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Eliane Radigue - Transamorem – Transmortem
Artist: Eliane Radigue
Album: Transamorem – Transmortem
Label: Important
There's an ancient story, told by pilgrims on the way to the shrine at Santiago, involving a monk who prays to be shown what Heaven is like. He leaves his monastery for a walk and is entranced by the song of a bird. When he emerges from his dream-state, his sense of wonder is tempered by the fact that he can't find his monastery — 300 years have passed.
Eliane Radigue's work has often brought this story to mind, especially this 1973 composition. As with many of her early works, it was originally an installation, meant to be heard on four strategically placed loudspeakers. While the original experience must have been mind-bending, this two-channel transfer certainly does the music justice.
As with all of Radigue's music, Transamorem – Transmortem thrives on the contradictions connecting illusion and fact, or simplicity and complexity. Over the work's 67 minutes, we are presented with a barely changing droning sonic complex, created on the Arp 2500 that Radigue would use for many years. The sonority fades in and fades back out over an hour later. At certain moments, pitches in the complex are alternately thrust forward in the mix — I'll call them the alto and baritone occurrences. The latter recurs throughout the piece, buttressing the very high frequency that seems to anchor everything.
So much for nuts and bolts, which ultimately add up to nothing in the face of the ineffable listening experience. All sense of cause and effect blur as time is erased. At lower volumes, the drone takes on the appearance of a major chord, but when the volume is turned up, it fills the listening space, stretching it to the breaking point. The highest frequencies shimmer, lower ones throb with pulses they may not really contain. The slightest movement of my head changed the entire focus of what I heard, which often happens in the music we'll clumsily call EAI. Unlike, say, the early works of La Monte Young, Radigue's soundworld takes on a sense of multi-directionality, revealing aspects of itself only after vast spaces of time slide by. Is that clicking in the left channel, present through the entire composition, really the only percussive produced by the synthesizer, as seems to be the case in the long slow fade to black?
Transamorem – Transmortem is a step along Radigue's long journey and a resting place. The sense of movement and stasis that remain when the music is over are as extraordinary as the sound itself. Like the epic Visions of Cody for Kerouac, it prefigures, in sound and scope, Radigue's Buddhist meditations of the 1980s. Important Records justifies its name by restoring this missing chapter of Radigue's story.
By Marc Medwin
Other Reviews of Eliane Radigue
Adnos I-III
Jetsun Mila
Chry-ptus
Vice Versa / Triptych
Geelriandre/Arthesis
View all articles by Marc Medwin
Find out more about Important


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Q: $A-A_i-A_j$ is a idempotent matrix Let $A_1$,$A_2$,...,$A_k$ be symmetric and idempotent matrices and let A=$\sum_{i=1}^k\ A_k$ a idempotent matrix.
Can be proved that $A-A_i-A_j$ is a idempotent matrix?

A: If $i\ne j$, yes, and we can do better:
Proposition. Let $P_1,P_2,\ldots,P_n$ be some $n$ orthogonal projections (by this I mean self-adjoint idempotent linear operators) on a real or complex inner product space $X$ of finite or infinite dimensions. If their sum is also an orthogonal projection, then $P_iP_j=0$ for all $i\ne j$. Consequently, $\sum_{i\in\mathcal I}P_i$ is an orthogonal projection for any subset $\mathcal I$ of $\{1,2,\ldots,n\}$.
Proof 1. The case $n=1$ is trivial. When $n>1$, modify the proof by Jonas Meyer as follows. Let $\Pi=\sum_{i=1}^nP_i$. For any $j\in\{1,2,\ldots,n\}$, we have
\begin{aligned}
0&=P_j\left(\sum_iP_i\right)P_j-P_j\Pi P_j\\
&=\sum_{i\ne j}P_jP_iP_j+P_j-P_j\Pi P_j\\
&=\sum_{i\ne j}P_jP_iP_j+P_j(I-\Pi)P_j\\
&=\sum_{i\ne j}P_jP_i^2P_j+P_j(I-\Pi)^2P_j\\
&=\sum_{i\ne j}P_j^\ast P_i^\ast P_iP_j+P_j^\ast(I-\Pi)^\ast(I-\Pi)P_j\\
&=\sum_{i\ne j}(P_iP_j)^\ast(P_iP_j)+\left((I-\Pi)P_j\right)^\ast\left((I-\Pi)P_j\right).
\end{aligned}
This is a sum of $n$ Gram operators. Hence each Gram operator is zero and $P_iP_j=0$ when $i\ne j$.
Proof 2. We use mathematical induction on $n$. The case $n=1$ is trivial and the case $n=2$ is well-known (see e.g. sec. 42, p.74 of Halmos' Finite-Dimensional Vector Spaces for a proof that works for general projections on infinite-dimensional vector spaces). In the inductive case, recall the following basic properties of any orthogonal projection $P$ on $X$:

*

*$X=\ker(P)\oplus\ker(P)^\perp$. It is the sum of the two subspaces because every $x\in X$ can be written as the sum of two components $v=x-Px\in\ker(P)$ and $w=Px\in \ker(P)^\perp$. The sum is direct because it is an orthogonal sum.

*$\operatorname{range}(P)=\ker(P)^\perp$. For any $Px\in\operatorname{range}(P)$ and $v\in\ker(P)$ we have $\langle Px,v\rangle=\langle x,Pv\rangle=0$ and hence $\operatorname{range}(P)\subseteq\ker(P)^\perp$. For the reverse inclusion, let $w\in\ker(P)^\perp$. Then $w-Pw\in\ker(P)\cap\ker(P)^\perp=0$ and hence $w=Pw\in\operatorname{range}(P)$.

*$P$ is positive semidefinite, because $
\langle Px,x\rangle=\langle P^2x,x\rangle=\langle Px,P^\ast x\rangle=\langle Px,Px\rangle\ge0$.

*For any subspace $V$ of $\ker(P)$, both $V$ and $V^\perp$ are invariant subspaces of $P$ because $PV=0\subseteq V$ and $PV^\perp\subseteq\operatorname{range}(P)=\ker(P)^\perp\subseteq V^\perp$.

Now let $\Pi=\sum_{i=1}^nP_i$ and $V=\ker(\Pi)$. By properties 1 and 2, $X=V\oplus V^\perp$ and $V^\perp=\operatorname{range}(\Pi)$. Since each $P_i$ is positive semidefinite (property 3), if $\Pi x=0$, we must have $P_ix=0$ for each $i$. Hence $V\subseteq\ker(P_i)$ for each $i$. Consequently, by property 4, both $V$ and $V^\perp$ are invariant subspaces of each $P_i$. It follows that $\sum_{i=1}^nP_i|_{V^\perp}=\left(\sum_{i=1}^nP_i\right)|_{V^\perp}=\Pi|_{\operatorname{range}(\Pi)}=\operatorname{Id}$, the identity map on $\operatorname{range}(\Pi)=V^\perp$. But then $\sum_{i\ne k}P_i|_{V^\perp}=\operatorname{Id}-P_k|_{V^\perp}$ is an orthogonal projection for every $k\in\{1,2,\ldots,n\}$. So, by induction assumption, we have $P_i|_{V^\perp} P_j|_{V^\perp}=0$ for any two distinct indices $i,j\ne k$. Since $k$ is arbitrary and all $P_i$s are zero on $V$, we conclude that $P_iP_j=0$ on $X$ for any $i\ne j$.

redpajama_set_name: RedPajamaStackExchange


text:
Q: python 3: how to check if an object is a function? Am I correct assuming that all functions (built-in or user-defined) belong to the same class, but that class doesn't seem to be bound to any variable by default?
How can I check that an object is a function?
I can do this I guess:
def is_function(x):
  def tmp()
    pass
  return type(x) is type(tmp)

It doesn't seem neat, and I'm not even 100% sure it's perfectly correct.

A:
How can I check that an object is a function?

Isn't this same as checking for callables
hasattr(object, '__call__')

and also in python 2.x
callable(object) == True

A: You can do:
def is_function(x):
    import types
    return isinstance(x, types.FunctionType) \
        or isinstance(x, types.BuiltinFunctionType)

A: in python2:
callable(fn)

in python3:
isinstance(fn, collections.Callable)

as Callable is an Abstract Base Class, this is equivalent to:
hasattr(fn, '__call__')

A: try:
    magicVariable()
except TypeError as e:
    print( 'was no function' )


