Mortality rates of coronavirus disease‐2019 (COVID‐19) continue to rise across the world. Information regarding the predictors of mortality in patients with COVID‐19 remains scarce. Herein, we performed a systematic review of published articles, from 1 January to 24 April 2020, to evaluate the risk factors associated with mortality in COVID‐19. Two investigators independently searched the articles and collected the data, in accordance with PRISMA guidelines. We looked for associations between mortality and patient characteristics, comorbidities, and laboratory abnormalities. A total of 14 studies documenting the outcomes of 4659 patients were included. The presence of comorbidities such as hypertension (odds ratio [OR], 2.5; 95% confidence interval [CI], 2.1‐3.1; P < .00001), coronary heart disease (OR, 3.8; 95% CI, 2.1‐6.9; P < .00001), and diabetes (OR, 2.0; 95% CI, 1.7‐2.3; P < .00001) were associated with significantly higher risk of death amongst patients with COVID‐19. Those who died, compared with those who survived, differed on multiple biomarkers on admission including elevated levels of cardiac troponin (+44.2 ng/L, 95% CI, 19.0‐69.4; P = .0006); C‐reactive protein (+66.3 µg/mL, 95% CI, 46.7‐85.9; P < .00001); interleukin‐6 (+4.6 ng/mL, 95% CI, 3.6‐5.6; P < .00001); D‐dimer (+4.6 µg/mL, 95% CI, 2.8‐6.4; P < .00001); creatinine (+15.3 µmol/L, 95% CI, 6.2‐24.3; P = .001); and alanine transaminase (+5.7 U/L, 95% CI, 2.6‐8.8; P = .0003); as well as decreased levels of albumin (−3.7 g/L, 95% CI, −5.3 to −2.1; P < .00001). Individuals with underlying cardiometabolic disease and that present with evidence for acute inflammation and end‐organ damage are at higher risk of mortality due to COVID‐19 infection and should be managed with greater intensity.

Loss of function mutations in the autoimmune regulator (Aire) gene in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients and mutant mice lead to autoimmune manifestations that segregate as a monogenic trait, but with wide variation in the spectrum of organs targeted. To investigate the cause of this variability, the Aire knockout mutation was backcrossed to mice of diverse genetic backgrounds. The background loci strongly influenced the pattern of organs that were targeted (stomach, eye, pancreas, liver, ovary, thyroid, and salivary gland) and the severity of the targeting (particularly strong on the nonobese diabetic background, but very mild on the C57BL/6 background). Autoantibodies mimicked the disease pattern, with oligoclonal reactivity to a few antigens that varied between Aire-deficient strains. Congenic analysis and a whole genome scan showed that autoimmunity to each organ had a distinctive pattern of genetic control and identified several regions that controlled the pattern of targeting, including the major histocompatibility complex and regions of Chr1 and Chr3 previously identified in controlling type 1 diabetes.

Immature thymocytes expressing autoreactive T-cell receptors (TCR) can adopt differing cell fates: clonal deletion by apoptosis or deviation into alternative lineages such as FoxP3 + regulatory T cells (Treg). We revisited the role of the transcription factor Nr4a1 (Nur77), an immediate-early response gene induced by TCR engagement. Nr4a1KO mice show clear quantitative defects in antigen-induced clonal deletion. The impact of the Nr4a1 deletion is not enhanced by deletion of the proapoptotic factor Bim. In addition, Nr4a1 curtails initial differentiation into the Treg lineage in TCR transgenic mice and in nontransgenic mice. Transcriptional profiling of Nr4a1KO thymocytes under selection conditions reveals that Nr4a1 activates the transcription of several targets, consistent with these diverse actions: (i) Nr4a1 partakes in the induction of Bim after TCR triggering; (ii) perhaps paradoxically, Nr4a1 positively controls several transcripts of the Treg signature, in particular Ikzf2 and Tnfrsf9; (iii) consistent with its prosurvival and metabolic role in the liver, Nr4a1 is also required for the induction by TCR of a coordinated set of enzymes of the glycolytic and Krebs cycle pathways, which we propose may antagonize Treg selection as does activation of mTOR/Akt. Thus, Nr4a1 appears to act as a balancing molecule in fate determination at a critical juncture of T-cell differentiation.glycolysis | immune tolerance | thymus | nuclear receptor A hallmark of the adaptive immune system is its ability to respond to the infinite repertoire of potential pathogens to which it might someday be exposed, but the undirected process of antigen receptor rearrangement in thymocytes generates receptors that are reactive to self and hence are potentially dangerous. Fledgling T cells carrying a nascent T-cell receptor (TCR) must undergo a rigorous process of negative selection, during which cells expressing a self-reactive TCR are eliminated by induced apoptosis or deviated to alternative differentiation pathways in which self-reactivity is defused [NKT, CD8αα, or FoxP3 + Triggering of mitochondrial apoptosis by signaling cascades downstream from the TCR is clearly established. Bim and Bax/ Bak, proapoptotic members of the mitochondrial apoptosis pathway, are essential for efficient negative selection (2, 3), but this may not be the sole mechanism. Early experiments involving blockade of RNA or protein synthesis suggested that negative selection is both transcription and translation dependent (4). Indeed, the transcription factor Nr4a1 has been implicated in negative selection (5, 6). An orphan member of the nuclear receptor superfamily and the Nr4a1/Nr4a2/Nr4a3 subfamily, Nr4a1 is a transcriptional activator, but can also promote mitochondrial apoptosis. In both tumor cell lines and thymocytes undergoing negative selection, Nr4a1 undergoes phosphorylation-dependent export from the nucleus to the mitochondria, where it conformationally alters Bcl-2 to promote apoptosis (7-10). Nr4a1 is associated with apoptosis in a number of phys...

