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The ɛ4 allele of the apolipoprotein E ( APOE ) gene is currently the strongest and most highly replicated genetic factor for risk and age of onset of late-onset Alzheimer's disease (LOAD). Using phylogenetic analysis, we have identified a polymorphic poly-T variant, rs10524523, in the translocase of outer mitochondrial membrane 40 homolog ( TOMM40 ) gene that provides greatly increased precision in the estimation of age of LOAD onset for APOE ɛ3 carriers. In two independent clinical cohorts, longer lengths of rs10524523 are associated with a higher risk for LOAD. For APOE ɛ3/4 patients who developed LOAD after 60 years of age, individuals with long poly-T repeats linked to APOE ɛ3 develop LOAD on an average of 7 years earlier than individuals with shorter poly-T repeats linked to APOE ɛ3 (70.5±1.2 years versus 77.6±2.1 years, P =0.02, n =34). Independent mutation events at rs10524523 that occurred during Caucasian evolution have given rise to multiple categories of poly-T length variants at this locus. On replication, these results will have clinical utility for predictive risk estimates for LOAD and for enabling clinical disease prevention studies. In addition, these results show the effective use of a phylogenetic approach for analysis of haplotypes of polymorphisms, including structural polymorphisms, which contribute to complex diseases.

Hepatitis B viremia and emergence of hepatitis B virus (HBV) YMDD variants with reduced susceptibility to lamivudine were analyzed in patient sera from a phase II study of extended lamivudine therapy. Within 12 weeks, all patients exhibited a marked virologic response to lamivudine: >99% reduction (median 5 log decrease) in serum HBV DNA levels. Virus remained at >104 genomes/mL in 11 patients and decreased to <104 genomes/mL in the remaining 12 patients. In 10 patients, detectable YMDD variants emerged during the course of treatment. Six patients, including 3 with YMDD variants, experienced hepatitis B e antigen seroconversion while on lamivudine therapy or soon after its discontinuation. No patients with HBV DNA levels >104 genomes/mL seroconverted. Thus, patients who respond to lamivudine therapy with dramatic reductions in viral DNA level (to <104 genomes/mL) appear more likely to seroconvert than patients who do not achieve this level of HBV clearance.

Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549 692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual’s cognitive changes were constructed. One SNP—rs2075650, located in TOMM40 ( translocase of the outer mitochondrial membrane 40 homolog )—had a genome-wide significant association with cognitive ageing ( P =2.5 × 10 −8 ). This result was replicated in a meta-analysis of three independent Swedish cohorts ( P =2.41 × 10 −6 ). An Apolipoprotein E ( APOE ) haplotype (adjacent to TOMM40 ), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample ( P =2.18 × 10 −8 ; females, P =1.66 × 10 −11 ; males, P =0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P =3.66 × 10 −11 ) and TOMM40 (rs11556505; P =2.45 × 10 −8 ) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear.

Metabolism is vital to every aspect of cell function, yet the metabolome of induced pluripotent stem cells （iPSCs） remains largely unexplored. Here we report, using an untargeted metabolomics approach, that human iPSCs share a pluripotent metabolomic signature with embryonic stem cells （ESCs） that is distinct from their parental cells, and that is characterized by changes in metabolites involved in cellular respiration. Examination of cellular bioenergetics corroborated with our metabolomic analysis, and demonstrated that somatic cells convert from an oxidative state to a glycolytic state in pluripotency. Interestingly, the bioenergetics of various somatic cells correlated with their repro- gramming efficiencies. We further identified metabolites that differ between iPSCs and ESCs, which revealed novel metabolic pathways that play a critical role in regulating somatic cell reprogramming. Our findings are the first to globally analyze the metabolome of iPSCs, and provide mechanistic insight into a new layer of regulation involved in inducing pluripotency, and in evaluating iPSC and ESC equivalence.

Genetic polymorphisms in the APOE ɛ and TOMM40 ‘523’ poly-T repeat gene loci have been associated with significantly increased risk of Alzheimer’s disease. This study investigated the independent effects of these polymorphisms on human cognitive ageing, and the extent to which nominally significant associations with cognitive ageing were mediated by previously reported genetic associations with brain white matter tract integrity in this sample. Most participants in the Lothian Birth Cohort 1936 completed a reasoning-type intelligence test at age 11 years, and detailed cognitive/physical assessments and structural diffusion tensor brain magnetic resonance imaging at a mean age of 72.70 years (s.d.=0.74). Participants were genotyped for APOE ɛ2/ɛ3/ɛ4 status and TOMM40 523 poly-T repeat length. Data were available from 758–814 subjects for cognitive analysis, and 522–543 for mediation analysis with brain imaging data. APOE genotype was significantly associated with performance on several different tests of cognitive ability, including general factors of intelligence, information processing speed and memory (raw P -values all<0.05), independently of childhood IQ and vascular disease history. Formal tests of mediation showed that several significant APOE -cognitive ageing associations—particularly those related to tests of information processing speed—were partially mediated by white matter tract integrity. TOMM40 523 genotype was not associated with cognitive ageing. A range of brain phenotypes are likely to form the anatomical basis for significant associations between APOE genotype and cognitive ageing, including white matter tract microstructural integrity.