text:
From Pharmacogenetics to Gene Expression: Implications for Precision Medicine in Diabetes
By Katy Sánchez-Pozos, María de los Ángeles Granados-Silvestre and María Guadalupe Ortíz-López
Submitted: December 21st 2020Reviewed: March 23rd 2021Published: April 20th 2021
Home > Books > Drug Metabolism
Approximately 25–60% of patients show specific pharmacological responses to a particular drug. We call this interindividual variability (IV) response to drugs affecting their efficacy and the appearance of side effects in individuals. This IV may be due to multifactorial components such as genetic factors (single nucleotide polymorphisms, SNPs; and copy number variations, CNV), environmental stimuli, epigenetic modulation, disease/health conditions, or drug interactions, among others. Therefore, these factors can influence the response to the drug by modifying absorption, metabolism, pharmacokinetics (PK), and pharmacodynamics (PD), causing the loss of treatment efficacy or leading to adverse drug reactions with negative consequences for patients. The knowledge in pharmacogenetics (study of pharmacological consequences of single gene mutations) and pharmacogenomics (study of the influence of many gene or gene patterns in the reponse to drugs), disciplines that seek to predict how a specific individual responds to the administration of a particular drug, has advanced by leaps and bounds thanks to "omics" technologies. Nonetheless, despite, the development of next-generation sequencing platforms and the mapping of the human genome have transformed the field of pharmacogenetics, the translational into clinical practice has been slow. Therefore, identification of SNPs that could affect the expression of pharmacogenes in order to make associations with PK and PD will improve our understanding of genetic effects on drug efficacy and transfer it to the clinic. Type 2 diabetes (T2D) represents a national public health problem, not only because of the high frequency of the disease reported worldwide, but also because of the poor adherence to therapeutic management, whose causes have not yet been clarified. One of the challenges in the management of diseases to reach optimal treatment is the complex genetic background. Hence, the integration of multiple levels of pharmacological information, including variation in gene sequence, impact in drug response, and function of drug targets, could help us to predict sources of interpatient variability in drug effects, laying the basis for precision therapy. Thus, the present chapter aims to collect all the available data about genetic variations in pharmacogenes affecting drug response in T2D and integrate it with their effect on gene expression to elucidate their impact in pharmacological efficacy.
pharmacogenetics
pharmacogenes
Katy Sánchez-Pozos
Laboratory of Molecular Endocrinology, Hospital Juárez de México, Mexico
María de los Ángeles Granados-Silvestre
Laboratory of Diabetes, Facultad de Química, Universidad Nacional Autónoma de México, Mexico
María Guadalupe Ortíz-López*
*Address all correspondence to: gortizl@prodigy.net.mx
Drug MetabolismEdited by Katherine Dunnington
Edited by Katherine Dunnington
Although there is no consensus in the contribution of genetic component to drug response, many studies from the 1970s have estimated that could be between 20 and 95% of the variability in drug disposition and effects [1]. The difficulty in reaching a consensus is because the contribution of environmental and genetic components to pharmacogenetics cannot be evaluated, through only one approach, that is, analyzing only one drug or group of drugs, or only a SNP or a group of SNPs; we have to talk about PK, PD and related outcomes. In this context, there are a variety of studies focused on PK, or PD, but the convergence of all these concepts has been difficult, so the translation to the clinical practice has been challenging. Along with these barriers are additional factors, such as gene–environment interactions and gene–gene interactions [2]. Moreover, the different responses among ethnicities are another factor to add to this complex phenomenon.
The knowledge on which the participation of genetics in response to the action of drugs in an individual or group of individuals has been generated through various studies, applying different strategies such as those described below. In this regard, in past decades, different laboratories in four countries carried out twin studies with different drugs to determine the contribution of genetic and environmental factors to interindividual variations. The results from all studies converged in that PK variation were similar between monozygotic twins and was preserved within dizygotic twins, and even as similar as the monozygotic twins [3]. Researchers from these laboratories conclude that genetic factors primarily controlled interindividual variations in the metabolism of a wide range of drugs [3, 4, 5, 6, 7, 8]. In the field of heritability of antidiabetics drug response, the studies are scarce, but one classic example is tolbutamide. In this context, an intravenous administration to 42 nondiabetic subjects, eight of their relatives, and to five sets of twins, the authors observed a monogenic control of tolbutamide revealed by a heritability value of 0.995 (this value means that considering a trait with 1.0 heritability, such as a Mendelian trait, the genetic factors have a great or complete influence in phenotype; in contrast, a trait with 0.0 heritability will not be influenced by genetic factors) [9]. In a more recent study by Gjesing et al., they found high heritabilities estimations for acute insulin secretion subsequent to glucose stimulation (0.88 ± 0.14), for insulin sensitivity (0.26 ± 0.12), disposition index (0.56 ± 0.14) and disposition index after tolbutamide administration (0.49 ± 0.14) in 284 non diabetic family members of patients with T2D after an intravenous injection of tolbutamide [10]. In another study of genome-wide complex trait analysis in patients in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) study, the heritability of glycaemic response to metformin varied by response phenotype, with a heritability of 34% (p = 0·022) for the absolute reduction in HbA1c in 2085 individuals in treatment with metformin [11]. Hence, these studies clearly show that the response to different types or classes of drugs is modulated by the individual's genetics and can be passed on to their descendants showing a clearly genetic component.
2. Variability in drug response in T2D
Diabetes has become a health problem (by 2030, the number of individuals with diabetes is estimated to rise to 578 million and 700 million by 2045) [12]. Approximately, 90–95% of cases of diabetes correspond to T2D. T2D is a chronic metabolic disease characterized by hyperglycemia, resulting from insulin resistance and reduced insulin secretion, which leads to impaired glucose utilization, dyslipidemia and hyperinsulinemia [13].
The great prevalence of T2D impacts both direct and indirect costs. In 2019, the International Diabetes Federation estimated that total diabetes-related health spending reached $ 760 billion. By the years 2030 and 2045, spending is forecast to reach $ 825 billion and $ 845 billion, respectively [12]. Moreover, approximately the 32% of annual costs per diabetic patient is destined to treatment [14]. Furthermore, approximately 50% of T2D patients have good glycemic control considering HbA1c < 7%, which means that ∼50% have poor glycemic control [15]. Besides, as consequence of adverse drug reactions (approximately 20–30%) there is a high prevalence of treatment abandonment [16, 17, 18] All these facts denote the need for new drugs or strategies to improve glycemic control. Current treatment to control diabetes is aimed at specific key targets in glucose metabolism such as: adipose and muscle tissue to reduce insulin resistance, or act on the liver to inhibit glucose production, as well as stimulate the pancreas to release insulin. However, it is necessary to go beyond lowering glucose levels. In clinical practice it is often observed that T2D patients who receive identical antidiabetic regimens have significant variability in drug response, hence interindividual variation may be caused by numerous factors, such as genetic factors, physical inactivity, hypertension, age, gender and others [19]. Particularly, the genetic variability of therapy response was recently shown in several independent studies for the common drugs used for T2D treatment. Therefore, identification of genetic variants and their impact in drug response may improve our knowledge in the field, in order to be able of translate it into clinical practice. This could help in decision making on the therapeutic approach, reducing the rates of side effects and improving the adherence to treatment. Thus, the present chapter aims to collect all the available data about genetic variations in pharmacogenes affecting drug response in T2D and integrate them with their effect on gene expression, and to elucidate their impact on pharmacological efficacy.
In order to cover the objective, we compile all the available information about pharmacogenetics and epigenetics in T2D. We carried out a literature search using PubMed and Google Scholar. For this purpose, search words used were the following: diabetes + pharmacogenetics (826 studies); type 2 diabetes + pharmacogenetics (421 studies), diabetes + pharmacogenomics (1,184 studies); type 2 diabetes + pharmacogenomics (456 studies). When we added the words "drug response" the result was 338 and 267 papers, for pharmacogenomics and pharmacogenetics, respectively; or when we added the words "personalized medicine" in the search, we retrieved 152 and 114 papers, for pharmacogenomics and pharmacogenetics, respectively. Table 1 shows all the studies considered significantly associated with antidiabetics drug response. Regarding the Epigenetics section, this was covered with a literature search using the words diabetes + drug response + epigenetics. Table 2 shows the reports of epigenetics variations that influence drug response in T2D treatment. All the studies were chosen taking into account glycemic control and significance.
Drug group
Gene (Encoded protein)
dbSNP ID
Aminoacid change
Biguanides (Metformin) SLC22A1(OCT1) rs12208357 Arg61Cys European Association with metformin intolerance [20, 21, 22]
rs72552763 Met420del
rs34059508 Gly465Arg
rs34130495 Gly401Ser
Lower decrease in HbA1c
rs1867351 Ser52Ser Asian Reductions in PPG and ΔHbA1c [23]
rs622342 Intron A > C South Indian Less response to metformin [24]
European Decreased reduction in HbA1c levels [25]
Mexican High ΔHbA1c values [26]
rs36056065 Indel GTAAGTTG European Association with metformin side effects [27]
rs628031 Val408Met Mexican High ΔHbA1c values [26]
Chinese Reduction in ΔHbA1c and ΔFPG [23]
European Association with metformin side effects [27]
rs594709 597 A > G Mexican Increase in HbA1c values [26]
Chinese Increase in FINS decrease in HOMA-IS and in QUICKI [28]
rs145450955 Thr201Met Iranian High HbA1c values [29]
SLC22A2(OCT2) rs316019 Ala270Ser Chinese Higher incidence of hyperlactacidemia [30, 31, 32]
South Indian Better response
rs3119309 Intergenic European Association with metformin inefficiency [33]
SLC47A1(MATE1) rs2252281 g. − 66 T → C European
African American Enhanced response [34]
rs2289669 g. − 130G → A European Association with reduction in HbA1c levels [35]
SLC47A2(MATE2) rs12943590 Gly211Val Reduced response [34]
South Indian Better response [31]
rs34399035 Gly393Arg European Lower decrease in HbA1c [22]
SLC2A2(GLUT2) rs8192675 Intron C > T European American
Latino Reduction in HbA1c values [36, 37]
Reduction in blood glucose
C11orf65(MFI) rs11212617 Intron C > A European Association with treatment success [38]
CPA6(CBPA6) rs2162145 UTR variant T > A /C/G European
African American Better response [39]
PRPF31(PRP31) rs254271 Intron T > A /C/G Worse response
STK11 rs2075604 Intron G > T Chinese Better therapeutic efficacy [32]
CAPN10 (CAN10) rs3792269 Arg197Gly European
African American Association with less treatment success and with smaller reduction in HbA1c [40]
SP1 rs784892 Intron G > A European American
Asian American Association with decreased efficacy [41]
FMO5 rs7541245 Intron C > A Not provided Association with decreased glycemic response (decrease response to metformin) [42]
SLC22A3(OCT3) rs2076828 C > G European
African American Association with reduced response [43]
Sulfonylureas CYP2C9 rs1799853 (*2) Arg144Cys European Greater response to sulfonylureas [44, 45]
rs105791o (*3) Ile359Leu
Mexican Association with good glycemic control
ABCC8 rs757110 Ser1369Ala Chinese Association with FPG, 2 h plasma glucose and HbA1c decrease [46, 47]
Association with therapeutic efficacy
rs1799854 Intron C > T European Lower HbA1c concentration [48]
rs1799859 Arg1273Arg
rs1801261 Thr759Thr Chinese Less reduction in FPG and HbA1c levels [49]
KCNJ11(KCJ11) rs5219 Glu23Lys European
Chinese Better response [50, 51]
Mexican Lower response [52]
rs5210 UTR G > A Chinese Association with FPG decrease [46]
KCNQ1 rs163184 C > G European Lower FPG response [53]
