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CD4 T cell-dependent antibody responses are essential for limiting Plasmodium parasite replication and the severity of malaria; however, the factors that regulate humoral immunity during highly inflammatory, Th1-biased systemic infections are poorly understood. Using genetic and biochemical approaches, we show that Plasmodium infection-induced type I interferons limit T follicular helper accumulation and constrain anti-malarial humoral immunity. Mechanistically we show that CD4 T cell-intrinsic type I interferon signaling induces T-bet and Blimp-1 expression, thereby promoting T regulatory 1 responses. We further show that the secreted effector cytokines of T regulatory 1 cells, IL-10 and IFN-γ, collaborate to restrict T follicular helper accumulation, limit parasite-specific antibody responses, and diminish parasite control. This circuit of interferon-mediated Blimp-1 induction is also operational during chronic virus infection and can occur independently of IL-2 signaling. Thus, type I interferon-mediated induction of Blimp-1 and subsequent expansion of T regulatory 1 cells represent generalizable features of systemic, inflammatory Th1-biased viral and parasitic infections that are associated with suppression of humoral immunity.

Current primary cell models for HIV latency correlate poorly with the reactivation behavior of patient cells. We have developed a new model, called QUECEL, which generates a large and homogenous population of latently infected CD4 + memory cells. By purifying HIV-infected cells and inducing cell quiescence with a defined cocktail of cytokines, we have eliminated the largest problems with previous primary cell models of HIV latency: variable infection levels, ill-defined polarization states, and inefficient shutdown of cellular transcription. Latency reversal in the QUECEL model by a wide range of agents correlates strongly with RNA induction in patient samples. This scalable and highly reproducible model of HIV latency will permit detailed analysis of cellular mechanisms controlling HIV latency and reactivation. The latent HIV reservoir is generated following HIV infection of activated effector CD4 T cells, which then transition to a memory phenotype. Here, we describe an ex vivo method, called QUECEL ( qu iescent e ffector ce ll l atency), that mimics this process efficiently and allows production of large numbers of latently infected CD4 + T cells. Naïve CD4 + T cells were polarized into the four major T cell subsets (Th1, Th2, Th17, and Treg) and subsequently infected with a single-round reporter virus which expressed GFP/CD8a. The infected cells were purified and coerced into quiescence using a defined cocktail of cytokines, including tumor growth factor beta, interleukin-10 (IL-10), and IL-8, producing a homogeneous population of latently infected cells. Flow cytometry and transcriptome sequencing (RNA-Seq) demonstrated that the cells maintained the correct polarization phenotypes and had withdrawn from the cell cycle. Key pathways and gene sets enriched during transition from quiescence to reactivation include E2F targets, G 2 M checkpoint, estrogen response late gene expression, and c-myc targets. Reactivation of HIV by latency-reversing agents (LRAs) closely mimics RNA induction profiles seen in cells from well-suppressed HIV patient samples using the envelope detection of in vitro transcription sequencing (EDITS) assay. Since homogeneous populations of latently infected cells can be recovered, the QUECEL model has an excellent signal-to-noise ratio and has been extremely consistent and reproducible in numerous experiments performed during the last 4 years. The ease, efficiency, and accuracy of the mimicking of physiological conditions make the QUECEL model a robust and reproducible tool to study the molecular mechanisms underlying HIV latency. IMPORTANCE Current primary cell models for HIV latency correlate poorly with the reactivation behavior of patient cells. We have developed a new model, called QUECEL, which generates a large and homogenous population of latently infected CD4 + memory cells. By purifying HIV-infected cells and inducing cell quiescence with a defined cocktail of cytokines, we have eliminated the largest problems with previous primary cell models of HIV latency: variable infection levels, ill-defined polarization states, and inefficient shutdown of cellular transcription. Latency reversal in the QUECEL model by a wide range of agents correlates strongly with RNA induction in patient samples. This scalable and highly reproducible model of HIV latency will permit detailed analysis of cellular mechanisms controlling HIV latency and reactivation.

