The Ly-4+ T Lymphocyte Subset in the Host Immune Response to the Asexual Stages of Plasmodium chabaudi chabaudi

T cells play a major role in acquired immunity to the asexual erythrocytic stages of malaria parasites. In different host/parasite combinations there is evidence that human CD4+ lymphocytes or their murine equivalent, Ly-4+, can act as helper cells in the production of protective Ab and also mediate cellular protective functions. The details of how the effector mechanisms operate in vivo, however, are not understood clearly. There is indirect evidence supporting an important role for Ly-4-bearing lymphocytes in the protective immune response to Plasmodium chabaudi chabaudi AS strain, a good animal model of P. falciparum infection. Experiments were performed to examine the nature of the Ly-4+ response to this parasite both in vivo and in vitro in order to characterise the cells responsible for the mediation of protective activity. Initial studies showed that during the course of a primary infection of P. c. chabaudi AS, there was a marked transient lymphocytosis in the peripheral blood, which occurred at a time just after peak parasitaemia (d 12-13 p. i. ). The adoptive transfer to syngeneic NIH recipients of either peripheral blood or splenic lymphocytes taken from donors at this early stage of infection conferred protection against homologous challenge. This was manifested in both competent and sublethally irradiated recipients as a reduced level and quickened remission of primary parasitaemia, and as a more rapid clearance of pRBC from the blood stream, compared to control mice receiving unprimed lymphocytes. Although it was possible to transfer immunity with preparations enriched for either T or B cells, optimal protection was conferred by an unfractionated population containing both lymphocyte phenotypes, suggesting that there was a degree of synergistic activity between parasite-primed T and B cells in the control of malarial infection. This concept was supported further by examination of serum Ab titres for recipients of semi-immune T, B or T & B spleen cells. In each instance, the level of specific anti-P. c. chabaudi AS Ig reached a peak between d 31-33 p. i. , at or just prior to recrudescence, but the highest titres were recorded for recipients of a mixed splenic population. Since serum Ig levels were quite low during the first wave of patent parasitaemia, it suggested that resolution of acute infection was achieved largely through Ab-independent mechanisms of immunity. This correlated well with a significantly quicker remission of primary parasitaemia observed in sublethally irradiated recipients of semi-immune T cells, compared to similarly treated mice receiving the same inoculum size of either B or T & B cells. To dissect further the protective immune response in this model, splenic T lymphocytes were taken from P. c. chabaudi AS strain-infected NIH mice on d 16 and d 20 of primary infection and after resolution of secondary and tertiary infections, and each of these preparations established as cell lines in vitro using a lysed extract of pRBC as the source of antigenic stimulation. All four lines were maintained in long term culture and all proliferated specifically in response to P. c. chabaudi AS Ag processed and presented by syngeneic APC. It was shown that recognition of the APC/Ag complex by T cells was an MHC class ll-restricted phenomenon, each cell line requiring APC of compatible H-2 haplotype for an in vitro proliferative response. By using surface immunofluorescence and the complement-mediated cytotoxicity assay, each line was characterised phenotypically as Ly-4+, i. e. belonging to the helper/inducer T cell subset. In vivo, adoptive transfer of each Ly-4+ line was effective in conferring protective immunity to naive and to immunocompromised mice. This was demonstrable, compared to controls given naive T and/or B cells, as both a reduced level and shortened duration of primary parasitaemia, and as a quicker parasite elimination. Inoculation of the P. c. chabaudi AS-reactive lines into non-immune mice challenged with genotypic or phenotypic variant pRBC indicated that there was a strain-specific element of the immunity transferred. Although mice were able to control infection with heterologous parasites, the greatest protection was conferred against challenge with the homologous pRBC to which the lines had been raised. For the two Ly-4+ lines taken from reinfected mice, the protective activity against P. c. chabaudi AS challenge upon adoptive transfer into adult-thymectomised, irradiated and bone marrow-reconstituted mice was improved significantly by the cotransfer of additional naive B cells. This suggested that these Ly-4-bearing lymphocytes act by Ab-mediated mechanisms in vivo. (Abstract shortened by ProQuest.)