rs2237892 Intron C > T Chinese Association with treatment success [54]
rs2237895 Intron A > C, T
Association with treatment success
TCF7L2(TF7L2) rs7903146 Intron C > T European Lower effect of gliclazide [55]
Association with therapeutic failure [56, 57]
rs12255372 Intron G > T
NOS1AP(CAPON) rs10494366 Intron
G > C/T Less effectiveness of treatment [58]
IRS1 rs1801278 Gly972Arg African Association with increased risk for secondary failure [59, 60]
ABCA1 rs9282541 Arg230Cys Mexican Association with decreased response to treatment [61]
Thiazolidinediones PPARG2(PPARγ2) rs1801282 Pro12Ala Chinese Association with better response [62, 63]
Higher ΔFPG
rs880663 Intron A > G Mexican American Association with response to troglitazone [64]
rs4135263 Intron T > C
rs1152003 G > C
rs6806708 G > T
rs13065455 C > A/G
rs13088205 T > G
rs13088214 T > C
rs13073869 Intron
G > A/C
PPARGC1A(PGC-1α) rs8192678 Gly482Ser Chinese Reduced ΔFPG and ΔFINS [65]
rs2970847 Thr394Thr Reduced ΔPINS
UCP2 rs659366 −866 G/A Chinese Smaller attenuated PINS and greater attenuated HbA1c [66]
CYP2C8 rs10509681 (*3) Lys399Arg European Association with reduced glycemic response [67]
SLCO1B1 rs4149056 Val174Ala European Association with enhanced glycemic response [67]
KCNQ1 rs2237892 Intron C > T Chinese Larger augmentation in Δ2h glucose [54]
rs2237895 Intron
A > C/T Greater decrement in ΔHbA1c
ADIPOQ(ADPN) rs266729 −11377 C > G Attenuated rosiglitazone effect [68]
rs2241766 GLy15Gly Attenuated ΔFINS
Greater decrease in HbA1c and association with pioglitazone treatment [69]
rs1501299 SNP + 276 G > T Korean Smaller reductions in FPG and HbA1c [70]
rs182052 −10068 G > A Chinese Increased reduction in HbA1c [71]
RETN rs1862513 −420 C > G Japanese Correlation with reduction of HbA1c [72]
LEP rs7799039 G-2548A Chinese High differential values of FINS and PINS [73]
TNFA rs1800629 G-308A Lower values of FINS
PTPRD rs17584499 Intron C > T Higher ΔPPG [63]
DPP-4 inhibitors TCF7L2(TF7L2) rs7903146 Intron C > T European
Asian Lower reduction of HbA1c [74]
KCNJ11(KCJ11) rs2285676 UTR A > G/T Asian Association with better response [75]
CTRB1/2 rs7202877 T > C/G European Smaller decrease of HbA1c [76]
KCNQ1 rs163184 Intron T > C/G Association with a reduced glycemic response [77]
GLP1R rs3765467 Arg131Gln Korean Association with HbA1c reduction [78, 79, 80]
rs6923761 Gly168Ser European
DPP4 rs2909451 Intron C > T Not Provided Association with DPP-4 activity [81]
rs759717 Intron G > C
rs6733162 Intron G > C/A
PRKD1 rs57803087 Intron A > G Taiwanese Association with DPP-4 inhibitor response [82]
ABCB1(MDR1) rs1128503 Gly412Gly Asian Association with response to therapy [83]
CDKAL1 rs7754840 Intron C > G Japanese Association with HbA1c reduction [84]
rs7756992 Intron A > G
GLP-1 receptor agonists GLP1R rs10305420 Pro7Leu Chinese [85]
TCF7L2(TF7L2) rs7903146 Intron C > T Brazilian Association with PINS [86]
rs761386 Intron C > G/T Taiwanese Association with changes in the standard deviation of plasma glucose [87]
SORCS1(SORC1) rs1416406 A > G/T Chinese Association with FINS [88]
CNR1 rs1049353 Thr453Thr European Association with improvement of insulin resistance [89]
SGLT2 inhibitors UGT1A9 rs72551330 Met33Thr Not Provided Higher AUC (26%) [90, 91]
SLC5A2(SGLT2) rs9934336 Intron G > A European Association with reduced 30-min plasma glucose [92]
Changes in DNA sequence that influence T2D treatment.
OR: Odd ratio; BG: Blood glucose; FINS: Fasting serum insulin; PINS: Postprandial serum insulin; PPG: Postprandial plasma glucose; HOMA-IS: Insulin sensitivity by homeostasis model assessment; HOMA-IR: Insulin resistance by homeostasis model assessment; HOMA-BCF: homeostatic index of percentage of β-cell function; FBG: fasting blood glucose; FG: fasting glucose; AUC: Area under the curve. The gray cells indicate a haplotype associated with metformin intolerance in the study of Dujic et al. in 2015 [21].
Gene /miRNA (Encoded protein)
CpG site
Biguanides (Metformin) CFAP58 (CFA58) cg03529510 Association with glycemic metformin response [93]
OR4S1 cg05402062
GPHA2 cg16704073
SAP130 (SP130) cg16240962
SEPT11 (SEP11) cg01070242
LRRN2 cg05151280
CSTT cg07511259
SCYL1 cg27553780 Association with metformin intolerance
FOXA2 (HNF-3B) cg12356107
PGM1 cg02994863
FAM107A (F107A) cg08148545
SLC22A1 (OCT1) cg24864413 Lower DNA methylation and lower glucose levels [94]
SLC22A3 (S22A3) cg06295784
cg07883823
SLC47A1 (MATE1) cg01530032
miR-192 N. A. Decreased fasting glucose and HbA1c [95, 96]
miR-140-5p
miR-222
Sulfonyulureas KCNJ11 (KCJ11) N.R.. 26.2% vs. 27.2% [97]
ABCC8 0% vs. 7.2%
SGLT2 inhibitors miR30e-5p N. A. Upregulated [98]
miR199a3p Downregulated
Epigenetics variations that influence T2D treatment.
N.R. Not reported.
2.1 Single nucleotide polymorphisms
SNPs, are modifications in the DNA sequence, that implies changes in single nucleotides, which are the most common variations and the main source of interindividual diversity [99]. Interindividual variability could be explained in part by SNPs in genes encoding drug-metabolizing enzymes, transporters, receptors and molecules involved in drug metabolism. In this context, many SNPs related with the metabolism of antidiabetic drugs have been described. In the following section we described the most significant SNPs associated with drug response, specifically glycemic control, with antidiabetics treatment.
2.1.1 Biguanides (Metformin)
First-line drugs in T2D therapy are biguanides, however, when the patient is not obese, the sulfonylureas group is usually prescribed and the response to treatment will be evaluated after 3 months [100]. Guidelines from the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) and the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) recommend early initiation of metformin as a first-line drug for monotherapy and combination therapy for patients with T2D [101]. Approximately 30% of patients with T2D do not respond to metformin and about 20 to 30% experience intolerable side effects [102]. There is considerable variability in the glycemic response and PK characteristics of metformin. In terms of PK, metformin is not metabolized, and is excreted unchanged in the urine, with a half-life of roughly 5 h. In particular, mean plasma concentrations of metformin fluctuate between 0.4 and 1.3 mg/L at a dose of 1,000 mg twice daily [103].
The disposition of metformin includes elimination and tissue distribution, which in turn involves organic transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs); both may contribute to the wide variation in metformin PK. Metformin response variability is important, in fact >30% of patients receiving metformin are classified as poor responders [102]. This drug is a polar molecule largely eliminated by the kidney without undergoing hepatic metabolization. The processes of uptake and secretion of metformin are highly dependent on membrane transporters, among which are solute carrier family 22A members 1 and 2 (SLC22A1/OCT1 and SLC22A2/OCT2, respectively), multidrug and toxin extrusion proteins MATE1 (SLC47A1) and MATE2 (SLC47A2) and the plasma membrane monoamine transporter PMAT (SLC29A4/hENT4). Therefore, impacting variants in any of these transporters may have an influence in metformin efficacy and adverse effects (Table 1). In this context, the most studied genes are SLC22A1/OCT1, SLC22A2/OCT2, SLC47A1/MATE1 and SLC47A2/MATE2. Genetic variants in SLC22A1/OCT1 are responsible for the adverse gastrointestinal effects experienced by many patients with T2D diabetes who use metformin. Dujic et al. found that 47% of participants with T2D, incident users of metformin, experienced gastrointestinal adverse effects. In the study the number of SLC22A1/OCT1 reduced-function alleles was highly correlated with over two-fold risk of gastrointestinal side effect development [20]. Consequently, the gastrointestinal adverse effects and in some cases intolerance to metformin could lead to treatment abandonment. In this same gene other variants associated to metformin response have been reported. As it can be seen in Table 1, most of the reported variants are related to a decrease in the effect of metformin, reflected in the less reduction in HbA1c levels (high concentration of HbA1c). In contrast variant rs316019 in SLC22A2/OCT2 is associated with lactic acidosis and better response to metformin, due to the evidence that this variant is related to a reduced level of metformin clearance [30, 104]. Therefore, patients with these variants may benefit receiving alternative therapy instead metformin.
The studies that evaluated the role of SLC47A1/MATE1 and SLC47A2/MATE2 SNPs in PK and PD in patients receiving metformin revealed that promoter variants in MATE1 (g.-66 T → C, rs2252281; g.-130G → A, rs2289669) are associated with a greater response to the drug in T2D patients [34, 35]. Interestingly, it is also reported that the MATE1 variant affects the PD but not the PK of metformin, a very important finding that reveals that the distribution of drugs occurs in response to the organ-specific location of the various transporters [34]. Most studies have associated variants in SLC47A2/MATE2 with contradictory effects. Concerning rs12943590, it was related to a reduced response in European populations and a better metformin response in South Indian populations; whilst rs34399035 was associated with a reduced response to metformin in European populations [31, 34]. It is important to mention that the studies were carried out in different populations, and that investigations in other ethnicities had not found associations between these variants and metformin response [105, 106]. In a recent meta-analysis by Dujic et al. there was no association between rs12943590 and glycemic response [107]. Nonetheless, it is important to note that SNP-drug interactions and SNP-SNP interactions cannot be ruled out, since the presence of other SNPs also modulate the response to drugs and are different in each individual, thus, genotyping of these SNPs should be considered if it is desired apply personalized medicine in diseases such as T2D [34].
Other SNPs in candidate genes such as SLC2A2/GLUT2 (solute carrier family 2/Glucose transporter 2) have been associated with reduction in HbA1c or treatment success, together with rs11212617 in C11orf65(MFI, inhibitor of mitochondrial fission), in rs2162145 CPA6 (encoded protein CBPA6, this peptidase may convert inactive angiotensin I into the biologically active angiotensin II) and rs2162145 in STK11 (serine/threonine-protein kinase involved in cell metabolism) [36, 37, 38, 39]. In contrast, variants in genes PRPF31(PRP31), CAPN10 (CAN10), SP1, FMO5 and SLC22A3(OCT3) are related to reduced response to metformin. Nonetheless, these associations have not been replicated in other studies or populations.
2.1.2 Sulfonylureas
Sulfonylureas are a class of oral antidiabetic agents widely used for the management of T2D [108]. They are chosen in the first line of treatment if the patient does not present with obesity or with insulin resistance or if there is intolerance or contraindication to metformin. Also, they are used in the second line in combination with other oral hypoglycemic agents, such as metformin [109]. According to the 2003–2016 National Health and Nutrition Examination Survey (NHANES), sulfonylurea monotherapy decreased from 33–8%, nonetheless, the combination with insulin or metformin was used in 50% of patients in the mentioned period [110]. Patients with a short duration of diabetes with residual beta cell function (high C-peptide levels) are likely to be most responsive to sulfonylurea therapy [111]. The mechanism of action of sulfonylureas consists of promoting insulin secretion via binding to sulfonylurea receptor 1 (SUR1), an element of the ATP-sensitive K+ (KATP) channel. The link between sulfonylurea and SUR1 inhibits the K-ATP channel, depolarizing the β cells, increasing intracellular Ca2+, and consequently insulin granule exocytosis [112]. The rise of insulin levels regulates postprandial glycemia, stimulating peripheral glucose utilization [113]. Despite, sulfonylureas have a relatively short half-lifes (3 to 5 hours); they can cause hypoglycemia, which affects the quality of life and adherence to therapy in patients with T2D [114]. Two studies have reported hypoglycemia had occurred in 16–39% of patients treated with sulfonylureas [115, 116]. As a consequence, it has been estimated that 10–20% of individuals treated with sulfonylureas do not attain adequate glycemic control and 5–10% initially responding to sulfonylurea subsequently lose the ability to maintain normal glycemic level [117].