Influenza A virus (IAV) is a widespread infectious agent commonly found in mammalian and avian species. In humans, IAV is a respiratory pathogen that causes seasonal infections associated with significant morbidity in young and elderly populations, and has a large economic impact. Moreover, IAV has the potential to cause both zoonotic spillover infection and global pandemics, which have significantly greater morbidity and mortality across all ages. The pathology associated with these pandemic and spillover infections appear to be the result of an excessive inflammatory response leading to severe lung damage, which likely predisposes the lungs for secondary bacterial infections. The lung is protected from pathogens by alveolar epithelial cells, endothelial cells, tissue resident alveolar macrophages, dendritic cells, and mast cells. The importance of mast cells during bacterial and parasitic infections has been extensively studied; yet, the role of these hematopoietic cells during viral infections is only beginning to emerge. Recently, it has been shown that mast cells can be directly activated in response to IAV, releasing mediators such histamine, proteases, leukotrienes, inflammatory cytokines, and antiviral chemokines, which participate in the excessive inflammatory and pathological response observed during IAV infections. In this review, we will examine the relationship between mast cells and IAV, and discuss the role of mast cells as a potential drug target during highly pathological IAV infections. Finally, we proposed an emerging role for mast cells in other viral infections associated with significant host pathology.

The purpose of this study was to examine the associations among race and socioeconomic factors (receiving social security disability, insurance type, and income) with undergoing bariatric surgery and weight loss outcomes in a racially diverse, urban cohort of bariatric surgery candidates (N = 314). Patients with private insurance and who identified as Caucasian were more likely to undergo bariatric surgery. Income significantly predicted percentage of excess weight loss 1 year after surgery, although this was no longer significant when accounting for race. Race and socioeconomic factors should be considered during psychosocial evaluations to support patients at risk of surgical attrition and poorer weight loss outcomes. Future research should explore policy solutions to improve access, while qualitative work may help with understanding racial disparities in bariatric surgery.

Hearing loss places a substantial burden on medical resources across the world and impacts quality of life for those affected. Further, it can occur peripherally and/or centrally. With many possible causes of hearing loss, there is scope for investigating the underlying mechanisms involved. Various signaling pathways connecting gut microbes and the brain (the gut-brain axis) have been identified and well established in a variety of diseases and disorders. However, the role of these pathways in providing links to other parts of the body has not been explored in much depth. Therefore, the aim of this review is to explore potential underlying mechanisms that connect the auditory system to the gut-brain axis. Using select keywords in PubMed, and additional hand-searching in google scholar, relevant studies were identified. In this review we summarize the key players in the auditory-gut-brain axis under four subheadings: anatomical, extracellular, immune and dietary. Firstly, we identify important anatomical structures in the auditory-gut-brain axis, particularly highlighting a direct connection provided by the vagus nerve. Leading on from this we discuss several extracellular signaling pathways which might connect the ear, gut and brain. A link is established between inflammatory responses in the ear and gut microbiome-altering interventions, highlighting a contribution of the immune system. Finally, we discuss the contribution of diet to the auditory-gut-brain axis. Based on the reviewed literature, we propose numerous possible key players connecting the auditory system to the gut-brain axis. In the future, a more thorough investigation of these key players in animal models and human research may provide insight and assist in developing effective interventions for treating hearing loss.

