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Severe respiratory illness is the most prominent manifestation of patients infected with SARS-CoV-2, and yet the molecular mechanisms underlying severe lung disease in COVID-19 affected patients still require elucidation. Human leukocyte antigen class I (HLA-I) expression is crucial for antigen presentation and the host's response to SARS-CoV-2. To gain insights into the immune response and molecular pathways involved in severe lung disease, we performed immunopeptidomic and proteomic analyses of lung tissues recovered at four COVID-19 autopsy and six non-COVID-19 transplants. We found signals of tissue injury and regeneration in lung fibroblast and alveolar type I/II cells, resulting in the production of highly immunogenic self-antigens within the lungs of COVID-19 patients. We also identified immune activation of the M2c macrophage as the primary source of HLA-I presentation and immunogenicity in this context. Additionally, we identified 28 lung signatures that can serve as early plasma markers for predicting infection and severe COVID-19 disease. These protein signatures were predominantly expressed in macrophages and epithelial cells and were associated with complement and coagulation cascades. Our findings emphasize the significant role of macrophage-mediated immunity in the development of severe lung disease in COVID-19 patients.

Cancers avoid immune surveillance through an array of mechanisms, including perturbation of HLA class I antigen presentation. Merkel cell carcinoma (MCC) is an aggressive, HLA-I-low, neuroendocrine carcinoma of the skin often caused by the Merkel cell polyomavirus (MCPyV). Through the characterization of 11 newly generated MCC patient-derived cell lines, we identified transcriptional suppression of several class I antigen presentation genes. To systematically identify regulators of HLA-I loss in MCC, we performed parallel, genome-scale, gain- and loss-of-function screens in a patient-derived MCPyV-positive cell line and identified MYCL and the non-canonical Polycomb repressive complex 1.1 (PRC1.1) as HLA-I repressors. We observed physical interaction of MYCL with the MCPyV small T viral antigen, supporting a mechanism of virally mediated HLA-I suppression. We further identify the PRC1.1 component USP7 as a pharmacologic target to restore HLA-I expression in MCC.

Cancers avoid immune surveillance through an array of mechanisms, including perturbation of HLA class I antigen presentation. Merkel cell carcinoma (MCC) is an aggressive, HLA-I-low, neuroendocrine carcinoma of the skin often caused by the Merkel cell polyomavirus (MCPyV). Through the characterization of 11 newly generated MCC patient-derived cell lines, we identified transcriptional suppression of several class I antigen presentation genes. To systematically identify regulators of HLA-I loss in MCC, we performed parallel, genome-scale, gain- and loss-of-function screens in a patient-derived MCPyV-positive cell line and identified MYCL and the non-canonical Polycomb repressive complex 1.1 (PRC1.1) as HLA-I repressors. We observed physical interaction of MYCL with the MCPyV small T viral antigen, supporting a mechanism of virally mediated HLA-I suppression. We further identify the PRC1.1 component USP7 as a pharmacologic target to restore HLA-I expression in MCC.

Tumor-infiltrating lymphocyte (TIL) therapy is FDA-approved for patients with treatment-resistant advanced melanoma, but the TIL subpopulations critical for tumor eradication remains incompletely understood. Using patient-derived TIL-melanoma co-cultures, we identified and characterized a novel subset of CD8 TIL, capable of class I HLA-independent cancer cell lysis. The lymphotoxin β receptor (LTβR) and interferon (IFN) sensing pathways were nominated as key determinants of TIL-mediated cancer cell killing from a whole-genome, loss-of-function CRISPR screen. Validation studies confirmed that dual LTβR and IFN sensing is necessary and sufficient for cancer cell lysis, and that expanded CD8 TIL express high lymphotoxin β ( ) and upregulate lymphotoxin α ( ) upon coculture with cancer cells. Leveraging paired scRNA-seq and scTCR-seq data, we confirmed that enrichment of T cells is associated with clinical response to TIL, and that TIL are expanded from putative neoantigen-reactive, CD8 T cells in resected tumors.

Digoxin is a widely used drug for ventricular rate control in patients with atrial fibrillation (AF), despite a scarcity of randomised trial data. We studied the use and outcomes of digoxin in patients in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). For this retrospective analysis, we included and classified patients from ROCKET AF on the basis of digoxin use at baseline and during the study. Patients in ROCKET AF were recruited from 45 countries and had AF and risk factors putting them at moderate-to-high risk of stroke, with or without heart failure. We used Cox proportional hazards regression models adjusted for baseline characteristics and drugs to investigate the association of digoxin with all-cause mortality, vascular death, and sudden death. ROCKET AF was registered with ClinicalTrials.gov, number NCT00403767. In 14 171 randomly assigned patients, digoxin was used at baseline in 5239 (37%). Patients given digoxin were more likely to be female (42% vs 38%) and have a history of heart failure (73% vs 56%), diabetes (43% vs 38%), and persistent AF (88% vs 77%; p<0·0001 for each comparison). After adjustment, digoxin was associated with increased all-cause mortality (5·41 vs 4·30 events per 100 patients-years; hazard ratio 1·17; 95% CI 1·04–1·32; p=0·0093), vascular death (3·55 vs 2·69 per 100 patient-years; 1·19; 1·03–1·39, p=0·0201), and sudden death (1·68 vs 1·12 events per 100 patient-years; 1·36; 1·08–1·70, p=0·0076). Digoxin treatment was associated with a significant increase in all-cause mortality, vascular death, and sudden death in patients with AF. This association was independent of other measured prognostic factors, and although residual confounding could account for these results, these data show the possibility of digoxin having these effects. A randomised trial of digoxin in treatment of AF patients with and without heart failure is needed. Janssen Research & Development and Bayer HealthCare AG.

