buffer. IEF was carried out for 2 h at 150 V, 2 h at 300 V, 5 h at 500 V, and 7 h at 3500 V. The second dimension was separated by 11--17% SDS-PAGE for 30 min at 15 mA and then for 7 h at 25 mA. Samples were also separated by SDS-PAGE according to standard protocols, using 8% acrylamide gels in order to afford good separation of proteins above 100 kDa, which are typically not well resolved on the 2D system. Gels were silver stained according to a previous protocol (Rabilloud [@CR33])*.*
Protein identification by means of mass spectrometry {#Sec4}
----------------------------------------------------
Proteins unique to the heat-stressed HSP16.6-Strep sample were excised from 1D or 2D gels and digested with trypsin, and peptides were prepared for MS as described previously (Basha et al. [@CR2]). Peptide extracts were introduced onto a 100-μm I.D. × 5-cm C18 column using an autosampler and separated with a 25-min gradient of 2--100% acetonitrile in 0.5% formic acid. The column eluate was directed into a Thermo Finnigan LCQ Deca ion trap mass spectrometer. The mass range scanned was 400 to 1500 *m*/*z*, and data-dependent scanning was used to select the three most abundant ions in each parent scan for tandem MS. Peptides were searched using SEQUEST and allowed for static modification of Cys (57 Da; iodoacetamidation), and differential modification of Met (16 Da; oxidation) was considered. X correlation cutoffs of 2.0 for 2+ ions, 3.0 for 3+ ions, and delta Xcorr \> 0.05 were applied, and data were sorted using DTASelect (Tabb et al. [@CR39]). The complete list of 83 proteins identified as HSP16.6 interaction partners from these and our previous experiments (Basha et al. [@CR2]) is given in Supplemental Table [1](#MOESM1){ref-type="media"}. For the purpose of comparisons and calculations, this set is considered to represent sHSP interactors and denoted *I*, where \|*I*\| = 83. Known protein-protein interactions (PPIs) from yeast-2-hybrid experiments are available for *Synechocystis* (Sato et al. [@CR38]). We identified all PPIs made by members of *I* (Supplemental Table [1](#MOESM1){ref-type="media"}), excluding PPIs that were not identified with multiple positive prey clones, in order to avoid false positives.
Bioinformatic analyses {#Sec5}
----------------------
The *Synechocystis* sp. PCC 6803 genome (Kaneko et al. [@CR22]; Kotani et al. [@CR23]) was obtained from CyanoBase, [http://genome.microbedb.jp/cyanobase/](http://genome.microbedb.jp/cyanobase) (Nakamura et al. [@CR31]). A set *G* representing the genome, containing all proteins such that *I* ⊆ *G*, was created from the protein-coding sequences in the genome. Only proteins with estimated isoelectric point (pI) within the range 4--9.5 and mass *m* between 10 and 200 kDa, corresponding to the range of proteins that could be identified in either the 1D or 2D gels, were included (see [Supporting Information](#Sec13){ref-type="sec"}). This filtering resulted in *G* comprising 3021 proteins (i.e., \|*G*\| = 3021), which amounts to \> 80% of the proteins encoded in the genome.
The mass, sequence length *n*~aa~, and abundance (absolute numbers *n*~*F*~ and frequencies *f*~*F*~ = *n*~*F*~/*n*~aa~) of various sequence features *F* were determined for every protein. These were DnaK-binding motifs; VQL, IXI, and \[I/L/V\]X\[I/L/V\] motifs (where X refers to any amino acid); charged (D,E,H,K,R), positive (H,K,R), negative (D,E), and hydrophobic (C,F,I,L,M,V,W) residues. DnaK-binding motifs were identified using a previously described algorithm (Van Durme et al. [@CR41]), and the other motifs were found through *regexp* pattern-matching using the Python Standard Library. Long-range disorder was predicted with IUPred (Dosztanyi et al. [@CR6], [@CR7]) using default parameters, and residues with a score \> 0.5 were considered unstructured. For the remainder, secondary structure was predicted from the sequences using the EMBOSS (Rice et al. [@CR34]) implementation of the GOR method. β-strands and β-turns were pooled together into "β-structures." Average abundances were calculated separately for *I* and *G*.
Statistical significance testing and representation {#Sec6}
---------------------------------------------------
A bootstrapping approach was employed to assess the statistical significance of any differences between *I* and *G*. First, a random subset, *R*, was taken from *G* by arbitrarily picking, with replacement, of 83 proteins (i.e., *R* ⊆ *G* and \|*R*\| = \|*I*\|). The mean, $\documentclass[12pt]{minimal}
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\begin{document}$$ {\overline{Q}}_R $$\end{document}$, was then calculated for the given quantity of interest *Q*, to allow comparison with $\documentclass[12pt]{minimal}
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\begin{document}$$ {\overline{Q}}_I $$\end{document}$, the mean calculated from *I* for the same quantity. This was repeated *N* times, after which the *p* value was calculated as the frequency by which $\documentclass[12pt]{minimal}
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\begin{document}$$ {\overline{Q}}_R\ge {\overline{Q}}_I $$\end{document}$ or $\documentclass[12pt]{minimal}
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\begin{document}$$ {\overline{Q}}_R\le {\overline{Q}}_I $$\end{document}$, in the respective cases of $\documentclass[12pt]{minimal}
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\begin{document}$$ {\overline{Q}}_I>{\overline{Q}}_G $$\end{document}$ and $\documentclass[12pt]{minimal}
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\begin{document}$$ {\overline{Q}}_I<{\overline{Q}}_G $$\end{document}$. For each quantity, a total of *N* = 100,000 iterations was run, and the statistical significance was tested at the 0.01 level.
Kernel density estimates were plotted for all quantities where a statistically significant difference was found. A Gaussian kernel with a bandwidth equal to 2% of the visible range was used in all cases and the amplitude was set such that the integrated density was equal to the number of proteins in each set. As such, the amplitudes are inversely proportional to the ranges along the *x*-axis, and their heights can thus differ substantially between distributions. Moreover, the *y*-axes' ranges were chosen to make the *I* and *G* distributions occupy the same visible area in the resulting plot.
Biological function analysis {#Sec7}
----------------------------
A PANTHER Overrepresentation Test (release 20170413) against the GO Ontology database (release 20170926) was made for all proteins in *I*, using the *Synechocystis* reference list and the "GO biological process complete" annotation data set. Bonferroni correction was applied for multiple testing, and a *p* value cut-off of 0.05 was used to filter the results. Proteins that were not mapped to any entry in the reference list were added to the set of "unclassified" proteins. Enrichment was defined as *n*~*p*~/E(*n*~*p*~), where *n*~*p*~ is the number of proteins in *I* being ascribed to biological process *p*, and E(*n*~*p*~) is the expected number of such proteins based on their frequency in *G* and the size of *I*. Proteins that were assigned to the GO-class "biological process" but not to any of its subclasses were given the collective label "other biological process." Since a single protein can have multiple classifications, the sum of proteins in the different classes exceeds \|*I*\|.
Protein BLAST (Altschul et al. [@CR1]) was used to find orthologs among the interactors identified for HSP16.6 in *Synechocystis*, IbpB in *E. coli* (Fu et al. [@CR10]), and HSP20.2 in *D. radiodurans* (Bepperling et al. [@CR4]). Three pairwise comparisons were made to define the overlap between the sets of interactors, where the list of interactors from one organism was used as the "database" and the list of interactors from the other as the "query." Using *E. coli* as the database yielded poorly annotated hits; hence, the primary database was set to be *Synechocystis* and the secondary database to be *D. radiodurans*. An *E* value cut-off of 10^−10^ was used for all BLAST searches, and whenever a protein in the query yielded several matches the one with the lowest *E* value was chosen. Lastly, the overlap between *E. coli* and *D. radiodurans* was used as a query against *Synechocystis* in order to find the overlap between the interactors in all three organisms. The triply overlapping set of proteins were also analyzed for an overrepresentation test in *Synechocystis* as described above, but without imposing a *p* value because of the small number of proteins in the query.
Results {#Sec8}
=======
Identification of proteins associated with HSP16.6 during heat stress in vivo {#Sec9}
-----------------------------------------------------------------------------
To identify a larger number of HSP16.6-associated proteins than we did previously (Basha et al. [@CR2]), we developed a *Synechocystis* strain in which the wild-type *HSP16.6* gene was replaced with an *HSP16.6* gene modified to encode a Strep-tag II at the C-terminus. HSP16.6-Strep was shown to complement HSP16.6 in vivo in thermotolerance assays (Basha et al. [@CR2]), as well as functioning in vitro to protect model interactors from irreversible heat-denaturation (Friedrich et al. [@CR9]).
The HSP16.6-Strep strain and an isogenic strain carrying wild-type HSP16.6 were subjected to mild heat stress to allow accumulation of the sHSP and then to a short, more severe heat stress to maximize association of thermally unstable proteins with the sHSP. The soluble cell fraction from control and heat-stressed cells of the HSP16.6-Strep and HSP16.6 strains was subjected to Strep-Tactin affinity chromatography and the recovered proteins compared by means of 2D electrophoresis (or, to examine high molecular mass proteins, by using 1D electrophoresis) (Fig. [1](#Fig1){ref-type="fig"}). Individual spots or bands unique to proteins affinity-purified with HSP16.6-Strep from the heat stress samples were excised and subjected to MS analysis.Fig. 1Identification of HSP16.6 interactors. **a** SDS-PAGE separation of proteins recovered in association with HSP16.6-Strep in cells grown at 30 °C and treated at 42 °C for 2 h plus 1 h recovery at 30 °C to allow sHSP accumulation (control sample, C) or further treated with an additional 30 min at 46 °C (heat-stressed sample, HS). To recover proteins in the high molecular mass range, separation was performed using an 8% acrylamide gel, and the position of molecular mass markers is indicated. Bands that were excised for analysis are annotated with red dashes. Double-width dashes indicate bands that gave hits for proteins associated with protein-folding processes. **b** 2D gel separation of samples prepared as described in **a**. The position of molecular mass markers and the acidic (+) and basic (−) sides of the silver-stained 2D gels are indicated. Spots that were excised and yielded the reported data are annotated with red circles (right panel). The ellipse in each panel indicates the spots due to HSP16.6
We identified a total of 72 proteins in these experiments which, when combined with others we had identified previously (Basha et al. [@CR2]), expanded to a total of 83. Notably, the proteins were recovered from the soluble fraction, so they do not represent those that underwent excessive aggregation, or associations with membranes and cytoskeletal elements that may have led to partitioning into the pellet. As such, these proteins represent potential sHSP interactors that have been prevented from insolubilization by interaction with HSP16.6. We denote this set of interactors *I*, representing a subset of the genome *G* detectable in our experiments. This allows us to test hypotheses about the features of these interactors to shed light on what distinguishes them from the other proteins in *Synechocystis*. Though many of the interactors have known PPIs, based on cross-referencing to genome-wide yeast-2-hybrid data (Sato et al. [@CR38]) (Supplementary Table [1](#MOESM1){ref-type="media"}), notably there are only three described pairwise PPIs within *I*, and all three of these are self-associations. To see if this low count was an artifact from our conservative approach of excluding PPIs that were identified with only one prey clone, we also tested including the latter, which presumably yields more false positives. This increased the number of pairwise PPIs within *I* to 12, including six self-interactions, which is still a small subset of *I*. Consequently, the proteins in *I* appear largely independent of each other in their interaction with HSP16.6, consistent with our affinity-isolate methodology being sensitive to stable interactors.
