Alzheimer's disease (AD) is associated with regional reductions in fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the cerebral metabolic rate for glucose, which may begin long before the onset of histopathological or clinical features, especially in carriers of a common AD susceptibility gene. Molecular evaluation of cells from metabolically affected brain regions could provide new information about the pathogenesis of AD and new targets at which to aim disease-slowing and prevention therapies. Data from a genome-wide transcriptomic study were used to compare the expression of 80 metabolically relevant nuclear genes from laser-capture microdissected non-tangle-bearing neurons from autopsy brains of AD cases and normal controls in posterior cingulate cortex, which is metabolically affected in the earliest stages; other brain regions metabolically affected in PET studies of AD or normal aging; and visual cortex, which is relatively spared. Compared with controls, AD cases had significantly lower expression of 70% of the nuclear genes encoding subunits of the mitochondrial electron transport chain in posterior cingulate cortex, 65% of those in the middle temporal gyrus, 61% of those in hippocampal CA1, 23% of those in entorhinal cortex, 16% of those in visual cortex, and 5% of those in the superior frontal gyrus. Western blots confirmed underexpression of those complex I–V subunits assessed at the protein level. Cerebral metabolic rate for glucose abnormalities in FDG PET studies of AD may be associated with reduced neuronal expression of nuclear genes encoding subunits of the mitochondrial electron transport chain.
Alzheimer's disease (AD) is associated with characteristic and progressive reductions in regional positron emission tomography (PET) measurements of the cerebral metabolic rate for glucose (CMRgl). These CMRgl reductions have been reported in the posterior cingulate, parietal, and temporal cortex, and in the frontal cortex and whole brain in more severely affected patients (1–5). Other studies have reported CMRgl reductions in anatomically well characterized hippocampal and entorhinal cortical regions of interest (6–10). The posterior cingulate cortex (PCC) and the neighboring precuneus are metabolically affected in the earliest clinical and preclinical stages of AD (4, 11), and the primary visual cortex is relatively spared (4, 11). In an ongoing series of studies, we have detected CMRgl reductions in cognitively normal carriers of the apolipoprotein E (APOE) ε4 allele (11–15), a common late-onset AD susceptibility gene (16–18). CMRgl reductions in AD-affected areas were correlated with APOE ε4 gene dose (i.e., three levels of genetic risk for AD) and were progressive in late-middle-aged persons (19). These reductions were also apparent in young adult APOE ε4 heterozygotes (13), more than four decades before the anticipated median onset of dementia, years before the expected onset of the major histopathological features of AD (neurofibrillary tangles and amyloid plaques), and, indeed, in anticipating the initial regional appearance of fibrillar amyloid deposition. (20, 21).
AD-related CMRgl reductions could reflect reductions in the density or activity of terminal neuronal fields or peri-synaptic glial cells (22, 23), a metabolic dysfunction in neurons or glial cells not related to neuronal activity (24, 25), or a combination of these factors. These changes do not appear to be solely attributable to the combined effects of atrophy and partial-volume averaging (26). In a postmortem histochemistry study, we previously found that AD cases had lower cytochrome c oxidase activity than controls in the PCC, and that this reduction was significantly greater than that in primary motor cortex (27), another region that is relatively spared. Based on this observation, we proposed that AD might be related to an impairment in neuronal metabolism.
Molecular evaluation of the cells from metabolically affected brain regions could provide new information about the pathogenesis of AD and new targets at which to aim disease-slowing and prevention therapies. Data from a genome-wide transcriptomic study were used to compare, in each of our sampled brain regions, the expression of metabolically relevant nuclear genes from laser-capture microdissected non-tangle-bearing neurons of expired cases with clinically characterized and histopathologically verified AD and expired controls who did meet clinical criteria for dementia and histopathological criteria for AD.
In particular, the data were used to compare cases and controls in the expression of 80 nuclear genes encoding mitochondrial electron transport chain (ETC) subunits along with translocases of the inner and outer mitochondrial membranes (TIMMs and TOMMs, respectively), in six brain regions. These nuclear genes included 39 complex I genes coding for NADH dehydrogenase, all 4 nuclear-encoded complex II genes coding for succinate dehydrogenase, 9 complex III genes coding for ubiquinol-cytochrome c reductase, 13 complex IV genes coding for cytochrome c oxidase, and 15 complex V genes coding for ATP synthase, as well as 11 TIMMs and 6 TOMMs, which regulate the transport of nuclear-encoded electron transport subunits into the mitochondria. These ETC complexes and translocases are illustrated in Fig. 1. The six brain regions included the PCC, which is associated with unusually early CMRgl reductions in AD (4, 28); the middle temporal gyrus (MTG); the hippocampal field CA1 (HIP) and entorhinal cortex (EC), which are also metabolically affected in AD (1, 20); the superior frontal gyrus (SFG), which is associated with preferential CMRgl reductions in normal aging (29–33); and the primary visual cortex (VC), which is relatively spared from CMRgl reductions in both aging and AD (4, 11).
Altered expression of mitochondrial energy metabolism elements. Energy metabolism-relevant elements showing statistically significant underexpression in the PCC are shown. These elements include the five complexes of the ETC and TIMMs and TOMMs. OM, outer mitochondrial membrane; IMS, intermembrane space; IM, inner mitochondrial membrane.
We initially tested the hypothesis that AD would be associated with reduced neuronal expression of metabolically relevant nuclear genes in the PCC and that these AD-related reductions would be significantly greater than those in VC. (Findings from our survey of 55,000 neuronal transcripts have been published in ref. 54.) AD-related reductions in the posterior cingulate neuronal expression of several of the implicated complexes I–IV and ATP synthase (complex V) subunits were subsequently validated at the protein level, suggesting that the reductions in the neuronal expression of metabolically relevant nuclear genes might be associated with the CMRgl reductions found in fluorodeoxyglucose positron emission tomography (FDG PET) studies of AD.
Fold change values and P values for the 80 ETC and translocase genes in each of the sampled regions are posted at www.tgen.org/neurogenomics/pcc, and additional expression results have been reported in ref. 54. The proportion of significantly underexpressed ETC and translocase genes in each of the sampled brain regions (P < 0.01 after correction for multiple comparisons) is shown in Table 1. In comparison with controls, AD cases had significantly lower expression of 70% of the nuclear genes encoding mitochondrial ETC subunits in PCC pyramidal neurons, 65% of those in MTG neurons, 61% in HIP neurons, 23% in EC layer II stellate neurons, 16% in VC neurons, and 5% in SFG neurons. By comparison, AD cases had significantly higher expression of only 4% of the nuclear genes encoding mitochondrial ETC subunits in PCC pyramidal neurons, 13% of those in MTG neurons, 8% of HIP neurons, 1% of EC neurons, 4% of VC neurons, and 0% of SFG neurons (data for these genes are listed on the supplementary data site). Additional factors that displayed statistically significant underexpression in the PCC, and which may influence mitochondrial energy metabolism, include the TIMMs and TOMMs (Table 1; individual P values and fold changes are located on the supplementary data site), which are required for the transportation of proteins, including ETC components, from the cytoplasm to the inner mitochondrial membrane and different compartments in the mitochondria (34–37). Overall, 35% of these translocases demonstrated underexpression in the PCC neurons, 47% in the MTG neurons, 41% in the HIP neurons, 35% in the EC neurons, 6% in the VC neurons, and 24% in the SFG neurons. By comparison, only 6% of the translocases showed overexpression in the PCC and HIP; 12% in the VC; and 0% in the MTG, EC, and SFG.
In a post hoc analysis, we compared the proportion of all genes underexpressed in the neurons of AD cases and controls. AD was associated with underexpression of 61% of statistically significant (P < 0.01, corrected for multiple comparisons) genes in the PCC, 43% of those in the MTG, 56% of those in the HIP, 69% of those in the EC, 81% of those in the SFG, and 58% of those in the VC. These findings suggest that although metabolism genes may not be disproportionately affected in AD, the regional pattern of underexpressed metabolic genes (PCC > SFG and VC) more closely reflects the pattern of metabolic reductions observed in PET studies.
Western blot validation. (A) Western blots using a five-antibody mixture labeling a subunit of each mitochondrial enzyme complex from PCC whole-brain extract. H, human heart for positive control; AD, Alzheimer's patient; NC, normal control. Apparent molecular mass scale is indicated on the right. From highest to lowest are complex V alpha subunit, complex III core 2 subunit, complex II 30-kDa subunit, complex IV subunit II, and complex I 20-kDA subunit. Results are representative of duplicate blots. (B) Western blot-band optical density, expressed as percentage of normal-aged control. Subunit protein expression was significantly lower (two-tailed t test, P < 0.01) for each subunit tested. n = 10 AD; n = 5 NC.
This study provides transcriptomic and protein evidence of neuronal metabolic impairments in AD brains, complementing previously established PET evidence of metabolic impairments in persons afflicted by or at risk for this disorder. In our analysis of the nuclear genes influencing mitochondrial energy metabolism (i.e., 80 nuclear genes encoding ETC subunits and 17 nuclear genes encoding mitochondrial translocases responsible for the entry of ETC subunits into the mitochondria), the largest proportion of underexpressed genes was in the PCC, a region which PET studies find to be metabolically affected in the earliest stages of AD. The proportion of underexpressed genes was significantly greater than those in the VC, which is relatively spared in PET studies of AD. The MTG, EC, and HIP, which are also affected in PET studies of AD, had proportions of underexpressed genes in between those in the PCC and VC.
Because our analysis was confined to laser-capture microdissected neurons, our findings suggest that the CMRgI reductions observed in PET studies of AD are at least partly related to molecular processes in neurons themselves, and are thus not solely attributable to a reduction in the activity of perisynaptic glial cells known to influence CMRgI (23). They also suggest that the CMRgI reductions could be at least partly related to molecular processes in neuronal cell bodies (i.e., changes in nuclear gene expression), even though alterations in PET CMRgI measurements have been suggested to be more strongly influenced by the activity of terminal neuronal fields (22). Furthermore, this differential pattern of ETC and metabolic involvement across the cortex highlights the differential vulnerability of various regions to the pathophysiology of AD. Our current transcriptomic findings and previous PET studies raise the possibility that the molecular processes involved in neuronal energy metabolism may be involved in the earliest pathogenesis of AD, possibly preceding the onset of neuritic plaques.
Earlier gene expression and functional activity studies provide confirmatory evidence of this regional pattern of ETC changes. Underexpression was found for mitochondrially-encoded and nuclear-encoded ETC subunits in the middle temporal cortex, but not in motor cortex, of AD patients (38, 39). In a laminar analysis, the PCC also showed the most prominent and significant functional declines across each cortical layer in complex IV activity, whereas the motor cortex was relatively spared (27). Middle temporal, superior temporal, and inferior parietal cortices showed significant layer III activity declines, in agreement with our gene expression data, with the midfrontal cortex showing the smallest decline (40). Further, as the layer III cell bodies from which the expression data were taken project apical dendrites (containing the highest metabolic demand) into the superficial layers of the cortex, these layers (I and II) showed globally, albeit not always significantly, reduced ETC activity that could result from decreased subunit expression in the layer III soma (40).
The regional pattern of underexpression in the genes encoding ETC subunits, which have been validated here with Western blots, corresponds to the regional pattern of CMRgI reductions observed in PET studies of patients with AD (28, 41–45) such that the PCC and precuneus are preferentially affected in AD (11, 16, 17, 19). Because PET studies have also identified the PCC as showing the earliest metabolic changes in cognitively normal carriers of the APOE ε4 allele (19), these changes may precede downstream development of AD pathologies including amyloid plaque and neurofibrillary tangle formation. Metabolic alterations in the PCC have also been implicated in maintaining the brain's "default" state when it is not engaged in the performance of specific tasks (46) or episodic memory tasks (20), as well as in the predisposition to initial hypometabolic (11–13) and subsequent fibrillar amyloid changes (20, 47, 48) associated with AD. The current study provides new information about the neuronal processes involved in these normal and pathological human behaviors.
This study capitalized on the genome-wide evaluation of gene transcripts from laser-capture microdissected neurons from extremely high-quality brain tissue [mean postmortem interval (PMI) = 2.5 h] in clinically and neuropathologically well-characterized AD cases and age-matched controls, and on the analysis of neurons from brain regions preferentially affected or spared in PET studies of AD. Although this study provides clues about the molecular processes related to the CMRgI reductions observed in persons afflicted by and at genetic risk for AD, it has several limitations. First, given the descriptive nature of our findings, it remains to be clarified whether the changes in the nuclear expression of mitochondrial metabolism genes cause reductions in the density or activity of terminal neuronal fields or instead are a consequence of the reduced metabolic demands associated with terminal neuronal changes in AD. Second, it also remains to be clarified whether or not AD is also associated with underexpression of mitochondrially encoded genes from the same neurons (a technically challenging question to address in laser-capture microdissected cells) or in the nuclear or mitochondrial genes of perisynaptic glial cells. Third, although we controlled for mean age at death and gender, there is a small possibility that other group differences in the agonal state preceding death contributed to some of the AD-related reductions in neuronal gene expression observed in this study. Finally, findings from our study suggest that a high proportion of genes are underexpressed in AD, whether or not they are known to directly influence neuronal metabolism. However, the regional pattern of underexpressed genes regulating mitochondrial metabolism appear to correspond to the pattern of CMRgI changes in AD.
