The rockefeller university

BackgroundIn China, addressing disparities in the HIV epidemic among men who have sex with men (MSM) requires targeted efforts to increase their engagement and retention in prevention. In an effort to advance MSM-friendly HIV services within China, and informed by community-based partnerships, we tested whether MSM who have ever versus never disclosed their same-sex behavior to healthcare providers (HCP) differ in sociodemographic and behavioral characteristics as well as the qualities of sexual health services each group would prefer to access.MethodsWe conducted a cross-sectional survey among HIV-negative MSM who went to MSM-focused voluntary counseling and testing clinics in four cities in China. The survey was anonymous and collected information on sociodemographic characteristics, testing behaviors, sexual-health related behavior, and sexual health service model preferences.ResultsOf 357 respondents, 68.1% participants had ever disclosed same-sex behavior to HCPs when seeking advice for sexual health. Younger age (aOR=1.04; 95% CI: 1.01-1.08), and worry of HIV acquisition (aOR=1.39; 95% CI: 1.05-1.84) were associated with higher odds of past disclosure. The availability of comprehensive sexual health services was one of the most valued characteristics of the ideal sexual health clinic. Those who ever disclosed and never disclosed differed significantly in their ranking of the importance of three out of ten dimensions: sexual health counseling services available (M=3.99 vs. M=3.65, p=.002), gay identity support available (M=3.91 vs. M=3.62, p=.016) and clinic collaborates with a gay CBO (M=3.81 vs. M=3.56, p=.036).ConclusionsOur hypothesis that MSM who had disclosed versus never disclosed same-sex behavior would differ in the value they placed on different dimensions of sexual health service was partially borne out. As health authorities in China decide on implementation models for pre-exposure prophylaxis (PrEP) delivery and specifically within which institutions to integrate PrEP services, the preferences of target populations should be considered to develop comprehensive, patient-centric and LGBT-friendly services.

OBJECTIVE: To describe social distancing practices in nine municipalities of the state of Rio Grande do Sul, Brazil, stratified by gender, age, and educational attainment. METHODS: Two sequential cross-sectional studies were conducted in the municipalities of Canoas, Caxias do Sul, Ijui, Passo Fundo, Pelotas, Porto Alegre, Santa Cruz do Sul, Santa Maria, and Uruguaiana to estimate the population prevalence of COVID-19. The study was designed to be representative of the urban population of these municipalities. A questionnaire including three questions about social distancing was also administered to the participants. Here, we present descriptive analyses of social distancing practices by subgroups and use chi-square tests for comparisons. RESULTS: In terms of degree of social distancing, 25.8% of the interviewees reported being essentially isolated and 41.1% reported being quite isolated. 20.1% of respondents reported staying at home all the time, while 44.5% left only for essential activities. More than half of households reported receiving no visits from non-residents. Adults aged 20 to 59 reported the least social distancing, while more than 80% of participants aged 60 years or older reported being essentially isolated or quite isolated. Women reported more stringent distancing than men. Groups with higher educational attainment reported going out for daily activities more frequently. CONCLUSIONS: The extremes of age are more protected by social distancing, but some groups remain highly exposed. This can be an important limiting factor in controlling progression of the COVID-19 pandemic.

In humans, the RNA exosome consists of an enzymatically inactive nine-subunit core, with ribonucleolytic activity contributed by additional components. Several cofactor complexes also interact with the exosome-these enable the recruitment of, and specify the activity upon, diverse substrates. Affinity capture coupled with mass spectrometry has proven to be an effective means to identify the compositions of RNA exosomes and their cofactor complexes: here, we describe a general experimental strategy for proteomic characterization of macromolecular complexes, applied to the exosome and an affiliated adapter protein, ZC3H18.

Background: Hidradenitis suppurativa (HS) is characterized by recurrent, painful nodules in flexural areas. Objective: The objective of this study was to explore the placebo response in HS randomized clinical trials and to compare it briefly with the placebo response in psoriasis and atopic dermatitis. Methods: A Cochrane Review on interventions in HS was used as a starting point, and a systematic review was then undertaken by using the PubMed database, yielding 7 HS randomized clinical trials for inclusion in this study. Results: This review demonstrates that there is a robust placebo response in HS that is most marked in physical signs but also marked in pain responses. Limitations: Multiple outcome measures utilized in these studies and reporting bias limited this review. Conclusion: This large placebo response has implications for clinical trial design. This knowledge can also help deliver improved clinical care by forming the basis of nonpharmacologic treatments and help optimize current medication use to maximize the placebo effect.