Primary- and secondary-structure features of HSP16.6 interactors {#Sec10}
----------------------------------------------------------------
We first compared the average mass and sequence lengths of the interactors to the genome. We found that these were very different, with the interactors being about 60% larger on average (Table [1](#Tab1){ref-type="table"}, Fig. [2](#Fig2){ref-type="fig"}a, b). While this is informative about the interactor profile of HSP16.6, it also means that the absolute number, *n*~*F*~ of any feature *F*, is likely to be larger for the interactors. To account for this, all subsequent analyses are consequently focused on fractional quantities, *f*~*F*~, which are normalized by sequence length in order to reveal distinctive features for the proteins associated with HSP16.6.Table 1Comparison of various primary- and secondary-structure features between interactors of HSP16.6 in *Synechocystis* with the wider genome. Mean values obtained for the proteins in *I* and *G*, along with *p* values for the differences between themQuantityInteractors, *I*Genome, *Gp* value*m*/Da**57,86036,561\< 10** ^**−5**^*n* ~aa~**525336\< 10** ^**−5**^*f* ~DNAK~**0.01980.285\< 10** ^**−5**^*f* ~VQL~0.0003350.0002740.27*f* ~IXI~0.003490.003050.15*f* ~\[ILV\]X\[ILV\]~**0.03780.04260.002**pI5.225.630.036*f* ~Charged~**0.2520.2306.0∙10** ^**−5**^*f* ~+~0.1180.1150.24*f* ~−~**0.1340.114\< 10** ^**−5**^*f* ~H-phobic~**0.3090.3311.0∙10** ^**−5**^*f* ~d~0.0860.0580.015*f* ~β~**0.3550.415\< 10** ^**−5**^*f* ~α~**0.3830.3383.1∙10** ^*−5*^Bold text indicates statistically significant differences, defined as *p* \< 0.01Fig. 2Probability distributions of the statistically significant differences identified in Table [1](#Tab1){ref-type="table"}. **a**, **b** The distributions of protein mass (**a**) and sequence length (**b**) for *I* and *G*. The proteins in *I* are on average approximately 60% larger than those in *G*, both in terms of mass and sequence length. **c**, **d** Distributions of frequencies of \[I/L/V\]X\[I/L/V\] motifs (**c**) and DnaK-binding motifs (**d**). Both sequence features are less frequent and more narrowly distributed in *I*. **e**--**g** The fraction of hydrophobic (**e**), charged (**f**), and negative (**g**) residues. Charged residues are more frequent in *I*, which can be attributed to a higher fraction of negatively charged residues and a lower fraction of hydrophobic residues. **h**, **i** Fraction of residues with predominately helical (α and 3~10~, **h**) propensity and β-structure (sheet and turn, **i**). The helix content is higher in *I* than in *G*, and conversely, the β-structure content is lower in *I*. The distributions were normalized such that their integral equals the number of proteins in each set. Consequently, the amplitudes are inversely proportional to the width of the distributions, and the amplitudes of the two distributions in each panel reflect the different sizes of the two sets
We judged that certain sequence motifs might be implicated in the association of interactors with sHSPs. To develop hypotheses for testing, we considered a model in which interfaces that allow the sHSP to self-assemble might be the same as interactor binding sites (Jacobs et al. [@CR20]). In this context, the inter-monomer contact made between the highly conserved "IXI" motif in the C-terminal region and the β4--β8 groove of the ACD has been proposed as an auto-inhibitory interface (Jehle et al. [@CR21]; van Montfort et al. [@CR42]). Theorizing that IXI motifs might mediate contacts with the sHSPs, we therefore asked whether they were differentially represented in the interactors. We also posed this question in a more general form, by searching for motifs matching the requirement \[I/L/V\]X\[I/L/V\], which is more encompassing across the breadth of sHSPs (Poulain et al. [@CR32]). Furthermore, we searched for VQL motifs, as this corresponds to the specific manifestation of the "IXI" in HSP16.6. Comparing the fractional abundance of these motifs (*f*~IXI~, *f*~\[ILV\]X\[ILV\]~, *f*~VQL~, respectively) between the interactors and the genome, we found there to be no meaningful difference for IXI and VQL, but the general form \[I/L/V\]X\[I/L/V\] was significantly under-represented in the interactors (Table [1](#Tab1){ref-type="table"}, Fig. [2](#Fig2){ref-type="fig"}c).
sHSPs are thought to transfer interactors to the DnaK (HSP70 in eukaryotes) system for ATP-dependent refolding (Haslbeck and Vierling [@CR16]). We therefore hypothesized that the presence of DnaK-binding motifs (Rudiger et al. [@CR36]), which mediate association with this downstream chaperone, might be different between the interactors and the genome. We found the fractional abundance of DnaK motifs (*f*~DnaK~) to be \> 30% lower in the interactors (Table [1](#Tab1){ref-type="table"}, Fig. [2](#Fig2){ref-type="fig"}d).
We next considered electrochemical properties of the proteins. The difference in pI between the interactors and genome was just outside our significance criterion (*p* = 0.036 \> 0.01). However, when examining the fraction of charged residues (*f*~Charged~), we discovered it to be higher in the interactors. By investigating negatively and positively charged residues separately (*f*~−~ and *f*~+~, respectively), we found this difference to be due to the former, with negatively charged residues \> 16% more abundant in the interactors. Conversely, the genome contains a higher fractional abundance of hydrophobic residues (*f*~H-phobic~) (Table [1](#Tab1){ref-type="table"}, Fig. [2](#Fig2){ref-type="fig"}e--g).
Lastly, we asked whether predicted secondary structure differed between the two sets. The fraction of residues in disordered regions (*f*~*d*~) is insignificantly higher in the interactors, albeit very near our threshold (*p* = 0.015 ≈ 0.01). For the structured regions, on average, the interactors had a higher fraction of residues in helices (*f*~α~) and lower fraction in β-structures (*f*~β~), compared to the proteins in the wider genome (Table [1](#Tab1){ref-type="table"}, Fig. [2](#Fig2){ref-type="fig"}h, i).
Functional classification of HSP16.6-associated proteins {#Sec11}
--------------------------------------------------------
Where possible, interactors were classified according to their gene-ontology annotation into either "metabolic process," "cellular process," or "other biological process." Many proteins were assigned to multiple classes, and 15 proteins could not be matched to the reference list and were added to the set of unclassified proteins, which then comprised 24 proteins. This classification yielded different distributions of processes in *I* and *G* (Fig. [3](#Fig3){ref-type="fig"}a), indicating that HSP16.6 has an interaction profile that reflects the biological function of its interactors. To quantify the differences, we calculated the overrepresentation of proteins involved in the various biological processes (Fig. [3](#Fig3){ref-type="fig"}b). The data reveal statistically significant enrichment of proteins ascribed to certain biological processes in the interactors, suggesting that HSP16.6 makes function-specific interactions. The most striking association was for proteins involved in protein folding, with 6 out of the 19 known such proteins being found in *I* (Table [2](#Tab2){ref-type="table"}), corresponding to a thirteen-fold enrichment.Fig. 3Classification of proteins involved in different gene-ontology annotations of biological processes. **a** Pie charts show the extent of different classes in *I* and *G*. The most fundamental classes have labels in bold face. Note that "cellular metabolic process" belongs to both "metabolic process" and "cellular process" and is therefore represented by two colors. **b** Enrichment within *I* of proteins taking part in the various biological processes. Circle areas reflect the number of proteins in *I*, and numbers indicate proteins in *I* and *G*. *I* contains a smaller fraction of unclassified proteins than *G*, and all classes are somewhat enriched in *I*. Proteins involved in protein folding are enriched thirteen-fold, with 6 of the 19 such proteins known being found among the interactors. Inset: Same analysis performed for the 10 overlapping proteins from the analysis in (**c**). In all featured classes, the fold-enrichment is higher. **c** Venn diagram showing the overlap of sHSP interactor ranges from *Synechocystis*, *E. coli*, and *D. radiodurans*. Note that, with the exception of the intersection of the three sets, all areas of the diagram reflect the number of elements withinTable 2The six interactors of *Synechocystis* HSP16.6 annotated as belonging to the "protein folding" categoryGeneUniProt IDNamesll0058Q55154DnaK 1sll0170P22358DnaK 2sll1932P73098DnaK 3slr2076Q0597260 kDa chaperonin 1sll0533Q55511Trigger factor (TF)slr1251P73789Peptidyl-prolyl cis-trans isomerase
To compare HSP16.6-interactors with those identified in other prokaryotes, we cross-referenced our list with those reported as IbpB interactors in *E*. *coli* (Fu et al. [@CR10]), and HSP20.2 in *D. radiodurans* (Bepperling et al. [@CR4]) (Fig. [3](#Fig3){ref-type="fig"}c). There were unique orthologs for 17 HSP16.6 interactors among the 113 IbpB interactors and 17 for the 101 HSP20.2 interactors. The overlap between IbpB and HSP20.2 interactors was larger still, comprising 36 unique orthologs. A total of 10 proteins were found in all three sets of interactors. Notably, these overlaps are much larger than one would expect by chance (approximately 3 for each pairwise overlap, and fewer than 1 for the triple overlap). Interestingly, these proteins were also diverse, spanning multiple biological processes, with only one eluding classification (Table [3](#Tab3){ref-type="table"}, Fig. [3](#Fig3){ref-type="fig"}b inset). With the exception of the "protein folding" and "other biological process," which were not represented at all in this subset, all categories were even more overrepresented than in the complete list of HSP16.6 interactors. We note that the small number of proteins precluded low *p* values for the levels of enrichment for the individual categories. Taken together, they nonetheless indicate that the enrichment pattern seen for the *Synechocystis* interactors is particularly prominent for the interactors that are common for all three sHSPs, with the striking exception of the protein-folding interactors, which might be a species- or sHSP-specific phenomenon, or the result of differences in the methods used for recovering interacting proteins.Table 3Proteins that we associated to all three of HSP16.6 (*Synechocystis*), IbpB (*E. coli*), and HSP20.2 (*D. radiodurans*). The GO annotations for biological processes are coded as follows: metabolic process (MP), cellular process (CP), nitrogen-compound metabolic process (NCMP), primary metabolic process (PMP), biosynthetic process (BP), organic substance metabolic process (OSMP), cellular metabolic process (CMP), and unclassified (U). In some cases, two distinct IbpB or HSP20.2 interactors would correspond to an HSP16.6 interactor, in which case, both UniProt IDs were included in the table*Synechocystis* geneUniProd ID\
*Synechocystis*\
*E. coli*\
*D. radiodurans*NameGO biological processsll0018Q55664\
G64976n\
NP_295312.1Fructose-bisphosphate aldolase, class IIMP, CP, NCMP, PMP, OSMP, CMPsll1099P74227\
NP_289744.1, pdb\|1EFC\|A\
NP_295522.1Elongation factor TuMP, CP, NCMP, PMP, BP, OSMP, CMPsll1180P74176\
NP_287490.1\
NP_295291.1Toxin secretion ABC transporter ATP-binding proteinCP, NCMP, PMP, OSMPsll1326P27179\
CAA23519.1\
NP_294424.1ATP synthase alpha chainMP, CP, NCMP, PMP, BP, OSMP, CMPsll1787P77965\
AAC43085.1\
NP_294636.1RNA polymerase beta subunitMP, CP, NCMP, PMP, BP, OSMP, CMPsll1789P73334\
NP_290619.1\
NP_294635.1RNA polymerase beta' subunitMP, CP, NCMP, PMP, BP, OSMP, CMPsll1818P73297\
CAA37838.1\
NP_295851.1RNA polymerase alpha subunitMP, CP, NCMP, PMP, BP, OSMP, CMPsll1841P74510\
NP_285811.1, NP_286443.1\
NP_293809.1, NP_293979.1Pyruvate dehydrogenase dihydrolipoamide acetyltransferase component (E2)MPslr0542P54416\
NP_286179.1\
NP_295695.1ATP-dependent protease ClpPMP, NCMP, PMP, OSMPslr1105P72749\
NP_289127.1\
NP_294922.1GTP-binding protein TypA/BipA homologU
Discussion {#Sec12}
==========
Here, we have examined the properties of 83 proteins that associate in vivo with HSP16.6 under conditions of heat stress. Given that the proteins were obtained from the soluble supernatant after centrifugation, they are likely to under-represent membrane- and cytoskeleton-associated proteins. Furthermore, as our experiment involves affinity pull-downs, these interactors are inevitably restricted to those that form interactions that are stable on the timescale of the experiment. In the context of the model proposed for sHSPs wherein they display both a low-affinity mode with high capacity, and a high-affinity mode with low capacity (McHaourab et al. [@CR28]), our interactors are likely representative of the latter. Notwithstanding these potential biases of the experiment, we have shown that the interactors were on average larger than the proteins in the genome, have a distinct electrochemical profile, an increased fraction of helical secondary structure, and a lower fraction of \[I/L/V\]X\[I/L/V\] and DnaK-binding motifs.
We observed that HSP16.6 preferentially binds longer, more massive, proteins. This is in agreement with analysis of sHSP interactors *E. coli* and *D. radiodurans* (Fu et al. [@CR11]) and is interesting in light of recent data noting that thermally unstable proteins in cells are typically longer than those that are stable (Leuenberger et al. [@CR26]). Longer proteins might therefore be overrepresented in the interactors by virtue of being more likely to be destabilized by the heat-shock condition assayed here. Alternatively, or in addition, it is possible that longer proteins, by virtue of having more binding sites, might be held tighter by the sHSPs. This would stem from avidity effects resulting from the multivalency of sHSP oligomers (Hilton et al. [@CR17]), similar to observations made for other molecular chaperones (Huang et al. [@CR19]; Saio et al. [@CR37]).