Drivers of habitat availability for terrestrial mammals: Unravelling the role of livestock, land conversion and intrinsic traits in the past 50 years

The global decline of terrestrial species is largely due to the degradation, loss and fragmentation of their habitats. The conversion of natural ecosystems for cropland, rangeland, forest products and human infrastructure are the primary causes of habitat deterioration. Due to the paucity of data on the past distribution of species and the scarcity of fine-scale habitat conversion maps, however, accurate assessment of the recent effects of habitat degradation, loss and fragmentation on the range of mammals has been near impossible. We aim to assess the proportions of available habitat within the lost and retained parts of mammals' distribution ranges, and to identify the drivers of habitat availability. We produced distribution maps for 475 terrestrial mammals for the range they occupied 50 years ago and compared them to current range maps. We then calculated the differences in the percentage of 'area of habitat' (habitat available to a species within its range) between the lost and retained range areas. Finally, we ran generalized linear mixed models to identify which variables were more influential in determining habitat availability in the lost and retained parts of the distribution ranges. We found that 59% of species had a lower proportion of available habitat in the lost range compared to the retained range, thus hypothesizing that habitat loss could have contributed to range declines. The most important factors negatively affecting habitat availability were the conversion of land to rangeland and high density of livestock. Significant intrinsic traits were those related to reproductive timing and output, habitat breadth and medium body size. Our findings emphasize the importance of implementing conservation strategies to mitigate the impacts caused by human activities on the habitats of mammals, and offer evidence indicating which species have the potential to reoccupy portions of their former range if other threats cease to occur.This study investigates the impact of habitat degradation on terrestrial mammal species. By comparing historic and current distribution maps for 475 species, we found that 59% of them have less available habitat in their lost ranges, suggesting habitat loss contributed to range declines. Factors like land conversion to rangeland and high livestock density negatively affected habitat availability. Intrinsic traits such as reproductive timing, habitat breadth and medium body size also played a role. The study underscores the need for conservation efforts to mitigate human-induced habitat threats and identifies species that could potentially reclaim lost range if threats are addressed.imag

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

VEGFR2 promotes central endothelial activation and the spread of pain in inflammatory arthritis

Chronic pain can develop in response to conditions such as inflammatory arthritis. The central mechanisms underlying the development and maintenance of chronic pain in humans are not well elucidated although there is evidence for a role of microglia and astrocytes. However in pre-clinical models of pain, including models of inflammatory arthritis, there is a wealth of evidence indicating roles for pathological glial reactivity within the CNS. In the spinal dorsal horn of rats with painful inflammatory arthritis we found both a significant increase in CD11b+ microglia-like cells and GFAP+ astrocytes associated with blood vessels, and the number of activated blood vessels expressing the adhesion molecule ICAM-1, indicating potential glio-vascular activation. Using pharmacological interventions targeting VEGFR2 in arthritic rats, to inhibit endothelial cell activation, the number of dorsal horn ICAM-1+ blood vessels, CD11b+ microglia and the development of secondary mechanical allodynia, an indicator of central sensitization, were all prevented. Targeting endothelial VEGFR2 by inducible Tie2-specific VEGFR2 knock-out also prevented secondary allodynia in mice and glio-vascular activation in the dorsal horn in response to inflammatory arthritis. Inhibition of VEGFR2 in vitro significantly blocked ICAM-1-dependent monocyte adhesion to brain microvascular endothelial cells, when stimulated with inflammatory mediators TNFa and VEGF-A165a. Taken together our findings suggest that a novel VEGFR2-mediated spinal cord gliovascular mechanism may promote peripheral CD11b+ circulating cell transmigration into the CNS parenchyma and contribute to the development of chronic pain in inflammatory arthritis. We hypothesise that preventing this glio-vascular activation and circulating cell translocation into the spinal cord could be a new therapeutic strategy for pain caused by rheumatoid arthritis

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes