Single-cell analysis of human MAIT cell transcriptional, functional and clonal diversity

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize microbial metabolites through a semi-invariant T cell receptor (TCR). Major questions remain regarding the extent of human MAIT cell functional and clonal diversity. To address these, we analyzed the single-cell transcriptome and TCR repertoire of blood and liver MAIT cells and developed functional RNA-sequencing, a method to integrate function and TCR clonotype at single-cell resolution. MAIT cell clonal diversity was comparable to conventional memory T cells, with private TCR repertoires shared across matched tissues. Baseline functional diversity was low and largely related to tissue site. MAIT cells showed stimulus-specific transcriptional responses in vitro, with cells positioned along gradients of activation. Clonal identity influenced resting and activated transcriptional profiles but intriguingly was not associated with the capacity to produce IL-17. Overall, MAIT cells show phenotypic and functional diversity according to tissue localization, stimulation environment and clonotype

Evidence of pervasive biologically functional secondary-structures within the genomes of eukaryotic single-stranded DNA viruses

Single-stranded DNA (ssDNA) viruses have genomes that are potentially capable of forming complex secondary-structures through Watson-Crick base-pairing between their constituent nucleotides. A few of the structural elements formed by such base-pairings are, in fact, known to have important functions during the replication of many ssDNA viruses. What is unknown, however, is (i) whether numerous additional ssDNA virus genomic structural elements predicted to exist by computational DNA folding methods actually exist, and (ii) whether those structures that do exist have any biological relevance. We therefore computationally inferred lists of the most evolutionarily conserved structures within a diverse selection of animal- and plant-infecting ssDNA viruses drawn from the families Circoviridae, Anelloviridae, Parvoviridae, Nanoviridae andGeminiviridae, and analysed these for evidence of natural selection favouring the maintenance of these structures. While we find evidence that is consistent with purifying selection being stronger at nucleotide sites that are predicted to be base-paired than it is at sites predicted to be unpaired, we also find strong associations between sites that are predicted to pair with one another and site pairs that are apparently coevolving in a complementary fashion. Collectively, these results indicate that natural selection actively preserves much of the pervasive secondary-structure that is evident within eukaryote-infecting ssDNA virus genomes and, therefore, that much of this structure is biologically functional. Lastly, we provide examples of various highly conserved but completely uncharacterised structural elements that likely have important functions within some of the ssDNA virus genomes analysed here

Stimulatory MAIT cell antigens reach the circulation and are efficiently metabolised and presented by human liver cells.

OBJECTIVE Mucosal-associated invariant T (MAIT) cells are the most abundant T cells in human liver. They respond to bacterial metabolites presented by major histocompatibility complex-like molecule MR1. MAIT cells exert regulatory and antimicrobial functions and are implicated in liver fibrogenesis. It is not well understood which liver cells function as antigen (Ag)-presenting cells for MAIT cells, and under which conditions stimulatory Ags reach the circulation. DESIGN We used different types of primary human liver cells in Ag-presentation assays to blood-derived and liver-derived MAIT cells. We assessed MAIT cell stimulatory potential of serum from healthy subjects and patients with portal hypertension undergoing transjugular intrahepatic portosystemic shunt stent, and patients with inflammatory bowel disease (IBD). RESULTS MAIT cells were dispersed throughout healthy human liver and all tested liver cell types stimulated MAIT cells, hepatocytes being most efficient. MAIT cell activation by liver cells occurred in response to bacterial lysate and pure Ag, and was prevented by non-activating MR1 ligands. Serum derived from peripheral and portal blood, and from patients with IBD stimulated MAIT cells in MR1-dependent manner. CONCLUSION Our findings reveal previously unrecognised roles of liver cells in Ag metabolism and activation of MAIT cells, repression of which creates an opportunity to design antifibrotic therapies. The presence of MAIT cell stimulatory Ags in serum rationalises the observed activated MAIT cell phenotype in liver. Increased serum levels of gut-derived MAIT cell stimulatory ligands in patients with impaired intestinal barrier function indicate that intrahepatic Ag-presentation may represent an important step in the development of liver disease

To swim or not to swim: an interpretation of farmed mink's motivation for a water bath