Upon considering amino acid motifs and composition, we found a lower fraction of \[I/L/V\]X\[I/L/V\] motifs in the interactors. This suggests that the β4--β8 groove, which binds this motif intra-molecularly in sHSP oligomers (Basha et al. [@CR3]; Hilton et al. [@CR17]), is not the binding site for these stable interactors. However, this does not preclude the β4--β8 groove being a site for low-affinity, or transient, interactions. This is consistent with the observation that the excised ACD can display potent chaperone activity (Cox et al. [@CR5]; Hochberg et al. [@CR18]). We also identified an overabundance of charged and, in particular negatively charged, residues in the interactors. A preponderance of charged residues was also observed for sHSP interactors in *E. coli* and *D. radiodurans* (Fu et al. [@CR11]). Notably, aspartates have been shown to be enriched in thermally unstable proteins (Leuenberger et al. [@CR26]), again hinting that thermal stability could be a key attribute for recognition by sHSPs. It is also interesting to consider the electrochemical profile of the sHSPs themselves, which have an overabundance of charged residues in the ACD and C-terminal region (Kriehuber et al. [@CR24]). As such, it is possible that there may be charge-complementarity aspects to binding.
The depletion of DnaK-binding motifs in the HSP16.6 interactors is striking, particularly when considering that DnaK is able to release interactors from the complexes made with HSP16.6. This suggests that the DnaK-binding motif is not responsible for the recognition events that mediate interactor transfer between the chaperones. Instead, the DnaK-binding motif may be more reflective of DnaK's holdase, rather than refoldase activity. In this way, proteins that are not protected by the sHSPs are captured by HSP70 instead (Mayer and Bukau [@CR27]). The interactors are also enriched in α-helical propensity and depleted in β-structure. It is possible that, based on the observation that there is little cooperativity in the folding of β-sheets (Wu and Zhao [@CR43]), this may be reflective of physico-chemical differences in re- or unfolding.
Gene-ontology analysis demonstrates that, while capable of associating with many interactors, HSP16.6 nonetheless does so with statistically significant specificity, evidenced by varying enrichments for different biological processes. This observation is validated by the overlap between *Synechocystis*, *E. coli*, and *D. radiodurans* sHSP interactors. The notion that sHSPs have specific interactors in the cell also extends to eukaryotes, where different sHSPs found in the same cellular compartment have differing interactor profiles (Fleckenstein et al. [@CR8]; McLoughlin et al. [@CR29]; Mymrikov et al. [@CR30]).
The most enriched groups of proteins associated with HSP16.6 were other components of the protein folding machinery. We interpret this as due to HSP16.6 being part of a tightly linked molecular chaperone network (Gong et al. [@CR15]), collaborating to prevent and reverse improper protein interactions in the wider heat-shock response of the cell (Richter et al. [@CR35]). Possibly, these interactions are indirect, captured due to HSP16.6 and other protein-folding components acting on the same substrates. An indirect interaction with protein-folding components could also explain the lack of equivalent proteins in the *E. coli* sHSP interactors (Fu et al. [@CR10]), as the previous report employed covalent-crosslinking and urea solubilization prior to immunoprecipitation. The *D. radiodurans* interactors were identified by a different method, employing ex vivo addition of purified HSP20.2 to cell lysates, prior to heat stress and immunoprecipitation. Given the differences in methodology between these studies, we suggest that those proteins comprising common interactors are highly significant (Table [3](#Tab3){ref-type="table"}).
In sum, our study provides an initial view of the functional interactome of prokaryotic sHSPs and of *Synechocystis* in particular. In addition, the statistical framework we have implemented for examining sequence determinants can be applied to the analysis of the likely future profusion of proteomic data identifying molecular chaperone interactors in cells.
Electronic supplementary material
=================================
{#Sec13}
ESM 1(DOCX 28 kb)
The original version of this article was revised: Table 1 needed corrections. The DOI of the Erratum is: 10.1007/s12192-018-0901-6
**Electronic supplementary material**
The online version of this article (10.1007/s12192-018-0884-3) contains supplementary material, which is available to authorized users.
A correction to this article is available online at <https://doi.org/10.1007/s12192-018-0901-6>.
**Change history**
5/3/2018
Table 1 in the original publication has been corrected.
We thank Linda Breci (University of Arizona) for performing MS experiments and Georg Hochberg (University of Chicago) for helpful discussions. This work was supported by the Swedish Research Council and the European Commission for a Marie Skodowska Curie International Career Grant (2015-00559) to EGM, the Biotechnology and Biological Sciences Research Council (BB/K004247/1) to JLPB, and the National Institutes of Health (RO1 GM42762) to EV.
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Buddha's Lost Children
Buddha's Lost Children is a 2006 documentary film by Dutch director Mark Verkerk. The feature film tells the story of Khru Bah Neua Chai Kositto, a Buddhist monk who has dedicated his life to orphaned children in the Golden Triangle area of Thailand. The film opened in Dutch cinemas in September 2006.
Awards
The film won the International Documentary Grand Jury Prize (2006) at the Los Angeles AFI Fest , the Jury Award for Documentary (2007) at the Newport Beach Film Festival, the Best Global Insight Film (2007) at the Jackson Hole Film Festival , the David L. Wolper Best Documentary Award (2007) at the Napa Sonoma Valley Film Festival , the City of Rome Award (2006) at the Asiaticafilmmediale in Rome, the Crystal Film (2006) at the Netherlands Film Festival, and the Silver Dove (2006) at the Dok Leipzig .
External links
Category:2006 films
Category:Dutch films
Category:Thai-language films
Category:Documentary films about Buddhism
Category:Dutch documentary films
Category:Documentary films about orphanages
Category:2000s documentary films
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Monte Carlo studies of three-dimensional O1 and O4 phi4 theory related to Bose-Einstein condensation phase transition temperatures.
The phase transition temperature for the Bose-Einstein condensation (BEC) of weakly interacting Bose gases in three dimensions is known to be related to certain nonuniversal properties of the phase transition of three-dimensional O(2) symmetric phi(4) theory. These properties have been measured previously in Monte Carlo lattice simulations. They have also been approximated analytically, with moderate success, by large N approximations to O(N) symmetric phi(4) theory. To begin investigating the region of validity of the large N approximation in this application, the same Monte Carlo technique developed for the O(2) model [P. Arnold and G. Moore, Phys. Rev. E 64, 066113 (2001)] to O(1) and O(4) theories has been applied. The results indicate that there might exist some theoretically unanticipated systematic errors in the extrapolation of the continuum value from lattice Monte Carlo results. The final results show that the difference between simulations and next-to-leading order large N calculations does not improve significantly from N=2 to N=4. This suggests that one would need to simulate yet larger N's to see true large N scaling of the difference. Quite unexpectedly (and presumably accidentally), the Monte Carlo result for N=1 seems to give the best agreement with the large N approximation among the three cases.
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Kevin Mansker
Kevin Mansker (born ) is an American male track cyclist. He competed in the sprint event at the 2012 UCI Track Cycling World Championships.
References
External links
Profile at cyclingarchives.com
Category:1989 births
Category:Living people
Category:American track cyclists
Category:American male cyclists
Category:Place of birth missing (living people)
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UNPUBLISHED
UNITED STATES COURT OF APPEALS
FOR THE FOURTH CIRCUIT
No. 12-1195
MARY T. LACLAIR, Individually and as Personal
Representative of the Estate of Cameron J. LaClair, Jr.,
Plaintiff – Appellant,
v.
SUBURBAN HOSPITAL, INCORPORATED,
Defendant – Appellee,
and
PHYSICAL THERAPY AND SPORTS MEDICINE BINH M. TRAN, P.T., INC.;
CATHERINE L. COELHO, M.P.T., f/k/a Catherine Chamberlain;
SUBURBAN HOSPITAL FOUNDATION, INC.; SUBURBAN HOSPITAL HEALTHCARE
SYSTEM, INC.,
Defendants.
Appeal from the United States District Court for the District of
Maryland, at Greenbelt. Peter J. Messitte, Senior District
Judge. (8:10-cv-00896-PJM)
ARGUED: January 31, 2013 Decided: April 15, 2013
Before TRAXLER, Chief Judge, and KEENAN, and THACKER, Circuit
Judges.
Affirmed by unpublished per curiam opinion.
ARGUED: Patrick Michael Regan, REGAN ZAMBRI LONG & BERTRAM,
Washington, D.C., for Appellant. Michael E. von Diezelski,
ADELMAN, SHEFF & SMITH, LLC, Annapolis, Maryland, for Appellee.
ON BRIEF: Jacqueline T. Colclough, REGAN ZAMBRI LONG & BERTRAM,
Washington, D.C., for Appellant.
Unpublished opinions are not binding precedent in this circuit.
2
PER CURIAM:
Mary T. LaClair, individually and as personal
representative of the estate of her husband, Cameron J. LaClair,
Jr., appeals the district court’s order finding that the
Appellee, Suburban Hospital, Inc. (“Suburban”), and Physical
Therapy and Sports Medicine (“PTSM”), were joint tortfeasors
with respect to her husband’s injuries sustained while he was a
patient at Suburban. Mr. LaClair was first injured while
receiving physical therapy at PTSM. After undergoing surgery at
Suburban for that injury, he was further injured by the actions
of Suburban’s patient care technicians. Suburban asks us to
affirm the district court’s conclusion that it is a joint
tortfeasor with PTSM because its actions did not constitute a
superseding cause of harm to Mr. LaClair.
In unraveling this appeal, Maryland law directs us to
several provisions of the Restatement (Second) of Torts, each of
which is grounded in the idea that an intervening act is not a
superseding cause if it was foreseeable at the time of the
primary negligence. Because the harm and injuries sustained at
Suburban were foreseeable consequences of the alleged negligence
of PTSM, Suburban’s actions were not a superseding cause of Mr.
LaClair’s injuries. Thus, Suburban and PTSM are joint
tortfeasors, and we affirm.
3
I.
A.
On November 1, 2007, Mr. LaClair, a “vibrant former
CIA officer” in his mid-80s, J.A. 211, 1 sustained an injury while
receiving physical therapy at the PTSM facility (the “November 1
incident”). He was attempting to secure himself in a piece of
exercise equipment and fell onto the floor, while his physical
therapist had stepped away. He was taken by ambulance to
Suburban, where he was diagnosed with a cervical fracture and
dislocation.
Dr. Alexandros Powers, a neurosurgeon, performed
surgery on Mr. LaClair on November 3, 2007. The surgery
entailed Dr. Powers inserting screws and rods to secure Mr.
LaClair’s spine. According to Dr. Powers, the surgery “was
successful and proceeded without complication, and Mr. LaClair’s
prognosis at that time included a complete and total recovery
free from future cervical spine surgery.” J.A. 227.
Dr. Powers stated that, as of the morning of November
6, 2007, Mr. LaClair was “recovered and was to be discharged
[from Suburban] to a rehabilitation facility” the next day, and
“there was no plan or expectation for subsequent cervical spine
1
Citations to the “J.A.” refer to the Joint Appendix filed
by the parties in this appeal.
4
surgeries due to the success of the November 3 surgery[.]” J.A.
228. Later on November 6, Mr. LaClair was transferred from ICU
to a regular room, and his catheter was removed. He needed
assistance using the bathroom, and, after Mrs. LaClair called
several times for assistance, two patient care technicians
responded. Mr. LaClair used the bathroom, and the patient care
technicians attempted to reposition him in his hospital bed.
Although Suburban claims Mrs. LaClair “resort[s] to
hyperbole when referring to the conduct of November 6,” and the
patient care technicians, while perhaps negligent, were
“performing their normal duties when they were aiding Mr.
LaClair and repositioning him in bed,” Br. of Appellee 6, Mrs.
LaClair views the incident as out of bounds because her
husband’s “head was violently pushed against the side rail of
the bed and he cried out in pain,” Br. of Appellant 4. Mrs.
LaClair testified that one of the patient care technicians was
“very rough,” explaining, “her motions were gross motions. They
weren’t careful motions. And I thought, with somebody with a
broken neck, I think I’d be careful, but there was none of
that.” J.A. 362-63 (the “November 6 incident”).
There is no dispute that Mr. LaClair sustained
additional injuries as a result of the November 6 incident. Dr.