Noting the pattern of metabolic changes in our PET studies of AD, Roses et al. have suggested that insulin sensitizers may be helpful in the treatment and prevention of AD (49, 50). Findings from our neurotranscriptomic study could provide clues about the molecular mechanisms that may be involved in the earliest pathogenesis of this disorder and potential targets at which to aim new disease-slowing and prevention therapies.
This study provides transcriptomic and protein evidence that the neuronal nuclear genes influencing mitochondrial energy metabolism are underexpressed in AD, particularly in brain regions like the PCC, which are found to be preferentially affected in PET studies of AD patients and cognitively normal persons at genetic risk for this disorder. In doing so, this study provides information about the molecular processes involved in the pathogenesis of AD and potential therapeutic targets at which to aim disease-slowing and prevention therapies.
Brain samples were collected at three Alzheimer's Disease Centers (Washington University, Duke University, and Sun Health Research Institute) from clinically and neuropathologically classified late-onset AD-afflicted individuals (15 males and 18 females) with a mean age of 79.9 ± 6.9 years. Tissue collection of healthy elderly controls was published in a previous report (51); Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuritic plaque density was infrequent and Braak stages ranged from I to II. All individuals were Caucasian and were matched as closely as possible for gender and mean age at death. Subjects in the AD group had a Braak stage of V or VI (47) with a CERAD score of moderate or frequent (52). Samples were collected (mean PMI of 2.5 h) from six brain regions that are either histopathologically or metabolically relevant to AD. These include the EC (BA 28 and 34), SFG (BA 10 and 11), HIP, VC (BA 17), MTG (BA 21 and 37), and PCC (BA 23 and 31). The EC and HIP are preferentially affected by intracellular neurofibrillary tangles, the MTG and PCC are preferentially affected by metabolism and extracellular β-amyloid plaques, the SFG is preferentially affected by aging, and the VC is relatively spared from both aging and AD pathologies. After dissection, samples were frozen, sectioned (10 μm), and mounted on glass slides.
As previously described (53), brain sections were stained with a combination of thioflavin-S (Sigma) and 1% neutral red (Fisher Scientific), pyramidal neurons were identified by their characteristic size, shape, and location within the region of interest, and tangles were identified by the bright green fluorescence of thioflavin-S staining. In the EC, the large stellate neurons lacking thioflavin-S staining were collected from layer II, and pyramidal cells lacking thioflavin-S staining were collected from CA1 of the HIP. The CA1 region was selected for study because this area is the most, and earliest, affected region in terms of tangle formation, and it has already been expression profiled in neurologically healthy elderly individuals. In all other regions, cortical layer III pyramidal neurons lacking thioflavin-S staining were collected (for all collected neurons, cell bodies were extracted). For each individual, ≈500 histopathologically normal pyramidal neurons were collected from the six brain regions by using laser-capture microdissection (Veritas automated laser-capture microdissection system; Arcturus). Cells were collected onto Arcturus CapSure Macro LCM caps and extracted according to the manufacturer's instructions. Total RNA was isolated from the cell lysate by using the Arcturus PicoPure RNA isolation kit with DNase I treatment using the Qiagen RNase-free DNase set.
Expression profiling was performed as previously described (51). Isolated total RNA was double-round amplified, cleaned, and biotin labeled with the Affymetrix GeneChip two-cycle target labeling kit with a T7 promoter and the Ambion MEGAscript T7 high-yield transcription kit according to the manufacturer's instructions. Amplified and labeled cRNA was quantitated on a spectrophotometer and run on a 1% TAE gel to check for an evenly distributed range of transcript sizes. Twenty micrograms of cRNA was fragmented to ≈35–200 bp by alkaline treatment (200 mM Tris-acetate, pH 8.2; 500 mM KOAc; 150 mM MgOAc) and run on a 1% TAE gel to verify fragmentation. Separate hybridization cocktails were made by using 15 μg of fragmented cRNA from each sample according to Affymetrix's instructions.
Two hundred microliters of each mixture was separately hybridized to an Affymetrix Human Genome U133 Plus 2.0 array for 16 h at 45°C in the Hybridization Oven 640. The Affymetrix human genome arrays measure the expression of over 47,000 transcripts and variants, including 38,500 characterized human genes. Hybridization cocktails for nine EC samples (normal neurons from AD brains) previously collected following the same profiling methodology used in this project (53) were reanalyzed on the U133 Plus 2.0 array to be evaluated in this study; a 10th EC sample was also separately processed for this sample group. Arrays are washed on the Affymetrix upgraded GeneChip Fluidics Station 450 by using a primary streptavidin phycoerythrin (SAPE) stain, subsequent biotinylated antibody stain, and secondary SAPE stain. Arrays are scanned on the Affymetrix GeneChip Scanner 3000 7G with AutoLoader. Scanned images obtained by the Affymetrix GeneChip Operating Software (GCOS) v1.2 were used to extract raw signal intensity values per probe set on the array and calculate detection calls (absent, marginal, or present). Assignment of detection calls is based on probe-pair intensities for which one probe is a perfect match of the reference sequence and the other is a mismatch probe for which the 13th base (of the 25-oligonucleotide reference sequence) is changed. All raw chip data were scaled to 150 in GCOS to normalize signal intensities for interarray comparisons. Reports generated by GCOS were reviewed for quality control; we looked for at least 20% present calls, a maximum 3′/5′ GAPDH ratio of 30, and a scaling factor <10. Twenty arrays that failed to pass these standards were not included in further analyses.
To ensure neuronal cell purity in the samples, we evaluated expression of GFAP, an astrocyte cell marker. Fourteen samples that had GFAP expression greater than one standard deviation from the mean were removed from statistical analyses.
Data for samples from neurologically healthy elderly controls were generated in a previous study (51). Microarray data files of the normal samples are available on the Gene Expression Omnibus site at www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc = GSE5281 (project accession no. GSE5281), and regional analyses are posted at www.tgen.org/neurogenomics/data/private3.
We compared AD cases and controls in the neuronal expression of 80 nuclear genes encoding subunits of the mitochondrial ETC in each of our sampled brain regions. The nuclear genes included 39 complex I genes coding for NADH dehydrogenase (NDUFA1–A13, NDUFAF1, NDUFAB1, NDUFB1–B11, NDUFC1 and -C2, NDUFS1–S8, and NDUFV1–V3), all 4 complex II genes coding for succinate dehydrogenase (SDHA, SDHB, SDHC, and SDHD), 9 complex III genes coding for ubiquinol-cytochrome c reductase (UCRC, UQCR, UQCRB, UQCRC1, UQCRC2, UQCRFS1, UQCRH, CYC1, and CYCS), 13 complex IV genes coding for cytochrome c oxidase (COX4I1, COX5A, COX5B, COX6A1, COX6A2, COX6B1, COX6C, COX7A2L, COX7B, COX7B2, COX7C, COX8A, and COX8C), and 15 complex V genes coding for ATP synthase (ATP5A1, ATP5B, ATP5C1, ATP5D, ATP5E, ATP5F1, ATP5G1–G3, ATP5H, ATP5I, ATP5J, ATP5J2, ATP5L, and ATP5O). TIMM and TOMM expression was also evaluated (TIMM8A, TIMM8B, TIMM9, TIMM10, TIMM13, TIMM17A, TIMM17B, TIMM22, TIMM23, TIMM44, TIMM50, TOMM7, TOMM20, TOMM22, TOMM34, TOMM40, and TOMM70A). Mitochondrial DNA-encoded subunits were not assessed in this study.
Direct comparisons between neurologically healthy and AD-afflicted brains were performed in all six regions to analyze expression differences in the above-listed ETC subunits. For each analysis, genes that did not demonstrate at least ≈10% present calls across all transcripts profiled for each region-specific comparison were removed by using Genespring GX 7.3 Expression Analysis software (Agilent Technologies). A two-tailed unpaired t test, assuming unequal variances (with a multiple testing correction using the Benjamini and Hochberg false discovery rate), was applied to each comparison for all genes that passed the 10% present-call criterion to locate genes that were statistically significant in differentiating expression between healthy brains and AD brains. (After the present-call filter, 32,153 genes in the PCC were used for P value correction, 30,897 genes in the EC, 32,265 genes in the MTG, 31,496 genes in the HIP, 32,482 genes in the VC, and 32,118 genes in the SFG.) For each analysis comparing AD expression levels with control levels, genes that had a corrected P value ≤ 0.01 were collected, and those genes whose average AD signal and average control signal were both below a threshold of 150 were removed. Fold-change values were determined by calculating the ratio between the average scaled expression signal (for all affected samples) for a gene from the AD sample region and the average scaled expression signal for the same gene from the normal samples across all regional comparisons.
Using this approach, we evaluated ETC and translocase genes that were differentially expressed in the AD cases versus controls for each of the six brain regions of study. Proportions of ETC and translocase genes demonstrating under- and overexpression were determined by calculating the number of subunits (at least ≈10% present calls with corrected P < 0.01) showing such changes over the total number of nuclear-encoded subunits (at least ≈10% present calls with corrected P < 0.01) on the Affymetrix human genome array. Evaluation of all human genes demonstrating underexpression in each region focused on only those genes with statistical significance (P < 0.01 with multiple testing corrections, after present-call filters) for each regional AD versus controls comparison; underexpression percentages were calculated based on a ratio of underexpressed statistically significant genes over all genes.
Minimum information about a microarray experiment (MIAME)-compliant microarray data files for control samples are located on the Gene Expression Omnibus (GEO) site at www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE5281 (project accession no. GSE5281). Fold changes and corrected and uncorrected P values for all ETC and translocase genes on the Affymetrix Human Genome Array for each of the six regional comparisons are available online at www.tgen.org/neurogenomics/pcc. Posted lists show respective genes that have at least ≈10% present calls across regional samples (no fold change thresholds have been applied on these lists). Additional expression results will be published in a separate report.
Based on availability, 10 profiled AD PCC cases and 5 profiled healthy control cases were collected for Western blot validation. Blots were run by researchers blind to subject condition. Sections were washed from slides by using PBS, and 35 μg of protein per lane was loaded into 10–20% 1.5 mm Tris-glycine 15-well minigels (Invitrogen) with Novex Tris-glycine SDS 2× sample buffer. Gels were run in Novex minicell (Invitrogen) for 90 min at constant 150 V with Novex Tris-glycine SDS running buffer. Proteins were transferred to Immobilon P (Millipore) PVDF membrane, fully submerged in CAPS transfer buffer (10 mM 3-[cyclohexylamino]-1-propane sulfonic acid, pH 11 with NaOH, 10% methanol) by using constant 150 mA for 2 h. Membranes were blocked overnight in 5% Carnation dry milk in PBS at 4°C and then probed with the total OXPHOS detection kit (MS601; 1:1,000 in 1% dry milk; Mitosciences) for 2 h at room temperature with gentle rocking. This five-antibody mixture marks the 20-kDa subunit of complex I (ND6; mitochondrially encoded), the 30-kDa iron–sulfur subunit of complex II, the core 2 subunit of complex III, COX II of complex IV (mitochondrially encoded), and the F1α subunit of ATP synthase. Goat anti-mouse alkaline phosphatase (AP)-conjugated secondary antibody (1:10,000 in 1% dry milk; Santa Cruz Biotechnology) was used (2 h at room temperature with rocking), followed by application of an AP substrate detection kit (Bio-Rad), according to the manufacturer's instructions. Membranes were dried overnight, then simultaneously scanned on a Mustek A3 EP flatbed scanner. All blots were performed in duplicate. The image was imported into Optimas image analysis software (Media Cybernetics), and average OD measures of each band were taken by using a sampling window of constant size. Groups were compared by using Student's two-tailed t tests, uncorrected for multiple comparisons, and 95% confidence intervals for each complex were calculated in Excel.
We thank Roger Higdon and Daniel McKeel for their support through Alzheimer's Disease Research Centers, Lucia Sue (Sun Health Research Institute) for assistance with clinical data, Nick Lehmans (Translational Genomics Research Institute) for setting up the supplementary data site, the National Institute on Aging's Alzheimer's Disease Centers (ADC) program, and the National Alzheimer's Coordinating Center for help in obtaining samples for analysis. This project was funded by the National Institute on Aging Grants K01AG024079 (to T.D.), 1-RO1-AG023193 (to D.A.S.), P30 AG19610 (to E.M.R. for Arizona ADC), P50 AG05681 (to J.C.M.), P01 AG03991 (to J.C.M.), AG05128 (for the Duke University Alzheimer's Disease Research Center), National Alzheimer's Coordinating Center Grant U01AG016976, the state of Arizona (E.M.R.), and the Barrow Neurological Foundation Women's Board (J.V.).
Author contributions: D.A.S. designed research; W.S.L., J.V., T.D., T.G.B., T.L.N., and L.E.S. performed research; A.G., D.M., R.C., W.K., J.C.M., C.M.H., D.S., and J.R. contributed new reagents/analytic tools; W.S.L. and J.V. analyzed data; and W.S.L., E.M.R., and J.V. wrote the paper.
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE5281).
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(1995) A diagnostic approach in Alzheimer's disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET. J Nucl Med 36:1238–1248.
(1993) Pattern of cerebral metabolic interactions in a subject with isolated amnesia at risk for Alzheimer's disease: A longitudinal evaluation. Dementia 4:94–101.
(1992) Topography of cross-sectional and longitudinal glucose metabolic deficits in Alzheimer's disease. Pathophysiologic implications. Arch Neurol 49:1142–1150.
(1991) The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II standardization of the neuropathologic assessment of Alzheimer's disease. Neurology 41:479–486.
(2006) Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics J 6:246–254.
(2007) Complex disease-associated pharmacogenetics: Drug efficacy, drug safety, and confirmation of a pathogenetic hypothesis (Alzheimer's disease) Pharmacogenomics J 7:10–28.
(2007) Gene expression profiles in anatomically and functionally distinct regions of the normal aged human brain. Physiol Genomics 28:311–322.
(1984) Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease. Neurology 34:939–944.
(2006) Gene expression correlates of neurofibrillary tangles in Alzheimer's disease. Neurobiol Aging 27:1359–1371.
(2008) Altered neuronal gene expression in brain regions differentially affected by Alzheimer's disease: A reference data set. Physiol Genomics, 10.1152-physiolgenomics.00242.2007.


