Murine and related chapparvoviruses are nephro-tropic and produce novel accessory proteins in infected kidneys.

Mouse kidney parvovirus (MKPV) is a member of the provisional genus Chapparvovirus that causes renal disease in immune-compromised mice, with a disease course reminiscent of polyomavirus-associated nephropathy in immune-suppressed kidney transplant patients. Here we map four major MKPV transcripts, created by alternative splicing, to a common initiator region, and use mass spectrometry to identify "p10" and "p15" as novel chapparvovirus accessory proteins produced in MKPV-infected kidneys. p15 and the splicing-dependent putative accessory protein NS2 are conserved in all near-complete amniote chapparvovirus genomes currently available (from mammals, birds and a reptile). In contrast, p10 may be encoded only by viruses with >60% amino acid identity to MKPV. We show that MKPV is kidney-tropic and that the bat chapparvovirus DrPV-1 and a non-human primate chapparvovirus, CKPV, are also found in the kidneys of their hosts. We propose, therefore, that many mammal chapparvoviruses are likely to be nephrotropic

Signatures of Environmental Genetic Adaptation Pinpoint Pathogens as the Main Selective Pressure through Human Evolution

Previous genome-wide scans of positive natural selection in humans have identified a number of non-neutrally evolving genes that play important roles in skin pigmentation, metabolism, or immune function. Recent studies have also shown that a genome-wide pattern of local adaptation can be detected by identifying correlations between patterns of allele frequencies and environmental variables. Despite these observations, the degree to which natural selection is primarily driven by adaptation to local environments, and the role of pathogens or other ecological factors as selective agents, is still under debate. To address this issue, we correlated the spatial allele frequency distribution of a large sample of SNPs from 55 distinct human populations to a set of environmental factors that describe local geographical features such as climate, diet regimes, and pathogen loads. In concordance with previous studies, we detected a significant enrichment of genic SNPs, and particularly non-synonymous SNPs associated with local adaptation. Furthermore, we show that the diversity of the local pathogenic environment is the predominant driver of local adaptation, and that climate, at least as measured here, only plays a relatively minor role. While background demography by far makes the strongest contribution in explaining the genetic variance among populations, we detected about 100 genes which show an unexpectedly strong correlation between allele frequencies and pathogenic environment, after correcting for demography. Conversely, for diet regimes and climatic conditions, no genes show a similar correlation between the environmental factor and allele frequencies. This result is validated using low-coverage sequencing data for multiple populations. Among the loci targeted by pathogen-driven selection, we found an enrichment of genes associated to autoimmune diseases, such as celiac disease, type 1 diabetes, and multiples sclerosis, which lends credence to the hypothesis that some susceptibility alleles for autoimmune diseases may be maintained in human population due to past selective processes

Biopsy confirmation of metastatic sites in breast cancer patients:clinical impact and future perspectives

Determination of hormone receptor (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2 status in the primary tumor is clinically relevant to define breast cancer subtypes, clinical outcome,and the choice of therapy. Retrospective and prospective studies suggest that there is substantial discordance in receptor status between primary and recurrent breast cancer. Despite this evidence and current recommendations,the acquisition of tissue from metastatic deposits is not routine practice. As a consequence, therapeutic decisions for treatment in the metastatic setting are based on the features of the primary tumor. Reasons for this attitude include the invasiveness of the procedure and the unreliable outcome of biopsy, in particular for biopsies of lesions at complex visceral sites. Improvements in interventional radiology techniques mean that most metastatic sites are now accessible by minimally invasive methods, including surgery. In our opinion, since biopsies are diagnostic and changes in biological features between the primary and secondary tumors can occur, the routine biopsy of metastatic disease needs to be performed. In this review, we discuss the rationale for biopsy of suspected breast cancer metastases, review issues and caveats surrounding discordance of biomarker status between primary and metastatic tumors, and provide insights for deciding when to perform biopsy of suspected metastases and which one (s) to biopsy. We also speculate on the future translational implications for biopsy of suspected metastatic lesions in the context of clinical trials and the establishment of bio-banks of biopsy material taken from metastatic sites. We believe that such bio-banks will be important for exploring mechanisms of metastasis. In the future,advances in targeted therapy will depend on the availability of metastatic tissue