How an animal’s behavioural (ethological) needs can be met is a pivotal issue in the assessment of welfare for captive animals. The value of swimming water for farmed mink is an example how scientific and societal questions relating to animal welfare can be answered. A number of studies have addressed the issue of the indispensability of swimming water for mink; however, so far with inconclusive evidence. In this paper, the results of these studies and related literature are reviewed. First, the biological definition of need is discussed. Subsequently, attention is paid to the effects of the presence, absence and the removal of swimming water on behavioural and physiological correlates of well-being including stereotypic and anticipatory behaviour and urinary cortisol. Thereafter we discuss individual differences in the use of swimming water, the price animals pay for access to a water bath, and the effect of access to swimming water on juvenile play. The main conclusions of the literature review are that 1) the use of a water bath for mink is most likely related to foraging behaviour (foraging areas: land and water); 2) absence of swimming water, without prior experience, does not lead to consistent changes in level of stereotypic behaviour, or anticipatory responses; 3) removal of a previously experienced water bath may induce short-term stress as indicated by behavioural parameters and elevated cortisol responses; 4) mink work hard for access to a swimming bath and running wheel in consumer demand studies. Other cage modifications such as tunnels and biting objects, may also provide environmental enrichment, if they are added to otherwise impoverished conditions; 5) There are individual differences in the use of swimming water: these are related in part to variation in prior experience of aquatic resources.; 6) As prior experience is important both with respect to individual use of swimming water and the response to deprivation, swimming water can not be described as biological need in the sense of a fixed requirement for survival. As swimming water appears to act as an incentive that induces its own motivation a more accurate term may be an “incentive induced or environmentally facilitated need”. Given the available evidence, it is not possible to conclude whether mink that have never experienced swimming water, suffer as a consequence of its absence. However, it is possible to predict that mink with access to water have improved quality of life, due to increased behavioural opportunities, in comparison to farmed mink without access to swimming water. In practical terms, it is still open to debate whether mink should be provided with swimming water, or if alternative, less valued, but easier to install and maintain forms of environmental enrichment, should be provided in mink housing. To clarify these issues a number of future studies would be valuable. These include; 1) whether specific environmental cues affect motivation to swim, such as the form of drinking water delivery systems ; 2) whether prior experience of swimming water affects its incentive value; in other words “can you miss what you never experienced?”; 3) do behavioural parameters such as stereotypic behaviour; rebound effects and vacuum activity have any general utility in assessing the value of absent resources; 4) what are preferences for and the value of alternative resources which may act as substitutes for swimming water. In addition we would recommend further work investigating: relationship between access to swimming water and positive indicators of welfare such as play and/or anticipatory behaviour; the effects of preventing the performance of rewarding behaviours and deprivation of a previous experienced resource; and health and hygeine issues related to provision of a water bath. In future work, it would be desirable to present be the actual percentages of animals using a water bath during the experiment and the use of power analyses, to aid their interpretation

The Spread of Tomato Yellow Leaf Curl Virus from the Middle East to the World

The ongoing global spread of Tomato yellow leaf curl virus (TYLCV; Genus Begomovirus, Family Geminiviridae) represents a serious looming threat to tomato production in all temperate parts of the world. Whereas determining where and when TYLCV movements have occurred could help curtail its spread and prevent future movements of related viruses, determining the consequences of past TYLCV movements could reveal the ecological and economic risks associated with similar viral invasions. Towards this end we applied Bayesian phylogeographic inference and recombination analyses to available TYLCV sequences (including those of 15 new Iranian full TYLCV genomes) and reconstructed a plausible history of TYLCV's diversification and movements throughout the world. In agreement with historical accounts, our results suggest that the first TYLCVs most probably arose somewhere in the Middle East between the 1930s and 1950s (with 95% highest probability density intervals 1905–1972) and that the global spread of TYLCV only began in the 1980s after the evolution of the TYLCV-Mld and -IL strains. Despite the global distribution of TYLCV we found no convincing evidence anywhere other than the Middle East and the Western Mediterranean of epidemiologically relevant TYLCV variants arising through recombination. Although the region around Iran is both the center of present day TYLCV diversity and the site of the most intensive ongoing TYLCV evolution, the evidence indicates that the region is epidemiologically isolated, which suggests that novel TYLCV variants found there are probably not direct global threats. We instead identify the Mediterranean basin as the main launch-pad of global TYLCV movements

Molecular diversity of Cotton leaf curl Gezira virus isolates and their satellite DNAs associated with okra leaf curl disease in Burkina Faso

Okra leaf curl disease (OLCD) is a major constraint on okra (Abelmoschus esculentus) production and is widespread in Africa. Using a large number of samples representative of the major growing regions in Burkina Faso (BF), we show that the disease is associated with a monopartite begomovirus and satellite DNA complexes. Twenty-three complete genomic sequences of Cotton leaf curl Gezira virus (CLCuGV) isolates associated with OLCD, sharing 95 to 99% nucleotide identity, were cloned and sequenced. Six betasatellite and four alphasatellite (DNA-1) molecules were also characterized. The six isolates of betasatellite associated with CLCuGV isolates correspond to Cotton leaf curl Gezira betasatellite (CLCuGB) (88 to 98% nucleotide identity). One isolate of alphasatellite is a variant of Cotton leaf curl Gezira alphasatellite (CLCuGA) (89% nucleotide identity), whereas the three others isolates appear to correspond to a new species of alphasatellite (CLCuGA most similar sequence present 52 to 60% nucleotide identity), provisionally named Okra leaf curl Burkina Faso alphasatellite (OLCBFA). Recombination analysis of the viruses demonstrated the interspecies recombinant origin of all CLCuGV isolates, with parents being close to Hollyhock leaf crumple virus (AY036009) and Tomato leaf curl Diana virus (AM701765). Combined with the presence of satellites DNA, these results highlight the complexity of begomoviruses associated with OLCD

Can bryophyte groups increase functional resolution in tundra ecosystems?