Powers examined Mr. LaClair and found “a fracture of the C7
endplate, dislocation at C6/C7, dislodging of the screws placed
5
in previous surgery, ligament damage and hemorrhage, nerve root
injury at the level of C7 and C8 and spinal cord injury.” J.A.
228. He determined Mr. LaClair could no longer be discharged on
November 7 as previously scheduled, but rather, needed to
undergo an additional surgery on November 8. Mr. LaClair later
underwent a third surgery on February 6, 2008, at Georgetown
University Hospital. He spent nearly five months hospitalized,
underwent plaster casting of his cervical spine, developed
bedsores, and ultimately required a feeding tube.
Mrs. LaClair presented evidence to the district court
that as a result of the November 6 incident, Mr. LaClair’s
medical bills totaled over $1.05 million and had a projected
future cost of $900,000. Another physician testified that
absent the November 6 incident, his medical and rehabilitation
expenses would have been only $75,000 to $125,000.
B.
The LaClairs filed two separate lawsuits: first,
against PTSM for injuries stemming from the November 1 incident
(filed March 19, 2009) (the “PTSM lawsuit”), and second, against
Suburban for “separate and distinct” injuries stemming from the
6
November 6 incident (filed April 15, 2010) (the “Suburban
lawsuit”). 2
The PTSM lawsuit alleged that PTSM was responsible for
not only the injuries and damages incurred from the November 1
incident at PTSM’s facility, but also the injuries and damages
incurred from the November 6 incident at Suburban. See J.A. 48
(PTSM Complaint) (“Plaintiff was taken via ambulance to Suburban
[] where he was diagnosed with a cervical fracture and
dislocation. Plaintiff remained at Suburban until November 13,
2007, where he underwent two surgical procedures to repair his
cervical fracture, among other things.”). During discovery,
however, Dr. Powers testified on January 5, 2010, that the
injuries stemming from the November 1 incident were “separate,
distinct, and divisible” from those sustained by the November 6
incident. Id. at 229, 262-329.
Subsequently, the LaClairs settled with PTSM for $1
million on March 5, 2010. The Settlement Agreement specifically
recognized that the LaClairs would be pursuing separate claims
against Suburban, in connection with the November 6 incident
alone:
2
Mr. LaClair passed away on November 4, 2011, during the
course of this litigation. Mrs. LaClair took over as personal
representative of his estate and was substituted as Plaintiff on
January 25, 2012.
7
In any future action against [Suburban], the
plaintiffs agree to file a pre-trial motion with the
court attempting to establish that the conduct of
Suburban . . . constituted superintervening
negligence, and that these defendants are not joint
tortfeasors with Suburban[.] The purpose of this
requirement is to obviate the need for [PTSM] to be
named as [a] part[y] in any future litigation.
J.A. 179.
The Suburban lawsuit, filed about six weeks after the
PTSM settlement, alleges that Mr. LaClair suffered injuries from
the November 6 incident that were separate and distinct from
those of the November 1 incident. This litigation settled on
May 31, 2011. Pursuant to the Settlement Agreement between the
LaClairs and Suburban, however, the parties agreed to submit to
the district court the question of whether PTSM and Suburban
were joint tortfeasors in connection with the November 6
incident, or whether those injuries were separate and distinct
such that Suburban alone would be liable. Pursuant to the
Settlement Agreement, Suburban agreed to make an initial
$650,000 payment to the LaClairs and further agreed to make an
additional payment of $600,000 in the event that the court found
PTSM and Suburban were not joint tortfeasors as to the November
6 incident.
C.
In accord with the PTSM Settlement Agreement, the
LaClairs filed a pre-trial motion in the Suburban lawsuit on
8
June 10, 2011, asking for judicial determination that Suburban
was a “successive tortfeasor” and therefore, not entitled to
joint tortfeasor credit for the November 6 incident. J.A. 140. 3
That same day, Suburban filed a memorandum explaining why it
should bear joint tortfeasor status with PTSM.
The district court held a motions hearing on January
20, 2012, and decided that Suburban was indeed a joint
tortfeasor with PTSM such that Mrs. LaClair could not recover
additional damages. The district court explained,
[T]his was not highly extraordinary. That this
kind of thing could well have happened, even if the
doctors did not see it or had seen it themselves. But
a reasonable man knowing what they knew at the time
would conclude that this sort of thing might happen.
. . . I am persuaded by the fact that if what happens
is reasonably close to the reason for the initial
hospitalization, which is what this was, then you
really do have a kind of a continuous flow here, and
whatever negligence you have is really part and parcel
of the initial negligence, too.
And so I do conclude on these facts that the
liability of the – the defendant, Suburban Hospital,
is joined and not independent.
J.A. 771. The court entered a short, one-page order to this
effect on January 24, 2012, naming Suburban as a joint
tortfeasor “for reasons stated in the record.” Id. at 797. It
is from that order that Mrs. LaClair appeals.
3
Solely for purposes of the motion on the causation issue,
Suburban conceded that it was negligent on November 6, 2007, but
it continued to dispute all issues of causation and damages.
9
II.
The parties submit that the district court’s order is
reviewed for clear error. However, this analysis necessarily
involves deciding whether the district court correctly applied
Maryland law, and thus, we approach this appeal “by inspecting
factual findings for clear error and examining de novo the legal
conclusions derived from those facts.” F.C. Wheat Mar. Corp. v.
United States, 663 F.3d 714, 723 (4th Cir. 2011). A finding is
clearly erroneous when “although there is evidence to support
it, the reviewing court on the entire evidence is left with the
definite and firm conviction that a mistake has been
committed.” Anderson v. City of Bessemer City, N.C., 470 U.S.
564, 573 (1985) (internal quotation marks omitted).
Because this case is in federal court based on
diversity jurisdiction, the substantive law of the forum state —
in this case, Maryland — applies. See Erie R.R. v. Tompkins,
304 U.S. 64, 78 (1938). We should determine:
how the [Court of Appeals of Maryland] would rule. If
th[at] [court] has spoken neither directly nor
indirectly on the particular issue before us, we are
called upon to predict how that court would rule if
presented with the issue. In making that prediction,
we may consider lower court opinions in [Maryland],
the teachings of treatises, and the practices in other
states.
10
Twin City Fire Ins. Co. v. Ben Arnold-Sunbelt Beverage Co., 433
F.3d 365, 369 (4th Cir. 2005) (internal quotation marks and
citations omitted).
III.
A.
PTSM will not be jointly liable for the November 6
incident “if it appears highly extraordinary and unforeseeable
that the plaintiffs’ injuries [on November 6] occurred as a
result of [PTSM’s] alleged tortious conduct.” Pittway Corp. v.
Collins, 973 A.2d 771, 788 (Md. 2009). Accordingly, PTSM avoids
liability for the November 6 incident “only if the intervening
negligent act,” i.e., Suburban’s conduct, “is considered a
superseding cause of the harm to” Mr. LaClair. Id. at 789; see
also Morgan v. Cohen, 523 A.2d 1003, 1004-05 (Md. 1987) (“It is
a general rule that a negligent actor is liable not only for
harm that he directly causes but also for any additional harm
resulting from normal efforts of third persons in rendering aid,
irrespective of whether such acts are done in a proper or a
negligent manner.”).
Maryland courts (and federal district courts sitting
in diversity) have addressed the superseding cause issue with
varying results. Pittway is the seminal Maryland case on
superseding cause, providing a framework for analyzing an
argument that an intervening act cuts off the liability of an
11
original tortfeasor. The Court of Appeals of Maryland
explained:
The defendant is liable where the intervening causes,
acts, or conditions were set in motion by his earlier
negligence, or naturally induced by such wrongful act
. . . or even it is generally held, if the intervening
acts or conditions were of a nature, the happening of
which was reasonably to have been anticipated[.]
Pittway, 973 A.2d at 789 (internal quotation marks and
alteration omitted). Pittway recognizes that Section 442 of the
Restatement (Second) of Torts establishes the test applied in
Maryland courts for analyzing superseding cause:
The following considerations are of importance in
determining whether an intervening force is a
superseding cause of harm to another:
(a) the fact that its intervention brings
about harm different in kind from that which
would otherwise have resulted from the
actor’s negligence;
(b) the fact that its operation or the
consequences thereof appear after the event
to be extraordinary rather than normal in
view of the circumstances existing at the
time of its operation;
(c) the fact that the intervening force is
operating independently of any situation
created by the actor’s negligence, or, on
the other hand, is or is not a normal result
of such a situation;
(d) the fact that the operation of the
intervening force is due to a third person’s
act or his failure to act;
(e) the fact that the intervening force is
due to an act of a third person which is
wrongful toward the other and as such
12
subjects the third person to liability to
him;
(f) the degree of culpability of a wrongful
act of a third person which sets the
intervening force in motion.
Restatement (Second) of Torts § 442 (1965); Pittway, 973 A.2d at
789.
B.
We conclude that the district court did not err in
finding that Suburban and PTSM were joint tortfeasors.
1.
The majority of the Restatement Section 442 factors
weigh in favor of a conclusion that Suburban and PTSM were joint
tortfeasors.
a.
As to factor (a), above, Mrs. LaClair attempts to show
that the injuries sustained on November 6 were “separate and
distinct” from those sustained on November 1, and thus,
“different in kind.” See Br. of Appellant 3-9. We first note
that we would be hard-pressed to find a case regarding
subsequent negligent medical care in which there was not a
“separate and distinct” injury after the injury caused by the
initial actor’s negligence. This, alone, does not lead us to
the conclusion that the negligent medical care is a superseding
cause of harm. See Underwood-Gary v. Mathews, 785 A.2d 708, 713
13
(Md. 2001) (“[W]hen a physician negligently treats the
plaintiff’s injuries, the physician becomes liable to the
plaintiff to the extent of the harm caused by the physician’s
negligence. Thus, the physician’s negligent treatment is a
subsequent tort for which both the doctor and the original
tortfeasor are jointly liable.” (internal citations omitted)).
In any event, the harm brought about by the November 6 incident
was not so different from the type of harm that is likely to
result from an 86-year-old man’s fall from a piece of exercise
equipment, even assuming, as Mrs. LaClair would have us do, that
a severe spinal cord injury resulted from Mr. LaClair’s
repositioning in his bed. For these reasons, factor (a) weighs
in favor of Suburban.
b.
In addressing factor (b), the Restatement directs us
to look to Restatement (Second) of Torts § 435(2), Comments (c)
and (d). Comment (c) provides, in part, “Where it appears to
the court in retrospect that it is highly extraordinary that an
intervening cause has come into operation, the court may declare
such a force to be a superseding cause.” Restatement (Second)
of Torts § 435(2) cmt. c (1965). Comment (d) provides, in part,
“The court’s judgment as to whether the harm is a highly
extraordinary result is made after the event with the full
knowledge of all that has happened. This includes those
14
surroundings of which at the time the actor knew nothing but
which the course of events discloses to the court.” Id. cmt. d.
Comment (d) continues:
[The court] also follows the effects of the actor’s
negligence as it passes from phase to phase until it
results in harm to the plaintiff. In advance, the
actor may not have any reason to expect that any
outside force would subsequently operate and change
the whole course of events from that which it would
have taken but for its intervention. None the less,
the court, knowing that such a force has intervened,
may see nothing extraordinary either in its
intervention or in the effect which it has upon the
further development of the injurious results of the
defendant’s conduct. This is particularly important
where the intervening force is supplied by the act of
a human being . . . , which is itself a reaction to
the stimulus of a situation for which the actor is
responsible.
Id.
Mrs. LaClair presents testimony from three
neurosurgeons that the “application of [the patient care
technicians’] force to the body of an elderly, post-operative
cervical spine patient . . . had never before been witnessed or
known to them in all their years of practice as
Neurosurgeons[.]” Br. of Appellant 27 (citing J.A. 190, 222,
229). However, as explained by Comment (d) above, PTSM may have
had no reason to expect that Mr. LaClair would be injured by
being repositioned in his hospital bed, but the proper way to
view the situation is after-the-fact: “knowing that such a
15
force has intervened.” Restatement (Second) Torts § 435 cmt. d
(emphasis added).
For example, in Henley v. Prince George’s Cnty., the
Court of Appeals of Maryland explained the difference between
foreseeability when considering the existence of a duty and, as
here, causation: “Foreseeability as a factor in the
determination of the existence of a duty involves a prospective
consideration of the facts existing at the time of the negligent
conduct. Foreseeability as an element of proximate cause
permits a retrospective consideration of the total facts of the
occurrence[.]” 503 A.2d 1333, 1341 (Md. 1986) (emphases added).
