Generation and transcriptional programming of intestinal dendritic cells: essential role of retinoic acid

The vitamin A metabolite retinoic acid (RA) regulates adaptive immunity in the intestines, with well-characterized effects on IgA responses, Treg induction and gut trafficking of T and B effector cells. It also controls the generation of cDC precursors in the bone marrow and regulates cDC subset representation, but its roles in the specialization of intestinal cDC subsets is understudied. Here we show that RA acts cell-intrinsically in developing gut-tropic pre-mucosal DC (pre-μDC) to effect the differentiation and drive the specialization of intestinal CD103+CD11b− (cDC1) and of CD103+CD11b+ (cDC2). Systemic deficiency or DC-restricted antagonism of RA signaling resulted in altered phenotypes of intestinal cDC1 and cDC2, and reduced numbers of cDC2. Effects of dietary deficiency were most apparent in the proximal small intestine, and were rapidly reversed by reintroducing vitamin A. In cultures of pre-μDC with Flt3L and GM-CSF, RA induced cDC with characteristic phenotypes of intestinal cDC1 and cDC2 by controlling subset-defining cell surface receptors, regulating subset-specific transcriptional programs, and suppressing proinflammatory NF-κB-dependent gene expression. Thus RA is required for transcriptional programming and maturation of intestinal cDC, and with GM-CSF and Flt3L provides a minimal environment for in vitro generation of intestinal cDC1- and cDC2-like cDC from specialized precursors

Genotyping pooled DNA using 100K SNP microarrays: a step towards genomewide association scans

The identification of quantitative trait loci (QTLs) of small effect size that underlie complex traits poses a particular challenge for geneticists due to the large sample sizes and large numbers of genetic markers required for genomewide association scans. An efficient solution for screening purposes is to combine single nucleotide polymorphism (SNP) microarrays and DNA pooling (SNP-MaP), an approach that has been shown to be valid, reliable and accurate in deriving relative allele frequency estimates from pooled DNA for groups such as cases and controls for 10K SNP microarrays. However, in order to conduct a genomewide association study many more SNP markers are needed. To this end, we assessed the validity and reliability of the SNP-MaP method using Affymetrix GeneChip(®) Mapping 100K Array set. Interpretable results emerged for 95% of the SNPs (nearly 110 000 SNPs). We found that SNP-MaP allele frequency estimates correlated 0.939 with allele frequencies for 97 605 SNPs that were genotyped individually in an independent population; the correlation was 0.971 for 26 SNPs that were genotyped individually for the 1028 individuals used to construct the DNA pools. We conclude that extending the SNP-MaP method to the Affymetrix GeneChip(®) Mapping 100K Array set provides a useful screen of >100 000 SNP markers for QTL association scans

Applicability of DNA pools on 500 K SNP microarrays for cost-effective initial screens in genomewide association studies

<p>Abstract</p> <p>Background</p> <p>Genetic influences underpinning complex traits are thought to involve multiple quantitative trait loci (QTLs) of small effect size. Detection of such QTL associations requires systematic screening of large numbers of DNA markers within large sample populations. Using pooled DNA on SNP microarrays to screen for allelic frequency differences between groups such as cases and controls (called SNP Microarray and Pooling, or SNP-MaP) has been validated as an efficient solution on both 10 k and 100 k platforms. We demonstrate that this approach can be effectively applied to the truly genomewide Affymetrix GeneChip^®Mapping 500 K Array.</p> <p>Results</p> <p>In comparisons between five independent DNA pools (<it>N </it>~200 per pool) on separate Affymetrix GeneChip^®Mapping 500 K Array sets, we show that, for SNPs with minor allele frequencies > 0.05, the reliability of the rank order of estimated allele frequencies, assessed as the average correlation between allele frequency estimates across the DNA pools, was 0.948 (average mean difference across the five pools = 0.069). Similarly, validity of the SNP-MaP approach was demonstrated by a rank-order correlation of 0.937 (average mean difference = 0.095) between the average DNA pool allele frequency estimates and the allele frequencies of an independent (CEPH) sample of 60 unrelated individually genotyped subjects.</p> <p>Conclusion</p> <p>We conclude that SNP-MaP can be extended for use on the Affymetrix GeneChip^®Mapping 500 K Array, providing a cost-effective, reliable and valid initial screen of 500 K SNP microarrays in genomewide association scans.</p

A Constructivist Study of Graduate Assistants\u27 Healthcare Experiences in a Research University