Background: The circulating immune phenotype was defined in adults and young children with early atopic dermatitis (AD), but chronologic changes in the blood of infants and children with AD through adolescence have not been explored. Objective: We sought to compare immune activation and cytokine polarization in the blood of 0- to 5-year-old (n = 39), 6- to 11-yearold (n = 26), 12- to 17-year-old (n = 21) and 18-year-old or older (n = 43) patients with AD versus age-matched control subjects. Methods: Flow cytometry was used to measure IFN-gamma, IL-9, IL-13, IL-17, and IL-22 cytokine levels in CD4(+)/CD8(+) T cells, with inducible costimulator molecule and HLA-DR defining midterm and long-term T-cell activation, respectively, within skin-homing/cutaneous lymphocyte antigen (CLA)(+) versus systemic/CLA(-)T cells. Unsupervised clustering differentiated patients based on their blood biomarker frequencies. Results: Although CLA(+)T(H)1 frequencies were significantly lower in infants with AD versus all older patients (P < .01), frequencies of CLA(+)T(H)2 T cells were similarly expanded across all AD age groups compared with control subjects (P < .05). After infancy, CLA(-)T(H)2 frequencies were increased in patients with AD in all age groups, suggesting systemic immune activation with disease chronicity. IL-22 frequencies serially increased from normal levels in infants to highly significant levels in adolescents and adults compared with levels in respective control subjects (P < .01). Unsupervised clustering aligned the AD profiles along an age-related spectrum from infancy to adulthood (eg, inducible costimulator molecule and IL-22). Conclusions: The adult AD phenotype is achieved only in adulthood. Unique cytokine signatures characterizing individual pediatric endotypes might require age-specific therapies. Future longitudinal studies, comparing the profile of patients with cleared versus persistent pediatric AD, might define age-specific changes that predict AD clearance.

Since 2013, the International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) has published an updated phenotypic classification of IEI, which accompanies and complements their genotypic classification into ten tables. This phenotypic classification is user-friendly and serves as a resource for clinicians at the bedside. There are now 430 single-gene IEI underlying phenotypes as diverse as infection, malignancy, allergy, autoimmunity, and autoinflammation. We herein report the 2019 phenotypic classification, including the 65 new conditions. The diagnostic algorithms are based on clinical and laboratory phenotypes for each of the ten broad categories of IEI.

Background The mitogen-activated protein kinases (MAPKs) are important for T cell survival and their effector function. Mixed lineage kinase 3 (MLK3) (MAP3K11) is an upstream regulator of MAP kinases and emerging as a potential candidate for targeted cancer therapy; yet, its role in T cell survival and effector function is not known. Methods T cell phenotypes, apoptosis and intracellular cytokine expressions were analyzed by flow cytometry. The apoptosis-associated gene expressions in CD8(+)CD38(+)T cells were measured using (RTPCR)-P-2 array. In vivo effect of combined blockade of MLK3 and CD70 was analyzed in 4T1 tumor model in immunocompetent mice. The serum level of tumor necrosis factor-alpha (TNF alpha) was quantified by enzyme-linked immunosorbent assay. Results We report that genetic loss or pharmacological inhibition of MLK3 induces CD70-TNF alpha-TNFRSF1a axis-mediated apoptosis in CD8(+)T cells. The genetic loss of MLK3 decreases CD8(+)T cell population, whereas CD4(+)T cells are partially increased under basal condition. Moreover, the loss of MLK3 induces CD70-mediated apoptosis in CD8(+)T cells but not in CD4(+)T cells. Among the activated CD8(+)T cell phenotypes, CD8(+)CD38(+)T cell population shows more than five fold increase in apoptosis due to loss of MLK3, and the expression of TNFRSF1a is significantly higher in CD8(+)CD38(+)T cells. In addition, we observed that CD70 is an upstream regulator of TNF alpha-TNFRSF1a axis and necessary for induction of apoptosis in CD8(+)T cells. Importantly, blockade of CD70 attenuates apoptosis and enhances effector function of CD8(+)T cells from MLK3(-/-)mice. In immune-competent breast cancer mouse model, pharmacological inhibition of MLK3 along with CD70 increased tumor infiltration of cytotoxic CD8(+)T cells, leading to reduction in tumor burden largely via mitochondrial apoptosis. Conclusion Together, these results demonstrate that MLK3 plays an important role in CD8(+)T cell survival and effector function and MLK3-CD70 axis could serve as a potential target in cancer.

Background Validated, reliable, globally accepted outcome measurement instruments for hidradenitis suppurativa (HS) are needed. Current tools to measure the physical signs domain for HS rely on lesion counts, which are time-consuming and unreliable. Objectives To assess the reliability and validity of the Hidradenitis suppurativa Area and Severity Index Revised (HASI-R) tool, a novel method for assessing HS severity, incorporating signs of inflammation and body surface area involved. Methods The measurement properties of the HASI-R tool were evaluated. The tool was created by combining the previously published HASI and Severity and Area Score for Hidradenitis instruments. Twenty raters evaluated 15 patients with HS in a hospital-based ambulatory dermatology clinic. The objectives of the study were to assess inter- and intra-rater reliability of the HASI-R and its components, as well as its construct and known-groups validity. Existing lesion count-based clinician-reported measures of HS and their components were also assessed. Raters were also asked their preferences regarding the various HS severity assessment tools. Results The HASI-R had moderate inter-rater reliability [intra-class correlation coefficients (ICC) 0 center dot 60]. This was better than all other HS physical sign outcome measures evaluated, which had poor inter-rater reliability (ICC < 0 center dot 5). HASI-R had the highest intra-rater reliability (ICC 0 center dot 91). The HASI-R had good construct validity and demonstrated known-groups validity. The HASI-R was also the most preferred tool by all raters. Conclusions Results from the clinometric assessment of the HASI-R are encouraging, and support continued evaluation of this clinician-reported outcome measure.

The peptidase-containing ATP-binding cassette transporters (PCATs) are unique members of the ABC transporter family that proteolytically process and export peptides and proteins. Each PCAT contains two peptidase domains that cleave off the secretion signal, two transmembrane domains forming a translocation pathway, and two nucleotide-binding domains that hydrolyze ATP. Previously the crystal structures of a PCAT from Clostridium thermocellum (PCAT1) were determined in the absence and presence of ATP, revealing how ATP binding regulates the protease activity and access to the translocation pathway. However, how the substrate CtA, a 90-residue polypeptide, is recognized by PCAT1 remained elusive. To address this question, we determined the structure of the PCAT1-CtA complex by electron cryo-microscopy (cryo-EM) to 3.4 angstrom resolution. The structure shows that two CtAs are bound via their N-terminal leader peptides, but only one is positioned for cleavage and translocation. Based on these results, we propose a model of how substrate cleavage, ATP hydrolysis, and substrate translocation are coordinated in a transport cycle.

Alpha thalassemia/mental retardation syndrome X-linked chromatin remodeler (ATRX), a DAXX (death domain-associated protein) interacting protein, is often lost in cells using the alternative lengthening of telomeres (ALT) pathway, but it is not known how ATRX loss leads to ALT. We report that ATRX deletion from mouse cells altered the repair of telomeric double-strand breaks (DSBs) and induced ALT-like phenotypes, including ALT-associated promyelocytic leukemia (PML) bodies (APBs), telomere sister chromatid exchanges (T-SCEs), and extrachromosomal telomeric signals (ECTSs). Mechanistically, we show that ATRX affects telomeric DSB repair by promoting cohesion of sister telomeres and that loss of ATRX in ALT cells results in diminished telomere cohesion. In addition, we document a role for DAXX in the repair of telomeric DSBs. Removal of telomeric cohesion in combination with DAXX deficiency recapitulates all telomeric DSB repair phenotypes associated with ATRX loss. The data reveal that ATRX has an effect on telomeric DSB repair and that this role involves both telomere cohesion and a DAXX-dependent pathway.