Viewing the facts of this case retrospectively, there is “an
appropriate nexus” between the November 1 incident and injuries
and the November 6 incident and injuries such that it is “at
least a permissible conclusion” that Mr. LaClair’s already-
injured spine would be further injured by being positioned into
a hospital bed. Id. at 1342.
Again, we agree with the district court that
Suburban’s actions were not “so extraordinary as to bring about
a conclusion of separate intervening cause.” J.A. 766. Thus,
factor (b) also weighs in favor of Suburban.
16
c.
Considering the cross-referencing set forth in
Restatement (Second) Section 442, factors (c), (e), and (f) 4 boil
down to the same core inquiries: whether Suburban’s actions
were “a normal consequence of a situation created by the actor’s
negligent conduct,” 5 and whether the manner in which the
intervening act was done was “extraordinarily negligent.”
Restatement (Second) Torts §§ 443, 447(c) (1965).
First, clearly, Mr. LaClair would not have sustained
the injuries on November 6 if PTSM’s negligence had not put him
in the hospital in the first place. 6 And the district court
4
As to factor (d), the district court dismissed this factor
as irrelevant to the inquiry, but it only appeared to analyze
the “failure to act” portion of § 442(d). See J.A. 767-68.
While this may have been legal error, even assuming factor (d)
weighs in favor of Mrs. LaClair, the balance of the factors
nonetheless weighs in favor of Suburban.
5
The comments to factor (c) explain that the “situation
created by the actor’s negligence” means any situation that the
original tortfeasor’s actions were a substantial factor in
bringing about. See Restatement (Second) of Torts §§ 447(c),
442(c) cmt. d.
6
Indeed, the LaClairs themselves believed the November 6
incident to be a foreseeable consequence of the November 1
incident. They recognized as much in their initial complaint
against PTSM, which sought to hold PTSM liable for “two surgical
procedures” at Suburban. J.A. 48 (emphasis added). In
addition, on July 12, 2009, the LaClairs answered
interrogatories and listed the following as caused by the PTSM’s
negligence: admission to Suburban from November 1 to November
13, 2007; admission to the rehabilitation center from November
13 to November 30; admission to Georgetown University for
(Continued)
17
found, “the act, . . . the putting back in bed is not itself
extraordinary.” J.A. 767. Mrs. LaClair’s attorney
agreed. See id. at 709 (The Court: “[T]he objective anyway was
to put this man back in bed. That’s not unforeseeable; correct?
Mr. Regan: Yes.”). The district court did not err in finding
that it is a “normal consequence,” (i.e., foreseeable) that a
cervical spine patient might sustain additional spinal injuries
at the hands of medical professionals.
As to the manner in which the negligent act was done,
we should consider the injuries and the degree of culpability of
the patient care technicians. Even if the patient care
technicians were “very rough,” J.A. 362, that does not quite get
us to the level of “extraordinarily negligent.” Restatement
(Second) of Torts § 447(c). Indeed, Maryland courts have held
that original tortfeasors are liable for more significant harm
inflicted by intervening negligent medical
professionals. See Underwood-Gary, 785 A.2d at 713 (“[An]
original tortfeasor is liable for additional harm caused by a
treating physician’s improper diagnosis and unnecessary
surgery[.] This rule is based on the premise that the negligent
actor, by his or her conduct, has placed the plaintiff in a
surgery from February 5 to February 25, 2008; and home nursing
care from April 2008 to July 2009. See id. at 64-78.
18
position of danger and should answer for the risks inherent in
treatment and rendering aid.” (citing Restatement (Second) of
Torts § 457 cmt. c, illus. 1)); Richards v. Freeman, 179 F.
Supp. 2d 556, 560-61 (D. Md. 2002) (where physicians negligently
performed surgeries that left car accident victim with a right
arterial tear in her heart, finding physicians and original
defendant driver to be “joint” yet “subsequent tortfeasors”
under Maryland’s Uniform Contribution Among Tort-Feasors Act
(UCATA)); see also Morgan, 523 A.2d at 1008 (stating that under
the UCATA, an original tortfeasor and a negligent health care
provider could be considered concurrent tortfeasors concurring
in producing the additional harm).
Kyte v. McMillion, 259 A.2d 532 (Md. 1969), cited by
Mrs. LaClair, does not change this result. There, a young woman
was involved in a car wreck due to a negligent driver, and she
was taken to the hospital and treated for broken bones. Upon
admission to the hospital, a physician ordered a blood
transfusion, but the nurse used the wrong type of
blood. See id. at 533. As a result of this mistake, the
plaintiff suffered “bleak prospects of future pregnancies” and
was projected to have “difficult gestation from both an
emotional and physical point of view.” Id. The plaintiff filed
suit against the hospital first, ultimately reaching an
agreement and signing a release as to damages stemming only from
19
the blood transfusion. See id. at 533-34. Later, when the
plaintiff filed suit against the allegedly negligent driver,
McMillion, the court held that McMillion was not included in the
release and thus, the damages awarded to the plaintiff from the
hospital should not be credited to McMillion. Id. at 543.
Notably, the Maryland Court of Special Appeals has
limited this case to its facts as “the Court [in Kyte] was
careful to point out that the injuries [broken bones and
inability to have children] were peculiarly separate and
divisible[.]” Sullivan v. Miller, 337 A.2d 185, 191 (Md. Ct.
Spec. App. 1975). Even the Kyte court itself declared, “It
should be understood . . . that the decision announced herein
goes no further than the unusual facts and circumstances of this
case.” See Kyte, 259 A.2d at 543. 7
Therefore, we cannot say that the negligence of the
patient care technicians, either in manner or consequence, was
7
In this appeal, Suburban also contends that the settlement
with PTSM already took into account the damages arising from the
November 6 incident, and points to the LaClairs’ answers to
interrogatories on July 12, 2009, in the PTSM lawsuit. See
supra, note 7. However, while this argument may have some
merit, we do not rely on it because it appears that the LaClairs
shifted gears in the middle of their litigation with PTSM (and
after the interrogatory answers were filed) due to the testimony
of Dr. Powers. Moreover, reliance on this basis is unnecessary
given the weight of other factors in favor of Suburban.
20
abnormal or extraordinary. Thus, factors (c), (e), and (f)
weigh in favor of Suburban.
2.
Examining the Restatement Section 442 factors does not
end our inquiry. The Court of Appeals of Maryland further
explains that Section 447 of the Restatement (Second) of Torts
illuminates these factors:
“The fact that an intervening act of a third person is
negligent in itself or is done in a negligent manner
does not make it a superseding cause of harm to
another which the actor’s negligent conduct is a
substantial factor in bringing about, if
(a) the actor at the time of his negligent
conduct should have realized that a third
person might so act, or
(b) a reasonable man knowing the situation
existing when the act of the third person
was done would not regard it as highly
extraordinary that the third person had so
acted, or
(c) the intervening act is a normal
consequence of a situation created by the
actor’s conduct and the manner in which it
is done is not extraordinarily negligent.”
Pittway, 973 A.2d at 789 (quoting Restatement (Second) of Torts
§ 447). Thus, “a superseding cause arises primarily when
unusual and extraordinary independent intervening negligent acts
occur that could not have been anticipated by the original
tortfeasor.” Id. (internal quotation marks omitted).
Therefore, courts should look to both the foreseeability of the
21
harm suffered by the plaintiff, as well as the foreseeability of
the intervening act itself. See id. at 792.
Any doubt that the Restatement Section 442 factors
weigh in favor of Suburban is resolved by an analysis of Section
447: PTSM should have realized that an elderly man injured by a
fall from its own exercise equipment would have to go to the
hospital, would receive medical care, and may possibly
experience negligent medical care there. Mr. LaClair’s ultimate
injuries and the manner in which they occurred were not
extraordinary, nor were these unfortunate consequences
unforeseeable.
IV.
For the foregoing reasons, the judgment of the
district court is
AFFIRMED.
22
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Topic of the Month
Micronutrient Deficiencies Throughout the World
April 24, 2017
Julia Bird
The discovery of vitamins a little over one century ago was incredibly important for the field of nutrition (1). At last, we had found the key to preventing vitamin deficiencies! Knowing about the vitamins meant that medical questions that had puzzled humans for centuries – why does fresh citrus fruit cure scurvy, but a syrup made from the juice does not? – could be reliably answered (2). Despite this grand leap in the understanding of nutrition, however, vitamin and mineral deficiencies still plague us around the globe. While we know in general which micronutrients and how much most people need to stay healthy, making sure that everyone has access to micronutrients is more problematic. Each region in the world has its own nutrition concerns. The problem of “hidden hunger,” when people may get enough calories but the micronutrient content of their diet is lacking, is improving but there is still a long way to go (3). Which micronutrient deficiencies are found throughout the world?
South Asia, East Asia and the Pacific
South Asia, East Asia and the Pacific, comprising countries such as China, Indonesia, Vietnam, India, Bangladesh and Malaysia, have mostly showed a large improvement in micronutrient status in their population over the past decades (3). General programs to support economic growth have raised the standard of living for many people living in developing Asian countries, and staple food fortification has been able to reduce specific micronutrient deficiencies such as iodine and iron. Despite these gains, deficiencies in iron and vitamin A are still prevalent in some risk groups: 27 million school age children, 7.5 million pregnant women and 96 million non-pregnant women in the region are affected by anemia, while 13 percent of pre-school children and 21 percent of pregnant women are affected by vitamin A deficiency (4).
Eastern Europe and Central Asia
Low- and middle-income countries in Europe and Central Asia have shown a modest improvement in reducing micronutrient deficiencies (3). In this region, however vitamins A and D, iodine, iron, zinc, folate and thiamine are marked as micronutrients of special concern (5). The rates of deficiencies vary depending on the country, as local laws, the economic situation, cultural trends and the environment can affect supply of vitamins and minerals. In particular, iodine deficiency in central Europe is common, and is very much impacted by national policies regarding iodine fortification (6). Seasonable variations in the availability of different foods can affect dietary intakes and nutrient status in Europe. For example, more fruits and vegetables are eaten in the summer and autumn months, leading to a better folate status in the general population in Slovakia (7). Certain vulnerable populations are at greater risk of micronutrient deficiency. These groups include pregnant women and young children, the elderly, people with a low socioeconomic status, and those affected by chronic disease (8-10).
Latin America and the Caribbean
Micronutrient nutrition in Latin American and the Caribbean has improved in the past few years, and rates of deficiency tend to be the lowest of the low- and middle-income countries (3). In fact, all countries in this area of the world reduced their prevalence of hidden hunger in the period 1995-2011 (3). Despite these relative improvements, micronutrient deficiencies have an impact on health for a significant proportion of people in this area of the world. Iron deficiency anemia and zinc deficiency remain a problem for women of childbearing age and children aged under 6 years (11, 12). While vitamin B12 deficiency is not monitored as well as other micronutrients, an incidence greater than 10 percent is reported for vulnerable groups in some countries, such as women aged 13 to 49 in Colombia, and children aged 6 months to 5 years in Guatemala. Rates of vitamin and mineral deficiencies can vary greatly between countries. For example, vitamin A deficiency in young children has been virtually eradicated in Guatemala and Nicaragua, yet is a severe public health problem in Colombia, Mexico, and Haiti (13).
One micronutrient success story has been the use of folic acid fortification to improve folate status and reduce the occurrence of neural tube defects in Latin American and the Caribbean. The introduction of mandatory folic acid fortification for almost all countries has led to a dramatic reduction in the percentage of the population with folate deficiency (14). In turn, surveillance of neural tube defects shows a decrease of one- to two-thirds compared to the pre-fortification period (15). Carefully designed interventions such as staple food fortification, and that focus on vulnerable groups, are needed to further improve micronutrient nutrition in Latin America and the Caribbean (12).
Middle East and North Africa
The nutrition situation in the Middle East and North Africa has improved substantially in the last decades. Many countries are undergoing an advanced nutrition transition, whereby there is a modest reduction in micronutrient malnutrition, while rates of overweight and obesity are rapidly increasing (16). Unfortunately, the complex security situation in several countries (Afghanistan, Libya, Somalia, Sudan, and Syria) has further increased food insecurity, leading to widespread acute and chronic under nutrition, especially in young children and pregnant women (16).
The vitamins and minerals most often found to be deficient in nutritional surveys in the region include calcium, iodine, iron, vitamin A, vitamin D, and folate (16). Food fortification programs in the area are patchy, and while many countries have dietary guidelines for individuals that promote a healthful diet, their uptake has been limited (16). Anemia is the most prevalent micronutrient deficiency in the Middle East, and can affect more than half of some countries. Vitamin D deficiency has been reported for many countries despite plentiful sunshine; this relates to few dietary sources and wearing traditional clothing that blocks sunlight from reaching the skin.