text:
Hale, Thomas (1818–1883)
There was a Thomas Hale, watchmaker and manufacturing goldsmith, who worked at King St, in Sydney. It is likely that it was he who married Eliza Holt as King St was given as Hale's address in the marriage notice.
death notice, Clarence and Richmond Examiner (Grafton, NSW), 20 March 1883, p 2
Hale, Thomas
Hale, Eliza Mary (wife)
Holt, Elizabeth (mother-in-law)
Holt, Joshua (father-in-law)
Holt, Ann Kingdon (sister-in-law)
Sparke, Mary Ann (sister-in-law)
Wilson, Esther (sister-in-law)
Rucker, Elizabeth (sister-in-law)
Wilson, Sarah Emma (sister-in-law)
Houston, Maria Jane (sister-in-law)
Holt, Winifred (sister-in-law)
Holt, Rebecca (sister-in-law)
Hardy, Louisa (sister-in-law)
Wilson, John (brother-in-law)
Wilson, Felix (brother-in-law)
Sparke, William (brother-in-law)
Rucker, John Henry (brother-in-law)
Holt, Joseph (brother-in-law)
Holt, John (brother-in-law)
Houston, William (brother-in-law)
Hemming, Thomas (brother-in-law)
Holt, Joshua (brother-in-law)
Hardy, John (brother-in-law)
Holt, Thomas (brother-in-law)
Holt, William Bowman (brother-in-law)
Hardy, Samuel (nephew by marriage)
'Hale, Thomas (1818–1883)', People Australia, National Centre of Biography, Australian National University, https://peopleaustralia.anu.edu.au/biography/hale-thomas-26753/text34370, accessed 22 January 2022.
Kent, England
Grafton, New South Wales, Australia
clock and watch maker
coalmine owner
gold broker
jeweller