This constructivist study explores 16 graduate assistants’ (GAs) healthcare experiences and uses grounded theory to create a model of graduate assistants’ experiences with university-provided healthcare in a large research university. The model is composed of four broad components: (a) systems; (b) access, care and coverage; (c) knowledge, quality and cost; and (d) self. Graduate assistants’ needs and expectations constantly negotiate various systems in the model. Expanding upon the limited research regarding graduate student healthcare, this study provides implications for higher education administrators and policy makers. Based on our study findings we argue that it is not sufficient for university administrations to simply provide paid health insurance “options” without robust support systems on campus. Because students are often stressed out, lack time and energy, and find it hard to navigate the complicated systems of profit-driven health care industry, the lack of direct support in graduate students’ day-to-day healthcare needs can cause tremendous loss on their success and productivity. Hence, universities have tremendous opportunities to better understand and address their graduate students’ real needs so as to add value to institutional success and productivity

Oceanographic conditions associated with white shark (Carcharodon carcharias) habitat use along eastern Australia

Management of species with wide-ranging migrations is a complex issue, made more challenging when the species is both protected and poses a risk to humans. Understanding the oceanic conditions associated with shark habitat use can help develop mitigation strategies or warning systems that meet both conservation and human safety objectives. Using satellite tracks from 77 juvenile and sub-adult white sharks tagged over 10 yr, we modelled individual movement patterns using hidden Markov models and applied generalised additive (mixed) models to explore correlations between movement patterns (presence−absence, habitat selection and behavioural state) and oceanographic and bathymetric variables. White sharks used the whole of the continental shelf, down to depths of 350 m on the continental slope. Sharks were present over a wide range of sea surface temperatures (SSTs; 10−27°C), with the highest probability of occurring at ~20°C. However, the number of average daily tag positions was greatest when SST was between 14 and 18°C, and sharks were more likely to exhibit area-restricted movement when SST was between ~19 and 23°C. Sharks were more likely to be present and selected habitats in productive areas with moderate to high surface chl a concentrations as well as thermal and productivity fronts. Although mesoscale eddies did not influence the likelihood of individuals being present in an area, there was a higher density of sharks in cold-core eddies compared to warm-core eddies. This study indicates that white shark presence and dispersal may be linked, perhaps via prey distribution, to oceanic conditions, potentially assisting development of suitable shark bite mitigation strategies

Genotyping DNA pools on microarrays: Tackling the QTL problem of large samples and large numbers of SNPs

BACKGROUND: Quantitative trait locus (QTL) theory predicts that genetic influence on complex traits involves multiple genes of small effect size. To detect QTL associations of small effect size, large samples and systematic screens of thousands of DNA markers are required. An efficient solution is to genotype case and control DNA pools using SNP microarrays. We demonstrate that this is practical using DNA pools of 100 individuals. RESULTS: Using standard microarray protocols for the Affymetrix GeneChip(® )Mapping 10 K Array Xba 131, we show that relative allele signal (RAS) values provide a quantitative index of allele frequencies in pooled DNA that correlate 0.986 with allele frequencies for 104 SNPs that were genotyped individually for 100 individuals. The sensitivity of the assay was demonstrated empirically in a spiking experiment in which 15% and 20% of one individual's DNA was added to a DNA pool. CONCLUSION: We conclude that this approach, which we call SNP-MaP (SNP microarrays and pooling), is rapid, cost effective and promises to be a valuable initial screening method in the hunt for QTLs

Global trends in ultraprocessed food and drink product sales and their association with adult body mass index trajectories

This study evaluated global trends in ultraprocessed food and drink (UPFD) volume sales/capita and associations with adult body mass index (BMI) trajectories. Total food/drink volume sales/capita from Euromonitor for 80 countries (2002‐2016) were matched to mean adult BMI from the NCD Risk Factor Collaboration (2002‐2014). Products were classified as UPFD/non‐UPFD according to the NOVA classification system. Mixed models for repeated measures were used to analyse associations between UPFD volume sales/capita and adult BMI trajectories, controlling for confounding factors. The increase in UPF volume sales was highest for South and Southeast Asia (67.3%) and North Africa and the Middle East (57.6%), while for UPD, the increase was highest for South and Southeast Asia (120.0%) and Africa (70.7%). In 2016, baked goods were the biggest contributor to UPF volume sales (13.1%‐44.5%), while carbonated drinks were the biggest contributor to UPD volume sales (40.2%‐86.0%). For every standard deviation increase (51 kg/capita, 2002) in UPD volume sales, mean BMI increased by 0.195 kg/m2 for men (P < .001) and 0.072 kg/m2 for women (P = .003). For every standard deviation (40 kg/capita, 2002) increase in UPF volume sales, mean BMI increased by 0.316 kg/m2 for men (P < .001), while the association was not significant for women. Increases in UPFD volume sales/capita were positively associated with population‐level BMI trajectories

Non-CG DNA methylation is a biomarker for assessing endodermal differentiation capacity in pluripotent stem cells.

