Structure of an archaeal PCNA1-PCNA2-FEN1 complex: elucidating PCNA subunit and client enzyme specificity.

The archaeal/eukaryotic proliferating cell nuclear antigen (PCNA) toroidal clamp interacts with a host of DNA modifying enzymes, providing a stable anchorage and enhancing their respective processivities. Given the broad range of enzymes with which PCNA has been shown to interact, relatively little is known about the mode of assembly of functionally meaningful combinations of enzymes on the PCNA clamp. We have determined the X-ray crystal structure of the Sulfolobus solfataricus PCNA1-PCNA2 heterodimer, bound to a single copy of the flap endonuclease FEN1 at 2.9 A resolution. We demonstrate the specificity of interaction of the PCNA subunits to form the PCNA1-PCNA2-PCNA3 heterotrimer, as well as providing a rationale for the specific interaction of the C-terminal PIP-box motif of FEN1 for the PCNA1 subunit. The structure explains the specificity of the individual archaeal PCNA subunits for selected repair enzyme 'clients', and provides insights into the co-ordinated assembly of sequential enzymatic steps in PCNA-scaffolded DNA repair cascades

Cardiovascular disease in a cohort exposed to the 1940-45 Channel Islands occupation

BACKGROUND To clarify the nature of the relationship between food deprivation/undernutrition during pre- and postnatal development and cardiovascular disease (CVD) in later life, this study examined the relationship between birth weight (as a marker of prenatal nutrition) and the incidence of hospital admissions for CVD from 1997–2005 amongst 873 Guernsey islanders (born in 1923–1937), 225 of whom had been exposed to food deprivation as children, adolescents or young adults (i.e. postnatal undernutrition) during the 1940–45 German occupation of the Channel Islands, and 648 of whom had left or been evacuated from the islands before the occupation began. METHODS Three sets of Cox regression models were used to investigate (A) the relationship between birth weight and CVD, (B) the relationship between postnatal exposure to the occupation and CVD and (C) any interaction between birth weight, postnatal exposure to the occupation and CVD. These models also tested for any interactions between birth weight and sex, and postnatal exposure to the occupation and parish of residence at birth (as a marker of parish residence during the occupation and related variation in the severity of food deprivation). RESULTS The first set of models (A) found no relationship between birth weight and CVD even after adjustment for potential confounders (hazard ratio (HR) per kg increase in birth weight: 1.12; 95% confidence intervals (CI): 0.70 – 1.78), and there was no significant interaction between birth weight and sex (p = 0.60). The second set of models (B) found a significant relationship between postnatal exposure to the occupation and CVD after adjustment for potential confounders (HR for exposed vs. unexposed group: 2.52; 95% CI: 1.54 – 4.13), as well as a significant interaction between postnatal exposure to the occupation and parish of residence at birth (p = 0.01), such that those born in urban parishes (where food deprivation was worst) had a greater HR for CVD than those born in rural parishes. The third model (C) found no interaction between birth weight and exposure to the occupation (p = 0.43). CONCLUSION These findings suggest that the levels of postnatal undernutrition experienced by children, adolescents and young adults exposed to food deprivation during the 1940–45 occupation of the Channel Islands were a more important determinant of CVD in later life than the levels of prenatal undernutrition experienced in utero prior to the occupatio

A global biophysical typology of mangroves and its relevance for ecosystem structure and deforestation

Mangrove forests provide many ecosystem services but are among the world's most threatened ecosystems. Mangroves vary substantially according to their geomorphic and sedimentary setting; while several conceptual frameworks describe these settings, their spatial distribution has not been quantified. Here, we present a new global mangrove biophysical typology and show that, based on their 2016 extent, 40.5% (54,972 km2) of mangrove systems were deltaic, 27.5% (37,411 km2) were estuarine and 21.0% (28,493 km2) were open coast, with lagoonal mangroves the least abundant (11.0%, 14,993 km2). Mangroves were also classified based on their sedimentary setting, with carbonate mangroves being less abundant than terrigenous, representing just 9.6% of global coverage. Our typology provides a basis for future research to incorporate geomorphic and sedimentary setting in analyses. We present two examples of such applications. Firstly, based on change in extent between 1996 and 2016, we show while all types exhibited considerable declines in area, losses of lagoonal mangroves (- 6.9%) were nearly twice that of other types. Secondly, we quantify differences in aboveground biomass between mangroves of different types, with it being significantly lower in lagoonal mangroves. Overall, our biophysical typology provides a baseline for assessing restoration potential and for quantifying mangrove ecosystem service provision

