DNA Methylation Profiling of the Human Major Histocompatibility Complex: A Pilot Study for the Human Epigenome Project

The Human Epigenome Project aims to identify, catalogue, and interpret genome-wide DNA methylation phenomena. Occurring naturally on cytosine bases at cytosine–guanine dinucleotides, DNA methylation is intimately involved in diverse biological processes and the aetiology of many diseases. Differentially methylated cytosines give rise to distinct profiles, thought to be specific for gene activity, tissue type, and disease state. The identification of such methylation variable positions will significantly improve our understanding of genome biology and our ability to diagnose disease. Here, we report the results of the pilot study for the Human Epigenome Project entailing the methylation analysis of the human major histocompatibility complex. This study involved the development of an integrated pipeline for high-throughput methylation analysis using bisulphite DNA sequencing, discovery of methylation variable positions, epigenotyping by matrix-assisted laser desorption/ionisation mass spectrometry, and development of an integrated public database available at http://www.epigenome.org. Our analysis of DNA methylation levels within the major histocompatibility complex, including regulatory exonic and intronic regions associated with 90 genes in multiple tissues and individuals, reveals a bimodal distribution of methylation profiles (i.e., the vast majority of the analysed regions were either hypo- or hypermethylated), tissue specificity, inter-individual variation, and correlation with independent gene expression data

Individual variation in hunger, energy intake and ghrelin responses to acute exercise

Purpose This study aimed to characterize the immediate and extended effect of acute exercise on hunger, energy intake, and circulating acylated ghrelin concentrations using a large data set of homogenous experimental trials and to describe the variation in responses between individuals. Methods Data from 17 of our group's experimental crossover trials were aggregated yielding a total sample of 192 young, healthy males. In these studies, single bouts of moderate to high-intensity aerobic exercise (69% ± 5% V˙O2 peak; mean ± SD) were completed with detailed participant assessments occurring during and for several hours postexercise. Mean hunger ratings were determined during (n = 178) and after (n = 118) exercise from visual analog scales completed at 30-min intervals, whereas ad libitum energy intake was measured within the first hour after exercise (n = 60) and at multiple meals (n = 128) during the remainder of trials. Venous concentrations of acylated ghrelin were determined at strategic time points during (n = 118) and after (n = 89) exercise. Results At group level, exercise transiently suppressed hunger (P < 0.010, Cohen's d = 0.77) but did not affect energy intake. Acylated ghrelin was suppressed during exercise (P < 0.001, Cohen's d = 0.10) and remained significantly lower than control (no exercise) afterward (P < 0.024, Cohen's d = 0.61). Between participants, there were notable differences in responses; however, a large proportion of this spread lay within the boundaries of normal variation associated with biological and technical assessment error. Conclusion In young men, acute exercise suppresses hunger and circulating acylated ghrelin concentrations with notable diversity between individuals. Care must be taken to distinguish true interindividual variation from random differences within normal limits

Entropic Forces Drive Clustering and Spatial Localization of Influenza A M2 During Viral Budding

The influenza A matrix 2 (M2) transmembrane protein facilitates virion release from the infected host cell. In particular, M2 plays a role in the induction of membrane curvature and/or in the scission process whereby the envelope is cut upon virion release. Here we show using coarse-grained computer simulations that various M2 assembly geometries emerge due to an entropic driving force, resulting in compact clusters or linearly extended aggregates as a direct consequence of the lateral membrane stresses. Conditions under which these protein assemblies will cause the lipid membrane to curve are explored and we predict that a critical cluster size is required for this to happen. We go on to demonstrate that under the stress conditions taking place in the cellular membrane as it undergoes large-scale membrane remodeling, the M2 protein will in principle be able to both contribute to curvature induction and sense curvature in order to line up in manifolds where local membrane line tension is high. M2 is found to exhibit linactant behavior in liquid-disordered/liquid-ordered phase-separated lipid mixtures and to be excluded from the liquid-ordered phase, in near-quantitative agreement with experimental observations. Our findings support a role for M2 in membrane remodeling during influenza viral budding both as an inducer and a sensor of membrane curvature, and they suggest a mechanism by which localization of M2 can occur as the virion assembles and releases from the host cell, independent of how the membrane curvature is produced