redpajama_set_name: RedPajamaCommonCrawl


Two Mid Sussex community projects have been awarded thousands of pounds from the Big Lottery Fund.
Age Concern in Hassocks has received £10,000 to purchase computers and to create computer classes for older people in the village.
The project will establish an IT resource to provide older people with computer and IT skills to help them access online services and stay connected, said a spokesman.
Music group New Harmonie has received £9,950 to help them deliver a series of music sessions for older people living with dementia.
The funds will help the group use live music as a care intervention, providing them with therapeutic respite, reducing anxiety and promoting wellbeing, added the spokesman.
As part of the quarterly announcement, the Big Lottery Fund revealed that it is making grants totalling £50.3 million going to more than 2,300 community organisations across England.
Last year it awarded almost £713 million and supported almost 14,000 projects across the UK for health, education, environment and charitable purposes.
The Big Lottery Fund is responsible for giving out 40 per cent of the money raised by National Lottery players for good causes.


text:
Cyclist struck, killed
A man was killed Tuesday morning when he was struck by a truck while riding his bicycle on U.S. Highway 82.
Cpl. Chris Ellis, spokesman for the Alabama State Troopers, said state troopers were notified that John Hill, 45, of Duncanville had been hit by a 2001 Ford F-150 pickup truck near the Shell gas station at 11:44 a.m.
Ellis said when troopers arrived on the scene Hill was already dead.
He said the truck�s driver remained at the location until troopers arrived. No further information was available Tuesday.


Your story | Your essence.
Capturing life's finest moments in a timeless format.
A boutique team dedicated to creating stunning wedding and corporate films, photos and memories. Starting out as filmmakers, writers and photographers, Ashlee and her team have been fortunate to find their passions early in life and have spent over ten years honing their skills in the creative industries. Whether it's a profile or corporate ad, an international elopement wedding or a dream wedding on the beautiful Sunshine Coast – Jensen & Young put their hearts into crafting amazing keepsakes and content.
Put your feet up, grab a cup of tea, let your imagination kick off and be inspired. What will your story look like?


