The rockefeller university

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.

The journey from plasma membrane to nuclear pore is a critical step in the lifecycle of DNA viruses, many of which must successfully deposit their genomes into the nucleus for replication. Viral capsids navigate this vast distance through the coordinated hijacking of a number of cellular host factors, many of which remain unknown. We performed a gene-trap screen in haploid cells to identify host factors for adenovirus (AdV), a DNA virus that can cause severe respiratory illness in immune-compromised individuals. This work identified Mindbomb 1 (MIB1), an E3 ubiquitin ligase involved in neurodevelopment, as critical for AdV infectivity. In the absence of MIB1, we observed that viral capsids successfully traffic to the proximity of the nucleus but ultimately fail to deposit their genomes within. The capacity of MIB1 to promote AdV infection was dependent on its ubiquitination activity, suggesting that MIB1 may mediate proteasomal degradation of one or more negative regulators of AdV infection. Employing complementary proteomic approaches to characterize proteins proximal to MIB1 upon AdV infection and differentially ubiquitinated in the presence or absence of MIB1, we observed an intersection between MIB1 and ribonucleoproteins (RNPs) largely unexplored in mammalian cells. This work uncovers yet another way that viruses utilize host cell machinery for their own replication, highlighting a potential target for therapeutic interventions that counter AdV infection.

IMPORTANCE Standard morphological terminology and definitions are vital for identification of lesion types in the clinical trial setting and communication about the condition. For hidradenitis suppurativa (HS), morphological definitions have been proposed by different groups, representing various regions of the world, but no international consensus has been reached regarding such definitions. A lack of globally harmonized terminology and definitions may contribute to poor-quality data collection in clinical trials as well as poor communication among clinicians, investigators, and patients. OBJECTIVE To establish and validate consensus definitions for typical morphological findings for HS lesions. METHODS This study was conducted from August 2019 to August 2020. A Delphi study technique was used to assess agreement and then resolve disagreement on HS terminology among international experts. After an initial preparation phase, the process consisted of 3 rounds. In each round, participants reviewed preliminary definitions and rated them as "keep, with no changes," "keep, with changes," or "remove." Eight HS primary lesions, including papule, pustule, nodule, plaque, ulcer, abscess, comedo, and tunnel, were selected because they are most frequently used in HS clinician-reported outcome measures. The initial definitions were based on extant literature, and modifications were made between rounds based on qualitative thematic analysis of open-ended responses or discussion. Consensus was defined as greater than 70% to accept a definition. Consensus stability across rounds was defined as less than 15% change in agreement. Reliability was evaluated using the Gwet agreement coefficient. Validation was based on assessment of face validity and stability across rounds. RESULTS A total of 31 experts participated. All 8 HS primary lesion definitions achieved greater than 70% consensus by Delphi round 3. Stability was achieved for papule, pustule, and abscess. The Gwet agreement coefficient increased from 0.49 (95% CI, 0.26-0.71) in round 1 to 0.78 (95% CI, 0.64-0.92) in round 3. Face validity was supported by expert endorsement to keep terms in survey responses. Previously unmeasured variation among clinicians' definition of tunnels was identified, and consensus was achieved. CONCLUSIONS AND RELEVANCE An international group of experts agreed on definitions for morphological features of HS lesions frequently included in HS clinical trials. These international consensus terms and definitions are needed to support consistency of lesion identification and quantification in clinical trials.

Brown and beige adipocytes are mitochondria-enriched cells capable of dissipating energy in the form of heat. These thermogenic fat cells were originally considered to function solely in heat generation through the action of the mitochondrial protein uncoupling protein 1 (UCP1). In recent years, significant advances have been made in our understanding of the ontogeny, bioenergetics and physiological functions of thermogenic fat. Distinct subtypes of thermogenic adipocytes have been identified with unique developmental origins, which have been increasingly dissected in cellular and molecular detail. Moreover, several UCP1-independent thermogenic mechanisms have been described, expanding the role of these cells in energy homeostasis. Recent studies have also delineated roles for these cells beyond the regulation of thermogenesis, including as dynamic secretory cells and as a metabolic sink. This Review presents our current understanding of thermogenic adipocytes with an emphasis on their development, biological functions and roles in systemic physiology. Brown and beige adipocytes are mammalian thermogenic fat cells that regulate whole-body energy metabolism. Notably, brown/beige adipocytes are heterogeneous and their functions extend beyond thermogenesis, encompassing roles as metabolite sinks, as secretory cells and as regulators of adipose tissue homeostasis. Thus, induction of brown/beige fat activity correlates with improved metabolic health.