Funding Information: This study was supported by a grant to SL from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie, Grant No. 797446 and by the Independent Research Fund Denmark, Grant no. 0135-00140B. Funding from the Academy of Finland (grant 322266), National Science Foundation (1504224, 1836839, PLR-1504381 and PLR-1836898), Independent Research Fund Denmark (9040-00314B), Moscow State University, (project No 121032500089-1), Natural Sciences and Engineering Research Council of Canada, ArcticNet, Polar Continental Shelf Program, Northern Science Training Program, Polar Knowledge Canada, Royal Canadian Mounted Police, Tomsk State University competitiveness improvement program and the Russian Science Foundation (grant No 20-67-46018) are gratefully acknowledged. Matthias Ahrens provided valuable insights on the cushion growth form, and we are most thankful. We thank Gaius Shaver and two anonymous reviewers for providing valuable critique and input to earlier versions of this manuscript. Publisher Copyright: © the author(s) or their institution(s).The relative contribution of bryophytes to plant diversity, primary productivity, and ecosystem functioning increases towards colder climates. Bryophytes respond to environmental changes at the species level, but because bryophyte species are relatively difficult to identify, they are often lumped into one functional group. Consequently, bryophyte function remains poorly resolved. Here, we explore how higher resolution of bryophyte functional diversity can be encouraged and implemented in tundra ecological studies. We briefly review previous bryophyte functional classifications and the roles of bryophytes in tundra ecosystems and their susceptibility to environmental change. Based on shoot morphology and colony organization, we then propose twelve easily distinguishable bryophyte functional groups. To illustrate how bryophyte functional groups can help elucidate variation in bryophyte effects and responses, we compiled existing data on water holding capacity, a key bryophyte trait. Although plant functional groups can mask potentially high interspecific and intraspecific variability, we found better separation of bryophyte functional group means compared with previous grouping systems regarding water holding capacity. This suggests that our bryophyte functional groups truly represent variation in the functional roles of bryophytes in tundra ecosystems. Lastly, we provide recommendations to improve the monitoring of bryophyte community changes in tundra study sites.Peer reviewe

White matter disturbances in major depressive disorder : a coordinated analysis across 20 international cohorts in the ENIGMA MDD working group