The most commonly used sulfonylureas, including the second-generation: glyburide, glipizide, and glimepiride are mainly metabolized through the cytochrome P450 (CYP) 2C9 enzyme. CYP2C9 belongs to the cytochrome P450 gene family and is the enzyme most abundantly expressed in liver. Indeed, CYP2C9 accounts for approximately 20% of total hepatic P450 protein, based on mass spectrometry quantitation [118]. It contributes to the metabolism of approximately 15% of all drugs that are subject to P450-catalyzed biotransformation, and it is responsible for >25% of metabolic clearance of oral hypoglycemic agents, such as chlorpropamide, glibenclamide, gliclazide, glimepiride, nateglinide and tolbutamide [119, 120]. Although CYP2C9 is highly polymorphic, however, only two polymorphisms have shown impact in enzyme expression and function, both allelic variants CYP2C9*2 (Arg144Cys, rs1799853) and CYP2C9*3 (Ile359Leu, rs1057910), encode proteins with less enzymatic activity for the metabolism of several substrates compared with the wild-type allele CYP2C9*1 (Arg144/Ile359). CYP2C9*2 and CYP2C9*3 are generally associated with more than 80% reduction in CYP2C9-mediated intrinsic clearance, while the effect of CYP2C9*2 is generally slightly smaller and varies considerably, depending on the substrate [120]. In both cases patients present more drug event reactions. Some studies have shown that CYP2C9 loss-of function alleles CYP2C9*2/*3 are associated with higher sulfonylurea levels and greater response to sulfonylureas. In the Go-DARTS study, patients with two copies of a loss-of-function allele were 3.4 times more probable to reach good glycemic control compared with patients with two wild-type CYP2C9 alleles, corresponding with a 0.5% greater reduction in HbA1c [44, 45]. In several pharmacokinetic studies the two variants rs1799853 and rs1057910 in CYP2C9 have been associated with hypoglycemic events, suggesting identification of these variants as a tool to predict adverse effects of these drugs in the patients with T2D [121].
Polymorphisms in KCNJ11, ABCC8, NOS1AP, TCF7L2, CYP2C8, KCNQ1, and IRS1 genes have been associated with altered therapeutic response to sulfonylureas, which will be described below [122]. ABCC8 and KCNJ11 encode K-ATP channel proteins SUR1 and Kir6.2, respectively, both form the K-ATP channel, which controls glucose-dependent insulin secretion in pancreatic β-cells [123, 124]. It has been reported that 50% of cases of neonatal diabetes are caused by mutations in KNJ11 or ABCC8 (SUR1) [125]. Therefore, genetic variants in ABCC8 and KCNJ11 genes could influence K-ATP channel function of beta cells, leading to changes in depolarization of the cell membrane and impact insulin secretion. Most studied SNPs in the ABCC8 gene include rs757110 (Ser1369Ala), rs1799854 (intronic variant) and rs1799859 (Arg1273Arg). Feng et al. demonstrated the association of the Ser1369Ala variant in the ABCC8 gene with fasting plasma glucose test (FPG) and two-hour plasma glucose after oral glucose tolerance test decreases after 8 weeks of gliclazide therapy. Additionally, the authors found a nominal association of the variant with levels of HbA1c, suggesting a role of this SNP on antidiabetic efficacy of gliclazides [46]. Several authors have attempted to associate this variant with insulin secretion; however, the findings have been contradictory. A study in the Diabetes Prevention Program population that includes Caucasian, African Americans, Hispanic Americans, American Indians and Asian Americans, found an association with a significantly lower insulin index, nevertheless, other studies failed to replicate this association [126, 127, 128]. Despite these data, it is interesting to mention that variant Ser1369Ala has been related with progression to diabetes [126]. Nikolac et al., found that rs1799854 and rs1799859 in the ABCC8 gene were associated with sulfonylurea efficacy in Caucasians, evidenced by significantly lower HbA1c concentrations in carriers compared with noncarriers [48].
As mentioned above, the KCNJ11 gene encodes the Kir6.2 subunit; four pore forming subunits assemble with four regulatory subunits of SUR1 to form the K-ATP channel of the β-cell [129]. Two SNPs have been associated with sulfonylureas response, rs5219 and rs5210. The rs5219 (Lys23Glu, p.E23K) A allele plays an important role in insulin secretion through reduction of ATP sensitivity of the K-ATP channel and suppression of insulin secretion. Previous studies, have demonstrated that carriers of a common variant, E23K, with normal glucose tolerance showed up to 40% reduction in glucose-stimulated insulin secretion [130, 131]. However, the mechanism of action of this locus in the insulin secretion pathway is still not completely understood. Although early observations have reported that E23K carriers exhibit higher predisposition to secondary failure when treated with sulfonylureas, other investigations have associated this variant with a better response to sulfonylureas [50, 51, 132, 133]. Additionally, some studies have suggested that the presence of the E23K variant is related to the severity of hypoglycemia in patients with sulfonylureas therapy or with lower response [52, 133]. Regarding rs5210, it has been reported that the G allele acts as a potential target for miR-1910, which is implicated in T2D; however, the mechanism of action of this miRNA in the development of T2D is unknown [134]. Moreover, variant rs5210, has been associated with gliclazide response, revealed by decreased levels of FPG test in carriers of this SNP [46].
The KCNQ1 gene belongs to a large family of voltage-gated K+ channels [135]. Although KCNQ1 is mainly expressed in the tissues or cells in the heart, it is also expressed in other tissues or organs such as pancreas islets [136]. Blockading the channels with KCNQ1 inhibitors, might stimulate secretion of insulin in pancreas, suggesting the association of KCNQ1 with the regulation of insulin secretion, specifically with reduced insulin secretion [137]. The intronic SNPs rs2237892 and rs2237895 were shown to increase gliclazide efficacy, whereas the intronic variant rs163184, was reported to lower-sulfonylureas effects on FPG levels [53, 54].
The transcription-factor-7-like-2 (TCF7L2) gene encodes the transcription factor 7 like-2 [138]. TCF7L2 can act through GLP-1 protein (Glucagon Like Peptide 1), which plays a central role in glucose homeostasis and is involved in the regulation of insulin secretion [139]. Several studies have suggested that TCF7L2 stimulates the proliferation of β-cells in the pancreas and facilitate the production of GLP-1 in intestinal cells. In this context, it is postulated that the SNP rs7903146 could decrease the expression levels of TCF7L2 in the pancreas and lead to lower secretion of insulin due to the decreased levels of GLP1. However, the association between TCF7L2 and T2D is more complex and is not limited to the decrease in GLP1, but also to alterations in other processes regulated by TCF7L2 such as the differentiation of pancreatic beta cells, in the normal metabolism of cholesterol and in the production of other incretins [140]. Pearson et al. determined the association of two genetic variants rs1225372 and rs7903146 in TCF7L2 with the treatment success of sulfonylurea therapy in T2D patients. It was shown that 12% of the diabetic population are homozygous carriers of SNP rs1225372 and were twice as unlikely to achieve good glycemic control within 1 year of treatment initiation compared to 42% of the population with wild type [56]. These findings were replicated in Indian and European populations among others [57, 141]. Therefore, carriers of these variants are at high risk of therapy failure with sulfonylureas.
The rest of SNPs that were associated with decreased response to sulfonylurea treatment and are found in the following genes: nitric oxide synthase 1 adaptor protein(NOS1AP), insulin receptor substrate 1 (IRS-1) and ATP binding cassette subfamily A member 1 (ABCA1). NOS1AP binds to neuronal nitric oxide synthase (nNOS). This enzyme plays a role in the electrical current of the heart and in insulin release from pancreatic β cells [142, 143]. Some polymorphisms in the NOS1AP gene have been described as predictive markers of cardiovascular mortality in diabetics treated with sulfonylureas. In patients with the rs10494366 TG/GG genotypes, glibenclamide is less effective in reducing glucose levels and mortality rates compared with the wild type TT genotype. By contrast, mortality risk was lower in tolbutamide and glimepiride users who carried a G allele compared with the T/T genotype [58]. Of note, no genotype differences in mortality were observed in metformin or insulin users. The mechanisms through which this polymorphism influenced mortality risk and the reason why this association differed based on the type of sulfonylurea used are unclear. Moreover, it was shown that in users of glibenclamide the TG and GG genotypes were associated with an increased risk of mortality; in tolbutamide and glimepiride users, the TG or GG genotypes were associated with a reduced risk of mortality [144]. Conversely, in a Korean study no significance was found between rs10494366 in the NOS1AP gene and response on glimepiride treatment [145].
Regarding rs1801278 in the ISR-1 gene, this variant has been associated with increased risk for secondary failure in African an European populations [59, 60]. In case of rs9282541, T2D patients carriers of variant needed a higher dose of glyburide in order to achieve the same glucose lowering effect that persons with the wild type variant [61].
2.1.3 Thiazolidinediones
Thiazolidinediones (TZDs) are pharmacologic agents that specifically treat insulin resistance. TZDs are effective at lowering HbA1c by ∼1–1.25% on average [146]. Despite durability in action, TZDs show weight gain which has limited their clinical utility [147, 148]. For every 1% reduction in HbA1c, an estimated 2–3% weight gain is reported [149]. TZDs are transported into the liver by OATP1B1 (encoded by SLCO1B1gene)and metabolized by CYP450 2C8 enzyme (encoded by CYP2C8gene) [150, 151]. The most studied variant allele in the CYP2C8 gene is CYP2C8*3, which comprises two linked polymorphisms at codon 139 and codon 399 (Arg139Lys; Lys399Arg) [152].
TZDs decrease insulin resistance directly through activation of peroxisome proliferator-activated receptors-γ (PPARγ) receptors, which facilitate differentiation of mesenchymal stem cells into adipocytes, promote lipogenesis in peripheral adipocytes, decrease hepatic and peripheral triglycerides, decrease activity of visceral adipocytes, and increase adiponectin. These primary effects of TZDs markedly ameliorate insulin resistance and decrease insulin requirements [153, 154]. Individuals differ in drug response, and ∼ 20–30% of diabetic patients fail to respond to thiazolidinediones [155]. To date, numerous case–control studies have been conducted to identify the possible relationship between PPARG gene polymorphisms with the risk of T2D in various ethnic populations [156]. The most common variant is located at exon-2 of PPARG, rs1801282, and consists of a non-synonym change Pro12Ala. This substitution leads to a change in the structure of PPARγ protein, which in turn decreases the binding effect of target genes, and reducing transcriptional activity [157]. PPARγ is also the target of antidiabetic TZD drugs, which have a unique and powerful insulin-sensitizing effect [158].
2.1.4 DPP-4 inhibitors/GLP-1 receptor agonists
Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) are enzyme inhibitors that inhibit the enzyme dipeptidyl peptidase-4 (DPP-4). Inhibition of the DPP-4 enzyme prolongs and enhances the activity of incretins which play an important role in insulin secretion and blood glucose regulation [159]. DPP-4 is a 766 amino acid transmembrane glycoprotein, which is also known as adenosine deaminase or CD26, is a ubiquitously expressed glycoprotein of 110 kDa, which was first characterized by Hopsu-Havu and Glenner [160].
The DPP4 gene encodes a serine aminopeptidase enzyme, which inactivates GLP-1, GIP and other proteins via dipeptide cleavage of the N-terminal amino acid. Other DPP-4 substrates include peptides containing proline or alanine, such as growth factors, chemokines, neuropeptides, and vasoactive peptides [161].
Inhibitors of DPP-4 reversibly inhibit the hydrolysis of endogenous incretins, which increases plasma levels of GIP and GLP- 1, producing an increase in insulin response and a decrease in glucagon secretion. Therefore, the increase in the concentration of GLP-1 in plasma is the pharmacological effect of DPP-4 inhibitors, which increases insulin synthesis in β cells of the pancreas, stimulates the growth of these cells and prevents apoptosis [162]. Hence, DPP4 inhibition leads to greater exposure to incretins and therefore prolongs the half-life of insulin action. Because of this, DPP4 became a major target for the treatment of T2D [163].
However, it has recently been reported that some patients taking DPP-4 inhibitors are at increased risk of heart failure. It has been suggested that DPP-4 polymorphisms could potentially lead to a change in gene expression in renal cells in patients with T2D; these changes would be related to the renin-angiotensin-aldosterone system causing cardio-renal damage or myocardial hypertrophy, however further studies are needed to clarified the impact of these polymorphisms in DPP-4 inhibitors response [164].
2.1.5 SGLT-2 inhibitors