Sensory Communication

Contains table of contents for Section 2, an introduction and reports on twelve research projects.National Institutes of Health Grant 5 R01 DC00117National Institutes of Health Contract 2 P01 DC00361National Institutes of Health Grant 5 R01 DC00126National Institutes of Health Grant R01-DC00270U.S. Air Force - Office of Scientific Research Contract AFOSR-90-0200National Institutes of Health Grant R29-DC00625U.S. Navy - Office of Naval Research Grant N00014-88-K-0604U.S. Navy - Office of Naval Research Grant N00014-91-J-1454U.S. Navy - Office of Naval Research Grant N00014-92-J-1814U.S. Navy - Naval Training Systems Center Contract N61339-93-M-1213U.S. Navy - Naval Training Systems Center Contract N61339-93-C-0055U.S. Navy - Naval Training Systems Center Contract N61339-93-C-0083U.S. Navy - Office of Naval Research Grant N00014-92-J-4005U.S. Navy - Office of Naval Research Grant N00014-93-1-119

An integrated ultrasound curriculum (iUSC) for medical students: 4-year experience

A review of the development and implementation of a 4-year medical student integrated ultrasound curriculum is presented. Multiple teaching and assessment modalities are discussed as well as results from testing and student surveys. Lessons learned while establishing the curriculum are summarized. It is concluded that ultrasound is a well received, valuable teaching tool across all 4 years of medical school, and students learn ultrasound well, and they feel their ultrasound experience enhances their medical education

Empirical Legal Studies Before 1940: A Bibliographic Essay

The modern empirical legal studies movement has well-known antecedents in the law and society and law and economics traditions of the latter half of the 20th century. Less well known is the body of empirical research on legal phenomena from the period prior to World War II. This paper is an extensive bibliographic essay that surveys the English language empirical legal research from approximately 1940 and earlier. The essay is arranged around the themes in the research: criminal justice, civil justice (general studies of civil litigation, auto accident litigation and compensation, divorce, small claims, jurisdiction and procedure, civil juries), debt and bankruptcy, banking, appellate courts, legal needs, legal profession (including legal education), and judicial staffing and selection. Accompanying the essay is an extensive bibliography of research articles, books, and reports

Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments.

International audienceSHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice

Variation analysis and gene annotation of eight MHC haplotypes: The MHC Haplotype Project

The human major histocompatibility complex (MHC) is contained within about 4 Mb on the short arm of chromosome 6 and is recognised as the most variable region in the human genome. The primary aim of the MHC Haplotype Project was to provide a comprehensively annotated reference sequence of a single, human leukocyte antigen-homozygous MHC haplotype and to use it as a basis against which variations could be assessed from seven other similarly homozygous cell lines, representative of the most common MHC haplotypes in the European population. Comparison of the haplotype sequences, including four haplotypes not previously analysed, resulted in the identification of >44,000 variations, both substitutions and indels (insertions and deletions), which have been submitted to the dbSNP database. The gene annotation uncovered haplotype-specific differences and confirmed the presence of more than 300 loci, including over 160 protein-coding genes. Combined analysis of the variation and annotation datasets revealed 122 gene loci with coding substitutions of which 97 were non-synonymous. The haplotype (A3-B7-DR15; PGF cell line) designated as the new MHC reference sequence, has been incorporated into the human genome assembly (NCBI35 and subsequent builds), and constitutes the largest single-haplotype sequence of the human genome to date. The extensive variation and annotation data derived from the analysis of seven further haplotypes have been made publicly available and provide a framework and resource for future association studies of all MHC-associated diseases and transplant medicine

The JWST Early Release Science Program for Direct Observations of Exoplanetary Systems II: A 1 to 20 Micron Spectrum of the Planetary-Mass Companion VHS 1256-1257 b

We present the highest fidelity spectrum to date of a planetary-mass object. VHS 1256 b is a $<$20 M$_\mathrm{Jup}$ widely separated ($\sim$8\arcsec, a = 150 au), young, planetary-mass companion that shares photometric colors and spectroscopic features with the directly imaged exoplanets HR 8799 c, d, and e. As an L-to-T transition object, VHS 1256 b exists along the region of the color-magnitude diagram where substellar atmospheres transition from cloudy to clear. We observed VHS 1256~b with \textit{JWST}'s NIRSpec IFU and MIRI MRS modes for coverage from 1 $\mu$m to 20 $\mu$m at resolutions of $\sim$1,000 - 3,700. Water, methane, carbon monoxide, carbon dioxide, sodium, and potassium are observed in several portions of the \textit{JWST} spectrum based on comparisons from template brown dwarf spectra, molecular opacities, and atmospheric models. The spectral shape of VHS 1256 b is influenced by disequilibrium chemistry and clouds. We directly detect silicate clouds, the first such detection reported for a planetary-mass companion.Comment: Accepted ApJL Iterations of spectra reduced by the ERS team are hosted at this link: https://github.com/bemiles/JWST_VHS1256b_Reduction/tree/main/reduced_spectr