Altres ajuts: The ENIGMA-Major Depressive Disorder working group gratefully acknowledges support from the NIH Big Data to Knowledge (BD2K) award (U54 EB020403 to PMT) and NIH grant R01 MH116147 (PMT). LS is supported by an NHMRC MRFF Career Development Fellowship (APP1140764). We wish to acknowledge the patients and control subjects that have particiaped int the study. We thank Rosa Schirmer, Elke Schreiter, Reinhold Borschke and Ines Eidner for image acquisition and data preparation, and Anna Oliynyk for quality checks. We thank Dorothee P. Auer and F. Holsboer for initiation of the RUD study. We wish to acknowledge the patients and control subjects that have particiaped int the study. We thank Rosa Schirmer, Elke Schreiter, Reinhold Borschke and Ines Eidner for image acquisition and data preparation, and Anna Oliynyk for quality checks. We thank Dorothee P. Auer and F. Holsboer for initiation of the RUD study. NESDA: The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw, grant number 10-000-1002) and is supported by participating universities (VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen) and mental health care organizations, see www.nesda.nl. M-JvT was supported by a VENI grant (NWO grant number 016.156.077). UCSF: This work was supported by the Brain and Behavior Research Foundation (formerly NARSAD) to TTY; the National Institute of Mental Health (R01MH085734 to TTY; K01MH117442 to TCH) and by the American Foundation for Suicide Prevention (PDF-1-064-13) to TCH. Stanford: This work was supported by NIMH Grants R01MH59259 and R37101495 to IHG. MS is partially supported by an award funded by the Phyllis and Jerome Lyle Rappaport Foundation. Muenster: This work was funded by the German Research Foundation (SFB-TRR58, Projects C09 and Z02 to UD) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD). Marburg: This work was funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5-1 and DA1151/5-2 to UD; KI 588/ 14-1, KI 588/14-2 to TK; KR 3822/7-1, KR 3822/7-2 to AK; JA 1890/ 7-1, JA 1890/7-2 to AJ). IMH-MDD: This work was supported by the National Healthcare Group Research Grant (SIG/15012) awarded to KS. Barcelona: This study was funded by two grants of the Fondo de Investigación Sanitaria from the Instituto de Salud Carlos III, by the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM). The author is funded through 'Miguel Servet' research contract (CP16-0020), co-financed by the European Regional Development Fund (ERDF) (2016-2019). QTIM: We thank the twins and singleton siblings who gave generously of their time to participate in the QTIM study. We also thank the many research assistants, radiographers, and IT support staff for data acquisition and DNA sample preparation. This study was funded by White matter disturbances in major depressive disorder: a coordinated analysis across 20 international. . . 1521 the National Institute of Child Health & Human Development (RO1 HD050735); National Institute of Biomedical Imaging and Bioengineering (Award 1U54EB020403-01, Subaward 56929223); National Health and Medical Research Council, Australia (Project Grants 496682, 1009064). NIH ENIGMA-BD2K U54 EB020403 (Thompson); R01 MH117601 (Jahanshad/Schmaal). Magdeburg: M.L. and M.W. are funded by SFB 779. Bipolar Family Study: This study has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013). This paper reflects only the author's views and the European Union is not liable for any use that may be made of the information contained therein. This work was also supported by a Wellcome Trust Strategic Award (104036/Z/14/Z). Minnesota Adolescent Depression Study: The study was funded by the National Institute of Mental Health (K23MH090421), the National Alliance for Research on Schizophrenia and Depression, the University of Minnesota Graduate School, the Minnesota Medical Foundation, and the Biotechnology Research Center (P41 RR008079 to the Center for Magnetic Resonance Research), University of Minnesota, and the Deborah E. Powell Center for Women's Health Seed Grant, University of Minnesota. Dublin: This study was supported by Science Foundation Ireland through a Stokes Professorhip grant to TF. MPIP: The MPIP Sample comprises patients included in the Recurrent Unipolar Depression (RUD) Case-Control study at the clinic of the Max Planck Institute of Psychiatry, Munich, German. The RUD study was supported by GlaxoSmithKline.Alterations in white matter (WM) microstructure have been implicated in the pathophysiology of major depressive disorder (MDD). However, previous findings have been inconsistent, partially due to low statistical power and the heterogeneity of depression. In the largest multi-site study to date, we examined WM anisotropy and diffusivity in 1305 MDD patients and 1602 healthy controls (age range 12-88 years) from 20 samples worldwide, which included both adults and adolescents, within the MDD Working Group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium. Processing of diffusion tensor imaging (DTI) data and statistical analyses were harmonized across sites and effects were meta-analyzed across studies. We observed subtle, but widespread, lower fractional anisotropy (FA) in adult MDD patients compared with controls in 16 out of 25 WM tracts of interest (Cohen's d between 0.12 and 0.26). The largest differences were observed in the corpus callosum and corona radiata. Widespread higher radial diffusivity (RD) was also observed (all Cohen's d between 0.12 and 0.18). Findings appeared to be driven by patients with recurrent MDD and an adult age of onset of depression. White matter microstructural differences in a smaller sample of adolescent MDD patients and controls did not survive correction for multiple testing. In this coordinated and harmonized multisite DTI study, we showed subtle, but widespread differences in WM microstructure in adult MDD, which may suggest structural disconnectivity in MDD

What we learn about bipolar disorder from large-scale neuroimaging:Findings and future directions from the ENIGMA Bipolar Disorder Working Group

MRI-derived brain measures offer a link between genes, the environment and behavior and have been widely studied in bipolar disorder (BD). However, many neuroimaging studies of BD have been underpowered, leading to varied results and uncertainty regarding effects. The Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Bipolar Disorder Working Group was formed in 2012 to empower discoveries, generate consensus findings and inform future hypothesis-driven studies of BD. Through this effort, over 150 researchers from 20 countries and 55 institutions pool data and resources to produce the largest neuroimaging studies of BD ever conducted. The ENIGMA Bipolar Disorder Working Group applies standardized processing and analysis techniques to empower large-scale meta- and mega-analyses of multimodal brain MRI and improve the replicability of studies relating brain variation to clinical and genetic data. Initial BD Working Group studies reveal widespread patterns of lower cortical thickness, subcortical volume and disrupted white matter integrity associated with BD. Findings also include mapping brain alterations of common medications like lithium, symptom patterns and clinical risk profiles and have provided further insights into the pathophysiological mechanisms of BD. Here we discuss key findings from the BD working group, its ongoing projects and future directions for large-scale, collaborative studies of mental illness