The rockefeller university

P53 has been implicated in the pathogenesis of obesity and diabetes; however, the mechanisms and tissue sites of action are incompletely defined. Therefore, we investigated the role of hepatocyte p53 in metabolic homeostasis using a hepatocyte-specific p53 knockout mouse model. To gain further mechanistic insight, we studied mice under two complementary conditions of restricted weight gain: vertical sleeve gastrectomy (VSG) or food restriction. VSG or sham surgery was performed in high-fat diet-fed male hepatocyte-specific p53 wild-type and knockout littermates. Sham-operated mice were fed ad libitum or food restricted to match their body weight to VSG-operated mice. Hepatocyte-specific p53 ablation in sham-operated ad libitum-fed mice impaired glucose homeostasis, increased body weight, and decreased energy expenditure without changing food intake. The metabolic deficits induced by hepatocyte-specific p53 ablation were corrected, in part by food restriction, and completely by VSG. Unlike food restriction, VSG corrected the effect of hepatocyte p53 ablation to lower energy expenditure, resulting in a greater improvement in glucose homeostasis compared with food restricted mice. These data reveal an important new role for hepatocyte p53 in the regulation of energy expenditure and body weight and suggest that VSG can improve alterations in energetics associated with p53 dysregulation.

Integrated use of an animal model, a biobank for common diseases and a rare Mendelian disease leads to the discovery of a new syndrome and its pathological mechanism. Discovery of genotype-phenotype relationships remains a major challenge in clinical medicine. Here, we combined three sources of phenotypic data to uncover a new mechanism for rare and common diseases resulting from collagen secretion deficits. Using a zebrafish genetic screen, we identified the ric1 gene as being essential for skeletal biology. Using a gene-based phenome-wide association study (PheWAS) in the EHR-linked BioVU biobank, we show that reduced genetically determined expression of RIC1 is associated with musculoskeletal and dental conditions. Whole-exome sequencing identified individuals homozygous-by-descent for a rare variant in RIC1 and, through a guided clinical re-evaluation, it was discovered that they share signs with the BioVU-associated phenome. We named this new Mendelian syndrome CATIFA (cleft lip, cataract, tooth abnormality, intellectual disability, facial dysmorphism, attention-deficit hyperactivity disorder) and revealed further disease mechanisms. This gene-based, PheWAS-guided approach can accelerate the discovery of clinically relevant disease phenome and associated biological mechanisms.

STUDY QUESTION: Does the ovarian sensitivity index (OSI) predict embryo quality, pregnancy and live birth in patients undergoing FSH/hMG stimulation for IVF? SUMMARY ANSWER: The OSI is predictive of pregnancy and live birth in older women with a more unfavorable prognosis undergoing FSH/hMG stimulation for IVF. WHAT IS KNOWN ALREADY: The OSI was previously reported to reflect gonadotrophin requirements among high, normal and poor responders and to predict pregnancy potential in younger patients undergoing ovarian stimulation with FSH. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study that included 1282 women undergoing IVF with FSH/hMG stimulation was carried out between January 2010 and December 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: We evaluated 1282 women who underwent fertility treatment with FSH/hMG stimulation and oocyte retrieval at an academically affiliated private fertility center. OSI was calculated as (oocytes x1000)/total gonadotrophin dose and grouped into two classes based on a receiver operating characteristic (ROC) curve analysis of a randomly selected development sample comprising one-third of the cycles. The remaining cycles comprised the validation group. ROC curves were also used to compare the predictive value of OSI to that of baseline FSH and anti-Mullerian hormone (AMH). Logistic regression models evaluated the effect of high (OSI >0.83) and low (OSI <= 0.83) on clinical pregnancy and live birth in the validation group. Models were adjusted for female age, baseline FSH, AMH and oocyte yield and gonadotrophin dose. MAIN RESULTS AND THE ROLE OF CHANCE: Women presented with a mean +/- SD age of 38.6 +/- 5.4 years and showed median AMH levels of 0.65 (95% CI 0.61-0.74) ng/ml. They received 5145 +/- 2477 IU of gonadotrophins and produced a median 5.2 (95% CI 5.0-5.5) oocytes. Pregnancy and live birth rates per oocyte retrieval for all women were 20.6% and 15.8%, respectively. Patients with higher OSI (less gonadotrophin required per oocyte retrieved) produced significantly more high-quality embryos than patients with low OSI (3.5 (95% CI 3.2-3.8) versus 0.6 (95% CI 0.5-0.7) (P = 0.0001)) and demonstrated higher pregnancy (23.2% versus 9.7%) and live birth rates (8.8% versus 5.3%) than their counterparts (P = 0.0001 and P = 0.0001, respectively). After adjustments for age, baseline AMH and FSH, total gonadotrophin dosage and oocyte yield, an OSI >0.83 was associated with greater odds of pregnancy (odds ratio 2.12, 95% CI 1.30-3.45, P < 0.003) and live birth (odds ratio 1.91, 95% CI 1.07-3.41, P < 0.028). LIMITATIONS, REASONS FOR CAUTION: The results may not be applicable to women with excellent pregnancy potential or FSH-only stimulation. WIDER IMPLICATIONS OF THE FINDINGS: The predictive capacity of OSI for embryo quality, pregnancy and live birth, which is independent of AMH or FSH, may help in counseling patients about their pregnancy potential and live birth chances.

Maternal consumption of ethanol during pregnancy is known to increase the offspring's risk for developing alcohol use disorders and associated behavioral disturbances. Studies in adolescent and adult animals suggest the involvement of neuroimmune and neurochemical systems in the brain that control these behaviors. To understand the origin of these effects during early developmental stages, we examined in the embryo and neonate the effects of maternal intraoral administration of ethanol (2 g/kg/day) from embryonic day 10 (E10) to E15 on the inflammatory chemokine C-C motif ligand 2 (CCL2) and its receptor CCR2 in a specific, dense population of neurons in the lateral hypothalamus (LH), where they are closely related to an orexigenic neuropeptide, melanin-concentrating hormone (MCH), known to promote ethanol consumption and related behaviors. We found that prenatal ethanol exposure increases the expression and density of CCL2 and CCR2 cells along with MCH neurons in the LH and the colocalization of CCL2 with MCH. We also discovered that these effects are sexually dimorphic, consistently stronger in female embryos, and are blocked by maternal administration of a CCL2 antibody (1 and 5 mu g/day, i.p., E10-E15) that neutralizes endogenous CCL2 and of a CCR2 antagonist INCB3344 (1 mg/day, i.p., E10-E15) that blocks CCL2's main receptor. These results, which in the embryo anatomically and functionally link the CCL2/CCR2 system to MCH neurons in the LH, suggest an important role for this neuroimmune system in mediating ethanol's sexually dimorphic, stimulatory effect on MCH neurons that may promote higher level of alcohol consumption described in females. Published by Elsevier Ltd on behalf of IBRO.

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.