Genetic polymorphisms in the APOE [varepsilon] and TOMM40 '523' poly-T repeat gene loci have been associated with significantly increased risk of Alzheimer's disease. This study investigated the independent effects of these polymorphisms on human cognitive ageing, and the extent to which nominally significant associations with cognitive ageing were mediated by previously reported genetic associations with brain white matter tract integrity in this sample. Most participants in the Lothian Birth Cohort 1936 completed a reasoning-type intelligence test at age 11 years, and detailed cognitive/physical assessments and structural diffusion tensor brain magnetic resonance imaging at a mean age of 72.70 years (s.d.=0.74). Participants were genotyped for APOE [varepsilon]2/[varepsilon]3/[varepsilon]4 status and TOMM40 523 poly-T repeat length. Data were available from 758-814 subjects for cognitive analysis, and 522-543 for mediation analysis with brain imaging data. APOE genotype was significantly associated with performance on several different tests of cognitive ability, including general factors of intelligence, information processing speed and memory (raw P-values all<0.05), independently of childhood IQ and vascular disease history. Formal tests of mediation showed that several significant APOE-cognitive ageing associations--particularly those related to tests of information processing speed--were partially mediated by white matter tract integrity. TOMM40 523 genotype was not associated with cognitive ageing. A range of brain phenotypes are likely to form the anatomical basis for significant associations between APOE genotype and cognitive ageing, including white matter tract microstructural integrity.

We investigate in detail the self-assembled nucleation and growth of vertically oriented GaN nanowires by molecular beam epitaxy on crystalline TiN films. We demonstrate that this type of substrate allows for the growth of long and thin GaN nanowires that do not suffer from coalescence, a problem common to the growth on Si and other substrates. Only beyond a certain nanowire length that depends on the nanowire density and exceeds here 1.5 bun, coalescence takes place by bundling, i.e. the same process as on Si. By analyzing the nearest neighbor distance distribution, we identify the diffusion-induced repulsion of neighboring nanowires as the main mechanism limiting nanowire density during nucleation on TiN. Since on Si the final density is determined by shadowing of the impinging molecular beams by existing nanowires, it is the difference in adatom surface diffusion that enables the formation of nanowire ensembles with reduced density on TiN. These nanowire ensembles combine properties that make them a promising basis for the growth of core-shell heterostructures.

Examines controversies over national and state standard setting (Goals 2000, outcome-based education) involving conservative citizen groups. Makes recommendations for widening public participation in educational policy-making and aligning public engagement with standards-based reform. (SK)

The Indus basin heavily depends on its upstream mountainous part for the downstream supply of water while downstream demands are high. Since downstream demands will likely continue to increase, accurate hydrological projections for the future supply are important. We use an ensemble of statistically downscaled CMIP5 General Circulation Model outputs for RCP4.5 and RCP8.5 to force a cryospheric-hydrological model and generate transient hydrological projections for the entire 21st century for the upper Indus basin. Three methodological advances are introduced: (i) A new precipitation dataset that corrects for the underestimation of high-altitude precipitation is used. (ii) The model is calibrated using data on river runoff, snow cover and geodetic glacier mass balance. (iii) An advanced statistical downscaling technique is used that accounts for changes in precipitation extremes. The analysis of the results focuses on changes in sources of runoff, seasonality and hydrological extremes. We conclude that the future of the upper Indus basin's water availability is highly uncertain in the long run, mainly due to the large spread in the future precipitation projections. Despite large uncertainties in the future climate and long-term water availability, basin-wide patterns and trends of seasonal shifts in water availability are consistent across climate change scenarios. Most prominent is the attenuation of the annual hydrograph and shift from summer peak flow towards the other seasons for most ensemble members. In addition there are distinct spatial patterns in the response that relate to monsoon influence and the importance of meltwater. Analysis of future hydrological extremes reveals that increases in intensity and frequency of extreme discharges are very likely for most of the upper Indus basin and most ensemble members.

Models show that even if global temperature rise can be limited to 1.5 degrees Celsius, only about 65 per cent of glacier mass will remain in the high mountains of Asia by the end of this century, and if temperatures rise by more than this the effects will be much more extreme. Climate target confronts glacier fate The Paris Agreement advocates that humanity should consider limiting global warming to no more than 1.5 degrees Celsius (°C) above pre-industrial temperatures, well below the previously discussed threshold of 2 °C. The announcement sparked a surge of research to understand the practicality and implications of the lower limit. Here, Philip Kraaijenbrink and colleagues simulate the effect of warming on the glaciers in the high mountains of Asia and show that, in a world that warms by just 1.5 °C, about 65 per cent of glacier mass will remain by 2100. But keeping warming below the 1.5 °C threshold is an ambitious goal. At the other extreme, scenarios that include continued high rates of greenhouse gas production instead suggest that only about 35 per cent of mass will remain by 2100. Glaciers in the high mountains of Asia (HMA) make a substantial contribution to the water supply of millions of people 1 , 2 , and they are retreating and losing mass as a result of anthropogenic climate change 3 at similar rates to those seen elsewhere 4 , 5 . In the Paris Agreement of 2015, 195 nations agreed on the aspiration to limit the level of global temperature rise to 1.5 degrees Celsius ( °C) above pre-industrial levels. However, it is not known what an increase of 1.5 °C would mean for the glaciers in HMA. Here we show that a global temperature rise of 1.5 °C will lead to a warming of 2.1 ± 0.1 °C in HMA, and that 64 ± 7 per cent of the present-day ice mass stored in the HMA glaciers will remain by the end of the century. The 1.5 °C goal is extremely ambitious and is projected by only a small number of climate models of the conservative IPCC’s Representative Concentration Pathway (RCP)2.6 ensemble. Projections for RCP4.5, RCP6.0 and RCP8.5 reveal that much of the glacier ice is likely to disappear, with projected mass losses of 49 ± 7 per cent, 51 ± 6 per cent and 64 ± 5 per cent, respectively, by the end of the century; these projections have potentially serious consequences for regional water management and mountain communities.