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g., the caveolae-dependent and fast endophilin-mediated endocytosis pathways). Finally, we consider the possible function of arrestins recruited to GPCRs that are endocytosed independently of arrestins, including the catalytic arrestin activation paradigm. Technological improvements in recent years have advanced the field further, and, combined with the important implications of endocytosis on drug responses, this makes endocytosis an obvious parameter to include in molecular pharmacological characterization of ligand-GPCR interactions. SIGNIFICANCE STATEMENT G protein-coupled receptor (GPCR) endocytosis is an important means to terminate receptor signaling, and arrestins play a central role in the widely accepted classical paradigm of GPCR endocytosis. In contrast to the canonical arrestin-mediated internalization, an increasing number of GPCRs are found to be endocytosed via alternate pathways, and the process appears more diverse than the previously defined "one pathway fits all."Acute respiratory tract infections (ARIs) are a leading cause of ill-health and death globally. Individual or multiple micronutrients have been shown to modulate immune function and affect the risk and severity of a number of infectious diseases. We systematically reviewed the evidence on the impact of micronutrient supplements to reduce the occurrence of ARIs and shorten the duration of ARI symptoms among adults. Random effects meta-analyses were conducted to estimate the pooled effects of vitamin D, vitamin C, zinc and multiple micronutrient supplementation (MMS) on the occurrence of ARIs and the duration of ARI symptoms. Vitamin D supplementation reduced the risk of ARI (risk ratio (RR)=0.97; 95% CI 0.94 to 1.00; p=0.028) and shortened the duration of symptoms (per cent difference -6% (95% CI -9% to -2%; p=0.003)). The RR of vitamin D to prevent ARI was farther from the null when diagnosis was based on clinical diagnosis or laboratory testing, compared with self-report and when the loading dose was less then 60 000 IU. Vitamin C supplementation reduced the risk of ARIs (RR=0.96; 95% CI 0.93 to 0.99; p=0.01) and shortened the duration of symptoms (per cent difference -9% (95% CI -16% to -2%; p=0.014)). The effect of vitamin C on preventing ARI was stronger among men and in middle-income countries, compared with women and high-income countries, respectively. Zinc supplementation did not reduce the risk of ARIs but shortened the duration of symptoms substantially (per cent difference -47% (95% CI -73% to -21%; p=0.0004)). Our synthesis of global evidence from randomised controlled trials indicates that micronutrient supplements including zinc, vitamins C and D, and multiple micronutrient supplements may be modestly effective in preventing ARIs and improving their clinical course. Further research is warranted to better understand the effectiveness that individual or multiple micronutrients have on SARS-CoV-2 infection and treatment outcomes.<br /><br /> Global health conferences are important platforms for knowledge exchange, decision-making and personal and professional growth for attendees. Neocolonial patterns in global health at large and recent opinion reports indicate that stakeholders from low- and middle-income countries (LMICs) may be under-represented at such conferences. This study aims to describe the factors that impact LMIC representation at global health conferences.<br /><br /> A systematic review of articles reporting factors determining global health conference attendance was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Articles presenting conference demographics and data on the barriers and/or facilitators to attendance were included. [https://www.selleckchem.com/products/GSK690693.html find more] Articles were screened at title and abstract level by four independent reviewers. Eligible articles were read in full text, analysed and evaluated with a risk of bias assessment.<br /><br /> Among 8765 articles screened, 46 articles met inclusion criteria. Thematic analysisns and lower acceptance rates for research presentations. This may be mitigated by relocating conferences to visa-friendly countries, providing travel scholarships and developing mentorship programmes to enable LMIC researchers to participate in global conferences.<br /><br /> Early identification of children at risk of severe febrile illness can optimise referral, admission and treatment decisions, particularly in resource-limited settings. We aimed to identify prognostic clinical and laboratory factors that predict progression to severe disease in febrile children presenting from the community.<br /><br /> We systematically reviewed publications retrieved from MEDLINE, Web of Science and Embase between 31 May 1999 and 30 April 2020, supplemented by hand search of reference lists and consultation with an expert Technical Advisory Panel. Studies evaluating prognostic factors or clinical prediction models in children presenting from the community with febrile illnesses were eligible. The primary outcome was any objective measure of disease severity ascertained within 30 days of enrolment. We calculated unadjusted likelihood ratios (LRs) for comparison of prognostic factors, and compared clinical prediction models using the area under the receiver operating characteristic curves (AUROCs). Riatients are required to explore generalisability and develop data-driven tools to support patient prioritisation and triage at the community level.<br /><br /> CRD42019140542.<br /><br />CRD42019140542.As vice president, Joe Biden was the cancer advocate-in-chief. As president, he has a different public health crisis to deal with-COVID-19-but given Biden's passion for cancer research, many expect he will build on the previous Moonshot initiative with another push to accelerate the pace of progress in cancer control.