Non-CG methylation is an unexplored epigenetic hallmark of pluripotent stem cells. Here we report that a reduction in non-CG methylation is associated with impaired differentiation capacity into endodermal lineages. Genome-wide analysis of 2,670 non-CG sites in a discovery cohort of 25 phenotyped human induced pluripotent stem cell (hiPSC) lines revealed unidirectional loss (Δβ=13%, P<7.4 × 10(-4)) of non-CG methylation that correctly identifies endodermal differentiation capacity in 23 out of 25 (92%) hiPSC lines. Translation into a simplified assay of only nine non-CG sites maintains predictive power in the discovery cohort (Δβ=23%, P<9.1 × 10(-6)) and correctly identifies endodermal differentiation capacity in nine out of ten pluripotent stem cell lines in an independent replication cohort consisting of hiPSCs reprogrammed from different cell types and different delivery systems, as well as human embryonic stem cell (hESC) lines. This finding infers non-CG methylation at these sites as a biomarker when assessing endodermal differentiation capacity as a readout.We thank Kerra Pearce (UCL Genomics) for array processing, and Tim Fell and Jonathan Best (CellCentric), Jason Wray (UCL) and Rosemary Drake (TAP Biosystems) for discussions. We also thank Minal Patel, Chris Kirton, Anja Kolb-Kokocinski, Willem H. Ouwehand, Richard Durbin and Fiona M. Watt on behalf of the Human Induced Pluripotent Stem Cell Initiative (HipSci) funded by grant WT098503 from the Wellcome Trust and the Medical Research Council, for sharing data and materials. This work was supported in part by a TSB/EPSRC grant (TS/H000933/1). The Vallier lab is supported by the Cambridge Hospitals National Institute for Health Research Biomedical Research Center and an ERC Starting Grant (Relieve IMDS). F.A.C.S. is funded by a PhD studentship from Fundação para a Ciência e a Tecnologia (SFRH/BD/69033/2010). The Ferguson-Smith lab is supported by grants from the MRC and Wellcome Trust, and EU-FP7 projects EPIGENESYS (257082) and BLUEPRINT (282510). The Beck lab is supported by the Wellcome Trust (084071), a Royal Society Wolfson Research Merit Award (WM100023), and EU-FP7 projects EPIGENESYS (257082) and BLUEPRINT (282510).This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms1045

N-(3,4-Dichloro­phen­yl)-3-oxo­butanamide

In the title compound. C10H9Cl2NO2, the acetamide residue is twisted out of the phenyl ring plane by 25.40 (9)°. An intra­molecular C—H⋯O close contact is observed. The N atom of the butanamide unit forms an inter­molecular N—H⋯O hydrogen bond with the symmetry-related carbonyl O atom, inter­linking mol­ecules into a C(4) chain along [100]. Additional C—H⋯O inter­molecular inter­actions and Cl⋯Cl contacts [3.4364 (8) Å] contribute to the stability of the crystal packing

The History of Galaxy Formation in Groups: An Observational Perspective

We present a pedagogical review on the formation and evolution of galaxies in groups, utilizing observational information from the Local Group to galaxies at z~6. The majority of galaxies in the nearby universe are found in groups, and galaxies at all redshifts up to z~6 tend to cluster on the scale of nearby groups (~1 Mpc). This suggests that the group environment may play a role in the formation of most galaxies. The Local Group, and other nearby groups, display a diversity in star formation and morphological properties that puts limits on how, and when, galaxies in groups formed. Effects that depend on an intragroup medium, such as ram-pressure and strangulation, are likely not major mechanisms driving group galaxy evolution. Simple dynamical friction arguments however show that galaxy mergers should be common, and a dominant process for driving evolution. While mergers between L_* galaxies are observed to be rare at z < 1, they are much more common at earlier times. This is due to the increased density of the universe, and to the fact that high mass galaxies are highly clustered on the scale of groups. We furthermore discus why the local number density environment of galaxies strongly correlates with galaxy properties, and why the group environment may be the preferred method for establishing the relationship between properties of galaxies and their local density.Comment: Invited review, 16 pages, to be published in ESO Astrophysics Symposia: "Groups of Galaxies in the Nearby Universe", eds. I. Saviane, V. Ivanov, J. Borissov