During the week of 23 - 27 January 2006 the first volunteers were trained at the Swaziland Reformed Church (Dwaleni). The training was given by three representatives from PSA (Project Support Association) which specialises in Home Based Care (HBC) projects. Logistically it was not a good time to have the training, as the Swazi schools were due to start on 24 January and many of the potential attendees have children who had to be enrolled at schools. However, this was the only time that we could arrange for the training without postponing it for too long. What we did not tell the potential attendees is that I was secretly relieved that the training fell within this week as I had received reports of a growing number of people wanting to attend the training and the 36 who had given their names were just too many to start with a HBC project.
On Monday morning the people started arriving and as the morning progressed the total number of attendees stabalised at 21 - more or less as many as I had prayed for and which I believed the Lord wanted there. The official opening of the training was done by the member of parliament for the Maseyisini region, Mr Magwagwa Mdluli, who, together with his wife have shown a great passion for caring for orphans (mainly due to AIDS) and vulnerable children.
Why is HIV different to other viruses?
How does the body defend itself?
What causes trauma and how do we handle it?
Why do so many people with AIDS also contract TB?
Judging by the response of the group and the way in which discussions took place within the larger group, it was clear that the trainers had succeeded in catching and keeping the attention of the trainees. One of the trainers, a young girl with the name of Bongi did all kinds of strange things with the group when she felt that they were getting sleepy, playing ball games, playing "Sam says" games and it was a treat to see the old amagogo (grandmothers) jumping up and down and running races. This was all the more necessary as the ceiling of the church structure in which the training took place had collapsed a few months ago during a hurricane and we still had not been able to repair the ceiling, which meant that the boiling hot corrugated iron roof reflected its heat directly upon the people, making some of them very sleepy.
On Tuesday a storm broke over Swaziland and it was pouring with rain. I really doubted whether many people would turn up for the training, as all of the trainees had to come by foot, some travelling several kilometers in the rain. Not 21 but 26 people turned up! The story had started spreading in the community. Throughout the day it rained while the training continued.
On Wednesday we were very privileged to receive a high-profile visit. (By the way, overnight the attendees had grown in number to 36!) This was something of God's providence, I believe. On the Friday preceeding the start of the training, I received an e-mail from a Christian friend in Swaziland with the following words: On the 25th a team from the US government is coming to Nhlangano to assess what HBC people are doing. I will keep you updated as to the time and everything. I had extremely mixed feelings about this message. We urgently need funds to proceed with this project. Was this God's provision to supply the funds? At the same time I am still not convinced that God wants us to depend upon funds from secular foundations and governments for this work. Many secular organisations have some "strings attached" to their funding and as Christians we cannot always accept some of these conditions. I therefore decided not to say too much about this to other people, but rather to leave this in the hands of the Lord to show us the way forward.
To our surprise, when the team arrived, consisting of a delegate of Interchurch Medical Assistance, we found that this was an organisation representing a great number of churches in the USA who had also become convinced that the answer for churches working with AIDS projects did not necessarily lie with secular foundations and governments and they had decided to form this organisation to give help from a Christian background. There was also a representative from USAID as well as representatives from Swaziland's Department of Health present. I had asked our local member of parliament and his wife, mr & mrs Mdluli, to be present in order to welcome the visitors and on his side he had also arranged for someone from Swazi TV to be there to give media coverage to what was happening.
A number of people, including a trainer, some of the community leaders who were attending the training and some of our church members who were also trainees were then asked to go with the visiting team to complete some questionnaires. The response we got from the visiting team as a whole was very positive, but we also received extremely valuable advice to avoid pitfalls and mistakes which other people had made in the past - advice which we carefully took note of. The question of course remains whether this visit will lead to financial support for our HBC project. We have learnt to trust the Lord in this regard and we sincerely believe that He will provide as the need arises. We were informed that a program of approximately 15 minutes would be broadcast on what they had seen happening at our church. Our wish is not to promote ourselves or our church, but to make people aware that a small group of willing people can make a difference in Swaziland.
On Thursday we were honoured with another visit from a member of Parliament, this time from an area known as Zombodza. Mr Titus Thwala had also heard about the training of volunteers and he wanted to see first-hand what was happening but also came with a request that the project be eventually expanded into his area as well.
What is the next step? We now have to determine how many zones can be serviced by this group as well as to appoint zone leaders. We will also be planning a celebration service at which time we will hand out certificates to those who attended the training faithfully. And then we have to start working!


text:
Nepal plane crash: At least 40 of 72 people onboard Yeti Airlines plane confirmed dead
The Yeti Airlines plane crashed at Pokhara International Airport had 72 people onboard, including 5 Indians and 4 crew members.
15 Jan, 2023, 11:13 am
At least 40 people were killed on Sunday when an aircraft of domestic carrier Yeti Airlines crashed in Pokhara in Nepal, a Nepal aviation authority official said.
"Rescue operations are on," said Jagannath Niroula, spokesman for Nepal civil aviation authority. "Weather was clear." Local television showed thick black smoke billowing from the crash site as rescue workers, and crowds of people gathered around the wreckage of the aircraft.
There were 72 people on the twin-engine ATR 72 aircraft operated by Nepal's Yeti Airlines, including two infants, four crew members, and 10 foreign nationals, said airline spokesman Sudarshan Bartaula. Hundreds of rescue workers were scouring the hillside crash site.
Miami airport plane crash: Red Air aircraft with 126 onboard catches fire after landing gear collapses. Watch
The plane was 15 years old, according to the flight tracking website FlightRadar24. The ATR72 is a widely used twin-engine turboprop plane manufactured by a joint venture of Airbus and Italy's Leonardo. Yeti Airlines has a fleet of six ATR72-500 planes, according to its website.
Air accidents are not uncommon in Nepal, home to eight of the world's 14 highest mountains, including Everest, as the weather can change suddenly and make for hazardous conditions. Nepal Prime Minister Pushpa Kamal Dahal has called an emergency cabinet meeting after the plane crash, a government statement said.
Yeti Airlines


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Music and Engagement are two concepts that truly complement each other: what better way to engage your class than with a music-inspired circuit breaker or curriculum-linked brain break?
Music is the perfect tool for refocusing students. Use these fun and effective activities in the classroom to add energy and focus to your students' classroom experience.


As one approaches Bhaunti, a small village 25 km west of the district headquarters of Kanpur, the smell of flowers becomes overpowering. It's coming out of a building where Ankit and Karan collects as much as 800 kilograms of waste flowers every day from the 29 temples in Kanpur, recycles them and turns them into incense sticks and organic vermicompost (made from a composting process using various species of worms). The founders, Ankit Agarwal and Karan Rastogi, have successfully trademarked the term "Flowercycle" for this process.
The duo was visiting the temples on the banks of the Ganga in Bithoor, Kanpur, in 2015, when they thought of the idea of recycling floral waste. "Pollution caused by flowers, unlike industrial waste, is often overlooked in the drive to clean the holy river," says Agarwal. And it's not just the flowers rotting in the river but also the pesticides used on them, which can affect marine life. Shortly after, the two left their jobs to launch Help Us Green. "When we started, everyone thought we were mad," says Rastogi. The vermicompost has a mix of 17 natural ingredients, including coffee grounds discarded by the local outposts of a coffee chain.
Later, IIT Kanpur chipped in with some funds. Later, they started making environment-friendly incense sticks, sans coal, in Sarsol village in Kanpur. And since devotees found it difficult to throw packets of incense products embossed with images of gods in dustbins and so threw them in the river, Help Us Green started selling its products in paper infused with Tulsi seeds that could be sowed once the incense was used. Another new product is in the pipeline: florafoam to replace thermocol. Help Us Green has brought respectability to more than 200 informal "scavengers"-usually women from lower castes.
Next Post: Zakir Hussain College Students Recycle Paper For Institutional Use.


