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We quantified genome-wide patterns of lysine H3K27 acetylation (H3K27ac) in entorhinal cortex samples from Alzheimer’s disease (AD) cases and matched controls using chromatin immunoprecipitation and highly parallel sequencing. We observed widespread acetylomic variation associated with AD neuropathology, identifying 4,162 differential peaks (false discovery rate < 0.05) between AD cases and controls. Differentially acetylated peaks were enriched in disease-related biological pathways and included regions annotated to genes involved in the progression of amyloid-β and tau pathology (for example, APP, PSEN1, PSEN2, and MAPT), as well as regions containing variants associated with sporadic late-onset AD. Partitioned heritability analysis highlighted a highly significant enrichment of AD risk variants in entorhinal cortex H3K27ac peak regions. AD-associated variable H3K27ac was associated with transcriptional variation at proximal genes including CR1, GPR22, KMO, PIM3, PSEN1, and RGCC. In addition to identifying molecular pathways associated with AD neuropathology, we present a framework for genome-wide studies of histone modifications in complex disease.

Background Schizophrenia is a highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated. Results We performed a multi-stage epigenome-wide association study, quantifying genome-wide patterns of DNA methylation in a total of 1714 individuals from three independent sample cohorts. We have identified multiple differentially methylated positions and regions consistently associated with schizophrenia across the three cohorts; these effects are independent of important confounders such as smoking. We also show that epigenetic variation at multiple loci across the genome contributes to the polygenic nature of schizophrenia. Finally, we show how DNA methylation quantitative trait loci in combination with Bayesian co-localization analyses can be used to annotate extended genomic regions nominated by studies of schizophrenia, and to identify potential regulatory variation causally involved in disease. Conclusions This study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological approach that can be used to inform epigenome-wide association study analyses of other complex traits and diseases. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with etiological variation, and of using DNA methylation quantitative trait loci to refine the functional and regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation.

Predicting insect responses to climate change is essential for preserving ecosystem services and biodiversity. Due to high daytime temperatures and low humidity levels, nocturnal insects are expected to have lower heat and desiccation tolerance compared to diurnal species. We estimated the lower (CT Min ) and upper (CT Max ) thermal limits of Megalopta , a group of neotropical, forest-dwelling bees. We calculated warming tolerance (WT) as a metric to assess vulnerability to global warming and measured survival rates during simulated heatwaves and desiccation stress events. We also assessed the impact of body size and reproductive status (ovary area) on bees’ thermal limits. Megalopta displayed lower CT Min , CT Max , and WTs than diurnal bees (stingless bees, orchid bees, and carpenter bees), but exhibited similar mortality during simulated heatwave and higher desiccation tolerance. CT Min increased with increasing body size across all bees but decreased with increasing body size and ovary area in Megalopta , suggesting a reproductive cost or differences in thermal environments. CT Max did not increase with increasing body size or ovary area. These results indicate a greater sensitivity of Megalopta to temperature than humidity and reinforce the idea that nocturnal insects are thermally constrained, which might threaten pollination services in nocturnal contexts during global warming.

Techniques to retrieve the atmospheric properties of exoplanets via direct observation of their reflected light have often been limited in scope owing to computational constraints imposed by the forward-model calculations. We have developed a new set of techniques that significantly decrease the time required to perform a retrieval while maintaining accurate results. We constructed a grid of 1.4 million precomputed geometric albedo spectra valued at discrete sets of parameter points. Spectra from this grid are used to produce models for a fast and efficient nested sampling routine called PSGnest. Beyond the upfront time to construct a spectral grid, the amount of time to complete a full retrieval using PSGnest is on the order of seconds to minutes using a personal computer. An extensive evaluation of the error induced from interpolating intermediate spectra from the grid indicates that this bias is insignificant compared to other retrieval error sources, with an average coefficient of determination between interpolated and true spectra of 0.998. We apply these new retrieval techniques to help constrain the optimal bandpass centers for retrieving various atmospheric and bulk parameters from a LuvEx-type mission observing several planetary archetypes. We show that spectral observations made using a 20% bandpass centered at 0.73 μm can be used alongside our new techniques to make detections of H2O and O2 without the need to increase observing time beyond what is necessary for a signal-to-noise ratio of 10. The methods introduced here will enable robust studies of the capabilities of future observatories to characterize exoplanets.