Several countries including Jordan, Egypt, the United Arab Emirates, Oman and Kuwait have mandatory wheat flour fortification policies in place. All these countries fortify with folic acid and iron, and some include zinc and other vitamins as well. However, rice and maize are also staple foods in these countries and are not fortified, hence micronutrient deficiencies remain widespread despite the existence of fortification.
West, Central and Sub-Saharan Africa
The majority of countries showing an increase in hidden hunger over the past years were located in West, Central and Southern Africa. These results do not bode well for the social and economic development in countries affected by a high prevalence of under nutrition (3). The causes of micronutrient deficiencies in Africa are multi-factorial and relate to poor economic development, unstable governments that neglect critical investments into education, health and infrastructure, and food insecurity related to harsh agricultural environments (17). The high prevalence of vitamin and mineral deficits, such as iron deficiency anemia, zinc deficiency and vitamin A deficiency will only be reduced when the underlying causes of poverty are alleviated.
In some countries in southern Africa, commitment to improving the nutritional status of the population has shown positive results. For example, a mandatory fortification program for maize and wheat flour in South Africa has been effective in improving vitamin and mineral intakes (18, 19). There is still room for improvement in South Africa, however; it is one of 48 countries worldwide prioritized as having an “unfinished fortification” program (20).
High-Income Countries
While developing countries bear the greatest burden of micronutrient deficiencies around the world, they still exist in high-income countries. The considerable resources of high-income countries mean that the micronutrient status of their populations is studied in greater detail than the rest of the world and give a better estimate of the true rate. Comprehensive a representative analyses of U.S. populations find that 5 percent or more is affected by deficiencies in vitamins B6, C and D, and almost 10 percent of women of child-bearing age are affected by low body iron (21). In Europe, international comparisons find that at least half of certain population groups do not meet recommendations. Intakes of thiamine in Italian women, B6 in women from many countries, and vitamin C in Scandinavian men and male smokers are clearly too low (22, 23). Also, intakes of both vitamin D and E are low for most people living in Northern, Western and Southern Europe (22, 23). A lack of education about nutrient-dense diets and poor food choices are a major contributor to micronutrient deficiencies in high-income countries.
Food and Agriculture Organization of the United Nations. Addressing social and economic burden of malnutrition through nutrition-sensitive agricultural and food policies in the region of Europe and Central Asia. 2015.
Papathakis PC, Pearson KE. Food fortification improves the intake of all fortified nutrients, but fails to meet the estimated dietary requirements for vitamins A and B6, riboflavin and zinc, in lactating South African women. Public Health Nutr 2012;15(10):1810-7. doi: 10.1017/S1368980012003072
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List of spouses of Prime Ministers of Japan
The is the wife or husband of the Prime Minister of Japan.
Role and duties
The role of the Prime Ministerial Consort is not an official office and as such they are not given a salary or official duties.
Spouse of the Prime Ministers of the Empire of Japan (1885–1947)
Spouse of the Prime Ministers during the Meiji period (1885–1912)
Under the Meiji Emperor
Spouse of the Prime Ministers during the Taishō period (1912–1926)
Under the Taishō Emperor
Spouse of the Prime Ministers during the Shōwa period (1926–1947)
Under the Shōwa Emperor
Spouse of the Prime Ministers of the State of Japan (1947–present)
Spouse of the Prime Ministers during the Shōwa period (1947–1989)
Under the Shōwa Emperor
Spouse of the Prime Ministers during the Akihito period (1989–present)
Under Emperor Akihito
References
*
*Spouse
Japan
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Preprint hep-ph/0006089
[Improved Conformal Mapping of the Borel Plane]{}
U. D. Jentschura and G. Soff
[*Institut für Theoretische Physik, TU Dresden, 01062 Dresden, Germany*]{}\
[**Email:**]{} [email protected], [email protected]
The conformal mapping of the Borel plane can be utilized for the analytic continuation of the Borel transform to the entire positive real semi-axis and is thus helpful in the resummation of divergent perturbation series in quantum field theory. We observe that the convergence can be accelerated by the application of Padé approximants to the Borel transform expressed as a function of the conformal variable, i.e. by a combination of the analytic continuation via conformal mapping and a subsequent numerical approximation by rational approximants. The method is primarily useful in those cases where the leading (but not sub-leading) large-order asymptotics of the perturbative coefficients are known.
11.15.Bt, 11.10.Jj General properties of perturbation theory;\
Asymptotic problems and properties
The problem of the resummation of quantum field theoretic series is of obvious importance in view of the divergent, asymptotic character of the perturbative expansions [@LGZJ1990; @ZJ1996; @Fi1997]. The convergence can be accelerated when additional information is available about large-order asymptotics of the perturbative coefficients [@JeWeSo2000]. In the example cases discussed in [@JeWeSo2000], the location of several poles in the Borel plane, known from the leading and next-to-leading large-order asymptotics of the perturbative coefficients, is utilized in order to construct specialized resummation prescriptions. Here, we consider a particular perturbation series, investigated in [@BrKr1999], where only the [*leading*]{} large-order asymptotics of the perturbative coefficients are known to sufficient accuracy, and the subleading asymptotics have – not yet – been determined. Therefore, the location of only a single pole – the one closest to the origin – in the Borel plane is available. In this case, as discussed in [@CaFi1999; @CaFi2000], the (asymptotically optimal) conformal mapping of the Borel plane is an attractive method for the analytic continuation of the Borel transform beyond its circle of convergence and, to a certain extent, for accelerating the convergence of the Borel transforms. Here, we argue that the convergence of the transformation can be accelerated further when the Borel transforms, expressed as a function of the conformal variable which mediates the analytic continuation, are additionally convergence-accelerated by the application of Padé approximants.
First we discuss, in general terms, the construction of the improved conformal mapping of the Borel plane which is used for the resummation of the perturbation series defined in Eqs. (\[gammaPhi4\]) and (\[gammaYukawa\]) below. The method uses as input data the numerical values of a finite number of perturbative coefficients and the leading large-order asymptotics of the perturbative coefficients, which can, under appropriate circumstances, be derived from an empirical investigation of a finite number of coefficients, as it has been done in [@BrKr1999]. We start from an asymptotic, divergent perturbative expansion of a physical observable $f(g)$ in powers of a coupling parameter $g$, $$\label{power}
f(g) \sim \sum_{n=0}^{\infty} c_n\,g^n\,,$$ and we consider the generalized Borel transform of the $(1,\lambda)$-type (see Eq. (4) in [@JeWeSo2000]), $$\label{BorelTrans}
f^{(\lambda)}_{\rm B}(u) \; \equiv \;
f^{(1,\lambda)}_{\rm B}(u) \; = \;
\sum_{n=0}^{\infty} \frac{c_n}{\Gamma(n+\lambda)}\,u^n\,.$$ The full physical solution can be reconstructed from the divergent series (\[power\]) by evaluating the Laplace-Borel integral, which is defined as $$\label{BorelIntegral}
f(g) = \frac{1}{g^\lambda} \,
\int_0^\infty {\rm d}u \,u^{\lambda - 1} \,
\exp\bigl(-u/g\bigr)\,
f^{(\lambda)}_{\rm B}(u)\,.$$ The integration variable $u$ is referred to as the Borel variable. The integration is carried out either along the real axis or infinitesimally above or below it (if Padé approximants are used for the analytic continuation, modified integration contours have been proposed [@Je2000]). The most prominent issue in the theory of the Borel resummation is the construction of an analytic continuation for the Borel transform (\[BorelTrans\]) from a finite-order partial sum of the perturbation series (\[power\]), which we denote by $$\label{PartialSum}
f^{(\lambda),m}_{\rm B}(u) =
\sum_{n=0}^{m} \frac{c_n}{\Gamma(n+\lambda)}\,u^n\,.$$ The analytic continuation can be accomplished using the direct application of Padé approximants to the partial sums of the Borel transform $f^{(\lambda),m}_{\rm B}(u)$ [@BrKr1999; @Je2000; @Raczka1991; @Pi1999] or by a conformal mapping [@SeZJ1979; @LGZJ1983; @GuKoSu1995; @CaFi1999; @CaFi2000]. We now assume that the [*leading*]{} large-order asymptotics of the perturbative coefficients $c_n$ defined in Eq. (\[power\]) is factorial, and that the coefficients display an alternating sign pattern. This indicates the existence of a singularity (branch point) along the negative real axis corresponding to the leading large-order growth of the perturbative coefficients, which we assume to be at $u=-1$. For Borel transforms which have only a single cut in the complex plane which extends from $u=-1$ to $u=-\infty$, the following conformal mapping has been recommended as optimal [@CaFi1999], $$\label{DefZ}
z = z(u) = \frac{\sqrt{1+u}-1}{\sqrt{1+u}+1}\,.$$ Here, $z$ is referred to as the conformal variable. The cut Borel plane is mapped unto the unit circle by the conformal mapping (\[DefZ\]). We briefly mention that a large variety of similar conformal mappings have been discussed in the literature .
It is worth noting that conformal mappings which are adopted for doubly-cut Borel planes have been discussed in [@CaFi1999; @CaFi2000]. We do not claim here that it would be impossible to construct conformal mappings which reflect the position of more than two renormalon poles or branch points in the complex plane. However, we stress that such a conformal mapping is likely to have a more complicated mathematical structure than, for example, the mapping defined in Eq. (27) in [@CaFi1999]. Using the alternative methods described in [@JeWeSo2000], poles (branch points) in the Borel plane corresponding to the subleading asymptotics can be incorporated easily provided their position in the Borel plane is known. In a concrete example (see Table 1 in [@JeWeSo2000]), 14 poles in the Borel plane have been fixed in the denominator of the Padé approximant constructed according to Eqs. (53)–(55) in [@JeWeSo2000], and accelerated convergence of the transforms is observed. In contrast to the investigation [@JeWeSo2000], we assume here that only the [*leading*]{} large-order factorial asymptotics of the perturbative coefficients are known.
We continue with the discussion of the conformal mapping (\[DefZ\]). It should be noted that for series whose leading singularity in the Borel plane is at $u = -u_0$ with $u_0 > 0$, an appropriate rescaling of the Borel variable $u \to |u_0|\, u$ is necessary on the right-hand side of Eq. (\[BorelIntegral\]). Then, $f^{(\lambda)}_{\rm B}(|u_0|\,u)$ as a function of $u$ has its leading singularity at $u = -1$ (see also Eq. (41.57) in [@ZJ1996]). The Borel integration variable $u$ can be expressed as a function of $z$ as follows, $$\label{UasFuncOfZ}
u(z) = \frac{4 \, z}{(z-1)^2}\,.$$ The $m$th partial sum of the Borel transform (\[PartialSum\]) can be rewritten, upon expansion of the $u$ in powers of $z$, as $$\label{PartialSumConformal}
f^{(\lambda),m}_{\rm B}(u) =
f^{(\lambda),m}_{\rm B}\bigl(u(z)\bigr) =
\sum_{n=0}^{m} C_n\,z^n + {\cal O}(z^{m+1})\,,$$ where the coefficients $C_n$ as a function of the $c_n$ are uniquely determined (see, e.g., Eqs. (36) and (37) of [@CaFi1999]). We define partial sum of the Borel transform, expressed as a function of the conformal variable $z$, as $$f'^{(\lambda),m}_{\rm B}(z) = \sum_{n=0}^{m} C_n\,z^n\,.$$ In a previous investigation [@CaFi1999], Caprini and Fischer evaluate the following transforms, $$\label{CaFiTrans}
{\cal T}'_m f(g) = \frac{1}{g^\lambda}\,
\int_0^\infty {\rm d}u \,u^{\lambda - 1} \,\exp\bigl(-u/g\bigr)\,
f'^{(\lambda),m}_{\rm B}(z(u))\,.$$ Caprini and Fischer [@CaFi1999] observe the apparent numerical convergence with increasing $m$. The limit as $m\to\infty$, provided it exists, is then assumed to represent the complete, physically relevant solution, $$f(g) = \lim_{m\to\infty} {\cal T}'_m f(g)\,.$$ We do not consider the question of the existence of this limit here (for an outline of questions related to these issues we refer to [@CaFi2000]).
