Gene expression data generated from whole blood via next generation sequencing is frequently used in studies aimed at identifying mRNA-based biomarker panels with utility for diagnosis or monitoring ...of human disease. These investigations often employ data normalization techniques more typically used for analysis of data originating from solid tissues, which largely operate under the general assumption that specimens have similar transcriptome composition. However, this assumption may be violated when working with data generated from whole blood, which is more cellularly dynamic, leading to potential confounds. In this study, we used next generation sequencing in combination with flow cytometry to assess the influence of donor leukocyte counts on the transcriptional composition of whole blood specimens sampled from a cohort of 138 human subjects, and then subsequently examined the effect of four frequently used data normalization approaches on our ability to detect inter-specimen biological variance, using the flow cytometry data to benchmark each specimens true cellular and molecular identity. Whole blood samples originating from donors with differing leukocyte counts exhibited dramatic differences in both genome-wide distributions of transcript abundance and gene-level expression patterns. Consequently, three of the normalization strategies we tested, including median ratio (MRN), trimmed mean of m-values (TMM), and quantile normalization, noticeably masked the true biological structure of the data and impaired our ability to detect true interspecimen differences in mRNA levels. The only strategy that improved our ability to detect true biological variance was simple scaling of read counts by sequencing depth, which unlike the aforementioned approaches, makes no assumptions regarding transcriptome composition.
To limit the spread of SARS-CoV-2, an evidence-based understanding of the symptoms is critical to inform guidelines for quarantining and testing. The most common features are purported to be fever ...and a new persistent cough, although the global prevalence of these symptoms remains unclear. The aim of this systematic review is to determine the prevalence of symptoms associated with COVID-19 worldwide.
We searched PubMed, Embase, CINAHL, AMED, medRxiv and bioRxiv on 5th April 2020 for studies of adults (>16 years) with laboratory test confirmed COVID-19. No language or publication status restrictions were applied. Data were independently extracted by two review authors into standardised forms. All datapoints were independently checked by three other review authors. A random-effects model for pooling of binomial data was applied to estimate the prevalence of symptoms, subgrouping estimates by country. I2 was used to assess inter-study heterogeneity.
Of 851 unique citations, 148 articles were included which comprised 24,410 adults with confirmed COVID-19 from 9 countries. The most prevalent symptoms were fever (78% 95% CI 75%-81%; 138 studies, 21,701 patients; I2 94%), a cough (57% 95% CI 54%-60%; 138 studies, 21,682 patients; I2 94%) and fatigue (31% 95% CI 27%-35%; 78 studies, 13,385 patients; I2 95%). Overall, 19% of hospitalised patients required non-invasive ventilation (44 studies, 6,513 patients), 17% required intensive care (33 studies, 7504 patients), 9% required invasive ventilation (45 studies, 6933 patients) and 2% required extra-corporeal membrane oxygenation (12 studies, 1,486 patients). The mortality rate was 7% (73 studies, 10,402 patients).
We confirm that fever and cough are the most prevalent symptoms of adults infected by SARS-CoV-2. However, there is a large proportion of infected adults which symptoms-alone do not identify.
Durant leur collaboration de 1972 à 1992, Gilles Deleuze and Félix Guattari ont développé un corpus de travaux théoriques qui s’inscrit dans la lignée du poststructuralisme français. A travers leur ...œuvre, un ouvrage en deux volumes intitulé « Capitalisme et schizophrénie », ils s’interrogent sur la nature du désir, les schémas organisationnels de la société ainsi que la structure métaphysique du monde. Cependant, malgré leur affirmation d’avoir produit un projet parfaitement égalitaire, leurs travaux sont sujets à une variété de développements d’exclusion et de limitations culturelles. Cet essai tente de combler ces lacunes par le biais d’hypothétiques mises en relation écologiques et théologiques avec l’œuvre de Gilles Deleuze and Félix Guattari. Dans un premier temps sera abordé le développement de la « théologie schizoanalytique», une application de leur notion de schizoanalyse qui bouleverse les conceptions transcendantales de la divinité pour ancrer la spiritualité dans la créativité du désir et la variabilité des processus écologiques. Vient ensuite l'exploration des théories d'Édouard Glissant, un théoricien francophone de la Martinique, dont le travail, fortement influencé par Deleuze et Guattari, se concentre sur le développement d'une ontologie cohérente avec les expériences culturelles des colonisés. L’interprétation que donne Glissant à l’œuvre de Deleuze et de Guattari, ainsi que sa divergence par rapport à cette dernière, est étudiée afin de mieux comprendre comment leur théorie peut être corrigée et reformulée pour tenir compte des nuances de perspectives à la fois des minorités et de la crise écologique. L’essai se termine par un dialogue entre la théorie de Guattari de «l'écosophie» et les conceptions socioculturelles de Glissant sur l'écologie, montrant ainsi la mise en œuvre et l’adaptabilité de la question de la schizoanalyse à diverses crises modernes qui trouvent leur point culminant dans la dégradation de l'environnement. Deleuze, Guattari, Glissant, crise écologique, théologie
Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening state of immune hyperactivation that arises in the setting of genetic mutations and infectious, inflammatory, or neoplastic ...triggers. Sustained, aberrant activation of cytotoxic CD8+ T cells and resultant inflammatory cytokine release are core pathogenic mechanisms. Key clinical features include high persistent fever, hepatosplenomegaly, blood cytopenia, elevated aminotransferase and ferritin levels, and coagulopathy. HLH is likely under-recognized, and mortality remains high, especially in adults; thus, prompt diagnosis and treatment are essential. Familial forms of HLH are currently treated with chemotherapy as a bridge to hematopoietic stem cell transplantation. HLH occurring in rheumatic disease (macrophage activation syndrome) is treated with glucocorticoids, IL-1 blockade, or cyclosporine A. In other forms of HLH, addressing the underlying trigger is essential. There remains a pressing need for more sensitive, context-specific diagnostic tools. Safer, more effective therapies will arise with improved understanding of the cellular and molecular mechanisms of HLH.