text:
Q: Django not passing data to views on POST request I've created a drop-down menu that is supposed to pass data to a view that'll help filter a queryset. However, it doesn't seem like the data is actually being passed to the view. Below is the relevant code I've written.
template.html
<!-- Query based content for dropdown menu -->
<form method="POST" action="{% url 'property-selected' %}" id="property-select">
    {% csrf_token %}
    <select class="dropdown-content" onchange="this.form.submit()" name="property-select">
        {% if current_user_meters %}
            <option disabled selected> -- select an option -- </option>
            {% for meter in current_user_meters %}
                <option class="dropdown-menu-option" value="{{meter.id}}">{{meter.name}}</option>
            {% endfor %}
        {% else %}
            <option>You don't have any meters</option>
        {% endif %}
    </select>
</form>

views.py
def property_selected(request):
    if request.method == 'POST':

        selection = request.POST.get('property-select')

        current_user_groups = Group.objects.filter(
            id__in=request.user.groups.all()
        )
        current_user_properties = Property.objects.filter(
            groups__in=current_user_groups
        )
        current_user_meters = Meter.objects.filter(
            meter_id__in=current_user_properties
        )

        selected_meters = Meter.objects.filter(name=selection)
        selected_meter_data = MeterData.objects.filter(
            name=selection
        ).order_by('date')

        return render(request, 'properties/property-selected.html', {
            'current_user_meters': current_user_meters,
            'selection': selection,
            'selectected_meters': selected_meters,
            'selected_meter_data': selected_meter_data,
        })

For the querysets in the views file, the selection variable doesn't seem to be getting anything, which is where I want the data from the POST request to go. I want the data from the POST request to go there so my selected_meters and selected_meter_data queries will work as intended.

A: The values in the property-select options are IDs, but you are trying to filter MeterData by name with those values. Either filter by id, or use the name attribute as the option values.

A: You need to either use a form to ingest your data (thereby providing cleaning and validation) or access request.body instead of request.post, and then parse it for yourself.
From the documentation, emphasis mine (https://docs.djangoproject.com/en/dev/ref/request-response/#django.http.HttpRequest.POST):

HttpRequest.POST¶ A dictionary-like object containing all given HTTP
  POST parameters, providing that the request contains form data. See
  the QueryDict documentation below. If you need to access raw or
  non-form data posted in the request, access this through the
  HttpRequest.body attribute instead.
It's possible that a request can come in via POST with an empty POST
  dictionary – if, say, a form is requested via the POST HTTP method but
  does not include form data. Therefore, you shouldn't use if
  request.POST to check for use of the POST method; instead, use if
  request.method == "POST" (see HttpRequest.method).

I'd recommend passing the request into a form. It gives you some nice functionality down the line, and lets you avoid parsing request.body for yourself, even if it's an extra step.

redpajama_set_name: RedPajamaStackExchange


The overall population of the municipality named Bacoachi is 1456 citizens, 743 males and 713 females.
The population of Bacoachi is divided into 477 minors and 979 adults, with 238 of them older than 60 years.
3 people in Bacoachi live in indigenous households. An indigenous language is spoken by 1 people who are older than 5 years. The number of people who only speak an indigenous language is 0 and 1 speak both an indigenous language and Spanish.
A legal claim on health care and social insurance benefits have 627 citizens of Bacoachi.
In Bacoachi about 447 households are registered.
450 of these households are common houses or apartments, 14 are without floor and about 5 consist of one room only.
417 of the normal households have sanitary installations, 375 are connected to the public water supply, 408 have access to electricity.
The economic situation allows 45 households to own a computer, 352 own a washing machine and 387 households are equipped with one ore more televisions.
Besides the 49 analphabets aged 15 or older, about 10 minors between 6 and 14 are not visiting a school.
45 inhabitants of the population of 15 years and older did not visit a school and 591 persons did not finish the school. 254 visited only the 6 years lasting primary school, 134 visited and finished the college or similar scholar institutions.
A total of 73 aged 15 to 24 years visited a school, the medium time school is visited through the whole population is 7 years.


text:
Why is Japan called the Land of the Rising Sun?
May 17, 2022 August 16, 2021 by Jon Peterson
Many folks who know about Japan's history wonder why Japan is called Japan. Mostly, Japan is an advanced country situated around mountains. It is, in fact, a collage of islands that are beautified with Onsen (hot springs). But have you ever considered why Japan is called Japan?
Japan as an island nation was not always known as Japan. In fact, the word Japan is a foreign word to native speakers of the Japanese language. It is an English version of the original names Nippon and Nihon. So in this article, we will discuss why Japan is called Japan.
Where does the name Japan come from?
The history of the name Japan can be traced back to the early times, centuries or decades ago. Then, trading was the primary means of interacting with people from different clans.
In those days, writing was not a very popular form; however, information was passed by word of mouth. Those who could write, like the merchants, documented their adventures and experiences.
Japan, as it is now popularly known by foreigners, was called by many names. These names largely influenced the current name it is called. For instance, the English word "Japan" has a circuitous derivation and has many influences.
Historically, Japan was referred to based on its archipelago and geographical location. Since the country comprises several islands, people referred to them as either land with eight islands or the land of the rising sun.
In Mandarin Chinese or Wu Chinese, Japan was referred to as "cipan-guo," which translates to mean "sun origin -kingdom" Guo in Chinese translates to a kingdom which means the Chinese people call Japan "land of the rising sun."
Interestingly, this name "cipanguo or cipangu" was recorded in Europe's account of Marco Polo, written by Marco Polo himself. A story of an adventurer and veteran merchant who journeyed through Asia to a land filled with silver and gold. Here, that land was Japan.
It is important to know that the emergence of the name Japan can also be traced to the Portuguese, who got introduced to the word after their encounters in Malacca during the 16th century. During their trade, they encountered the Malay word Jepang, Jepun, and Jepang.
Based on history, it was recorded that Malay and Indonesian borrowed the word from non-Mandarin Chinese languages, and the Portuguese traders were the first to introduce the word to Europe. In 1577, Japan was first recorded in English as "Gaipan."
READ MORE: 8 Best Japanese Movies On Amazon Prime that make me moved
Fast forward to the modern-day, the country's official name in English is "Japan." You should have in mind that before Japan was called any of these above names in several languages, it was known as "Wakoku."
Why is Japan called Japan?
Though Japan is called many names, the country is called Japan in English based on the influence of recorded history and general acceptance. Natives of the country within themselves refer to Japan as Nihon-koku or Nippon-koku. However, to the rest of the world, Japan is Japan.
Since the English people recorded Japan as the official English equivalent of Nippon or Nihon, foreigners have widely accepted it as the country's name. In fact, Japan is used in Japanese for foreign branding.
As mentioned earlier, Japan is called Japan due to various influences over the years. The name came from a large chain of influences and interactions during trade between Japan and the Chinese, Indonesians, Portuguese, and English people.
Regardless, a large percentage was drawn from the influence of Mandarin Chinese or possibly Wu Chinese. Also, when writing was introduced, Japan borrowed the Chinese writing form while still maintaining Japanese pronunciation. This form of writing was known as classical Japanese.
Names of Japan.
Over centuries ago, Japan has been called many names. These names have largely shaped the history and emergence of the current name and the official English translation. Before ever the name Japan was written, it was first spoken. Though we cannot ascertain what the earliest people of Japan called themselves, they have been called several names. Here are the names Japan has been called;
Nihon and Nippon
In Japanese, Nihon and Nippon are the official names of Japan. While it is called Nihon, it is also called Nippon. Technically, they are both correct. However, Nippon is more popularly used for official purposes like money stamps and international sporting events.
Japan is also called Nippon-koku, which translates to "The State of Japan" In Kanji, "Nichi" means sun while "hon" means origin. The pronunciation of these names differs based on the influences the Japanese language has received over the years.
READ MORE: Top 10 Japanese Electric Guitar Brands
In addition, there are no fixed rules to how these words are pronounced. So you can either call it Nihon or Nippon in Japanese. Though they are both different, they are accepted as the official names of Japan.
Jipangu
Jipangu is believed to have been derived from the Portuguese recording of the Mandarin Chinese word of Japan, which means "sun kingdom" when translated. It is this record of Japan's name that informed and influenced the English derivation "Japan. "
Firstly, Cipangu was mentioned in Marco Polo's account and appeared on the European map and the Fra Mauro map in 1457.
Classical names of Japan
Classical names of Japan were invented after introducing Chinese into the Japanese language. These words appear in historical texts, Japanese emperors, and gods.
Oyashima
In 711 – 712CE, the oldest Japanese text tells the mythical story of the creation of Japan. This text known as the Kojiki describes the birth of Japanese land as "Oyashima," meaning Eight Great Islands. These islands are what we know now to be Honshu, Kyushu, and Shikoku.
You should know that it is still not clear if the ancient people of Japan used the name. Since the Kojiki (Record of Ancient Matters) was written in the 8th century. The kojiki is a Japanese religious text written in classical Japanese, pairing Chinese characters with Japanese sounds.
The name Wa, also known as Wa-koku, was given to Japan by the Chinese. This was after they encountered some Japanese people who lived in the southern part of the country. According to historical records, Emperor Guangwu of Han gave a golden seal to the first Japanese envoy that visited China. This was in 57CE.
In Japan currently, a national treasure of Japan has a seal inscribed with "King of Na, Land of Wa, Vassal to Han Dynasty." Though it is not recorded when Japan went by this name, they were called Wa.
In the Chinese Old Book of Tang, it was recorded that a Japanese envoy requested for the name to be changed from 'Wa," which had a derogatory connotation and was seen as offensive.
The question of why Japan is called the land of the rising sun is based on certain reasons. Between the 7th and 8th centuries, Japan was no longer called "Wa-koku" but "Nihon." This change of name has no definite story.
READ MORE: 10 Best Japanese Anime Series on Netflix 2022
While in some records, it is said that a Japanese envoy to China requested a change of name because he did not like it, others recorded that the Chinese empress of the time, Wu Zetian ordered Japan to change its name.
Regardless of which of these stories proves true, Japan changed its name from Wakoku to Nihon, also pronounced as Nippon in Japanese. As an archipelago, Japan is located on the east of China, technically where the sun rises, while China is located where the sunsets.
The name Nihon, which means "Land of the rising sun or sun origin," made so much sense. Interestingly, this is tied to the story of Japan's origin since the goddess of the sun holds an important place in the history of Japan, as well as Japanese mythology.
Japan in itself reflects the importance of the sun. Its association can also be linked to why they are and were called the land of the rising sun. In 607, there was an official history that recorded Prince Shotoku of the Sui dynasty.
Since he was the regent of Japan at that time, he sent a mission to China with a letter where he addressed himself as the "Son of heaven of the land where the sun rises. In his letter, he wrote;
"The son of Heaven, in the land of the rising sun, sends this letter to the Son of heaven of the land where the sun sets and wishes him well."
For this reason, Japan is called the land of the rising sun, apart from its association with Japanese religion and mythology.
There are several reasons why Japan is called Japan. Though not all are clear cut, the influence of different countries led to the derivation of the name japan. You should note that in the Japanese language, Japan is either called Nihon or Nippon or both. In Japanese phonology, both words mean "sun origin," which is called "Land of the Rising Sun" in English.
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Best ATV Brands in Japan Today.
22 Best Japanese Anime Of All Time 2022 | Best Anime To Watch


