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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has accumulated genomic mutations at an approximately linear rate since it first infected human populations in late 2019. Controversies remain regarding the identity, proportion, and effects of adaptive mutations as SARS-CoV-2 evolves from a bat-to a human-adapted virus. The potential for vaccine-escape mutations poses additional challenges in pandemic control. Despite being of great interest to therapeutic and vaccine development, human-adaptive mutations in SARS-CoV-2 are masked by a genome-wide linkage disequilibrium under which neutral and even deleterious mutations can reach fixation by chance or through hitchhiking. Furthermore, genome-wide linkage equilibrium imposes clonal interference by which multiple adaptive mutations compete against one another. Informed by insights from microbial experimental evolution, we analyzed close to one million SARS-CoV-2 genomes sequenced during the first year of the COVID-19 pandemic and identified putative human-adaptive mutations according to the rates of synonymous and missense mutations, temporal linkage, and mutation recurrence. Furthermore, we developed a forward-evolution simulator with the realistic SARS-CoV-2 genome structure and base substitution probabilities able to predict viral genome diversity under neutral, background selection, and adaptive evolutionary models. We conclude that adaptive mutations have emerged early, rapidly, and constantly to dominate SARS-CoV-2 populations despite clonal interference and purifying selection. Our analysis underscores a need for genomic surveillance of mutation trajectories at the local level for early detection of adaptive and immune-escape variants. Putative human-adaptive mutations are over-represented in viral proteins interfering host immunity and binding host-cell receptors and thus may serve as priority targets for designing therapeutics and vaccines against human-adapted forms of SARS-CoV-2.
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BackgroundThe goal of the present work was to examine risk factors for mortality in a 1,387 COVID+ patients admitted to a hospital in Suffolk County, NY. MethodsData were collated by the hospital epidemiological service for patients admitted from 3/7/2020-9/1/2020. Time until final discharge or death was the outcome. Cox proportional hazards models were used to estimate time until death among admitted patients. FindingsIn total, 99.06% of cases had resolved leading to 1,179 discharges and 211 deaths. Length of stay was significantly longer in those who died as compared to those who did not p=0.007). Of patients who had been discharged (n=1,179), 54 were readmitted and 9 subsequently died. Multivariable-adjusted Cox proportional hazards regression revealed that in addition to older age, male sex, and heart failure that a history of premorbid depression was a risk factors for COVI-19 mortality (HR = 2.64 [1.54-4.54] P<0.001), and that this association remained after adjusting for age and for neuropsychiatric conditions as well as medical comorbidities including cardiovascular disease and pulmonary conditions. Sex-stratified analyses revealed that associations between mortality and depression was strongest in males (aHR = 4.45 [2.04-9.72], P<0.001), and that the association between heart failure and mortality was strongest in participants aged <65 years old (aHR = 30.50 [9.17-101.48], P<0.001). InterpretationWhile an increasing number of studies have identified a number of comorbid medical conditions and age of patient as risk factors for mortality in COVID+ patients, this study reports that history of depression is a risk factor for COVID mortality. FundingNo funding was received for this study.
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<p><b>OBJECTIVE</b>To study, at the cytological level, the basic concept of Chinese medicine that "the Kidney (Shen) controls the bone".</p><p><b>METHODS</b>Kaempferol was isolated form Rhizoma Drynariae (Gu Sui Bu, GSB) and at several concentrations was incubated with opossum kidney (OK) cells, osteoblasts (MC3T3 E1) and human fibroblasts (HF) at cell concentrations of 2×10(4)/mL. Opossum kidney cell-conditioned culture media with kaempferol at 70 nmol/L (70kaeOKM) and without kaempferol (0OKM) were used to stimulate MC3T3 E1 and HF proliferation. The bone morphological protein receptors I and II (BMPR I and II) in OK cells were identified by immune-fluorescence staining and Western blot analysis.</p><p><b>RESULTS</b>Kaempferol was found to increase OK cell growth (P<0.05), but alone did not promote MC3T3 E1 or HF cell proliferation. However, although OKM by itself increased MC3T3 E1 growth by 198% (P<0.01), the 70kaeOKM further increased the growth of these cells by an additional 127% (P<0.01). It indicates that the kidney cell generates a previously unknown osteoblast growth factor (OGF) and kaempferol increases kidney cell secretion of OGF. Neither of these media had any significant effect on HF growth. Kaempferol also was found to increase the level of the BMPR II in OK cells.</p><p><b>CONCLUSIONS</b>This lends strong support to the original idea that the Kidney has a significant influence over bone-formation, as suggested by some long-standing Chinese medical beliefs, kaempferol may also serve to stimulate kidney repair and indirectly stimulate bone formation.</p>