In the absence of further information on the analyticity domain of the Borel transform (\[BorelTrans\]), we cannot necessarily conclude that $f^{(\lambda)}_{\rm B}{\mathbf (}u(z){\mathbf )}$ as a function of $z$ is analytic inside the unit circle of the complex $z$-plane, or that, for example, the conditions of Theorem 5.2.1 of [@BaGr1996] are fulfilled. Therefore, we propose a modification of the transforms (\[CaFiTrans\]). In particular, we advocate the evaluation of (lower-diagonal) Padé approximants [@BaGr1996; @BeOr1978] to the function $f'^{(\lambda),m}_{\rm B}(z)$, expressed as a function of $z$, $$\label{ConformalPade}
f''^{(\lambda),m}_{\rm B}(z) =
\bigg[ [\mkern - 2.5 mu [m/2] \mkern - 2.5 mu ] \bigg/
[\mkern - 2.5 mu [(m+1)/2] \mkern - 2.5 mu ]
\bigg]_{f'^{(\lambda),m}_{\rm B}}\!\!\!\left(z\right)\,.$$ We define the following transforms, $$\label{AccelTrans}
{\cal T}''_m f(g) = \frac{1}{g^\lambda}\,
\int_{C_j} {\rm d}u \,u^{\lambda - 1} \,\exp\bigl(-u/g\bigr)\,
f''^{(\lambda),m}_{\rm B}\bigl(z(u)\bigr)$$ where the integration contour $C_j$ ($j=-1,0,1$) have been defined in [@Je2000]. These integration contours have been shown to to provide the physically correct analytic continuation of resummed perturbation series for those cases where the evaluation of the standard Laplace-Borel integral (\[BorelIntegral\]) is impossible due to an insufficient analyticity domain of the integrand (possibly due to multiple branch cuts) or due to spurious singularities in view of the finite order of the Padé approximations defined in (\[ConformalPade\]). We should mention potential complications due to multi-instanton contributions, as discussed for example in Ch. 43 of [@ZJ1996] (these are not encountered in the current investigation). In this letter, we use exclusively the contour $C_0$ which is defined as the half sum of the contours $C_{-1}$ and $C_{+1}$ displayed in Fig. 1 in [@Je2000]. At increasing $m$, the limit as $m\to\infty$, provided it exists, is then again assumed to represent the complete, physically relevant solution, $$f(g) = \lim_{m\to\infty} {\cal T}''_m f(g)\,.$$ Because we take advantage of the special integration contours $C_j$, analyticity of the Borel transform $f^{(\lambda)}_{\rm B}{\mathbf (}u(z){\mathbf )}$ inside the unit circle of the complex $z$-plane is not required, and additional acceleration of the convergence is mediated by employing Padé approximants in the conformal variable $z$.
[cr@[.]{}lr@[.]{}lr@[.]{}lr@[.]{}l]{}
------------------------------------------------------------------------
$m$ & & & &\
------------------------------------------------------------------------
28 & $-0$ & $501~565~232$ & $-0$ & $538~352~234$ & $-0$ & $573~969~740$ & $-0$ & $827~506~173$\
------------------------------------------------------------------------
29 & $-0$ & $501~565~232$ & $-0$ & $538~352~233$ & $-0$ & $573~969~738$ & $-0$ & $827~506~143$\
------------------------------------------------------------------------
30 & $-0$ & $501~565~231$ & $-0$ & $538~352~233$ & $-0$ & $573~969~738$ & $-0$ & $827~506~136$\
[cr@[.]{}lr@[.]{}lr@[.]{}lr@[.]{}l]{}
------------------------------------------------------------------------
$m$ & & & &\
------------------------------------------------------------------------
28 & $-1$ & $669~071~213$ & $-1$ & $800~550~588$ & $-1$ & $928~740~624$ & $-1$ & $852~027~809$\
------------------------------------------------------------------------
29 & $-1$ & $669~071~214$ & $-1$ & $800~550~589$ & $-1$ & $928~740~626$ & $-1$ & $852~027~810$\
------------------------------------------------------------------------
30 & $-1$ & $669~071~214$ & $-1$ & $800~550~589$ & $-1$ & $928~740~625$ & $-1$ & $852~027~810$\
We consider the resummation of two particular perturbation series discussed in [@BrKr1999] for the anomalous dimension $\gamma$ function of the $\phi^3$ theory in 6 dimensions and the Yukawa coupling in 4 dimensions. The perturbation series for the $\phi^3$ theory is given in Eq. (16) in [@BrKr1999], $$\label{gammaPhi4}
\gamma_{\rm hopf}(g) \sim
\sum_{n=1}^{\infty} (-1)^n \, \frac{G_n}{6^{2 n - 1}} \, g^n\,,$$ where the coefficients $G_n$ are given in Table 1 in [@BrKr1999] for $n=1,\dots,30$ (the $G_n$ are real and positive). We denote the coupling parameter $a$ used in [@BrKr1999] as $g$; this is done in order to ensure compatibility with the general power series given in Eq. (\[power\]). Empirically, Broadhurst and Kreimer derive the large-order asymptotics $$G_n \sim {\rm const.} \; \times \;
12^{n-1} \, \Gamma(n+2)\,, \qquad n\to\infty\,,$$ by investigating the explicit numerical values of the coefficients $G_1,\dots,G_{30}$. The leading asymptotics of the perturbative coefficients $c_n$ are therefore (up to a constant prefactor) $$\label{LeadingPhi4}
c_n \sim (-1)^n \frac{\Gamma(n+2)}{3^n}\,, \qquad n\to\infty\,.$$ This implies that the $\lambda$-parameter in the Borel transform (\[BorelTrans\]) should be set to $\lambda=2$ (see also the notion of an asymptotically optimized Borel transform discussed in [@JeWeSo2000]). In view of Eq. (\[LeadingPhi4\]), the pole closest to the origin of the Borel transform (\[BorelTrans\]) is expected at $$u = u^{\rm hopf}_0 = -3\,,$$ and a rescaling of the Borel variable $u \to 3\,u$ in Eq. (\[BorelIntegral\]) then leads to an expression to which the method defined in Eqs. (\[power\])–(\[AccelTrans\]) can be applied directly. For the Yukawa coupling, the $\gamma$-function reads $$\label{gammaYukawa}
{\tilde \gamma}_{\rm hopf}(g) \sim
\sum_{n=1}^{\infty} (-1)^n \,
\frac{{\tilde G}_n}{2^{2 n - 1}} \, g^n\,,$$ where the ${\tilde G}_n$ are given in Table 2 in [@BrKr1999] for $n=1,\dots,30$. Empirically, i.e. from an investigation of the numerical values of ${\tilde G}_1,\dots,{\tilde G}_{30}$, the following factorial growth in large order is derived [@BrKr1999], $${\tilde G}_n \sim {\rm const.'} \; \times \;
2^{n-1} \, \Gamma(n+1/2)\,, \qquad n\to\infty\,.$$ This leads to the following asymptotics for the perturbative coefficients (up to a constant prefactor), $$c_n \sim (-1)^n \frac{\Gamma(n+1/2)}{2^n} \,, \qquad n\to\infty\,.$$ This implies that an asymptotically optimal choice [@JeWeSo2000] for the $\lambda$-parameter in (\[BorelTrans\]) is $\lambda=1/2$. The first pole of the Borel transform (\[BorelTrans\]) is therefore expected at $$u = {\tilde u}^{\rm hopf}_0 = -2\,.$$ A rescaling of the Borel variable according to $u \to 2\,u$ in (\[BorelIntegral\]) enables the application of the resummation method defined in Eqs. (\[power\])–(\[AccelTrans\]).
In Table \[table1\], numerical values for the transforms ${\cal
T}''_m \gamma_{\rm hopf}(g)$ are given, which have been evaluated according to Eq. (\[AccelTrans\]). The transformation order is in the range $m=28~,29,~30$, and we consider coupling parameters $g=5.0,~5.5,~6.0$ and $g=10.0$. The numerical values of the transforms display apparent convergence to about 9 significant figures for $g \leq 6.0$ and to about 7 figures for $g=10.0$. In Table \[table2\], numerical values for the transforms ${\cal T}''_m
{\tilde \gamma}_{\rm hopf}(g)$ calculated according to Eq. (\[AccelTrans\]) are shown in the range $m=28,~29,~30$ for (large) coupling strengths $g=5.0,~5.5,~6.0$. Additionally, the value $g = 30^2/(4\,\pi)^2 = 5.69932\dots$ is considered as a special case (as it has been done in [@BrKr1999]). Again, the numerical values of the transforms display apparent convergence to about 9 significant figures. At large coupling $g = 12.0$, the apparent convergence of the transforms suggests the following values: $\gamma_{\rm hopf}(12.0) =
-0.939\,114\,3(2)$ and ${\tilde \gamma}_{\rm hopf}(12.0) =
-3.287\,176\,9(2)$. The numerical results for the Yukawa case, i.e. for the function ${\tilde
\gamma}_{\rm hopf}$, have recently been confirmed by an improved analytic, nonperturbative investigation [@BrKr2000prep] which extends the perturbative calculation [@BrKr1999].
We note that the transforms ${\cal T}'_m \gamma_{\rm hopf}(g)$ and ${\cal T}'_m {\tilde \gamma}_{\rm hopf}(g)$ calculated according to Eq. (\[CaFiTrans\]), i.e. by the unmodified conformal mapping, typically exhibit apparent convergence to 5–6 significant figures in the transformation order $m=28,~29,~30$ and at large coupling $g \geq 5$. Specifically, the numerical values for $g=5.0$ are $$\begin{aligned}
{\cal T}'_{28} \gamma_{\rm hopf}(g = 5.0) \; &=& \;
-0.501~567~294\,, \nonumber\\[2ex]
{\cal T}'_{29} \gamma_{\rm hopf}(g = 5.0) \; &=& \;
-0.501~564~509\,, \nonumber\\[2ex]
{\cal T}'_{30} \gamma_{\rm hopf}(g = 5.0) \; &=& \;
-0.501~563~626\,. \nonumber\end{aligned}$$ These results, when compared to the data in Table \[table1\], exemplify the acceleration of the convergence by the additional Padé approximation of the Borel transform [*expressed as a function of the conformal variable*]{} \[see Eq. (\[ConformalPade\])\].
It is not claimed here that the resummation method defined in Eqs. (\[power\])–(\[AccelTrans\]) necessarily provides the fastest possible rate of convergence for the perturbation series defined in Eq. (\[gammaPhi4\]) and (\[gammaYukawa\]). Further improvements should be feasible, especially if particular properties of the input series are known and exploited (see in part the methods described in [@JeWeSo2000]). We also note possible improvements based on a large-coupling expansion [@We1996d], in particular for excessively large values of the coupling parameter $g$, or methods based on order-dependent mappings (see [@SeZJ1979; @LGZJ1983] or the discussion following Eq. (41.67) in [@ZJ1996]).
The conformal mapping [@CaFi1999; @CaFi2000] is capable of accomplishing the analytic continuation of the Borel transform (\[BorelTrans\]) beyond the circle of convergence. Padé approximants, applied directly to the partial sums of the Borel transform (\[PartialSum\]), provide an alternative to this method [@Raczka1991; @Pi1999; @BrKr1999; @Je2000; @JeWeSo2000]. Improved rates of convergence can be achieved when the convergence of the transforms obtained by conformal mapping in Eq. (\[PartialSumConformal\]) is accelerated by evaluating Padé approximants as in Eq. (\[ConformalPade\]), and conditions on analyticity domains can be relaxed in a favorable way when these methods are combined with the integration contours from Ref. [@Je2000]. Numerical results for the resummed values of the perturbation series (\[gammaPhi4\]) and (\[gammaYukawa\]) are provided in the Tables \[table1\] and \[table2\]. By the improved conformal mapping and other optimized resummation techniques (see, e.g., the methods introduced in Ref. [@JeWeSo2000]) the applicability of perturbative (small-coupling) expansions can be generalized to the regime of large coupling and still lead to results of relatively high accuracy.\
U.J. acknowledges helpful conversations with E. J. Weniger, I. Nándori, S. Roether and P. J. Mohr. G.S. acknowledges continued support from BMBF, DFG and GSI.