Phlebotomy is one of the most in demand jobs in Texas' medical community. Several large training institutes and several smaller phlebotomy program in Texas make it easy to get trained for this profession and start working. Here are some of the facts on phlebotomy careers and training in Texas.
The core of the course lies in learning to collect and analyze blood and urine samples. Students need to master the knowledge behind the process as well as the technical skills involved. Supervisors make sure that students learn each skill set correctly.
Now is a good time to choose a career in phlebotomy. Searches on traditional and online job boards turn up hundreds of jobs across the state of Texas. These jobs can be found at hospitals and at specialty health centers such as university medical centers or nursing homes. The salary for a phlebotomy technician in Texas is between $25,000 and $30,000, but this varies based on the city of the work, the type of clinic, and the amount of experience a technician has.
There are so many phlebotomy programs in Texas that it is necessary to be critical of each possible program. Some are better than others. Likewise, some prepare you well for the national test while others leave out critical parts of the training that you will need. It is always a good idea to make sure that your school is accredited. Before signing up with the school, compare the competencies that you'll need to pass the test with the course work offered at the institution. If there are some areas that don't seem to be covered, you should make sure that they are.
Talking with a representative from each institution can help you decide which school is the best fit for you. You will want to be sure to ask about the support you'll be given.
Schools that offer extra practice or reviews for students who aren't grasping parts of the material will prepare their students better for their future careers. The number or students per class is also a key fact. Those schools that have large classes may not offer their students enough one on one supervision. When class sizes are small, students have more access to help and can progress faster. Doing a good job in choosing a phlebotomy school takes time, but it's a necessary step to succeeding in this career.


text:
using System;
using System.Linq;
using Strategies.VxvPricePredictionStrategy;

namespace Strategies.CointegratedPairsStrategy
{
    public class CointegratedPairsAlgorithm
    {
        /*static void Main(string[] args)
        {
            Random randNum = new Random();
            var a = Enumerable
                .Repeat(0, 100)
                .Select(i => randNum.NextDouble())
                .ToArray();

            Console.WriteLine(new AugmentedDickeyFuller(a).NeedsDiff);
            Console.ReadKey();
        }*/
    }
}

redpajama_set_name: RedPajamaGithub


Rev. Dr. Chuck Currie: When You Count All The Votes…..
When You Count All The Votes…..
Democrats win. Congratulations, Governor-elect Christine Gregoire of Washington State.
Republicans really have to come up with a better election strategy than demanding that valid votes not be counted unless they are for their candidate. When you count every vote democracy works.


On the occasion of the Liberation of Saigon April 30 and The Labour Day May 1, the event organizers of Da Nang is going to corporate with the External Affair Department of the city to hold the Da Nang International Culture and Food Day 2013.
This is the first time Da Nang organize an international food day in attempt to introduce to the local civilization and foreign visitors the quintessence of the cultures and gastronomy of America, Russia, Japan, Italian and Vietnam. Dishes presented at the event bear strongly the tradition of each country.
More specially, people come to the event may also explore further the cultures of the five indicated countries in a mutual cultural space, under the sponsor of the Russian Consulate General in Da Nang, the Italian Embassy in Vietnam and the Center for Japanese cultural exchange in Vietnam through photo exhibition, specialties displays and art shows such as origami, calligraphy, sand paintings, rock paintings, etc.
The event takes place from April 27 to May 30 in the campus of the Integrated Science Library, No. 46 Bach Dang.


Abstract Indian agriculture was transforming from a cereal-based production system toward high-value crops (HVC) during the 1990s. However, food security concerns resurfaced during the first decade of the 21st century, and the policy environment tilted in favor of cereal-based production systems, especially rice and wheat. This paper revisits an earlier study to evaluate how the policy shift influences the patterns and the sources of agricultural growth in India and assesses their implications for regional priorities for higher, more sustainable, and more inclusive agricultural growth.