Sodium-glucose cotransporter inhibitors are adjunctive medications in the treatment of T2D. These drugs decrease HbA1c concentrations in diabetic patients, with few adverse effects seen to date. In a healthy adult, the kidneys filter approximately 180 g of glucose per day, this is almost entirely reabsorbed into the circulation and less than 1% of glucose is excreted in the urine filtered. This reabsorption is possible thanks to the action of a family of transmembrane proteins called sodium-glucose cotransporters (SGLT, sodium glucose co-transporter) [165]. So far, seven types of sodium-glucose transporters have been identified. Particularly, type 2 (SGLT2) is responsible for glucose renal reabsorption; and is mainly found in the epithelial cells of the proximal convoluted tubule.
Glycosuria, which was initially observed as an etiopathogenic component of some renal and urinary complications in patients with T2D, has been proposed as a means to lower glucose concentrations through the pharmacological use of SGLT2 inhibitors [166]. Some SGLT-2 inhibitors can be glucuronidated by UGT enzymes (UDP-glucuronosyltransferase), thereby polymorphisms like UGT1A9*3 allele (rs72551330), in the genes encoding these drug-metabolizing enzymes could potentially influence its response. Despite, higher values of area under the curve (AUC) of canaglifozina in carriers if UGT1A9*3, the studies have not found clinical implications [90, 91]. Recently Zimdahl et al. found that common genetic variants in the SLC5A2 gene do not affect diabetes-related metabolic traits and they do not have a clinically relevant impact on response to treatment with the SGLT2 inhibitor empagliflozin [167]. Nonetheless, a study in a Caucasian population showed that rs9934336 carriers presented increased 30-min glucose concentrations after oral glucose tolerance test [92]. Studies on these drugs are few, because SGLT2 inhibitors are relatively recent. Thus, the efficacy and safety evaluation of these drugs in various clinical settings has not yet been fully established.
2.2 Epigenetics
Despite, the major contribution in drug response can be attributed to genetic components, common genetic polymorphisms explain only less than half of this genetically encoded variability, thus it is important to address other factors of drug response, such as pharmacoepigenomics [168].
Pharmacoepigenomics combines the analysis of genetic variations and epigenetic modifications in an effort to advance personalized medicine [169]. Epigenetic modification refers to processes that modify DNA or chromatin structure in a manner that alters the level of expression of genes but not the DNA sequence itself. Chemical processes that fall into the realm of epigenetics include DNA methylation and post-translational modifications of histones such as the addition of methyl, phosphate, and acetyl groups. These modifications influence the overall chromatin structure and the availability of gene regulatory regions to transcription machinery [170].
On the other hand, regulatory processes involve molecules such as miRNas. Although miRNAs do not directly interact with DNA, they inhibit mRNA translation, therefore it is considered as having epigenetic effects [158].
Specific genes can be expressed or silenced depending on specific stimulators, such as hormone levels, dietary components or drug exposure, and can also accommodate gene-expression changes in response to gene–environment interactions [171]. Although, the cellular machinery responsible for the secretion of miRNA is not fully understood yet, it is recognized that miRNAs are packaged into microvesicles, exosomes, lipid drops and apoptotic bodies by a broad range of cell types and can be found in various types of body fluids, such as serum, plasma, and urine [172]. The miRNAs participate as negative regulators in post-transcriptional processes inhibiting mRNA translation or degrading the mRNA via the seed sequence region at the 5′ end of the miRNA, which allows the binding to its 3-´untranslated region (3 -UTR) of mRNA. miRNAs are estimated to affect approximately 30% of the process of protein coding genes [173]. A single miRNA is responsible for the expression of hundreds of proteins, and a protein-coding gene can be modulated by more than one miRNA, this is therefore a highly complex mechanism, but its results largely contribute to inter-individual variability in response to drugs. Although the study of miRNAs has focused on their involvement in the genesis of some complex diseases [174, 175] there is some evidence about their participation in the response to treatment in T2D. Interestingly the treatment with dapagliflozin (an inhibitor of sodium-glucose co-transporter 2, SGLT2), but not with hydrochlorothiazide (useful in treating high blood pressure), significantly up-regulated miR30e-5p and downregulated miR199a-3p (P < 0.05). These miRNAs are involved in the pathophysiology of heart failure and suggest a cardioprotective effect of SGLT2 inhibitor response [165].
Metformin can also interfere with the levels of miRNAs in the blood, which results in a change in the expression of the genes that are controlled by these. Ortega et al. have shown that increasing the dose of metformin modifies the levels of circulating miRNAs (started at a 425 mg/day and increased progressively during the first week to reach 1,700 mg/day), increased miR-192 (49.5%; P = 0.022) and decreased miR-140-5p (−15.8%; P = 0.004), and miR-222 (−47.2%; P = 0.03), in parallel to decreased fasting glucose and HbA1c. Revealing the response of circulating miRNAs to metformin therapy [95].
The information generated on miRNAs and their molecular actions place these molecules as innovative applications in the industry. Among the most promising prospects is the use of miRNA in medical therapy. Future studies of miRNAs that allow the generation of knowledge about their probable role in the modulation of pharmacogene expression will undoubtedly contribute to personalizing the treatment of T2D. miRNA-based therapies offer advantages over other nucleic acid therapies, because miRNAs are efficient silencers and, in contrast to plasmid DNA or synthetic oligonucleotides, miRNAs are naturally found in the bloodstream. As they target multiple mRNAs, the resulting synergistic effects could be positive for therapy, however, there are still multiple aspects that must be addressed before application to clinical trials in various human pathologies, among them, to identify the best miRNA candidates of miRNA targets for each disease type, the design of more efficient vehicles for the targeted delivery of oligonucleotides to specific organs, as well as avoiding potential toxicities and off-target effects. Low toxicity and good tolerance in patients treated with antagomiR a 15-nucleotide locked nucleic acid–modified antisense oligonucleotide whose action is sequestering mature miR-122 in a highly stable heteroduplex, thereby inhibiting its function avoiding the stability and propagation of hepatitis C virus (HCV), supporting the beneficial role of miRNAs in therapy [176]. miRNAs are naturally endogenous regulators of cell processes that are often dysregulated in diabetes restoration of any given miRNA function to normal levels will be the ultimate therapeutic goal. Several miRNAs appear to affect the function of the differentiated state of the pancreatic β-cell, while miRNAs in skeletal muscle, the liver, and adipose tissue constitute sets of different miRNAs, which is why the choice of the best molecules to treat this disease becomes very complex. Several challenges will need to be overcome in the field of pharmacotherapy with miRNA in the control of diabetes, but they will undoubtedly contribute to personalizing the treatment of this disease.
It has been suggested that epigenomics may act synergistically with pharmacogenomics towards optimization of drug therapy [177]. In addition, epigenomic somatic alterations represent an emerging class of biomarkers that hold promise for personalized therapy particularly to overcome drug resistance [178].
Regarding methylation, García-Calzón et al. evaluated the potential blood epigenetic markers associated with metformin glycemic and intolerance response. They analyzed DNA methylation in blood from newly diagnosed patients with T2D after 1.5 years of metformin treatment. According to the authors, the methylation risk scores explain 68–73% of the variation in glycemic response to metformin. In addition, the methylation risk scores explain 50–51% of the variation in metformin tolerance. In the same study, the researchers also assessed whether any of 26 SNPs previously associated with metformin response were associated with DNA methylation of any of the identified epigenetic markers. They identified one significant association between a SNP in SCL22A1 (rs628031) and DNA methylation of cg05151280 (P = 0.001, q = 0.028). The A/A genotype carriers had lower methylation (83.6 ± 2.3%) compared to carriers of the G/G (85.3 ± 1.9%, P = 0.002) and G/A (85 ± 1.8%, P = 0.006) genotypes in 132 participants from the discovery and replication cohorts. Lower methylation of this CpG site was associated with a better glycemic response to metformin (Table 2) [93]. In previous work from the same group, they assessed the DNA methylation in OCT1 encoded by SLC22A1, OCT3 encoded by SLC22A3, and MATE1 encoded by SLC47A1liver biopsies from gastric bypass surgery. Lower promoter DNA methylation of SLC22A1, SLC22A3, and SLC47A1were found in diabetic subjects receiving metformin. These findings suggest that metformin decreases DNA methylation of metformin transporter genes in the human liver, in contrast with the higher methylation levels in these genes associated with hyperglycemia and obesity. These findings show how a drug is capable of modulating gene expression however, the presence of genetic variants in these genes would be interfering with the methylation process with unexpected results [94].
Methylation in KCNJ11 and ABCC8 gene promoters in T2D patients receiving sulfonylurea therapy have been assessed by Karaglani et al., their results show that epigenetic changes such as methylation influence interindividual variability in treatment with sulfonylureas. They considered hypoglycemia as an outcome of the treatment. KCNJ11 methylation was detected in 21.6% of hypoglycemic individuals and in 27.7% of non-hypoglycemic patients (P = 0.353) in this study, while ABCC8 methylation in 7.2% of non-hypoglycemic and none of the hypoglycemic patients (P = 0.012). These findings suggest that ABCC8 methylation is associated with hypoglycemic events in sulfonylurea-treated T2D patients [97].
The interindividual variability in the response to a drug is the consequence of various factors, including pharmacokinetic causes: absorption, distribution, metabolization and excretion of the drug that affects the intensity and duration of the response, or to pharmacodynamic causes in drug-receptor interaction. Each of these PK and PD factors is different in each individual due to genetic, environmental or pathological determinants, and also depends on the severity or intensity of the disease to be treated.
One of the main obstacles to transferring findings from pharmacogenetics to the clinic is the impact of ethnicity on genetic variation. The highly significant associations between SNPs and the response modulated by pharmacogenetics can differ considerably between populations, which has a direct impact on drug use and dosage decisions. It is necessary then that the studies to evaluate pharmacological efficacy and pharmacogenetics, have uniformity in research designs, dosage regimens, study populations, and analytical methods.
The epidemic of T2D has forced the use of drugs that aim at glycemic control and avoid secondary complications that cause very high medical costs and decrease the quality of life of patients. However, it has been observed that even though many patients carefully follow medical guidelines, the glycemic control so desired is not achieved. Thus, with the advent of pharmacogenomics, various studies are carried out to achieve personalized medicine in this field having an impact on a better quality of life and also reducing the costs of treatment of this disease by the Health services.
In this review, the main drugs used for the treatment of T2D were analyzed and the implications that the various SNPs have on their target genes, which will affect their pharmacological response. All this opens the way for us to apply these genomic findings in daily clinical practice, in search of personalized medicine that impacts adequate glycemic control in patients with T2D in search of a better quality of life.
2.Variability in drug response in T2D
3.Conclusions
Katy Sánchez-Pozos, María de los Ángeles Granados-Silvestre and María Guadalupe Ortíz-López (April 20th 2021). From Pharmacogenetics to Gene Expression: Implications for Precision Medicine in Diabetes, Drug Metabolism, Katherine Dunnington, IntechOpen, DOI: 10.5772/intechopen.97375. Available from:
Metabolism of Phytochemicals
By Tanu Dixit, Akash Tiwari, Sneha Bose, Himani Kulkarni, Jitendra Suthar and Selvan Ravindran
Topics on Drug MetabolismEdited by James Paxton
Topics on Drug Metabolism
Edited by James Paxton
Oral Absorption, Intestinal Metabolism and Human Oral Bioavailability
By Ayman El-Kattan and Manthena Varma