[10]{}
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GT300
The GT300 may refer to:
A Super GT car category
The GT300 family of graphics processors from Nvidia
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#coding=utf-8
'''
Created on 2015-11-4
@author: zhangtiande
'''
from django.shortcuts import HttpResponse
from teamvision.project.models import Project,Tag
from django.contrib.auth.models import User
from business.ucenter.account_service import AccountService
class VM_AdminUser(object):
'''
classdocs
'''
def __init__(self,user,is_create=False):
self.user=user
self.is_create=is_create
self.admin=""
self.manager=""
self.default_group=""
self.set_user_group()
def user_active(self):
result="finished-check fa-check-square"
if not self.user.is_active:
result="fa-square-o unfinished-check"
return result
def user_name(self):
return self.user.email
def user_full_name(self):
result=self.user.username
if self.user.last_name and self.user.first_name:
result=self.user.last_name+self.user.first_name
return result
def user_avatar(self):
result="/static/global/images/fruit-avatar/Fruit-1.png"
if self.user.extend_info:
result=AccountService.get_avatar_url(self.user)
return result
def user_groups(self):
return self.user.groups.all()
def form_id(self):
result="user_edit_form"
if self.is_create:
result="user_create_form"
return result
def set_user_group(self):
if self.user:
if self.user.groups.all().filter(id=27):
self.admin="checked"
elif self.user.groups.all().filter(id=28):
self.manager="checked"
else:
self.default_group="checked"
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Sigma Beauty Angled Brow Brush
Sigma Beauty Angled Brow Brush
The E75 Angled Brow Brush features a short, slightly stiff angled brush head. Use this brush with brow powder to fill in the brows using a sketching motion for a natural effect. Pairs well with Brow Powder Duo - choose from Light, Medium, or Dark.
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Maizey Coming In
Maizey hasn’t ever been inside this house.
Dropped off here at the farm long ago,
she has always been a farm dog,
making her rounds,
keeping a keen nose to the slightest
change in the air
and barking at whatever she felt needed
fending off.
In winter, she and her son Joe,
kept each other company,
curling up in the hay in the barn.
But Joe died in the fall
and Maizey, a good 15 years old,
shivers now
alone.
It has taken gentle pushing
to get her to cross over the doorstep
and come inside.
Temperature tonight is predicted to be 3 degrees F,
with a windchill of -9. It is imperative
that Maizey come in.
Her first evening indoors,
night before last,
there was much pacing,
tentative sniffing
and more gentle pushing
to get her to step across the threshold
to go out
and come back in again.
She now goes in and out without hesitation—
well, when she sniffed the snow out the backdoor
early this morning,
she turned around and came back in. Later,
she stepped out onto the porch—
and came back after one trot round
around the yard.
She likes sleeping on the rug in the bedroom,
the mat in front of the wood-burning stove.
I like her inside
wherever she wants to be.
The warmth is critical for her,
as is the warmth of her company
for me.
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The quantum computing apocalypse is imminent
Shlomi Dolev is the Chair Professor and founder of the Computer Science department of Ben-Gurion University of the Negev. He is the author of Self-Stabilization. Shlomi also is a cybersecurity entrepreneur and the co-founder and chief scientist of Secret Double Octopus.
In the ancient world, they used cubits as an important data unit, but the new data unit of the future is the qubit — the quantum bits that will change the face of computing.
Quantum bits are the basic units of information in quantum computing, a new type of computer in which particles like electrons or photons can be utilized to process information, with both “sides” (polarizations) acting as a positive or negative (i.e. the zeros and ones of traditional computer processing) alternatively or at the same time.
According to experts, quantum computers will be able to create breakthroughs in many of the most complicated data processing problems, leading to the development of new medicines, building molecular structures and doing analysis going far beyond the capabilities of today’s binary computers.
The elements of quantum computing have been around for decades, but it’s only in the past few years that a commercial computer that could be called “quantum” has been built by a company called D-Wave. Announced in January, the D-Wave 2000Q can “solve larger problems than was previously possible, with faster performance, providing a big step toward production applications in optimization, cybersecurity, machine learning and sampling.”
IBM recently announced that it had gone even further — and that it expected that by the end of 2017 it would be able to commercialize quantum computing with a 50-qubit processor prototype, as well as provide online access to 20-qubit processors. IBM’s announcement followed the September Microsoft announcement of a new quantum computing programming language and stable topological qubit technology that can be used to scale up the number of qubits.
Taking advantage of the physical “spin” of quantum elements, a quantum computer will be able to process simultaneously the same data in different ways, enabling it to make projections and analyses much more quickly and efficiently than is now possible.
There are significant physical issues that must be worked out, such as the fact that quantum computers can only operate at cryogenic temperatures (at 250 times colder than deep space) — but Intel, working with Netherlands firm QuTech, is convinced that it is just a matter of time before the full power of quantum computing is unleashed.
“Our quantum research has progressed to the point where our partner QuTech is simulating quantum algorithm workloads, and Intel is fabricating new qubit test chips on a regular basis in our leading-edge manufacturing facilities,” said Dr. Michael Mayberry, corporate vice president and managing director of Intel Labs. “Intel’s expertise in fabrication, control electronics and architecture sets us apart and will serve us well as we venture into new computing paradigms, from neuromorphic to quantum computing.”
The difficulty in achieving a cold enough environment for a quantum computer to operate is the main reason they are still experimental, and can only process a few qubits at a time — but the system is so powerful that even these early quantum computers are shaking up the world of data processing. On the one hand, quantum computers are going to be a boon for cybersecurity, capable of processing algorithms at a speed unapproachable by any other system.
By looking at problems from all directions — simultaneously — a quantum computer could discover anomalies that no other system would notice, and project to thousands of scenarios where an anomaly could turn into a security risk. Like with a top-performing supercomputer programmed to play chess, a quantum-based cybersecurity system could see the “moves” an anomaly could make later on — and quash it on the spot.
The National Security Agency, too, has sounded the alarm on the risks to cybersecurity in the quantum computing age.
“Quantum computing will definitely be applied anywhere where we’re using machine learning, cloud computing, data analysis. In security that [means] intrusion detection, looking for patterns in the data, and more sophisticated forms of parallel computing,” according to Kevin Curran, a cybersecurity researcher at Ulster University and IEEE senior member.
But the computing power that gives cyber-defenders super-tools to detect attacks can be misused, as well. Last year, scientists at MIT and the University of Innsbruck were able to build a quantum computer with just five qubits, conceptually demonstrating the ability of future quantum computers to break the RSA encryption scheme.
That ability to process the zeros and ones at the same time means that no formula based on a mathematical scheme is safe. The MIT/Innsbruck team is not the only one to have developed cybersecurity-breaking schemes, even on these early machines; the problem is significant enough that representatives of NIST, Toshiba, Amazon, Cisco, Microsoft, Intel and some of the top academics in the cybersecurity and mathematics worlds met in Toronto for the yearly Workshop on Quantum-Safe Cryptography last year.
The National Security Agency, too, has sounded the alarm on the risks to cybersecurity in the quantum computing age. The NSA’s “Commercial National Security Algorithm Suite and Quantum Computing FAQ” says that “many experts predict a quantum computer capable of effectively breaking public key cryptography” within “a few decades,” and that the time to come up with solutions is now.
According to many experts, the NSA is far too conservative in its prediction; many experts believe that the timeline is more like a decade to a decade and a half, while others believe that it could happen even sooner.
And given the leaps in progress that are being made on almost a daily process, a commercially viable quantum computer offering cloud services could happen even more quickly; the D-Wave 2000Q is called that because it can process 2,000 qubits. That kind of power in the hands of hackers makes possible all sorts of scams that don’t even exist yet.
For example, forward-looking hackers could begin storing encrypted information now, awaiting the day that fast, cryptography-breaking quantum computing-based algorithms are developed. While there’s a possibility that the data in those encrypted files might be outdated, there is likely to be more than enough data for hackers to use in various identity theft schemes, among other things.
It’s certain that the threats to privacy and information security will only multiply in the coming decades.
In fact, why wait? Hackers are very well-funded today, and it certainly wouldn’t be beyond their financial abilities to buy a quantum computer and begin selling encryption-busting services right now. It’s likely that not all the cryptography-breaking algorithms will work on all data, at least for now — this is a threat-in-formation — but chances are that at least some of them will, meaning that even now, cyber-criminals could utilize the cryptography-breaking capabilities of quantum computers, and perhaps sell those services to hackers via the Dark Web.
That NSA document that predicted “decades” before quantum computers become a reality was written at the beginning of 2016, which shows how much progress has been made in barely a year and a half. The solution lies in the development of quantum-safe cryptography, consisting of information theoretically secure schemes, hash-based cryptography, code-based cryptography and exotic-sounding technologies like lattice-based cryptography, multivariate cryptography (like the “Unbalanced Oil and Vinegar scheme”), and even supersingular elliptic curve isogeny cryptography.
These, and other post-quantum cryptography schemes, will have to involve “algorithms that are resistant to cryptographic attacks from both classical and quantum computers,” according to the NSA. Whatever the case, it’s certain that the threats to privacy and information security will only multiply in the coming decades, and that data encryption will proceed in lockstep with new technological advances.
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Tissue reparative effects of macrolide antibiotics in chronic inflammatory sinopulmonary diseases.
It is well established that macrolide antibiotics are efficacious in treating sinopulmonary infections in humans. However, a growing body of experimental and clinical evidence indicates that they also express distinct salutary effects that promote and sustain the reparative process in the chronically inflamed upper and lower respiratory tract. Unlike the anti-infective properties, these distinct effects are manifested at lower doses, usually after a relatively prolonged period (weeks) of treatment, and in the absence of an identifiable, viable pathogen. Long-term, low-dose administration of macrolide antibiotics has been used most commonly for sinusitis, diffuse panbronchiolitis, asthma, bronchiectasis, and cystic fibrosis. It is associated with down-regulation of nonspecific host inflammatory response to injury and promotion of tissue repair. Although large-scale trials are lacking, the prolonged use of these drugs has not been associated with emergence of clinically significant bacterial resistance or immunosuppression. Long-term, low-dose administration of 14- and 15-membered ring macrolide antibiotics may represent an important adjunct in the treatment of chronic inflammatory sinopulmonary diseases in humans.
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Whatever You Love, You Are
Whatever You Love, You Are is the fifth studio album by Australian trio, Dirty Three, which was released in March 2000. Cover art is by their guitarist, Mick Turner. Australian musicologist, Ian McFarlane, felt that it showed "deep, rich, emotional musical vistas, and furthered the band’s connection to the music and approach of jazz great John Coltrane".
Reception
Track listing
"Some Summers They Drop Like Flies" – 6:20
"I Really Should've Gone Out Last Night" – 6:55
"I Offered It Up to the Stars & the Night Sky" – 13:41
"Some Things I Just Don't Want to Know" – 6:07
"Stellar" – 7:29
"Lullabye for Christie" – 7:45
References
General
Note: Archived [on-line] copy has limited functionality.
Specific
Category:2000 albums
Category:ARIA Award-winning albums
Category:Dirty Three albums
Category:Touch and Go Records albums
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/** @file
Intel Processor Power Management ACPI Code.
Copyright (c) 2018 - 2019, Intel Corporation. All rights reserved.<BR>
SPDX-License-Identifier: BSD-2-Clause-Patent
**/
#include "CpuPowerMgmt.h"
DefinitionBlock (
"CPU0PSD.aml",
"SSDT",
0x02,
"PmRef",
"Cpu0Psd",
0x3000
)
{
External(\PC00, IntObj)
External(\TCNT, FieldUnitObj)
External(\_SB.CFGD, FieldUnitObj)
External(\_SB.PR00, DeviceObj)
Scope(\_SB.PR00)
{
Name(HPSD,Package() // HW_ALL
{
Package() {5, // NumEntries. Current Value is 5.
0, // Revision. Current Value is 0.
0, // Domain.
0xFE, // Coordination type 0xFE = HW_ALL
0x80 // Number of processors.
}
})
Name(SPSD,Package() // SW_ALL
{
Package() {5, // NumEntries. Current Value is 5.
0, // Revision. Current Value is 0.
0, // Domain.
0xFC, // Coordination type 0xFC = SW_ALL
0x80 // Number of processors.
}
})
//
// The _PSD object provides information to the OSPM related
// to P-State coordination between processors in a multi-processor
// configurations.
//
Method(_PSD,0)
{
If (And(\_SB.CFGD, PPM_TURBO_BOOST_MAX)) // Intel Turbo Boost Max 3.0
{
Store (0, Index(DerefOf(Index(HPSD, 0)),2)) // Domain
Store (1, Index(DerefOf(Index(HPSD, 0)),4)) // Number of processors belonging to the domain.
} Else {
Store (TCNT, Index(DerefOf(Index(HPSD, 0)),4))
Store (TCNT, Index(DerefOf(Index(SPSD, 0)),4))
}
If(And(PC00,0x0800)) // If Hardware co-ordination of P states
{
Return(HPSD)
}
Return(SPSD)
}
} // End of Scope(\_SB.PR00)
} // End of Definition Block
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