抗精神病薬によるジストニアの発現機序に関する実験的研究 σ (sigma) sites の関与について

Published ErratumBurkholderia pseudomallei (Bp) is the causative agent of the infectious disease melioidosis. To investigate population diversity, recombination, and horizontal gene transfer in closely related Bp isolates, we performed whole-genome sequencing (WGS) on 106 clinical, animal, and environmental strains from a restricted Asian locale. Whole-genome phylogenies resolved multiple genomic clades of Bp, largely congruent with multilocus sequence typing (MLST). We discovered widespread recombination in the Bp core genome, involving hundreds of regions associated with multiple haplotypes. Highly recombinant regions exhibited functional enrichments that may contribute to virulence. We observed clade-specific patterns of recombination and accessory gene exchange, and provide evidence that this is likely due to ongoing recombination between clade members. Reciprocally, interclade exchanges were rarely observed, suggesting mechanisms restricting gene flow between clades. Interrogation of accessory elements revealed that each clade harbored a distinct complement of restriction-modification (RM) systems, predicted to cause clade-specific patterns of DNA methylation. Using methylome sequencing, we confirmed that representative strains from separate clades indeed exhibit distinct methylation profiles. Finally, using an E. coli system, we demonstrate that Bp RM systems can inhibit uptake of non-self DNA. Our data suggest that RM systems borne on mobile elements, besides preventing foreign DNA invasion, may also contribute to limiting exchanges of genetic material between individuals of the same species. Genomic clades may thus represent functional units of genetic isolation in Bp, modulating intraspecies genetic diversity.Wellcome Trus

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Neuroinflammation in Alzheimer's Disease Contributes to A2-type Reactive Astrocytic Profile in iPSC Derived Patient Astrocytes

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by loss of neurons and synapses throughout the brain. Increased neuroinflammation has been observed in the brains of AD patients and is hypothesized to play a role in the pathology of the disease. Inflammation in the brain is thought to be primarily initiated by the non-neuronal cells of the brain, glia cells. One type of glia, astrocytes, are suspected to play a role in the onset and progression of AD through inflammation. Recent characterization of reactive astrocytes has identified two activated astrocyte states: a harmful, pro-inflammatory A1 state or a helpful, anti-inflammatory A2 state when exposed to CNS injury. In this thesis, I asked if A1 or A2 astrocyte states were different between AD and control astrocytes. Here, I analyzed RNA-sequencing data from AD astrocytes generated from patient-derived induced pluripotent stem cells (iPSCs) along with age-matched controls to identify the relative proportions of A1 and A2 states. Surprisingly, I found that AD astrocytes have an increase in A2-type, “helpful” astrocytes relative to age-matched cognitively normal controls. These results reflect the complexity of AD and suggest new ways of thinking about inflammation in AD

Neuroinflammation in Alzheimer's Disease Contributes to A2-type Reactive Astrocytic Profile in iPSC Derived Patient Astrocytes

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by loss of neurons and synapses throughout the brain. Increased neuroinflammation has been observed in the brains of AD patients and is hypothesized to play a role in the pathology of the disease. Inflammation in the brain is thought to be primarily initiated by the non-neuronal cells of the brain, glia cells. One type of glia, astrocytes, are suspected to play a role in the onset and progression of AD through inflammation. Recent characterization of reactive astrocytes has identified two activated astrocyte states: a harmful, pro-inflammatory A1 state or a helpful, anti-inflammatory A2 state when exposed to CNS injury. In this thesis, I asked if A1 or A2 astrocyte states were different between AD and control astrocytes. Here, I analyzed RNA-sequencing data from AD astrocytes generated from patient-derived induced pluripotent stem cells (iPSCs) along with age-matched controls to identify the relative proportions of A1 and A2 states. Surprisingly, I found that AD astrocytes have an increase in A2-type, “helpful” astrocytes relative to age-matched cognitively normal controls. These results reflect the complexity of AD and suggest new ways of thinking about inflammation in AD

Data from: Experience matters: context-dependent decisions explain spatial foraging patterns in the deposit-feeding crab Scopimera intermedia

Behavioural decisions are often context-dependent, where information from immediate experience is incorporated into an individual's decision-making, particularly in complex environments. To test whether such mechanism is adopted by foragers in heterogeneous environments, we investigated the foraging behaviour of the deposit-feeding sand-bubbler crab, Scopimera intermedia. An individual-based model was constructed, based on an optimal-patch selection criterion, which implicitly assumed that individuals adjust foraging decisions based on immediate past experience. The model's predictions were tested on the shore by manipulating the location of food patches, where the crab showed a strong context-dependent foraging pattern. When resources were randomly distributed, the crab responded by spending 56% of time in enriched patches compared with only 28% in the same area when patches were composed of natural sediments. Shore manipulations varying resource distribution supported the underlying principles of the model mechanism, and highlighted the benefits of such a strategy in heterogeneous environments such as intertidal sediments where food resources vary at different spatial and temporal scales. The proposed model therefore provides a mechanistic process, based on optimal foraging, to predict foraging decisions and movement patterns of animals feeding in heterogeneous landscapes