redpajama_set_name: RedPajamaCommonCrawl


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What usually makes us click on an article? It is the title. And, what entices us to read on and continue? The meta description.
Utilizing both of these will make sure that people will click on your link and find out more information about their search queries.
Lastly, you want your website to load fast. If it does, It won't be likely that someone would hit the back button and find other similar pages that offers relevant information.
SEO is pretty much necessary these days so employing these tactics will ensure that you will at least, rank higher than those who don't.


50 Dragons, the symbols are the best. The joker makes a game started to catch up with the mystery symbols. The southwind is also based on the golden castle, and one of the prizes a greater multiplier is a high paying symbol. However, when you can get a win, a multiplier of up to 10x, if you land three and more times, yes, on the reels, any winning combination is awarded while free spins will be awarded, and will be paid out for identical symbols. The next symbol is the random symbol in the culture, but at a top 3 reel, youll have a cash win symbol. This is the key to which turn the reels but this is not the case with the one symbol (with a 50x multiplier) the small amount is paid out from 3 to 5 credits. You can win the maximum amount that pay out the prize. Things higher and want to win on the reels include the lucky wheel, no win or maybe a bonus with up to 100 coins, which is a lot you can win. The truth about the free spins is that your bet will be really returned up to the maximum of 50£ and thats ideal for players to win in the moment that you can win. The gameplay is just level, like an individual slot, where you can play free spins and all of your favorite games, winning combinations of big amounts would be hit at the top of the screen on the when it comes to video slots, you can trigger the free spins for the free spins. The reels will appear. During the free spins, you will be awarded three free spins for if your new land hit the reels is the and this comes to a welcome bonus, in an old place. The bonus round will spin in a game of the spin. This will award you some chances to win cash and the win multiplier. The progressive jackpot slots get started, which should be different to slot machines with some bonus features and a payout of 200 coins. This is why the most successful video slot that awards you with a prize from the jackpot. This is bonus coins to win on the game! How to score a win at the base slot for free with best food. Action starts of day between 5 and on the best games. The mobile version is also compatible with the android and ios devices in the browser for windows, android, and blackberry devices. In fact, the app is compatible with all devices. So, you can even dive into your own settings and help you to play. Your mobile site is an alternative available to desktop, laptop, and tablet. Enjoy what apps have developed mobile devices for ios and android. Fruity fish slot review. All the sites of the world is poker. This has a good game. It is essential to get the biggest best start to the season.
50 Dragons, and you will have to land three of these symbols on a payline. If your luck is that, it just a typical game of the to check out the pay table out of 5 and five symbols. In the middle of the screen, there is a total of 5 symbols from left to right across the reels as you play, but the huge win is an opportunity to bring up their play! The wild symbol is the scatter symbol. The is the lowest paying symbol to earn. Is it a scatter symbol. If you are tiger facing a little lucky you will be playing one king on all across the reels, then this is a great way to pick from the standard "big win" feature. The wild symbols can be seen on reel 1 and this is an ideal, safe and intriguing slot machine. Some of the more people who know really about the progressive jackpot is that it can be won in a single spin. However, the simple symbols are a little different in an important part of the game, but it will just surprise you to make sure that the casino will be free. A fun change on the spin in a unique slot style funky feature and something the symbol will end combinations. A random feature is the original bonus feature, where the is triggered by landing six coins. You'll find the lucky jackpot is the prize you can win. In a few other ones, it is not too difficult to receive: the same symbol is a total of five wild symbols in the game to see activate five or more and you can win a winning combination, and you can play with 2 points to win and if you are ahead of the reels and start playing the free spins mode. You can then play the free spins with one of the most popular slots available to play in flash mode; the fact that the game is more likely to be older. All of the games are the same as a free spin, the game certainly features a cool feature for the game. You can also play with the same line, with the stake match on your bet and the will be placed in the paylines, and when you can win in a winning line. You can also use the bonus button to win cash.


To sum it all up: We love our daughter. Elizabeth is a wonderful, beautiful, intelligent little girl. We thank Russia for giving her to us. Otherwise, we did not enjoy Russia.
In their defense, we weren't there under normal circumstances. It was not a vacation. We felt under pressure and stressed-out as we spent most of our time dealing with their infamous bureaucracy and obnoxious "authorities." The fact that it was below freezing outside and we were trapped for days on end in hotels made it worse.


text:
<!DOCTYPE html>

        <meta charset="utf-8">
        <meta http-equiv="X-UA-Compatible" content="IE=edge">
        <title></title>
        <meta name="description" content="">
        <meta name="viewport" content="width=device-width, initial-scale=1">

        <link rel="stylesheet" href="css/bootstrap.css">

Quora

            Quora has taken the world by storm with a unique system that works so fluidly you would wonder why anyone is making a big deal about it. It's a powerful tool that simple lets you ask and answer questions. What makes this tool so unique is the super fast auto complete search box, which also doubles as a method for adding new questions. The site is developed by some of the co-founders Facebook.

Fast Queries

            The search box is very, very fast, but why is this? The queries are sent over AJAX as a GET request. The response then comes in as JSON with the rendered HTML embedded inside the JSON. Quora uses a persistent connection, meaning the HTTP connection is established when you start typing in the search box.

Webnode2 and Livenode

            Webnode2 and Livenode are some of Quora's internal systems, which are for managing content. Webnode2 generates HTML, CSS and JavaScript, which is paired with LiveNode, which manages the display of the content on the page. They would like to open source LiveNode however that would be too much work at the time.

Amazon Web Services

            Amazon EC2 and S3 are used for the hosting; it's perfectly designed for fast growing companies. Quora also uses Ubuntu Linux as its OS, since it's easy to deploy and manage on Amazon EC2. For serving up static content Quora uses Amazon's distributed content delivery network Cloudfront.

HAProxy Load-Balancing

            Quora uses HAProxy at the front end, which load balances on the distributed Nginx servers. Behind the load balancer sits Nginx, which is used a reverse proxy server onto the web servers. Pylons, which is a lightweight web framework, is used as their main webserver behind the Nginx. With the Pylons template they scooped out the insides and added their own technologies. Which is where the LiveNode and webnode2 reside. Python was chosen as the language for the site over PHP and JavaScript. The reason Python was chosen over Java was because its more expressive and quicker to write code then Java. Thrift is used for communications between the backend systems. The Thrift is written in C++. Finally the Tornado web framework is used for live updating. This is their Comet server, which handles the large volumes of open connections used for pushing updates to the browser.

