The rockefeller university

Facial and vocal cues provide critical social information about other humans, including their emotional and attentional states and the content of their speech. Recent work has shown that the face-responsive region of posterior superior temporal sulcus ("fSTS") also responds strongly to vocal sounds. Here, we investigate the functional role of this region and the broader STS by measuring responses to a range of face movements, vocal sounds, and hand movements using fMRI. We find that the fSTS responds broadly to different types of audio and visual face action, including both richly social communicative actions, as well as minimally social noncommunicative actions, ruling out hypotheses of specialization for processing speech signals, or communicative signals more generally. Strikingly, however, responses to hand movements were very low, whether communicative or not, indicating a specific role in the analysis of face actions (facial and vocal), not a general role in the perception of any human action. Furthermore, spatial patterns of response in this region were able to decode communicative from noncommunicative face actions, both within and across modality (facial/vocal cues), indicating sensitivity to an abstract social dimension. These functional properties of the fSTS contrast with a region of middle STS that has a selective, largely unimodal auditory response to speech sounds over both communicative and noncommunicative vocal nonspeech sounds, and nonvocal sounds. Region of interest analyses were corroborated by a data-driven independent component analysis, identifying face-voice and auditory speech responses as dominant sources of voxelwise variance across the STS. These results suggest that the STS contains separate processing streams for the audiovisual analysis of face actions and auditory speech processing.

Background: Hidradenitis suppurativa is an autoinflammatory disorder of keratinization, with dysregulation of T helper type 17 cytokines. Brodalumab is a monoclonal antibody that targets the interleukin (IL) 17 receptor A receptor. Objectives: To assess the safety and tolerability and clinical response at weeks 12 and 24 of brodalumab in moderate to severe HS. Ten participants with no history of inflammatory bowel disease were administered brodalumab 210 mg/1.5 mL subcutaneously at weeks 0, 1, and 2 and every 2 weeks thereafter until week 24. Participants were assessed for adverse events (grade 2/3 adverse events) and clinical response (Hidradenitis Suppurativa Clinical Response [ HiSCR], Sartorius, International Hidradenitis Suppurativa Severity Scoring System [IHS4]), including ultrasonography and skin biopsies. Results: All 10 participants completed the study. No grade 2/3 adverse events associated with the use of brodalumab were reported. All patients (100%) achieved HiSCR, and 80% achieved IHS4 category change at week 12. HiSCR achievement occurred as early as week 2, likely due to the unique blockade of IL-17A, IL-17C, and IL-17F by brodalumab. Significant improvements were seen in pain, itch, quality of life, and depression. Conclusions: Brodalumab was well tolerated in this HS cohort, with no serious adverse events and improvement in clinical outcomes. Alterations in dose frequency may be required in those with advanced disease, which requires further exploration.

Adolescence is a critical period of development with robust behavioral, morphological, hormonal, and neurochemical changes including changes in brain regions implicated in the reinforcing effects of drugs such as opioids. Here we examine the preclinical and, where appropriate complementary clinical literature, for the behavioral and neurological changes induced by adolescent opioid exposure/use and their long-term consequences during adulthood. Adolescent opioid exposure results in a widened biphasic shift in reinforcement with increased impact of positive rewarding aspects during initial use and profound negative reinforcement during adulthood. Females may have enhanced vulnerability due to fast onset of antinociceptive tolerance and reduced severity of somatic withdrawal symptoms during adolescence. Overall, adolescent opioid exposure, be it legally prescribed protracted intake or illicit consumption, results in significant and prolonged consequences of increased opioid reward concomitant with reduced analgesic efficacy and exacerbated somatic withdrawal severity during opioid use/exposure in adulthood. These findings are highly relevant to physicians, parents, law makers, and the general public as adolescent opioid exposure/misuse results in heightened risk for substance use disorders.

Yellow fever virus (YFV), a member of the Flaviviridae family, is an arthropod-borne virus that can cause severe disease in humans with a lethality rate of up to 60%. Since 2017, increases in YFV activity in areas of South America and Africa have been described. Although a vaccine is available, named strain 17D (Theiler and Smith, 1937), it is contraindicated for use in the elderly, expectant mothers, immunocompromised people, among others. To this day there is no antiviral treatment against YFV to reduce the severity of viral infection. Here, we used a circular polymerase extension reaction (CPER)-based reverse genetics approach to generate a full-length reporter virus (YFVhb) by introducing a small HiBit tag in the NS1 protein. The reporter virus replicates at a similar rate to the parental YFV in HuH-7 cells. Using YFVhb, we designed a high throughput antiviral screening luciferase-based assay to identify inhibitors that target any step of the viral replication cycle. We validated our assay by using a range of inhibitors including drugs, immune sera and neutralizing single chain variable fragments (scFv). In light of the recent upsurge in YFV and a potential spread of the virus, this assay is a further tool in the development of antiviral therapy against YFV.

Malignant gliomas are central nervous system tumors and remain among the most treatment-resistant cancers. Exome sequencing has revealed significant heterogeneity and important insights into the molecular pathogenesis of gliomas. Mutations in chromatin modifiers-proteins that shape the epigenomic landscape through remodeling and regulation of post-translational modifications on chromatin-are very frequent and often define specific glioma subtypes. This suggests that epigenomic reprogramming may be a fundamental driver of glioma. Here, we describe the key chromatin regulatory pathways disrupted in gliomas, delineating their physiological function and our current understanding of how their dysregulation may contribute to gliomagenesis.

BACKGROUND: Recent data suggest that patients with atopic dermatitis (AD) have increased systemic immune activation and cardiovascular risk. However, unlike psoriasis, evaluation of active vascular inflammation using state-of-the-art imaging is lacking in AD. OBJECTIVE: To assess aortic and carotid vascular inflammation using F-18-fluorodeoxyglucose-positron emission tomography/ magnetic resonance imaging (F-18-FDG-PET/MRI) imaging in moderate-to-severe AD versus healthy individuals. METHODS: A total of 27 patients with moderate-to-severe AD and 12 healthy controls were imaged using F-18-FDG-PET/MRI. Target-to-background ratio (TBR) values were calculated in multiple segments of the aorta and carotid vessels. RESULTS: Patients with AD had elevated aortic max TBR (fold change [FCH] = 1.45, P = .057) versus healthy controls and significantly elevated mean TBR (FCH = 1.20; P< .05) in the right carotid (RC) arteries versus controls. When examining greatest focal inflammation (most diseased segment [MDS] TBR), patients with AD had higher aortic inflammation (FCH = 1.28; P = .052). AD clinical severity significantly correlated with C-reactive protein (p = 0.60, P< .01) and with RC mean TBR levels (p = 0.60, P = .04). Stratifying patients into moderate-to-severe and very severe AD showed greater RC mean TBR in patients with very severe AD versus controls (FCH = 1.31; P = .02) and versus patients with moderate/severe AD (FCH = 1.23, P = .05). Aortic inflammation was also significantly greater in patients with very severe AD versus controls (max TBR: FCH = 1.6, P = .04; MDS TBR: FCH = 1.73, P = .03). CONCLUSIONS: This preliminary study is the first that establishes greater vascular (aorta and carotid) inflammation in moderate-to-severe AD versus healthy controls. Furthermore, very severe AD showed higher inflammation than both moderate/severe patients and healthy controls. Future studies with larger patient cohorts and evaluation before and after treatment are needed to determine the extent to which vascular inflammation in AD is modifiable. (C) 2020 American Academy of Allergy, Asthma & Immunology

We developed a first-of-kind dasatinib-derivative imaging agent, F-18-SKI-249380 (F-18-SKI), and validated its use for noninvasive in vivo tyrosine kinase-targeted tumor detection in preclinical models. In this study, we assessed the feasibility of using F-18-SKI for PET imaging in patients with malignancies. Methods: Five patients with a prior diagnosis of breast cancer, renal cell cancer, or leukemia underwent whole-body PET/CT imaging 90 min after injection of F-18-SKI (mean, 241.24 +/- 116.36 MBq) as part of a prospective study. In addition, patients underwent either a 30-min dynamic scan of the upper abdomen including, at least partly, cardiac left ventricle, liver, spleen, and kidney (n = 2) or three 10-min whole-body PET/CT scans (n = 3) immediately after injection and blood-based radioactivity measurements to determine the time course of tracer distribution and facilitate radiation dose estimates. A subset of 3 patients had a delayed whole-body PET/CT scan at 180 min. Biodistribution, dosimetry, and tumor uptake were quantified. Absorbed doses were calculated using OLINDA/EXM 1.0. Results: No adverse events occurred after injection of F-18-SKI. In total, 27 tumor lesions were analyzed, with a median SUVpeak of 1.4 (range, 0.7-2.3) and tumor-to-blood ratios of 1.6 (range, 0.8-2.5) at 90 min after injection. The intratumoral drug concentrations calculated for 4 reference lesions ranged from 0.03 to 0.07 nM. In all reference lesions, constant tracer accumulation was observed between 30 and 90 min after injection. A blood radioassay indicated that radiotracer clearance from blood and plasma was initially rapid (blood half-time, 1.31 +/- 0.81 min; plasma, 1.07 +/- 0.66 min; n = 4), followed variably by either a prolonged terminal phase (blood half-time, 285 +/- 148.49 min; plasma, 240 +/- 84.85 min; n = 2) or a small rise to a plateau (n = 2). Like dasatinib, F-18-SKI underwent extensive metabolism after administration, as evidenced by metabolite analysis. Radioactivity was predominantly cleared via the hepatobiliary route. The highest absorbed dose estimates (mGy/MBq) in normal tissues were to the right colon (0.167 +/- 0.04) and small intestine (0.153 +/- 0.03). The effective dose was 0.0258 mSv/MBq (SD, 0.0034 mSv/MBq). Conclusion: F-18-SKI demonstrated significant tumor uptake, distinct image contrast despite low injected doses, and rapid clearance from blood.

Background Population-based data on COVID-19 are essential for guiding policies. There are few such studies, particularly from low or middle-income countries. Brazil is currently a hotspot for COVID-19 globally. We aimed to investigate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody prevalence by city and according to sex, age, ethnicity group, and socioeconomic status, and compare seroprevalence estimates with official statistics on deaths and cases. Methods In this repeated cross-sectional study, we did two seroprevalence surveys in 133 sentinel cities in all Brazilian states. We randomly selected households and randomly selected one individual from all household members. We excluded children younger than 1 year. Presence of antibodies against SARS-CoV-2 was assessed using a lateral flow point-of-care test, the WONDFO SARS-CoV-2 Antibody Test (Wondfo Biotech, Guangzhou, China), using two drops of blood from finger prick samples. This lateral-flow assay detects IgG and IgM isotypes that are specific to the SARS-CoV-2 receptor binding domain of the spike protein. Participants also answered short questionnaires on sociodemographic information (sex, age, education, ethnicity, household size, and household assets) and compliance with physical distancing measures. Findings We included 25 025 participants in the first survey (May 14-21) and 31165 in the second (June 4-7). For the 83 (62%) cities with sample sizes of more than 200 participants in both surveys, the pooled seroprevalence increased from 1.9% (95% CI 1.7-2.1) to 3.1% (2.8-3.4). City-level prevalence ranged from 0% to 25.4% in both surveys. 11(69%) of 16 cities with prevalence above 2.0% in the first survey were located in a stretch along a 2000 km of the Amazon river in the northern region. In the second survey, we found 34 cities with prevalence above 2.0%, which included the same 11 Amazon cities plus 14 from the northeast region, where prevalence was increasing rapidly. Prevalence levels were lower in the south and centre-west, and intermediate in the southeast, where the highest level was found in Rio de Janeiro (7.5% [4.2-12.2]). In the second survey, prevalence was similar in men and women, but an increased prevalence was observed in participants aged 20-59 years and those living in crowded conditions (4.4% [3.5-5.6] for those living with households with six or more people). Prevalence among Indigenous people was 6.4% (4.1-9.4) compared with 1.4% (1.2-1.7) among White people. Prevalence in the poorest socioeconomic quintile was 3.7% (3- 2-4.3) compared with 1.7% (1.4-2-2) in the wealthiest quintile. Interpretation Antibody prevalence was highly heterogeneous by country region, with rapid initial escalation in Brazil's north and northeast. Prevalence is strongly associated with Indigenous ancestry and low socioeconomic status. These population subgroups are unlikely to be protected if the policy response to the pandemic by the national government continues to downplay scientific evidence. Copyright (C) 2020 The Author(s). Published by Elsevier Ltd.