Changing disturbance regimes and climate can overcome forest ecosystem resilience. Following high-severity fire, forest recovery may be compromised by lack of tree seed sources, warmer and drier postfire climate, or short-interval reburning. A potential outcome of the loss of resilience is the conversion of the prefire forest to a different forest type or nonforest vegetation. Conversion implies major, extensive, and enduring changes in dominant species, life forms, or functions, with impacts on ecosystem services. In the present article, we synthesize a growing body of evidence of fire-driven conversion and our understanding of its causes across western North America. We assess our capacity to predict conversion and highlight important uncertainties. Increasing forest vulnerability to changing fire activity and climate compels shifts in management approaches, and we propose key themes for applied research coproduced by scientists and managers to support decision-making in an era when the prefire forest may not return.

The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to <10 ml per minute per 1.73 m , a sustained decrease in eGFR of ≥40% from baseline, or death from renal causes) or death from cardiovascular causes. A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P<0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P = 0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo. (Funded by Boehringer Ingelheim and others; EMPA-KIDNEY ClinicalTrials.gov number, NCT03594110; EudraCT number, 2017-002971-24.).

Deficiencies in essential vitamins and minerals-also termed hidden hunger-are pervasive and hold negative consequences for the cognitive and physical development of children. This analysis evaluates the change in hidden hunger over time in the form of one composite indicator-the Hidden Hunger Index (HHI)-using an unweighted average of prevalence estimates from the Nutrition Impact Model Study for anemia due to iron deficiency, vitamin A deficiency, and stunting (used as a proxy indicator for zinc deficiency). Net changes from 1995-2011 and population weighted regional means for various time periods are measured. Globally, hidden hunger improved (-6.7 net change in HHI) from 1995-2011. Africa was the only region to see a deterioration in hidden hunger (+1.9) over the studied time period; East Asia and the Pacific performed exceptionally well (-13.0), while other regions improved only slightly. Improvements in HHI were mostly due to reductions in zinc and vitamin A deficiencies, while anemia due to iron deficiency persisted and even increased. This analysis is critical for informing and tracking the impact of policy and programmatic efforts to reduce micronutrient deficiencies, to advance the global nutrition agenda, and to achieve the Millennium Development Goals (MDGs). However, there remains an unmet need to invest in gathering frequent, nationally representative, high-quality micronutrient data as we renew our efforts to scale up nutrition, and as we enter the post-2015 development agenda. Preparation of this manuscript was funded by Sight and Life. There was no funding involved in the study design, data collection, analysis, or decision to publish.

Rituximab is a monoclonal antibody that selectively depletes CD20+ B cells. In this randomized trial involving patients with poorly controlled rheumatoid arthritis despite methotrexate treatment, rituximab was found to be an intriguing new therapy for alleviating symptoms in rheumatoid arthritis. However, use of rituximab led to serious infections in some cases. Rituximab is a monoclonal antibody that selectively depletes CD20+ B cells. It is a promising new therapy for rheumatoid arthritis. Rheumatoid arthritis is a systemic autoimmune disease that affects approximately 1 percent of the adult population. 1 It is characterized by chronic inflammation in the synovial membrane of affected joints that ultimately leads to loss of daily function due to chronic pain and fatigue. The majority of patients also have deterioration of cartilage and bone in the affected joints, which may eventually lead to permanent disability. Rheumatoid arthritis is associated with increased morbidity and mortality. 2 Although the precise pathogenesis of rheumatoid arthritis remains unclear, it has been postulated that multiple exogenous or endogenous antigenic triggers, or both, act in the presence . . .

Heteromorphic sex chromosomes are usually thought to have originated from a pair of autosomes that acquired a sex-determining locus and subsequently stopped recombining, leading to degeneration of the sex-limited chromosome. The majority of nematode species lack heteromorphic sex chromosomes and determine sex using an X-chromosome counting mechanism, with males being hemizygous for one or more X chromosomes (XX/X0). Some filarial nematode species, including important parasites of humans, have heteromorphic XX/XY karyotypes. It has been assumed that sex is determined by a Y-linked locus in these species. However, karyotypic analyses suggested that filarial Y chromosomes are derived from the unfused homologue of an autosome involved in an X-autosome fusion event. Here, we generated a chromosome-level reference genome for Litomosoides sigmodontis , a filarial nematode with the ancestral filarial karyotype and sex determination mechanism (XX/X0). By mapping the assembled chromosomes to the rhabditid nematode ancestral linkage (or Nigon) elements, we infer that the ancestral filarial X chromosome was the product of a fusion between NigonX (the ancestrally X-linked element) and NigonD (ancestrally autosomal). In the two filarial lineages with XY systems, there have been two independent X-autosome chromosome fusion events involving different autosomal Nigon elements. In both lineages, the region shared by the neo-X and neo-Y chromosomes is within the ancestrally autosomal portion of the X, confirming that the filarial Y chromosomes are derived from the unfused homologue of the autosome. Sex determination in XY filarial nematodes therefore likely continues to operate via the ancestral X-chromosome counting mechanism, rather than via a Y-linked sex-determining locus.