The stellar and sub-stellar IMF of simple and composite populations

The current knowledge on the stellar IMF is documented. It appears to become top-heavy when the star-formation rate density surpasses about 0.1Msun/(yr pc^3) on a pc scale and it may become increasingly bottom-heavy with increasing metallicity and in increasingly massive early-type galaxies. It declines quite steeply below about 0.07Msun with brown dwarfs (BDs) and very low mass stars having their own IMF. The most massive star of mass mmax formed in an embedded cluster with stellar mass Mecl correlates strongly with Mecl being a result of gravitation-driven but resource-limited growth and fragmentation induced starvation. There is no convincing evidence whatsoever that massive stars do form in isolation. Various methods of discretising a stellar population are introduced: optimal sampling leads to a mass distribution that perfectly represents the exact form of the desired IMF and the mmax-to-Mecl relation, while random sampling results in statistical variations of the shape of the IMF. The observed mmax-to-Mecl correlation and the small spread of IMF power-law indices together suggest that optimally sampling the IMF may be the more realistic description of star formation than random sampling from a universal IMF with a constant upper mass limit. Composite populations on galaxy scales, which are formed from many pc scale star formation events, need to be described by the integrated galactic IMF. This IGIMF varies systematically from top-light to top-heavy in dependence of galaxy type and star formation rate, with dramatic implications for theories of galaxy formation and evolution.Comment: 167 pages, 37 figures, 3 tables, published in Stellar Systems and Galactic Structure, Vol.5, Springer. This revised version is consistent with the published version and includes additional references and minor additions to the text as well as a recomputed Table 1. ISBN 978-90-481-8817-

Changes in arginase isoforms in a murine model of neonatal brain hypoxia-ischemia.

BackgroundArginases (ARG isoforms, ARG-1/ARG-2) are key regulatory enzymes of inflammation and tissue repair; however, their role after neonatal brain hypoxia (H) and hypoxia-ischemia (HI) remains unknown.MethodsC57BL/6 mice subjected to the Vannucci procedure on postnatal day (P9) were sacrificed at different timepoints. The degree of brain damage was assessed histologically. ARG spatiotemporal localization was determined via immunohistochemistry. ARG expression was measured by Western blot and activity spectrophotometrically.ResultsARG isoform expression increased during neurodevelopment (P9-P17) in the cortex and hippocampus. This was suppressed with H and HI only in the hippocampus. In the cortex, both isoforms increased with H alone and only ARG-2 increased with HI at 3 days. ARG activity during neurodevelopment remained unchanged, but increased at 1 day with H and not HI. ARG-1 localized with microglia at the injury site as early as 4 h after injury, while ARG-2 localized with neurons.ConclusionsARG isoform expression increases with age from P9 to P17, but is suppressed by injury specifically in the hippocampus and not in the cortex. Both levels and activity of ARG isoforms increase with H, while ARG-1 immunolabelling is upregulated in the HI cortex. Evidently, ARG isoforms in the brain differ in spatiotemporal localization, expression, and activity during neurodevelopment and after injury.ImpactArginase isoforms change during neurodevelopment and after neonatal brain HI. This is the first study investigating the key enzymes of inflammation and tissue repair called arginases following murine neonatal brain HI. The highly region- and cell-specific expression suggests the possibility of specific functions of arginases. ARG-1 in microglia at the injury site may regulate neuroinflammation, while ARG-2 in neurons of developmental structures may impact neurodevelopment. While further studies are needed to describe the exact role of ARGs after neonatal brain HI, our study adds valuable data on anatomical localization and expression of ARGs in brain during development and after stroke

Modeling and discretization of flow in porous media with thin, full-tensor permeability inclusions

When modeling fluid flow in fractured reservoirs, it is common to represent the fractures as lower-dimensional inclusions embedded in the host medium. Existing discretizations of flow in porous media with thin inclusions assume that the principal directions of the inclusion permeability tensor are aligned with the inclusion orientation. While this modeling assumption works well with tensile fractures, it may fail in the context of faults, where the damage zone surrounding the main slip surface may introduce anisotropy that is not aligned with the main fault orientation. In this article, we introduce a generalized dimensional reduced model which preserves full-tensor permeability effects also in the out-of-plane direction of the inclusion. The governing equations of flow for the lower-dimensional objects are obtained through vertical averaging. We present a framework for discretization of the resulting mixed-dimensional problem, aimed at easy adaptation of existing simulation tools. We give numerical examples that show the failure of existing formulations when applied to anisotropic faulted porous media, and go on to show the convergence of our method in both two-dimensional and three-dimensional.publishedVersio