Parkinson’s disease (PD) is a common movement disorder, estimated to affect 4% of individuals by the age of 80. Mutations in the glucocerebrosidase 1 (GBA1) gene represent the most common genetic risk factor for PD, with at least 7–10% of non-Ashkenazi PD individuals carrying a GBA1 mutation (PD-GBA1). Although similar to idiopathic PD, the clinical presentation of PD-GBA1 includes a slightly younger age of onset, a higher incidence of neuropsychiatric symptoms, and a tendency to earlier, more prevalent and more significant cognitive impairment. The pathophysiological mechanisms underlying PD-GBA1 are incompletely understood, but, as in idiopathic PD, α-synuclein accumulation is thought to play a key role. It has been hypothesized that this overexpression of α-synuclein is caused by epigenetic modifications. In this paper, we analyze DNA methylation levels at 17 CpG sites located within intron 1 and the promoter of the α-synuclein (SNCA) gene in three different brain regions (frontal cortex, putamen and substantia nigra) in idiopathic PD, PD-GBA1 and elderly non-PD controls. In all three brain regions we find a tendency towards a decrease in DNA methylation within an eight CpG region of intron 1 in both idiopathic PD and PD-GBA1. The trend towards a reduction in DNA methylation was more pronounced in PD-GBA1, with a significant decrease in the frontal cortex. This suggests that PD-GBA1 and idiopathic PD have distinct epigenetic profiles, and highlights the importance of separating idiopathic PD and PD-GBA1 cases. This work also provides initial evidence that different genetic subtypes might exist within PD, each characterized by its own pathological mechanism. This may have important implications for how PD is diagnosed and treated.

Most weakly electric fish navigate and communicate by sensing electric signals generated by their muscle-derived electric organs. Adults of one lineage (Apteronotidae), which discharge their electric organs in excess of 1 kHz, instead have an electric organ derived from the axons of specialized spinal neurons (electromotorneurons [EMNs]). EMNs fire spontaneously and are the fastest-firing neurons known. This biophysically extreme phenotype depends upon a persistent sodium current, the molecular underpinnings of which remain unknown. We show that a skeletal muscle-specific sodium channel gene duplicated in this lineage and, within approximately 2 million years, began expressing in the spinal cord, a novel site of expression for this isoform. Concurrently, amino acid replacements that cause a persistent sodium current accumulated in the regions of the channel underlying inactivation. Therefore, a novel adaptation allowing extreme neuronal firing arose from the duplication, change in expression, and rapid sequence evolution of a muscle-expressing sodium channel gene.

Non-invasive imaging biomarkers of cellular proliferation hold great promise for quantifying response to personalized medicine in oncology. An emerging approach to assess tumor proliferation utilizes the positron emission tomography (PET) tracer 3'-deoxy-3'[(18)F]-fluorothymidine, [(18)F]-FLT. Though several studies have associated serial changes in [(18)F]-FLT-PET with elements of therapeutic response, the degree to which [(18)F]-FLT-PET quantitatively reflects proliferative index has been continuously debated for more that a decade. The goal of this study was to elucidate quantitative relationships between [(18)F]-FLT-PET and cellular metrics of proliferation in treatment naïve human cell line xenografts commonly employed in cancer research. [(18)F]-FLT-PET was conducted in human cancer xenograft-bearing mice. Quantitative relationships between PET, thymidine kinase 1 (TK1) protein levels and immunostaining for proliferation markers (Ki67, TK1, PCNA) were evaluated using imaging-matched tumor specimens. Overall, we determined that [(18)F]-FLT-PET reflects TK1 protein levels, yet the cell cycle specificity of TK1 expression and the extent to which tumors utilize thymidine salvage for DNA synthesis decouple [(18)F]-FLT-PET data from standard estimates of proliferative index. Our findings illustrate that [(18)F]-FLT-PET reflects tumor proliferation as a function of thymidine salvage pathway utilization. Unlike more general proliferation markers, such as Ki67, [(18)F]-FLT PET reflects proliferative indices to variable and potentially unreliable extents. [(18)F]-FLT-PET cannot discriminate moderately proliferative, thymidine salvage-driven tumors from those of high proliferative index that rely primarily upon de novo thymidine synthesis. Accordingly, the magnitude of [(18)F]-FLT uptake should not be considered a surrogate of proliferative index. These data rationalize the diversity of [(18)F]-FLT-PET correlative results previously reported and suggest future best-practices when [(18)F]-FLT-PET is employed in oncology.