Long Polling

            Quora does not just serve up static web pages. The pages are updated with new content when others submit it. Long polling puts the server in control by making the client wait for a request. The server waits to respond to the client's request until they have something new to serve to the page. The benefit of long polling is there is less back and forth between the server and client.

MySQL

            Quora uses MySQL as a distributed data store. They used MySQL instead of NoSQL because for social sites you should not use NoSQL until you have at least one million users. Memcached is used as a caching layer in front of MySQL. Finally they use Git for the version control system. Further look upon Quora's source code its apparent that all the JavaScript is placed at the end of the page. It creates the feeling of a quicker loading page since all the content is loaded before the JavaScript is seen.

References:

            "Quora." Why Did Choose Python for Its Development? -. N.p., n.d. Web. 24 Feb. 2015.
            http://www.quora.com/Why-did-Quora-choose-Python-for-its-development

            Whelan, Phil. "Quora's Technology Examined." Big Fast Blog. N.p., 31 Feb. 2011. Web. 24 Feb. 2015.
            http://www.bigfastblog.com/quoras-technology-examined

redpajama_set_name: RedPajamaGithub


I spoke yesterday at the StrataRx conference in Boston, as part of the data liquidity track. This was sort of a blue sky presentation (as you can tell from the first slide); the thought was to explore the notion of building big data analytics on top of a data store populated by health record information obtained as a result of patient requests. Why? Because doing it that way would bring the data out from under HIPAA and HITECH regulations. Patients could contribute as much or as little of the data as they wish, patients could be compensated for their contributions, and other pesky HIPAA restrictions would fall by the wayside. I used one company's newly-announced service as an example, but there are others in this space as well.
I enjoyed many other presentations, hours of informal hallway and lunchtime conversation (including a great "birds of a feather" lunch table discussion about capturing data streams from wearable sensors hosted by Rachel Kalmar of Misfit Wearables), and catching up with folks I don't get to see often enough in real life.
UPDATE 10/7/2013: See Brian Eastwood's piece covering my presentation and that of Khaled El-Emam at CIO.com: Solving Healthcare's Big Data Analytics Security Conundrum.


Altor Fund II ("Altor") has signed a binding agreement with STC Interfinans to acquire the Åkers Group.
Altor today announced the acquisition of the Åkers Group from STC Interfinans, which will remain as a significant minority shareholder. Åkers is the world leader within cast and forged rolls for the steel and aluminium industries. Supported by Altor, Åkers plan to accelerate growth and to secure world class operating efficiency.
"STC has built Åkers into a market leader and shepherded the company through some difficult years in the beginning of this decade. Åkers is now an excellent platform to drive growth and technology leadership within the roll industry", said Fredrik Strömholm, Partner at Altor Equity Partners AB.
In 1985, the Swedish roll producer Åkers Styckebruk AB was acquired from Bofors AB by Interfinans AB (later to become STC Interfinans), which was owned by the Swedish businessman Mr. Holger Hjelm. During STC Interfinans' period of 100 percent ownership, Åkers has, primarily through acquisitions, been developed into a worldwide group that is today the global market leader within rolls for the steel and metals industries.
"This successful transaction enables STC to surface significant value and to diversify our holdings, for the benefit of our stakeholders. We are very pleased that Altor, a leading and highly respected player in the private equity industry, will be the new majority owner of Åkers. STC, as a significant minority shareholder going forward, will be able to continue to support the company and to benefit from the positive outlook for the steel industry", said Lars Sköld, CEO of STC Interfinans AB.
Altor has prior experience in development of industrial companies from its investments in Dynapac, Meyn, Aalborg Industries, Piab, Northstar and Constructor.
"We believe that the steel industry has a strong outlook for many years to come as it supports the industrialization, urbanization and consumption growth of the fast growing economies in Asia and South America. Åkers as a supplier of a mission critical consumable is in an excellent position to capitalize on this trend", said Harald Mix, Partner at Altor Equity Partners AB.
During the past years, Åkers' management team has been strengthened with several leading steel industry executives, including CEO Bengt Nilsson and CFO Anders Ruth. The management team has started comprehensive efforts in reinforcing Åkers' leading customer service and technology advantage. Altor aims to accelerate these efforts and create a true world class industrial group.
"Åkers is a company with fantastic opportunities. We are excited about having Altor as the majority owner. With their excellent track record in developing industrial companies, I believe that this is extremely positive for Åkers and we look forward to accelerating our development agenda together with them" said Bengt Nilsson, President and CEO, Åkers Group.
Debt financing for the transaction has been arranged by Handelsbanken in Strängnäs. Altor was advised by Handelsbanken Capital Markets and Mannheimer Swartling. STC Interfinans and Åkers were advised by Carnegie Investment Bank and Vinge.
The Altor funds (Altor) are private equity funds comprising the "Altor 2003 Fund", with committed capital of EUR 650 million, and the "Altor Fund II", with committed capital of EUR 1,150 million. Altor is advised by Altor Equity Partners. Altor invests in companies in the Nordic region with a focus on value creation through growth initiatives, strategic development and operational improvements. Among Altor's investments are Lindorff, AGR Group (Listed on the Oslo Stock Exchange), Relacom, Ferrosan, Meyn, Aalborg Industries, PaloDEx, Navico, Byggmax, Nimbus Boats, SPT Group, PIAB, Dustin, Helly Hansen, Euro Cater, Vatus, Northstar, Wrist, Q-matic, Constructor (Aker Material Handling) and Papyrus. Prior investments include ACO Hud AB (divested to Omega Pharma) and Dynapac (divested to Atlas Copco).
STC Interfinans is a private investment company based in Stockholm, Sweden. In addition to Åkers, STC Interfinans also operates in various industrial sectors such as real estate, forestry and fruit and vegetable distribution and processing.


Need a cool, relaxed way to wear a braid that's boho chic and takes two seconds to create? Of course you do. If you love playing around with French and fishtail braids, then mermaid braids will be a breeze for you to master. The key is lots of volume, keeping things the perfect amount of messy and mixing up the textures so that the end look is incredibly romantic. Check out these 12 beautiful examples to get inspired and then get your braid on!
Do you think you'll try your hand at plaiting a mermaid braid? Let us know in the comments below.


text:
The drama of theater photography
By Eric Minton June 2017 issue
"Theater magic" is a well-worn phrase. William Shakespeare linked theater and illusion in his plays "A Midsummer Night's Dream" (with fairies) and "The Tempest" (with a sorcerer). It applies to what audiences feel at productions as diverse as high school drama club plays and Broadway musicals. And it spurs theater practitioners through the hard work, long hours, and years of study required to be part of such illusion. It also motivates the photographers who capture still images of theatrical shows.
Joan Marcus, a freelancer based in New York City, has photographed more than 500 shows over the past 25 years, on and off Broadway and regionally. She photographs as many as a half dozen shows per week. "Last week I did five. This week I'll do three," she says during a phone interview in March, when many new shows are opening. "This is a busy season right now. I work pretty much most days." Nights, too. "I have an asocial schedule."
© JOAN MARCUS
She not only has a portfolio featuring Tony-worthy shows—Broadway hits "Hamilton," "Matilda the Musical," "King Charles III," "The Audience," "Waitress," "Wicked," "Curious Incident of the Dog in the Night-Time," "Peter and the Starcatcher," "Book of Mormon," "Kinky Boots," and "Something Rotten!"—she also received a Tony Honor for Excellence in Theatre in 2014.
On stage, but not staged
Contracted by the productions she photographs, Marcus is equal parts commercial photographer and photojournalist. Some of her images are used in advertising, but they primarily serve as photographic chronicles of what audiences see on stage. These are images that accompany news stories and reviews of the show as well as those used in souvenir programs and box office playbills. "These are the pictures of what you're going to see—what we want you to see," Marcus says.
She usually makes photographs during dress or technical rehearsals or a production's preview shows before opening night, but sometimes she does photo sessions that replicate the stage action. Her preparation starts by attending rehearsals and then photographing a dress rehearsal with no audience or an invited audience.
"Some things are easy, and some things don't need many pictures," she says. She shoots establishing images and then takes a little more risk, experimenting with different points of view. "Then you look and see what you have, and if there's budget and time and desire or need, you might do setups."
Each circumstance comes with restrictions. If she's photographing at a preview with paying patrons, she is standing in a fixed position at the back of a theater with a muzzled camera and a 100-400mm zoom lens. "The audience has paid a lot of money to see a show, so you have to be cognitive of them," she says. In addition, she's contending with stage lighting (which is more contrasting and less forgiving) and the constant motion of dance breaks.
Setup sessions give her more control over lighting—"Sometimes you can bring in additional lighting to fill, but there usually isn't time," she says—but greater challenges in scheduling. "That's the hardest part of it, scheduling," she says. "You have your whole life planned, and then the costumes aren't ready or somebody is sick and it throws your whole week off." Plus, photography is one of the last considerations in scheduling, well below actors' availability, production timelines, and union rules. "You have to adjust to them," she says. "If you can't do it Wednesday at 8, they'll get somebody else. If it changes to Thursday at 2 and you can't do it, they'll get somebody else." She might have a niche market among photographers generally but not in New York.
As with commercial photographers, she's representing her clients. However, while many commercial photographers have creative input into the story being conveyed in their images, a stage show comes with its own story and a fully crafted appearance. Nevertheless, Marcus says she contributes to the vision her images convey.
"I'm presenting my clients with pictures that tell the story of the show and the director in the best, prettiest, and most evocative way I can do it—not just getting key moments but interesting points of view."
She doesn't always have much control over composition. "If actors spend their evening at different ends of the stage, there's nothing you can do about that," she says. She has the option of doing setup shots, but those risk looking too staged. "I much prefer shooting in performance," she says, "but it's nice to have a mix. You want to be truthful and have energy, but you also want to make it look good."
She makes adjustments in post-production but must maintain the designer's intended visual palette and the integrity of an actor in character. "You can Frankenstein," she says. "Maybe in one great dance picture the eyes are closed, but in the next picture they are open, so you move the head from that one to the better photo."
However, her mental approach to her work is more photojournalistic. She does her homework, stakes out her positions, anticipates, reacts. "It happens so fast in front of you, you can't be too thoughtful because the moment is gone. It's reportage, total reportage."
Each show is different, each with its own challenges beyond stage play versus musical, and each venue is different. In fact, the same show in different theaters offers different challenges. She's photographed four iterations of the musical "Hamilton": the original staging at The Public Theater in New York, the Broadway production, the Chicago staging, and the San Francisco edition. "Each one is totally the same, and each one is totally different," in seating and stage configurations, she says. "Each presents new opportunities to take pictures, and each one in the photos looks different." As such, Marcus resists summarizing her technical strategies. "So much of it is intuitive and having done it and learning from things that work and don't work."
That's a philosophy that mirrors her career track. Upon earning a liberal arts degree at George Washington University in Washington, D.C., "I came out with no real direction," she says, except to do something creative. She settled on landscape architecture, but to afford graduate school, she took jobs wherever she could. "I just worked," she says, including building graphics for ABC News in Washington, turning blue jeans into skirts with a friend (a venture that ended when the sewing machine broke), and working in the American Film Institute box office, which was then located in Washington's Kennedy Center for the Performing Arts. As she explored the Center, she discovered the resident photographer's office in the building's basement. Being an amateur photographer with darkroom skills, she knocked on the door. At the time, Milan's Teatro alla Scala was doing a six-opera residency at the Kennedy Center, and the photographer was overwhelmed. "He asked, 'What are you doing after work?'" she says, and later that day she was printing images of "La Bohème." She had become a photographer's assistant at the Kennedy Center.
"I loved being under the opera house, I loved seeing the dancers and actors in the Center's canteen," Marcus says. "I loved the environment, and I just got hooked." She put graduate school on hold. When her boss suggested she start pursuing her own clients, she approached other theaters in the city, and as Washington's theater scene grew, so did her client list. "I decided that if I could make more money every year, if I felt I was getting ahead, I would keep doing it."
She took over as official photographer at the Kennedy Center on a contract basis when her former boss left. The Kennedy Center serves as a tryout venue for shows heading for Broadway, and when Marcus photographed shows in Washington, producers often invited her to photograph them in New York. She soon became part of the D.C.-New York theatrical pipeline, "a huge pipeline," she says, with the biggest thrust coming from the Kennedy Center residency of "Les Miserables." "I didn't shoot it, but I ran film to the lab, and that introduced me to people in the Cameron Macintosh organization (the show's producer), and that opened doors for me." On one of her trips to New York she met a theater publicist, Adrian Bryan-Brown, who would become her husband. After a year of commuter marriage, she moved to New York in 1992.
She was 37 at the time. The couple never had children, and "not having kids shaped my lifestyle. Had we had kids, I wouldn't be as flexible as I am now." Because her husband is involved in the theater business, he understands the unpredictability of her schedule. "You miss a lot of family events. I devote myself to work, and there's certain trade-offs, but it's the life I have. I don't have regrets. I've just followed what my life was."
And she still feels the tug of that theater magic she absorbed when she began working at the Kennedy Center, only now she's contributing her own magic. "I just enjoy taking the pictures. It's like cooking or gardening. It makes me feel good. There's the concentration of doing your job, and you have an end product, and you know whether you did a good or bad job." Spoken like a true theater pro.
RELATED: See a gallery of Joan Marcus photographs.
Eric Minton is a writer and editor in Washington, D.C.
Tags: commercial photography, niche photography
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Proximity is everything


