The rockefeller university

Obesity is a global epidemic health disorder and associated with several diseases. Body weight-reducing effects of melatonin have been reported; however, no investigation toward examining whether the beneficial effects of melatonin are associated with preadipocyte heterogeneity has been reported. In this study, we profiled 25 071 transcriptomes of normal and melatonin-treated preadipocytes using scRNA-seq. By tSNE analysis, we present a cellular-state landscape for melatonin-treated preadipocytes that covers multiple-cell subpopulations, defined as cluster 0 to cluster 13. Cluster 0 and cluster 1 were the largest components of normal and melatonin-treated preadipocytes, respectively. G0S2, an inhibitor of adipose triglyceride lipase (ATGL), was significantly upregulated in cluster 0 and downregulated in cluster 1. We redefined cluster 0 as the G0S2-positive cluster (G0S2(+)) and cluster 1 as the G0S2-negative cluster (G0S2(-)). Through pseudotime analysis, the G0S2(-) cluster cell differentiation trajectory was divided into three major structures, that is, the prebranch, the lipid catabolism branch, and the cell fate 2 branch. In vitro, G0S2 knockdown enhanced the expression levels of ATGL, BAT markers and fatty acid oxidation-related genes, but inhibited C/EBP alpha and PPAR gamma expression. In vivo, knockdown of G0S2 reduced the body weight gain in high-fat-fed mice. The beneficial effects of the G0S2(-) cell cluster in promoting lipolysis and inhibiting adipogenesis are dependent on two major aspects: first, downregulation of the G0S2 gene in the G0S2(-) cluster, resulting in activation of ATGL, which is responsible for the bulk of triacylglycerol hydrolase activity; and second, upregulation of FABP4 in the G0S2(-) cluster, resulting in inhibition of PPAR gamma and further reducing adipogenesis.

Among the hallmarks of major depressive disorders (MDD) are molecular, functional, and morphological impairments in the hippocampus. Recent studies suggested a key role for hippocampal GABAergic interneurons both in depression and in the response to its treatments. These interneurons highly express the chromatin-remodeler SMARCA3 which mediates the response to chronic antidepressants in an unknown mechanism. Using cell-type-specific molecular and physiological approaches, we report that SMARCA3 mediates the glutamatergic signaling in interneurons by repressing the expression of the neuronal protein, Neurensin-2. This vesicular protein associates with endosomes and postsynaptic proteins and is highly and selectively expressed in subpopulations of GABAergic interneurons. Upregulation of Neurensin-2 in the hippocampus either by stress, viral overexpression, or by SMARCA3 deletion, results in depressive-like behaviors. In contrast, the deletion of Neurensin-2 confers resilience to stress and induces AMPA receptor localization to synapses. This pathway which bidirectionally affects emotional behavior could be involved in neuropsychiatric disorders, and suggests novel therapeutic approaches.

Human herpes simplex virus 1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway, resulting in impairment of CNS cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism is thought to involve impaired IFN-alpha/beta induction by the TLR3 recognition of dsRNA viral intermediates or by-products. However, we show here that human TLR3 controls constitutive levels of IFNB mRNA and secreted bioactive IFN-beta protein, and thereby also controls constitutive mRNA levels for IFN-stimulated genes (ISGs) in fibroblasts. Tlr3(-/-) mouse embryonic fibroblasts also have lower basal ISG levels. Moreover, human TLR3 controls basal levels of IFN-beta secretion and ISG mRNA in induced pluripotent stem cell-derived cortical neurons. Consistently, TLR3-deficient human fibroblasts and cortical neurons are vulnerable not only to both VSV and HSV-1, but also to several other families of viruses. The mechanism by which TLR3 restricts viral growth in human fibroblasts and cortical neurons in vitro and, by inference, by which the human CNS prevents infection by HSV-1 in vivo, is therefore based on the control of early viral infection by basal IFN-1 beta immunity.

Background: Our current understanding of atopic dermatitis (AD) and psoriasis pathophysiology is largely derived from skin biopsy studies that cause scarring and may be impractical in large-scale clinical trials. Although tape strips show promise as a minimally invasive technique in these common diseases, a comprehensive molecular profiling characterizing and differentiating the 2 diseases in tape strips is unavailable. Objective: Our aim was to construct a global transcriptome of tape strips from lesional and nonlesional skin of adults with moderate-to-severe AD and psoriasis. Methods: A total of 20 tape strips were obtained from lesional and nonlesional skin of patients with AD and psoriasis and skin from controls (n = 20 each); the strips were subjected to RNA sequencing (RNA-seq), with quantitative RT-PCR validation of immune and barrier biomarkers. Results: We detected RNA-seq profiles in 96 of 100 of samples (96%), with 4123 and 5390 genes differentially expressed in AD and psoriasis lesions versus in controls, respectively (fold change >= 2; false discovery rate [FDR] < 0.05). Nonlesional tape stripped skin from patients with AD was more similar to lesional skin than to nonlesional skin of patients with psoriasis, which showed larger differentiation from lesions. AD and psoriasis tissues shared increases in levels of dendritic cell and T-cell markers (CD3, ITGAX/CD11c, and CD83), but AD tissues showed preferential T(H)2 skewing (IL-13, CCL17/TARC, and CCL18), whereas psoriasis was characterized by higher levels of expression of T(H)17-related (IL-17A/F and IL-36A/IL-36G), T(H)1-related (IFN-gamma and CXCL9/CXCL10), and innate immunity-related (nitric oxide synthase 2/inducible nitric oxide synthase and IL-17C) products (FDR < 0.05). Terminal differentiation (FLG2 and LCE5A), tight junction (CLDN8), and lipid biosynthesis and metabolism (FA2H and ALOXE3) products were significantly downregulated in both AD and psoriasis (FDR < 0.05). Nitric oxide synthase 2/inducible nitric oxide synthase expression (determined by quantitative PCR) differentiated AD and psoriasis with 100% accuracy. Conclusion: RNA-seq tape strip profiling detected distinct immune and barrier signatures in lesional and nonlesional AD and psoriasis skin, suggesting their utility as a minimally invasive alternative to biopsies for detecting disease biomarkers.