Many insects show plasticity in the area of the brain called the mushroom bodies (MB) with foraging and social experience. MBs are paired neuropils associated with learning and memory. MB volume is typically greater in mature foragers relative to young and/or inexperienced individuals. Long-term studies show that extended experience may further increase MB volume, but long-term studies have only been performed on non-reproductive social insect workers. Here we use the subsocial bee Ceratina calcarata to test the effect of extended foraging experience on MB volume among reproductive females. Ceratina calcarata females forage to provision their immature offspring in the spring, and then again to provision their adult daughters in the late summer. We measured the volume of the MB calyces and peduncle, antennal lobes (AL), optic lobes (OL), central complex (CX), and whole brains of three groups of bees: newly emerged females, reproductive females in spring (foundresses), and post-reproductive mothers feeding their adult daughters in late summer. Post-reproductive late summer mothers had smaller MB calyces and ALs than foundresses. Moreover, among late mothers (but not other bees), wing wear, which is a measure of foraging experience, negatively correlated with both MB and OL volume. This is contrary to previously studied non-reproductive social insect workers in which foraging experience correlates postiviely with MB volume, and suggests that post-reproductive bees may reduce neural investment near the end of their lives.

Background Alzheimer’s disease is a progressive neurodegenerative disorder that is hypothesized to involve epigenetic dysfunction. Previous studies of DNA modifications in Alzheimer’s disease have been unable to distinguish between DNA methylation and DNA hydroxymethylation. DNA hydroxymethylation has been shown to be enriched in the human brain, although its role in Alzheimer’s disease has not yet been fully explored. Here, we utilize oxidative bisulfite conversion, in conjunction with the Illumina Infinium Human Methylation 450K microarray, to identify neuropathology-associated differential DNA methylation and DNA hydroxymethylation in the entorhinal cortex. Results We identified one experiment-wide significant differentially methylated position residing in the WNT5B gene. Next, we investigated pathology-associated regions consisting of multiple adjacent loci. We identified one significant differentially hydroxymethylated region consisting of four probes spanning 104 bases in the FBXL16 gene. We also identified two significant differentially methylated regions: one consisting of two probes in a 93 base-pair region in the ANK1 gene and the other consisting of six probes in a 99-base pair region in the ARID5B gene. We also highlighted three regions that show alterations in unmodified cytosine: two probes in a 39-base pair region of ALLC , two probes in a 69-base pair region in JAG2 , and the same six probes in ARID5B that were differentially methylated. Finally, we replicated significant ANK1 disease-associated hypermethylation and hypohydroxymethylation patterns across eight CpG sites in an extended 118-base pair region in an independent cohort using oxidative-bisulfite pyrosequencing. Conclusions Our study represents the first epigenome-wide association study of both DNA methylation and hydroxymethylation in Alzheimer’s disease entorhinal cortex. We demonstrate that previous estimates of DNA hypermethylation in ANK1 in Alzheimer’s disease were underestimates as it is confounded by hypohydroxymethylation.

Background Mitochondrial dysregulation and aberrant epigenetic mechanisms have been frequently reported in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), and several researchers suggested that epigenetic dysregulation in mitochondrial DNA (mtDNA) could contribute to the neurodegenerative process. We recently screened families with mutations in the major ALS causative genes, namely C9orf72 , SOD1 , FUS , and TARDBP , observing reduced methylation levels of the mtDNA regulatory region (D-loop) only in peripheral lymphocytes of SOD1 carriers. However, until now no studies investigated the potential role of mtDNA methylation impairment in the sporadic form of ALS, which accounts for the majority of disease cases. The aim of the current study was to investigate the D-loop methylation levels and the mtDNA copy number in sporadic ALS patients and compare them to those observed in healthy controls and in familial ALS patients. Pyrosequencing analysis of D-loop methylation levels and quantitative analysis of mtDNA copy number were performed in peripheral white blood cells from 36 sporadic ALS patients, 51 age- and sex-matched controls, and 27 familial ALS patients with germinal mutations in SOD1 or C9orf72 that represent the major familial ALS forms. Results In the total sample, D-loop methylation levels were significantly lower in ALS patients compared to controls, and a significant inverse correlation between D-loop methylation levels and the mtDNA copy number was observed. Stratification of ALS patients into different subtypes revealed that both SOD1 -mutant and sporadic ALS patients showed lower D-loop methylation levels compared to controls, while C9orf72 -ALS patients showed similar D-loop methylation levels than controls. In healthy controls, but not in ALS patients, D-loop methylation levels decreased with increasing age at sampling and were higher in males compared to females. Conclusions Present data reveal altered D-loop methylation levels in sporadic ALS and confirm previous evidence of an inverse correlation between D-loop methylation levels and the mtDNA copy number, as well as differences among the major familial ALS subtypes. Overall, present results suggest that D-loop methylation and mitochondrial replication are strictly related to each other and could represent compensatory mechanisms to counteract mitochondrial impairment in sporadic and SOD1 -related ALS forms.