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Review: Witness in Death by J. D. Robb ★★★
Witness in Death by J. D. Robb
Genre: Futuristic Suspense
Series: In Death #11
Review Copy: Audiobook
When a celebrity is killed right before her eyes, New York detective Eve Dallas takes a new place in crime - as both officer and witness to murder...
Opening night at New York's New Globe Theater turns from stage scene to crime scene when the leading man is stabbed to death center stage. Now Eve Dallas has a high-profile, celebrity homicide on her hands. Not only is she lead detective, she's also a witness - and when the press discovers that her husband owns the theater, there's more media spotlight than either can handle. The only way out is to move fast. Question everyone and everything...and in the meantime, try to tell the difference between the truth - and really good acting...
Murder on stage. But is it simply a case art imitating life for Detective Eve Dallas?
This was a slight dip in the road for me for the In Death series. The quality of the wrting was at its usual exceptional level; fast-paced, gritty, funny, sentimental. All the usual good stuff. But unfortunately this time the subject matter of the crime simply didn't ignite my imagination. I'm sure it was just a personal thing.
There's a murder within the first few paragraphs right on the stage in front of Eve during a performance of a play that's being backed by her squillionaire husband, Roarke. So the killer is known right from the beginning, but the question really is, who switched the fake knife for a very real one?
I didn't really like the cast of self-adsorbed, borderline narcissistic actors and luvvies. They weren't supposed to be enjoyable, I don't suppose, but it also had a somewhat old fashioned feeling to the format. A bit like an old Agatha Christie or Hercule Poirot, where all the players are known, and it's just a question of interrogating each of them until somebody spills their guts. Like I said, it just wasn't for me.
However, I'd say it was worth reading it for one hilarious scene alone. Eve gets her new computer unit in her office at Cop Central. Funniest. Scene. Ever. The narrator truly outdid herself on it.
I'm also loving the developments with MacNab and Peabody. So cute, I really hope it keeps going.
So, all in all not my favourite of the series, but not without a few high points, either.
3 Stars ★★★
Jonetta (Ejaygirl) 11 September 2012 at 18:00
This play in this book is based on the movie, Witness for the Prosecution, a pretty old movie. Since I'd seen it, it had more appeal for me (not by much). However, the highlight for me was the scene where Eve tries to plan and orchestrate dinner for Roarke. That's a classic:)
Ah, I did not know that. Well it's not going to affect my love of the series. Like I said, it just wasn't to my personal taste. I prefer the ones that concentrate more on the futuristic elements; the drugs, gadgets and weapons of the time, and this didn't really utilise any of those.
That was a great scene (the dinner) "Who has 50 different kinds of plates?" lol
Lynsey Book Reviewer
My love of reading and being able to pay my bills became such that I had to enter a deal with the Netgalley Devils - books in exchange for reviews. This blog is the result of that servitude. More
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Mailbox Monday: All the books that arrived on my shelf this week.
Mailbox Monday is the weekly meme where readers can share the books that came into their house in the last week, whether real or virtu...
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It's hard to imagine this smiley seal as anything but friendly and playful, but leopard seals can actually be quite ferocious. These spotted swimmers have long, sharp teeth that are used to rip through other warm-blooded animals, including smaller seals. As if their cannibalistic tendencies weren't scary enough, leopard seals can stalk prey on land as well as underwater, sometimes beating their soon-to-be meal against the ground until it's rendered lifeless.


You might also hear lame jokes about hunting mammoths or concerns with you eating all that meat and being close to a heart attack.
Be aware that there will always be some form of resistance. Whenever you deviate from the norm people might often feel a little bit uncomfortable. The Paleo concept is not that well known yet. The vegetarian diet had to go through the same resistance stage.
For the same reason try to not take it personally. Especially people closest to you will withhold their support if they are worried about you or worry that they do not fit into your new lifestyle. It's a matter of time. I had long discussions with the husband when switching to Paleo. He was worried about the amount of saturated fats I was consuming and also a bit sad that we could not do our monthly bread, wine and cheese nights any more. He later was convinced though when he saw that I barely got sick even during flu season and that I was not only eating meat but also tons of vegetables. Try to openly communicate with your friends and loved ones and address the issues they might have.
Another important rule for a harmonious co-existence is not to be in your face Paleo. Steer away from the missionary zeal to convert people. It's natural wanting to spread the word especially after you have experienced great results. But you cannot force people if they do not want to. Live and let eat. It's up to them to decide. Answer their questions if they want to know more, keep discussions level-headed and agree to disagree. A vegan can still be your friend.
Realize You Deserve To Be Happy. You haven't done any injustice to humanity. [...] You run your own life and make decisions on what you need, not what somebody else thinks you need. [...] You'll be able to say "no"when you need to say "no" and not feel guilty. And, as you find yourself creating the kind of body you want, you'll find your self-worth increasing.
The only solution is to be your own person. You're the boss. You're responsible for your diet and you must make the decisions and conduct yourself accordingly.
Comfortably stand your ground without being a push over. Accept your right to change for the better. And people who truly care about you will accept the 'better you' .That's all what matters.
I had almost a big row with my mum because of my diet. I was Vegetarian before and she was concerned I couldn't handle the influx in meat. At least it only took one Dr. Oz episode on Paleo to turn her around. Will forward this article to her. Keep up the good work.


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Celebration of homeless woman's birthday warms hearts (video)
by Narayan Buckley December 20, 2012
A video of a homeless Colombian woman enjoying a surprise birthday with strangers on the streets of Bogota struck an emotional chord and became an internet sensation.
Emilio Aparicio on Monday surprised Andrea Chaparro in her usual spot on Avenida Jimenez. Aparicio, a photography student, met Chaparro five years ago when he was taking photos for his school thesis.
"I know Andrea because five years ago I began to develop an interest in people that live on the street, I had concerns and a real sensitivity for them [and their position]," Aparicio told Colombia Reports.
"I took pictures but also gave them [the homeless models] a copy, so I began to break down those barriers, which looked very big at first," explained the young photographer.
In addition to the birthday cake — equipped with a sparkling candle — Aparicio surprised his old friend with a birthday hat, a beautiful print of a photo he had taken of her, and a surprise she will never forget.
"Happy birthday!" Aparicio shouted over Andrea's squeals of delight. The two shared a long embrace, "mi niño, mi niño," [my son, my son] Andrea repeated over and over. Emilio then placed a birthday hat upon her head, handed her a balloon, placed a small cake in front of Andrea and asked random strangers nearby if they would join him in singing Andrea happy birthday.
"It was very special with Andrea, I liked that many people helped to sing for her, and for her it was amazing that so many people gave their hands in celebration," said Aparicio.
Emilio urged Andrea to write a wish on the balloon before releasing it into the air, but she told him she did not know how to write.
"Doesn't matter," replied Emilio, who told her to verbalize her wish instead, but Andrea, visibily taken aback, claimed she did not know what to say.
"Doesn't matter," Emilio said again.
Upon more urging, Andrea released the balloon and as it floated away she shouted at the top of her lungs, "everyone be happy!"
"Simple things are those that matter most — people are always thinking about having the best car or house, and here was this [homeless] woman who needs food, and affection [but] her one wish was [simply] for everyone to be happy. And I think that desire that [accompanied] the release the balloon was so strong that it is reflected in the number of messages and [the enormous amount of] positive feedback [from] people," said Aparicio.


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Centre looking to merge regional rural banks within same state, says report
Updated : February 27, 2019 10:22 AM IST
There are 56 RRBs operating in the country and India's biggest lender, State Bank of India sponsors 14 of them.
"Ideally, we will like to have them reduced by 36 by the end of this fiscal," an official was quoted as saying in the report.
CNBC-TV18
Finance ministry has asked the state-owned banks to explore possibilities to merge regional rural banks (RRBs) operating within the same states, in an effort to consolidate such RRBs and eventually bring them down to a manageable number of 10-15, The Economic Times reported, citing people familiar with the matter.
There are 56 RRBs operating in the country and India's biggest lender, State Bank of India sponsors 14 of them, the report said, adding that around 10 RRBs have been merged and will be effective from April 1 this year.
According to the report, a senior government official said that the idea of merging the regional banks is that of one bank leveraging its strong regional and market connect instead of 3-4 regional lenders in the state. "Ideally, we will like to have them reduced by 36 by the end of this fiscal," the official was quoted as saying in the report.
Currently, the centre holds about 50 percent stake in RRBs, while the sponsor bank holds 35 percent and state government holds 15 percent, the report added. "In some lead banks which have more presence in a particular area, they can take over the stake of another lender in an RRB for purposes of synergy and efficiencies," the sources were quoted as saying in the report.
Tags Finance Finance Ministry Regional Rural Banks regional rural banks merger rrbs State Bank of India state regional rural banks merger
Ex-Bhushan Power CMD Sanjay Singal's Rs 204 crore worth assets...


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