A REGIONAL EXPERIMENT TO EVALUATE EFFECTS OF FIRE AND FIRE SURROGATE TREATMENTS IN THE SAGEBRUSH BIOME

SageSTEP is a comprehensive regional experiment that provides critical information to managers faced with a sagebrush steppe ecosystem that is increasingly at risk from wildfire, invasive plants, and climate change. The experiment provides managers with information that can be used to restore ecological communities across the 100+ million acres of the sagebrush biome. It is designed to match the temporal and spatial scales at which managers operate, is intended to reduce management risk and uncertainty of catastrophic wildfire to the greatest degree possible, and provides managers with information that allows them to better understand tradeoffs inherent in the choice of management alternatives. The project has several features that make it ideal for testing hypotheses from state‐andtransition theory, and for discovering information that can be directly applied in a management context ‐‐ it is long‐term, experimental, multisite, multivariate, and treatments are applied across condition gradients, allowing for potential identification of biotic thresholds. The project is designed to distinguish communities that have conditions that will allow them to recover on their own following fuel or restoration treatments, versus communities that have crossed biotic thresholds, and will therefore require more expensive active restoration. SageSTEP is designed as a long‐term study, such that measurements are planned for at least 10 years after treatment implementation, or through the 2018 field season. This final report therefore describes the short‐term effects of treatments, 2‐4 years after treatment implementation., or through the 2010 field season. The Joint Fire Science Program generously funded SageSTEP for its first six years, and this funding was crucial for building an infrastructure that has now set the stage for an unprecedented long‐term study that will provide badly needed information on sagebrush steppe restoration and fuel treatment effectiveness. The infrastructure we’ve built consists of the following eight features: 1. A network of 18 sites distributed across the Great Basin, Snake River Basin, and Columbia Basin, 11 sites in a replicated woodland experiment, and 7 sites in a replicated sage‐cheat experiment (Figure 1). Each site is equivalent to a statistical block consisting of an unmanipulated control, and a set of fire and fire surrogate treatments. 2. A network of weather and soil moisture stations distributed along with the sites, that provides information on inter‐annual and geographic variation in moisture and temperature, and that is being used to interpret patterns of ecological response. 3. A small by efficient staff, consisting of scientists and technicians, responsible for continued monitoring of ecological variables through time, and maintenance of the projects’ infrastructure. 4. A funding stream from several agency sources, with current resources adequate to run the project for at least three more years, and with agreements in place to fund the project through fiscal year 2015. 5. A web of partnerships among managers, scientists, students, stakeholders, and policymakers that has worked together to design the study, implement the treatments, and learn about how sagebrush steppe system respond to alternative restoration treatments. 6. A highly effective and influential outreach program, anchored by a popular website, designed to interpret and deliver scientific information collected by SageSTEP scientists, and to distribute other relevant information originating from outside the project. 7. An on‐line database, called the SageSTEP Data Store, that offers fully proofed and validated data to analysts working within SageSTEP, and which will eventually provide the same information to other interested users. 8. The Great Basin NEON Site, NSF’s atmospheric sampling station that will soon be built at the SageSTEP Onaqui site. This link with NSF provides SageSTEP with leverage for established additional vegetation and soil monitoring facilities at Onaqui. Over the past three years, since post‐treatment data collection commenced, SageSTEP has produced a considerable amount of information, most of it now published in a total of 32 scientific papers. Key outreach products include: ● Active web site (sagestep.org), anchoring a comprehensive outreach program ● User\u27s Guides for Western Juniper & Pinyon‐Juniper woodlands ● Two Fuel Guides, one each for pre‐treatment and post‐treatment conditions ● 15 quarterly newsletters ● Six manager workshops ● 11 tours or field trips ● Three national conference symposia, consisting of 24 papers (2 symposia planned) ● 57 contributed papers at conferences ● Seven Master’s Theses and two Ph.D. Dissertations ● 15 papers published in proceedings or reports ● Ten papers published in peer‐reviewed journals (17 papers currently in review

Recipient mucosal-associated invariant T cells control GVHD within the colon

Mucosal-associated invariant T (MAIT) cells are a unique innate-like T cell subset that responds to a wide array of bacteria and yeast through recognition of riboflavin metabolites presented by the MHC class I–like molecule MR1. Here, we demonstrate using MR1 tetramers that recipient MAIT cells are present in small but definable numbers in graft-versus-host disease (GVHD) target organs and protect from acute GVHD in the colon following bone marrow transplantation (BMT). Consistent with their preferential juxtaposition to microbial signals in the colon, recipient MAIT cells generate large amounts of IL-17A, promote gastrointestinal tract integrity, and limit the donor alloantigen presentation that in turn drives donor Th1 and Th17 expansion specifically in the colon after BMT. Allogeneic BMT recipients deficient in IL-17A also develop accelerated GVHD, suggesting MAIT cells likely regulate GVHD, at least in part, by the generation of this cytokine. Indeed, analysis of stool microbiota and colon tissue from IL-17A–/– and MR1–/– mice identified analogous shifts in microbiome operational taxonomic units (OTU) and mediators of barrier integrity that appear to represent pathways controlled by similar, IL-17A–dependent mechanisms. Thus, MAIT cells act to control barrier function to attenuate pathogenic T cell responses in the colon and, given their very high frequency in humans, likely represent an important population in clinical BMT

Harnessing big data to support the conservation and rehabilitation of mangrove forests globally