Here we have generated 3D structures of glycoforms of the spike (S) glycoprotein from SARS-CoV-2, based on reported 3D structures and glycomics data for the protein produced in HEK293 cells. We also ...analyze structures for glycoforms representing those present in the nascent glycoproteins (prior to enzymatic modifications in the Golgi), as well as those that are commonly observed on antigens present in other viruses. These models were subjected to molecular dynamics (MD) simulation to determine the extent to which glycan microheterogeneity impacts the antigenicity of the S glycoprotein. Lastly, we have identified peptides in the S glycoprotein that are likely to be presented in human leukocyte antigen (HLA) complexes, and discuss the role of S protein glycosylation in potentially modulating the innate and adaptive immune response to the SARS-CoV-2 virus or to a related vaccine. The 3D structures show that the protein surface is extensively shielded from antibody recognition by glycans, with the notable exception of the ACE2 receptor binding domain, and also that the degree of shielding is largely insensitive to the specific glycoform. Despite the relatively modest contribution of the glycans to the total molecular weight of the S trimer (17% for the HEK293 glycoform) they shield approximately 40% of the protein surface.
Abstract Sexual dimorphism in human immune systems is most apparent in the female predominance of certain autoimmune diseases (ADs) like systemic lupus erythematosus (SLE). Epidemiologic, ...observational and experimental evidence strongly suggest sex steroids are important modulators of genetic risk in human AD. In this regard, the roles of progesterone (Pg), an immunomodulatory female sex steroid, are poorly understood. Several lines of investigation indicate Pg and synthetic progestins impact risk of AD and immune-mediated injury in different ways depending on their concentrations and their engagement of various Pg receptors expressed in immune organs, immune cells or tissues targeted by immune attack. At low physiologic levels, Pg may enhance interferon-alpha (IFN-α) pathways important in SLE pathogenesis. Commonly used synthetic progestins may have the opposite effect. At pregnancy levels, Pg may suppress disease activity in rheumatoid arthritis (RA) and multiple sclerosis (MS) via inhibition of T helper type 1 (Th1) and Th17 pathways and induction of anti-inflammatory molecules. Importantly, Pg's immunomodulatory effects differ from those of estrogens and androgens. An additional layer of complexity arises from apparent interdependence of sex hormone signaling pathways. Identifying mechanisms by which Pg and other sex steroids modulate risk of AD and immune-mediated injury will require clarification of their cellular and molecular targets in vivo. These future studies should be informed by recent genetic discoveries in human AD, particularly those revealing their sex-specific genetic associations.
Protected areas provide major benefits for humans in the form of ecosystem services, but landscape degradation by human activity at their edges may compromise their ecological functioning. Using ...multiple lines of evidence from 40 years of research in the Serengeti-Mara ecosystem, we find that such edge degradation has effectively "squeezed" wildlife into the core protected area and has altered the ecosystem's dynamics even within this 40,000-square-kilometer ecosystem. This spatial cascade reduced resilience in the core and was mediated by the movement of grazers, which reduced grass fuel and fires, weakened the capacity of soils to sequester nutrients and carbon, and decreased the responsiveness of primary production to rainfall. Similar effects in other protected ecosystems worldwide may require rethinking of natural resource management outside protected areas.
Block copolymers (BCPs) must necessarily have high interaction parameters (χ), a fundamental measure of block incompatibility, to self-assemble into sub-10-nanometer features. Unfortunately, a high χ ...often results from blocks that have disparate interfacial energies, which makes the formation of useful thin-film domain orientations challenging. To mitigate interfacial forces, polymers composed of maleic anhydride and two other components have been designed as top coats that can be spin-coated from basic aqueous solution in the ring-opened, acid salt form. When baked, the anhydride reforms and switches polarity to create a neutral layer enabling BCP feature alignment not possible by thermal annealing alone. Top coats were applied to the lamella-forming block copolymers poly(styrene-block-trimethyilylstyrene-block-styrene) and poly(trimethylsilylstyrene-block-lactide), which were thermally annealed to produce perpendicular features with linewidths of 15 and 9 nanometers, respectively.
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