MKPV (aka MuCPV) and related chapparvoviruses are nephro-tropic and encode novel accessory proteins p15 and NS2

Abstract Mouse kidney parvovirus (MKPV) is a member of the provisional Chapparvovirus genus that causes renal disease in immune-compromised mice, with a disease course reminiscent of polyomavirus-associated nephropathy in immune-suppressed kidney transplant patients. Here we map four MKPV transcripts, created by alternative splicing, to a common transcription initiation region, and use mass spectrometry to identify “p10” and “p15” as novel chapparvovirus accessory proteins produced in MKPV-infected kidneys. p15 and a splicing-dependent putative accessory protein NS2 are conserved in all near-complete tetrapod chapparvovirus genomes currently available (from mammals, birds and a reptile). In contrast, p10 may be encoded only by viruses with >60% amino acid identity to MKPV. We show that MKPV is kidney-tropic and that the bat chapparvovirus DrPV-1 and a non-human primate chapparvovirus, CKPV, are also found in the kidneys of their hosts. We propose, therefore, that chapparvoviruses with >60% VP1 amino acid identity to MKPV be classified into a genus dubbed Nephroparvovirus , which is consistent with nomenclature for the genus Erythroparvovirus

Proposed follow up programme after curative resection for lower third oesophageal cancer

The incidence of oesophageal adenocarcinoma has risen throughout the Western world over the last three decades. The prognosis remains poor as many patients are elderly and present with advanced disease. Those patients who are suitable for resection remain at high risk of disease recurrence. It is important that cancer patients take part in a follow up protocol to detect disease recurrence, offer psychological support, manage nutritional disorders and facilitate audit of surgical outcomes. Despite the recognition that regular postoperative follow up plays a key role in ongoing care of cancer patients, there is little consensus on the nature of the process. This paper reviews the published literature to determine the optimal timing and type of patient follow up for those after curative oesophageal resection

Parallel Adaptive Divergence among Geographically Diverse Human Populations

Few genetic differences between human populations conform to the classic model of positive selection, in which a newly arisen mutation rapidly approaches fixation in one lineage, suggesting that adaptation more commonly occurs via moderate changes in standing variation at many loci. Detecting and characterizing this type of complex selection requires integrating individually ambiguous signatures across genomically and geographically extensive data. Here, we develop a novel approach to test the hypothesis that selection has favored modest divergence at particular loci multiple times in independent human populations. We find an excess of SNPs showing non-neutral parallel divergence, enriched for genic and nonsynonymous polymorphisms in genes encompassing diverse and often disease related functions. Repeated parallel evolution in the same direction suggests common selective pressures in disparate habitats. We test our method with extensive coalescent simulations and show that it is robust to a wide range of demographic events. Our results demonstrate phylogenetically orthogonal patterns of local adaptation caused by subtle shifts at many widespread polymorphisms that likely underlie substantial phenotypic diversity

Genome-Wide Interrogation of Mammalian Stem Cell Fate Determinants by Nested Chromosome Deletions

Understanding the function of important DNA elements in mammalian stem cell genomes would be enhanced by the availability of deletion collections in which segmental haploidies are precisely characterized. Using a modified Cre-loxP–based system, we now report the creation and characterization of a collection of ∼1,300 independent embryonic stem cell (ESC) clones enriched for nested chromosomal deletions. Mapping experiments indicate that this collection spans over 25% of the mouse genome with good representative coverage of protein-coding genes, regulatory RNAs, and other non-coding sequences. This collection of clones was screened for in vitro defects in differentiation of ESC into embryoid bodies (EB). Several putative novel haploinsufficient regions, critical for EB development, were identified. Functional characterization of one of these regions, through BAC complementation, identified the ribosomal gene Rps14 as a novel haploinsufficient determinant of embryoid body formation. This new library of chromosomal deletions in ESC (DelES: http://bioinfo.iric.ca/deles) will serve as a unique resource for elucidation of novel protein-coding and non-coding regulators of ESC activity