Mangrove forests are found on sheltered coastlines in tropical, subtropical, and some warm temperate regions. These forests support unique biodiversity and provide a range of benefits to coastal communities, but as a result of large-scale conversion for aquaculture, agriculture, and urbanization, mangroves are considered increasingly threatened ecosystems. Scientific advances have led to accurate and comprehensive global datasets on mangrove extent, structure, and condition, and these can support evaluation of ecosystem services and stimulate greater conservation and rehabilitation efforts. To increase the utility and uptake of these products, in this Perspective we provide an overview of these recent and forthcoming global datasets and explore the challenges of translating these new analyses into policy action and on-the-ground conservation. We describe a new platform for visualizing and disseminating these datasets to the global science community, non-governmental organizations, government officials, and rehabilitation practitioners and highlight future directions and collaborations to increase the uptake and impact of large-scale mangrove research. This Perspective reviews the role of global-scale research in stimulating policy action and on-the-ground conservation for mangrove ecosystems. We outline the current state of knowledge in terms of global analyses and examine the challenge of translating this research in action

US Cosmic Visions: New Ideas in Dark Matter 2017: Community Report

This white paper summarizes the workshop "U.S. Cosmic Visions: New Ideas in Dark Matter" held at University of Maryland on March 23-25, 2017.Comment: 102 pages + reference

Implementation of exon arrays: alternative splicing during T-cell proliferation as determined by whole genome analysis

<p>Abstract</p> <p>Background</p> <p>The contribution of alternative splicing and isoform expression to cellular response is emerging as an area of considerable interest, and the newly developed exon arrays allow for systematic study of these processes. We use this pilot study to report on the feasibility of exon array implementation looking to replace the 3' <it>in vitro </it>transcription expression arrays in our laboratory.</p> <p>One of the most widely studied models of cellular response is T-cell activation from exogenous stimulation. Microarray studies have contributed to our understanding of key pathways activated during T-cell stimulation. We use this system to examine whole genome transcription and alternate exon usage events that are regulated during lymphocyte proliferation in an attempt to evaluate the exon arrays.</p> <p>Results</p> <p>Peripheral blood mononuclear cells form healthy donors were activated using phytohemagglutinin, IL2 and ionomycin and harvested at 5 points over a 7 day period. Flow cytometry measured cell cycle events and the Affymetrix exon array platform was used to identify the gene expression and alternate exon usage changes. Gene expression changes were noted in a total of 2105 transcripts, and alternate exon usage identified in 472 transcript clusters. There was an overlap of 263 transcripts which showed both differential expression and alternate exon usage over time. Gene ontology enrichment analysis showed a broader range of biological changes in biological processes for the differentially expressed genes, which include cell cycle, cell division, cell proliferation, chromosome segregation, cell death, component organization and biogenesis and metabolic process ontologies. The alternate exon usage ontological enrichments are in metabolism and component organization and biogenesis. We focus on alternate exon usage changes in the transcripts of the spliceosome complex. The real-time PCR validation rates were 86% for transcript expression and 71% for alternate exon usage.</p> <p>Conclusions</p> <p>This study illustrates that the Exon array technology has the potential to provide information on both transcript expression and isoform usage, with very little increase in expense.</p

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Repercussion of megakaryocyte-specific Gata1 Loss on megakaryopoiesis and the hematopoietic precursor compartment

During hematopoiesis, transcriptional programs are essential for the commitment and differentiation of progenitors into the different blood lineages. GATA1 is a transcription factor expressed in several hematopoietic lineages and essential for proper erythropoiesis and megakaryopoiesis. Megakaryocyte-specific genes, such as GP1BA, are known to be directly regulated by GATA1. Mutations in GATA1 can lead to dyserythropoietic anemia and pseudo gray-platelet syndrome. Selective loss of Gata1 expression in adult mice results in macrothrombocytopenia with platelet dysfunction, characterized by an excess of immature megakaryocytes. To specifically analyze the impact of Gata1 loss in mature committed megakaryocytes, we generated Gata1-Lox|Pf4-Cre mice (Gata1cKOMK). Consistent with previous findings, Gata1cKOMK mice are macrothrombocytopenic with platelet dysfunction. Supporting this notion we demonstrate that Gata1 regulates directly the transcription of Syk, a tyrosine kinase that functions downstream of Clec2 and GPVI receptors in megakaryocytes and platelets. Furthermore, we show that Gata1cKOMK mice display an additional aberrant megakaryocyte differentiation stage. Interestingly, these mice present a misbalance of the multipotent progenitor compartment and the erythroid lineage, which translates into compensatory stress erythropoiesis and splenomegaly. Despite the severe thrombocytopenia, Gata1cKOMK mice display a mild reduction of TPO plasma levels, and Gata1cK-OMK megakaryocytes show a mild increase in Pf4 mRNA levels; such a misbalance might be behind the general hematopoietic defects observed, affecting locally normal TPO and Pf4 levels at hematopoietic stem cell niches. © 2016 Meinders et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited