The role of CD8+ T-cell clones in immune thrombocytopenia.

Immune thrombocytopenia (ITP) is traditionally considered an antibody-mediated disease. However, a number of features suggest alternative mechanisms of platelet destruction. In this study, we use a multidimensional approach to explore the role of cytotoxic CD8+ T cells in ITP. We characterized patients with ITP and compared them with age-matched controls using immunophenotyping, next-generation sequencing of T-cell receptor (TCR) genes, single-cell RNA sequencing, and functional T-cell and platelet assays. We found that adults with chronic ITP have increased polyfunctional, terminally differentiated effector memory CD8+ T cells (CD45RA+CD62L-) expressing intracellular interferon gamma, tumor necrosis factor α, and granzyme B, defining them as TEMRA cells. These TEMRA cells expand when the platelet count falls and show no evidence of physiological exhaustion. Deep sequencing of the TCR showed expanded T-cell clones in patients with ITP. T-cell clones persisted over many years, were more prominent in patients with refractory disease, and expanded when the platelet count was low. Combined single-cell RNA and TCR sequencing of CD8+ T cells confirmed that the expanded clones are TEMRA cells. Using in vitro model systems, we show that CD8+ T cells from patients with ITP form aggregates with autologous platelets, release interferon gamma, and trigger platelet activation and apoptosis via the TCR-mediated release of cytotoxic granules. These findings of clonally expanded CD8+ T cells causing platelet activation and apoptosis provide an antibody-independent mechanism of platelet destruction, indicating that targeting specific T-cell clones could be a novel therapeutic approach for patients with refractory ITP

Multigene phylogeny of the Mustelidae: Resolving relationships, tempo and biogeographic history of a mammalian adaptive radiation

<p>Abstract</p> <p>Background</p> <p>Adaptive radiation, the evolution of ecological and phenotypic diversity from a common ancestor, is a central concept in evolutionary biology and characterizes the evolutionary histories of many groups of organisms. One such group is the Mustelidae, the most species-rich family within the mammalian order Carnivora, encompassing 59 species classified into 22 genera. Extant mustelids display extensive ecomorphological diversity, with different lineages having evolved into an array of adaptive zones, from fossorial badgers to semi-aquatic otters. Mustelids are also widely distributed, with multiple genera found on different continents. As with other groups that have undergone adaptive radiation, resolving the phylogenetic history of mustelids presents a number of challenges because ecomorphological convergence may potentially confound morphologically based phylogenetic inferences, and because adaptive radiations often include one or more periods of rapid cladogenesis that require a large amount of data to resolve.</p> <p>Results</p> <p>We constructed a nearly complete generic-level phylogeny of the Mustelidae using a data matrix comprising 22 gene segments (~12,000 base pairs) analyzed with maximum parsimony, maximum likelihood and Bayesian inference methods. We show that mustelids are consistently resolved with high nodal support into four major clades and three monotypic lineages. Using Bayesian dating techniques, we provide evidence that mustelids underwent two bursts of diversification that coincide with major paleoenvironmental and biotic changes that occurred during the Neogene and correspond with similar bursts of cladogenesis in other vertebrate groups. Biogeographical analyses indicate that most of the extant diversity of mustelids originated in Eurasia and mustelids have colonized Africa, North America and South America on multiple occasions.</p> <p>Conclusion</p> <p>Combined with information from the fossil record, our phylogenetic and dating analyses suggest that mustelid diversification may have been spurred by a combination of faunal turnover events and diversification at lower trophic levels, ultimately caused by climatically driven environmental changes. Our biogeographic analyses show Eurasia as the center of origin of mustelid diversity and that mustelids in Africa, North America and South America have been assembled over time largely via dispersal, which has important implications for understanding the ecology of mustelid communities.</p