<br /><br /> Use of high-flow nasal cannula (HFNC) for bronchiolitis has increased, but data describing the current use and impact of this therapy are limited. Our objective with this study was to describe the use of HFNC for bronchiolitis in a pediatric emergency department (ED) from 2013 to 2019 and to explore associations with clinical outcomes.<br /><br /> This was a retrospective cohort study of children aged 2 to 24 months with the diagnosis of bronchiolitis. The primary outcome was HFNC initiation in the ED. Secondary outcomes included admission rate, ICU (PICU) admission, transfer to PICU from floor, and endotracheal intubation. An adjusted interrupted times series analysis was performed to analyze changes in rates of primary and secondary outcomes over time.<br /><br /> In total 11 149 children met inclusion criteria; 902 (8.1%) were initiated on HFNC. The rate of HFNC initiation increased from 1.3% in 2012-2013 to 17.0% in 2018-2019 (<br /><br /> <br /><br /> ≤ .001). Less than 30% of children initiated on HFNC were hypoxic. There were no significant changes over time in rates of hospital admission, PICU admission, or PICU transfer, adjusting for clinical severity, seasonality, and provider variation. Intubation rate increased over the study period.<br /><br /> We found a 13-fold increase in HFNC use over a 6-year period with no evidence of improvement in clinically meaningful outcomes. Clinical benefit should be clearly defined before further expansion of the use of HFNC for bronchiolitis in the ED.<br /><br />We found a 13-fold increase in HFNC use over a 6-year period with no evidence of improvement in clinically meaningful outcomes. Clinical benefit should be clearly defined before further expansion of the use of HFNC for bronchiolitis in the ED.The default mode network (DMN) is often associated with representing semantic, social, and situational content of contexts and episodes. The DMN may therefore be important for contextual decision-making, through representing situational constraints and simulating common courses of events. Most decision-making paradigms, however, use symbolic stimuli and instead implicate cognitive control regions, such as the multiple demand (MD) system. This fMRI study aimed to contrast the brain mechanisms underlying decision-making based on rich naturalistic contexts or symbolic cues. While performing an ongoing task, 40 human participants (25 female) responded to different sounds. For one sound, the stimulus-response mapping was fixed; responses for the other sounds depended on the visual context either lifelike scenes or letter symbols, varying across participants. Despite minimal behavioral differences between the groups, posterior DMN regions showed increased activity during context-dependent decision-making using the ons based on symbolic cues, we find that both multiple demand regions and default mode regions may contribute to the cognitive control of behavior. Rich semantic context enhances representation not just of the context itself, but also of the contents of the decision that it controls. Dependence of a decision on naturalistic context can also reverse the common pattern of multiple demand regions responding more, and default mode regions responding less, to more difficult decisions.The dentate gyrus (DG) of the hippocampus is important for cognition and behavior. However, the circuits underlying these functions are unclear. DG mossy cells (MCs) are potentially important because of their excitatory synapses on the primary cell type, granule cells (GCs). However, MCs also activate GABAergic neurons, which inhibit GCs. We used viral delivery of designer receptors exclusively activated by designer drugs (DREADDs) in mice to implement a gain- and loss-of-function study of MCs in diverse behaviors. Using this approach, manipulations of MCs could bidirectionally regulate behavior. The results suggest that inhibiting MCs can reduce anxiety-like behavior and improve cognitive performance. However, not all cognitive or anxiety-related behaviors were influenced, suggesting specific roles of MCs in some, but not all, types of cognition and anxiety. Notably, several behaviors showed sex-specific effects, with females often showing more pronounced effects than the males. We also used the immediate ea, surprisingly, that activating MCs can lead to adverse behavioral outcomes, and inhibiting MCs have an opposite effect. Importantly, the results appeared to be task-dependent and showed that testing both sexes was important. Additional experiments indicated what MC and GC circuitry was involved. Together, the results suggest how MCs influence behaviors that involve the DG.The proinflammatory cytokine IFN-γ, which is chronically elevated in multiple sclerosis, induces pathologic quiescence in human oligodendrocyte progenitor cells (OPCs) via upregulation of the transcription factor PRRX1. In this study using animals of both sexes, we investigated the role of heparan sulfate proteoglycans in the modulation of IFN-γ signaling following demyelination. We found that IFN-γ profoundly impaired OPC proliferation and recruitment following adult spinal cord demyelination. IFN-γ-induced quiescence was mediated by direct signaling in OPCs as conditional genetic ablation of IFNγR1 (Ifngr1) in adult NG2+ OPCs completely abrogated these inhibitory effects. Intriguingly, OPC-specific IFN-γ signaling contributed to failed oligodendrocyte differentiation, which was associated with hyperactive Wnt/Bmp target gene expression in OPCs. We found that PI-88, a heparan sulfate mimetic, directly antagonized IFN-γ to rescue human OPC proliferation and differentiation in vitro and blocked the IFN-γ-mediated inhibitory effects on OPC recruitment in vivo Importantly, heparanase modulation by PI-88 or OGT2155 in demyelinated lesions rescued IFN-γ-mediated axonal damage and demyelination.