Purpose To report four cases of life-threatening COVID-19 pneumonia in patients with high blood concentrations of neutralizing autoantibodies against type I interferons (IFNs), who were treated with plasma exchange (PE) as a rescue therapy. Methods Prospective case series, which included patients, diagnosed with RT-PCR-confirmed SARS-CoV-2 infection and positive autoantibodies against type I IFNs in two French intensive care units (ICUs) between October 8 and November 14, 2020. Six critically ill COVID-19 patients with no anti-IFN antibodies were used as controls. Anti-IFN autoantibodies and IFN concentrations, together with the levels of anti-SARS-CoV-2 antibodies, were measured sequentially in serum. Viral load was determined in the upper and lower respiratory tract. Patients were followed during hospital stay. Results Three men and one woman were included. Three of the patients had four PE sessions each, while another had three PE sessions. PE decreased the concentrations of autoantibodies against type I IFN in all four patients, whereas anti-SARS-CoV-2 antibody levels remained stable. Autoantibodies against type I IFN levels were high in tracheal aspirates of one patient and decreased after three PE sessions. By contrast, anti-IFN autoantibodies were not detected in tracheal aspirates from five control patients without detectable anti-IFN autoantibodies in serum. During PE, serum IFN-alpha levels slightly increased in three out of four patients, and upper respiratory tract viral load decreased in all patients. All patients were alive at day 28 of ICU admission. Two patients eventually died in the ICU, while the two survivors were discharged from the ICU at days 50 and 66. Conclusions PE efficiently removes autoantibodies against type I IFNs, including those detected in tracheal aspirates, without affecting anti-SARS-CoV-2 antibody levels, in patients with life-threatening COVID-19 pneumonia. The clinical benefit of PE in patients with autoantibodies against type I IFNs should be tested in a larger study.

Understanding the spatial and temporal distributions and fluctuations of living populations is a central goal in ecology and demography. A scaling pattern called Taylor's law has been used to quantify the distributions of populations. Taylor's law asserts a linear relationship between the logarithm of the mean and the logarithm of the variance of population size. Here, extending previous work, we use generalized least-squares models to describe three types of Taylor's law. These models incorporate the temporal and spatial autocorrelations in the mean-variance data. Moreover, we analyze three purely statistical models to predict the form and slope of Taylor's law. We apply these descriptive and predictive models of Taylor's law to the county population counts of the United States decennial censuses (1790-2010). We find that the temporal and spatial autocorrelations strongly affect estimates of the slope of Taylor's law, and generalized least-squares models that take account of these autocorrelations are often superior to ordinary least-squares models. Temporal and spatial autocorrelations combine with demographic factors (e.g., population growth and historical events) to influence Taylor's law for human population data. Our results show that the assumptions of a descriptive model must be carefully evaluated when it is used to estimate and interpret the slope of Taylor's law.

Hidradenitis suppurativa (HS) is a complex inflammatory disease in need of novel therapeutic options. HS treatment is always challenging and requires a medical and surgical approach together with multidisciplinary evaluation. Multiple monoclonal antibody therapies (including interleukin IL-17, IL-23 and IL-1 inhibitors) are currently in clinical trials, with a number of these therapies identified from their use in psoriasis. However, it should be noted that while the pathogenesis of HS is incompletely defined it demonstrates a number of unique characteristics which do not overlap with psoriasis and may require unique approaches to therapy. This review aims to cover the therapeutic agents currently in clinical trials for HS as well as those which based upon our current understanding of HS pathogenesis may be candidates for future proof-of-concept studies and clinical investigation (including IL-36, IL-6R, IRAK-4 and BTK inhibitors). Additionally, the role of assessing clinical response in clinical trials is discussed given the known issues with outcome measures, placebo response rates and the natural variability of untreated disease.

Tumor necrosis factor-alpha inhibitors, adalimumab and infliximab, are at the forefront of biologic therapy for the management of moderate-to-severe hidradenitis suppurativa, with adalimumab as currently the only approved medication for this condition. In treating patients, primary or secondary lack of response (also termed suboptimal response) is a major burden for both patients and healthcare systems and is a challenge with biologics in part owing to the development of anti-drug antibodies following treatment. To overcome this, therapeutic drug monitoring may be conducted proactively or reactively to a patient's suboptimal response guided by measurements of trough serum drug concentrations and levels of anti-drug antibodies. While strong evidence to support the utility of therapeutic drug monitoring exists in patients with inflammatory bowel disease, current information is limited in the context of hidradenitis suppurativa. We sought to summarize the available evidence and to present the role of therapeutic drug monitoring and other dose optimization strategies in improving clinical response in patients with hidradenitis suppurativa treated with tumor necrosis factor-alpha inhibitors.