Advances in chemistry and massively parallel detection underlie DNA sequencing platforms that are poised for application in personalized medicine. In stark contrast, systematic generation of protein-level data lags well-behind genomics in virtually every aspect: depth of coverage, throughput, ease of sample preparation, and experimental time. Here, to bridge this gap, we develop an approach based on simple detergent lysis and single-enzyme digest, extreme, orthogonal separation of peptides, and true nanoflow LC-MS/MS that provides high peak capacity and ionization efficiency. This automated, deep efficient peptide sequencing and quantification (DEEP SEQ) mass spectrometry platform provides genome-scale proteome coverage equivalent to RNA-seq ribosomal profiling and accurate quantification for multiplexed isotope labels. In a model of the embryonic to epiblast transition in murine stem cells, we unambiguously quantify 11,352 gene products that span 70% of Swiss-Prot and capture protein regulation across the full detectable range of high-throughput gene expression and protein translation.

FoxP3 ؉ CD4 ؉ regulatory T cells (Tregs) play a key role in the maintenance of peripheral self-tolerance, and it has been suggested that diabetes-susceptible nonobese diabetic (NOD) mice are defective in the generation and numbers of Tregs. We found thymic selection of Tregs to be under genetic control. Fetal thymic organ cultures on the NOD background required 3-to 10-fold more antigen than corresponding cultures on the B6 background for optimal induction of Tregs, but once the threshold for induction was reached the NOD background yielded close to 10-fold more Tregs. This increased selection of Tregs was also found in nontransgenic NOD mice in fetal through adult stages. This trait did not map to the MHC, idd3, or the chromosome 3 (Chr3) regions that control clonal deletion, but mainly to two regions on Chr1 and Chr11. Thus, NOD mice do not have a global defect in the generation or maintenance of Tregs; if anything, they show the opposite.genetic ͉ lineage commitment ͉ thymus

Type 1 diabetes is characterized by infiltration of pancreatic islets with immune cells, leading to insulin deficiency. Although infiltrating immune cells are traditionally considered to negatively impact β-cells by promoting their death, their contribution to proliferation is not fully understood. Here we report that islets exhibiting insulitis also manifested proliferation of β-cells that positively correlated with the extent of lymphocyte infiltration. Adoptive transfer of diabetogenic CD4+ and CD8+ T cells, but not B cells, selectively promoted β-cell proliferation in vivo independent from the effects of blood glucose or circulating insulin or by modulating apoptosis. Complementary to our in vivo approach, coculture of diabetogenic CD4+ and CD8+ T cells with NOD.RAG1−/− islets in an in vitro transwell system led to a dose-dependent secretion of candidate cytokines/chemokines (interleukin-2 [IL-2], IL-6, IL-10, MIP-1α, and RANTES) that together enhanced β-cell proliferation. These data suggest that soluble factors secreted from T cells are potential therapeutic candidates to enhance β-cell proliferation in efforts to prevent and/or delay the onset of type 1 diabetes.

Background: Risk stratification of COVID-19 patients upon hospital admission is key for their successful treatment and efficient utilization of hospital resources. We sought to evaluate the risk factors on admission (including comorbidities, vital signs, and initial laboratory assessment) associated with ventilation need and in-hospital mortality in COVID-19. Methods: We established a retrospective cohort of COVID-19 patients from Mass General Brigham hospitals. Demographic, clinical, and admission laboratory data were obtained from electronic medical records of patients admitted to the hospital with laboratory-confirmed COVID-19 before May 19, 2020. Multivariable logistic regression analyses were used to construct and validate the Ventilation in COVID Estimator (VICE) and Death in COVID Estimator (DICE) risk scores. Findings: The entire cohort included 1042 patients (median age, 64 years; 56.8% male). The derivation and validation cohorts for the risk scores included 578 and 464 patients, respectively. We found four factors to be independently predictive for mechanical ventilation requirement (diabetes mellitus, SpO 2 :FiO 2 ratio, C-reactive protein, and lactate dehydrogenase), and 10 factors to be predictors of in-hospital mortality (age, male sex, coronary artery disease, diabetes mellitus, chronic statin use, SpO 2 :FiO 2 ratio, body mass index, neutrophil to lymphocyte ratio, platelet count, and procalcitonin). Using these factors, we constructed the VICE and DICE risk scores, which performed with C-statistics of 0.84 and 0.91, respectively. Importantly, the chronic use of a statin was associated with protection against death due to COVID-19. The VICE and DICE score calculators have been placed on an interactive website freely available to healthcare providers and researchers (https://covid-calculator.com/). Interpretation: The risk scores developed in this study may help clinicians more appropriately determine which COVID-19 patients will need to be managed with greater intensity. Funding: COVID-19 Fast Grant (fastgrants.org).

Kisspeptin and its G protein-coupled receptor KISS1R play key roles in mammalian reproduction due to their involvement in the onset of puberty and control of the hypothalamic-pituitary-gonadal axis. However, recent studies have indicated a potential role of extra-hypothalamic kisspeptin in reproductive function. Here, we summarize recent advances in our understanding of the physiological significance of kisspeptin/KISS1R in the peripheral reproductive system (including the ovary, testis, uterus, and placenta) and the potential role of kisspeptin/KISS1R in reproductive diseases. A comprehensive understanding of the expression, function, and potential molecular mechanisms of kisspeptin/KISS1R in the peripheral reproductive system will contribute to the diagnosis, treatment and prevention of reproductive diseases.