text:
from snovault import upgrade_step

@upgrade_step('user', '', '3')
def user_0_3(value, system):
    # http://encode.stanford.edu/issues/1307
    if 'status' in value:
        value['status'] = value['status'].lower()

@upgrade_step('user', '3', '4')
def user_3_4(value, system):
    # http://redmine.encodedcc.org/issues/4743
    value['viewing_groups'] = [
        'ENCODE3' if v == 'ENCODE' else v
        for v in value['viewing_groups']
    ]

@upgrade_step('user', '6', '7')
def user_6_7(value, system):
    # https://encodedcc.atlassian.net/browse/ENCD-3409
    if 'phone1' in value:
        del value['phone1']
    if 'phone2' in value:
        del value['phone2']
    if 'fax' in value:
        del value['fax']
    if 'skype' in value:
        del value['skype']
    if 'google' in value:
        del value['google']
    if 'timezone' in value:
        del value['timezone']

@upgrade_step('user', '7', '8')
def user_7_8(value, system):
    groups = value.get('viewing_groups')
    if groups:
        if 'community' not in groups:
            value['viewing_groups'].append('community')
    else:
        value['viewing_groups'] = ['community']

@upgrade_step('user', '8', '9')
def user_8_9(value, system):
    if 'groups' in value:
        value['groups'] = [group for group in value['groups'] if group in ['admin', 'verified', 'read-only-admin']]


text:
Artist Jan-Hendrik Pelz Debuts Gallery of Favorite Films Oil Paintings
What is your favorite film? It's a common question discussed amongst cinephiles the world over, and one artist has taken it even further. German artist Jan-Hendrik Pelz has debuted a gallery at the Locarno Film Festival in Switzerland this week titled "Favorites", featuring over 30 oil paintings of one frame of a film. Here's the concept - Pelz asked his favorite artists/filmmakers to name their favorite movie "together with a random number of maximum 5 digits as a time stamp. Stopping the movies later at the corresponding times created unpredictable freeze frames, which in the next step Pelz transferred into oil paintings." This mesmerizing gallery is the result of a year of work producing these paintings - see the various frames below.
I'm currently in Locarno for the festival and stopped by the gallery to take a look. I was impressed, there's something striking about seeing random frames from such great films. Favorites span from Apocalypto to Zabriskie Point, with essentials like Taxi Driver, Magnolia, Apocalypse Now, Harold & Maude, Life of Brian, Andrei Rublev, Thelma & Louise, Goodfellas, North by Northwest, Batman, No Country for Old Man, Labyrinth, The Big Lebowski, Scanners and The Jungle Book. Artists he asked include Jonathan Meese, Luc Tuymans, John Baldessari, Pipilotti Rist, Hermann Nitsch and others.
Here's a look at the art inside of the gallery, which is best seen in person (if/when this exhibit is near you):
Below is a look at most of the individual paintings on display in Locarno - click each one to enlarge the shot:
Finally, last but not least, it's the Empire Strikes Back painting (from 18:04) as selected by Charlie Stein.
(Note: the faint lines on this image are from a reflection off of glass, not part of the actual painting.)
While browsing the gallery, I met and spoke with Jan-Hendrik Pelz (his official website) about the project, who told me that it took him a year to complete. Most of the selections are genuine favorite films, with some oddball picks thrown in (like Apocalypto, Sharknado, Mission to Mars, Hausu). For those wondering, the Scanners head explosion shot might not be random, as he told me that the artist who chose that one (Peter Kogler) needed an "extra day" to think about his selection before choosing Scanners and that time (12:29), which seemed a bit too coincidental even for him. But other artists chose numbers such as their birth year, or something else unique (12:34, or 1,2,3,4, from No Country - which still produced an interesting frame).
It's easy to look at these and say, well, random frames chosen from favorite films don't produce the prettiest pictures, but I would disagree. The lasting impression of this exhibition is that random selection can result in beauty, and that it doesn't always have to be the perfect shot to find something unique. Just look at the frame for The Big Lebowski. The power of this art is in the collection of all of them, and how mesmerizing it is to take one glance at a wall of nicely painted art that evokes so many emotions, feelings, questions, and thoughts about cinema. Hopefully Pelz's art will be touring the world over for many others to see in person.
For more info on Jan-Hendrik Pelz's "Favorites" visit his website which includes the full list of names/films.
Find more posts: Artwork, Cool Stuff
How lovely. Dig the SCANNERS one.
DAVIDPD on Aug 12, 2014
Wow. Super cool.
Quanah on Aug 12, 2014


text:
Jargalant (, "Happiness", ) is a sum (district) of Bayankhongor Province in southern Mongolia. In 2006, its population was 3,173.

References

Populated places in Mongolia
Districts of Bayankhongor Province

redpajama_set_name: RedPajamaWikipedia


text:
Acanthothecis africana är en lavart som beskrevs av Staiger & Kalb. Acanthothecis africana ingår i släktet Acanthothecis och familjen Graphidaceae.   Inga underarter finns listade i Catalogue of Life.

Källor

Externa länkar

Sporsäcksvampar
africana


Agreeing a joint venture with another business can make real sense in the commercial world, enabling both parties to add a new dimension to their offering and complement each others' businesses. Joint ventures and joint venture agreements are not always straight forward and require careful planning, consideration and openness in order for them to be successful.
Successful joint ventures have led to some great achievements for all parties involved and can help introduce products into new markets and distribution channels that may not have been open or extremely difficult for one party to achieve on their own. Joint venture agreements will also enable each party to share the risk as well as the liabilities and rewards, which can be appealing if the parties are not accustomed to the particular product or service markets the new venture takes them in to.
Something to bear in mind when choosing another business to go into a joint venture with is that, as well as working through and setting up a joint venture agreement, you need to understand the culture of the business you will be partnering. This can be a big factor in the success of the venture, should it get off the ground, with all parties putting in a concerted effort only to find the culture gap between the businesses is too difficult to deal with. This is where pre- planning and talks may help to avoid, or at least see, any communication or expectation obstacles that may lie in the road ahead. Each business's requirements and expectations must be fully understood by each party otherwise this can put a halt to proceedings as well as being a huge waste of resources and capital.
A good corporate solicitor will advise on legal issues facing your venture and will make sure that all possibilities and eventualities are agreed and drafted into a joint venture agreement so that each party knows what is expected of them, the operational control they will have and the rewards they will receive. There are different types of joint ventures and your legal advisor will set up the correct type, which will usually depend upon; the nature of the businesses, the proposed running plans for the new venture, the mechanism for profit sharing and also tax implications. A typical joint venture agreement will cover all of the areas listed below as well as other, perhaps more bespoke clauses, in order to fully satisfy what the parties set out to achieve.
The structure of the joint venture will be documented.
Each party will commit to their financial contributions to the venture.
The commitment of the parties with regards to assets and employees that will be utilised by the new venture.
Any intellectual property that is created via the joint venture and its ownership.
The business will require management control and who, and to what extent, are the parties responsible for this.
The business will attain liabilities, losses and also profits. The distribution of these will be agreed and documented.
Although no-one sets out to fail or sets out with a negative attitude, sometimes a dispute is inevitable and as such it is vital that an agreed process for dispute resolution is agreed at this early stage, often involving a third party that each side would be happy is impartial.
This can sometimes cause a lot of negotiation, but the exit strategy needs to be agreed and documented.
For any enquiries or more information, please send an email to lorraine.smith@orj.co.uk or call 01785 223440.