T2K neutrino flux prediction

cited By 15 art_number: 012001 affiliation: Centre for Particle Physics, Department of Physics, University of Alberta, Edmonton, AB, Canada; Albert Einstein Center for Fundamental Physics, Laboratory for High Energy Physics (LHEP), University of Bern, Bern, Switzerland; Department of Physics, Boston University, Boston, MA, United States; Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada; Department of Physics and Astronomy, University of California Irvine, Irvine, CA, United States; IRFU, CEA Saclay, Gif-sur-Yvette, France; Institute for Universe and Elementary Particles, Chonnam National University, Gwangju, South Korea; Department of Physics, University of Colorado at Boulder, Boulder, CO, United States; Department of Physics, Colorado State University, Fort Collins, CO, United States; Department of Physics, Dongshin University, Naju, South Korea; Department of Physics, Duke University, Durham, NC, United States; IN2P3-CNRS, Laboratoire Leprince-Ringuet, Ecole Polytechnique, Palaiseau, France; Institute for Particle Physics, ETH Zurich, Zurich, Switzerland; Section de Physique, DPNC, University of Geneva, Geneva, Switzerland; H. Niewodniczanski Institute of Nuclear Physics PAN, Cracow, Poland; High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki, Japan; Institut de Fisica d’Altes Energies (IFAE), Bellaterra (Barcelona), Spain; IFIC (CSIC and University of Valencia), Valencia, Spain; Department of Physics, Imperial College London, London, United Kingdom; INFN Sezione di Bari, Dipartimento Interuniversitario di Fisica, Università e Politecnico di Bari, Bari, Italy; INFN Sezione di Napoli and Dipartimento di Fisica, Università di Napoli, Napoli, Italy; INFN Sezione di Padova, Dipartimento di Fisica, Università di Padova, Padova, Italy; INFN Sezione di Roma, Università di Roma la Sapienza, Roma, Italy; Institute for Nuclear Research, Russian Academy of Sciences, Moscow, Russian Federation; Kobe University, Kobe, Japan; Department of Physics, Kyoto University, Kyoto, Japan; Physics Department, Lancaster University, Lancaster, United Kingdom; Department of Physics, University of Liverpool, Liverpool, United Kingdom; Department of Physics and Astronomy, Louisiana State University, Baton Rouge, LA, United States; Université de Lyon, Université Claude Bernard Lyon 1, IPN Lyon (IN2P3), Villeurbanne, France; Department of Physics, Miyagi University of Education, Sendai, Japan; National Centre for Nuclear Research, Warsaw, Poland; State University of New York at Stony Brook, Stony Brook, NY, United States; Department of Physics and Astronomy, Osaka City University, Department of Physics, Osaka, Japan; Department of Physics, Oxford University, Oxford, United Kingdom; UPMC, Université Paris Diderot, Laboratoire de Physique Nucléaire et de Hautes Energies (LPNHE), Paris, France; Department of Physics and Astronomy, University of Pittsburgh, Pittsburgh, PA, United States; School of Physics, Queen Mary University of London, London, United Kingdom; Department of Physics, University of Regina, Regina, SK, Canada; Department of Physics and Astronomy, University of Rochester, Rochester, NY, United States; III. Physikalisches Institut, RWTH Aachen University, Aachen, Germany; Department of Physics and Astronomy, Seoul National University, Seoul, South Korea; Department of Physics and Astronomy, University of Sheffield, Sheffield, United Kingdom; University of Silesia, Institute of Physics, Katowice, Poland; STFC, Rutherford Appleton Laboratory, Harwell Oxford, Warrington, United Kingdom; Department of Physics, University of Tokyo, Tokyo, Japan; Institute for Cosmic Ray Research, Kamioka Observatory, University of Tokyo, Kamioka, Japan; Institute for Cosmic Ray Research, Research Center for Cosmic Neutrinos, University of Tokyo, Kashiwa, Japan; Department of Physics, University of Toronto, Toronto, ON, Canada; TRIUMF, Vancouver, BC, Canada; Department of Physics and Astronomy, University of Victoria, Victoria, BC, Canada; Faculty of Physics, University of Warsaw, Warsaw, Poland; Institute of Radioelectronics, Warsaw University of Technology, Warsaw, Poland; Department of Physics, University of Warwick, Coventry, United Kingdom; Department of Physics, University of Washington, Seattle, WA, United States; Department of Physics, University of Winnipeg, Winnipeg, MB, Canada; Faculty of Physics and Astronomy, Wroclaw University, Wroclaw, Poland; Department of Physics and Astronomy, York University, Toronto, ON, Canada references: Astier, P., (2003) Nucl. 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Adaptive responses of animals to climate change are most likely insufficient

Biological responses to climate change have been widely documented across taxa and regions, but it remains unclear whether species are maintaining a good match between phenotype and environment, i.e. whether observed trait changes are adaptive. Here we reviewed 10,090 abstracts and extracted data from 71 studies reported in 58 relevant publications, to assess quantitatively whether phenotypic trait changes associated with climate change are adaptive in animals. A meta-analysis focussing on birds, the taxon best represented in our dataset, suggests that global warming has not systematically affected morphological traits, but has advanced phenological traits. We demonstrate that these advances are adaptive for some species, but imperfect as evidenced by the observed consistent selection for earlier timing. Application of a theoretical model indicates that the evolutionary load imposed by incomplete adaptive responses to ongoing climate change may already be threatening the persistence of species

Reproduction triggers adaptive increases in body size in female mole-rats

In social mole-rats, breeding females are larger and more elongated than nonbreeding female helpers. The status-related morphological divergence is thought to arise from modifications of skeletal growth following the death or removal of the previous breeder and the transition of their successors from a nonbreeding to a breeding role. However, it is not clear what changes in growth are involved, whether they are stimulated by the relaxation of reproductive suppression or by changes in breeding status, or whether they are associated with fecundity increases. Here, we show that, in captive Damaraland mole-rats (Fukomys damarensis) where breeding was experimentally controlled in age-matched siblings, individuals changed in size and shape through a lengthening of the lumbar vertebrae when they began breeding. This skeletal remodelling results from changes in breeding status since i) females removed from a group setting and placed solitarily showed no increases in growth, and ii) females dispersing from natural groups that have not yet bred do not differ in size and shape from helpers in established groups. Growth patterns consequently resemble other social vertebrates where contrasts in size and shape follow acquisition of the breeding role. Our results also suggest that the increases in female body size provide fecundity benefits. Similar forms of socially responsive growth might be more prevalent in vertebrates than is currently recognised, but the extent to which this is the case, and the implications for the structuring of mammalian dominance hierarchies, is as yet poorly understood.The Kalahari Mole-rat Project is supported by a European Research Council Grant awarded to TCB (#294494); JT was funded by a Natural Environment Research Council Doctoral Training Program; Parts of the fieldwork were funded by a British Ecological Society Grant awarded to Markus Zöttl (#5301/6343)

Data for "No task specialisation among Damaraland mole-rat helpers"

Behavioural data of captive Damaraland mole-rats followed longitudinally across development. Data takes the form of all occurrence scan sampling conducted at 4-minute sampling intervals (within an overall observation period of 12 hours); each row represents a single observation at one of the sampling intervals