To decarbonise the built environment, it is widely assumed that ‘fabric-first’ building upgrades are essential. An alternative, people-first approach is proposed that could deliver energy and carbon reductions at scale and speed. The approach begins by re-examining some rarely questioned assumptions around historical practices and building science. Physics and thermal physiology can inform a reassessment of the causes of thermal discomfort, and show why using air temperature alone as a measure of the thermal environment is inherently problematic. Historical sources reveal the forgotten ways people were made more comfortable in the days before space-conditioning. Together, these encourage a deeper examination of how buildings were constructed, maintained and operated prior to the Industrial Revolution. These insights can be harnessed to develop a practical new trajectory for building operation and retrofit. Preliminary results are reported from two ongoing UK field studies. Co-creation workshops and simple environmental monitoring are being used to encourage occupants to learn to ‘sail’ (i.e. passively manage) their own buildings more effectively to support their own needs. It is not yet possible to put numbers on the energy and carbon saved, but these early experiments may encourage professionals and policymakers to give much greater consideration to ‘people-first’ climate action. Policy relevance A common approach to decarbonising buildings is a focus on ‘fabric-first’ retrofits, which tend to be disruptive, carbon-intensive, expensive and will take decades to convert the stock. Feedback is also exposing disappointing savings, and risks to both building fabric and occupant health. This approach often seeks to update buildings to ‘modern’ standards, using models that have proved problematic, and frequently ignoring in-use performance. Conversely, a ‘people-first’ approach can empower occupants to identify what might improve things, trial simple interventions, and make rapid, low-risk alterations to improve their health and thermal comfort. This can draw on and adapt proven, low-cost historical methods. This alternative ‘soft’ approach uses facilitators to help occupants ‘learn to sail’ (i.e. effectively operate) buildings more effectively and sustainably. The insights will also enable any capital measures to be more precisely targeted.

With the pending implementation of the Closing the Gap 2020 recommendations, there is an urgent need to better understand the contributing factors of, and pathways to positive educational outcomes for both Aboriginal and non-Aboriginal children. This deeper understanding is particularly important in the Northern Territory (NT) of Australia, in which the majority of Aboriginal children lived in remote communities and have language backgrounds other than English (i.e. 75%). This study linked the Australian Early Development Census (AEDC) to the attendance data (i.e. government preschool and primary schools) and Year 3 National Assessment Program for Literacy and Numeracy (NAPLAN). Structural equation modelling was used to investigate the pathway from self-regulation and executive function (SR-EF) at age 5 to early academic achievement (i.e. Year 3 reading/numeracy at age 8) for 3,199 NT children. The study confirms the expected importance of SR-EF for all children but suggests the different pathways for Aboriginal and non-Aboriginal children. For non-Aboriginal children, there was a significant indirect effect of SR-EF (β = 0.38, p<0.001) on early academic achievement, mediated by early literacy/numeracy skills (at age 5). For Aboriginal children, there were significant indirect effects of SR-EF (β = 0.19, p<0.001) and preschool attendance (β = 0.20, p<0.001), mediated by early literacy/numeracy skills and early primary school attendance (i.e. Transition Years to Year 2 (age 5-7)). This study highlights the need for further investigation and development of culturally, linguistically and contextually responsive programs and policies to support SR-EF skills in the current Australian education context. There is a pressing need to better understand how current policies and programs enhance children and their families' sense of safety and support to nurture these skills. This study also confirms the critical importance of school attendance for improved educational outcomes of Aboriginal children. However, the factors contributing to non-attendance are complex, hence the solutions require multi-sectoral collaboration in place-based design for effective implementation.

Listeria monocytogenes (LM) is a gram-positive bacterium that is a common contaminant of processed meats and dairy products. In humans, ingestion of LM can result in intracellular infection of the spleen and liver, which can ultimately lead to septicemia, meningitis, and spontaneous abortion. Interleukin (IL)-23 is a cytokine that regulates innate and adaptive immune responses by inducing the production of IL-17A, IL-17F, and IL-22. We have recently demonstrated that the IL-23/IL-17 axis is required for optimal recruitment of neutrophils to the liver, but not the spleen, during LM infection. Furthermore, these cytokines are required for the clearance of LM during systemic infection. In other infectious models, IL-22 induces the secretion of anti-microbial peptides and protects tissues from damage by preventing apoptosis. However, the role of IL-22 has not been thoroughly investigated during LM infection. In the present study, we show that LM induces the production of IL-22 in vivo. Interestingly, IL-23 is required for the production of IL-22 during primary, but not secondary, LM infection. Our findings suggest that IL-22 is not required for clearance of LM during primary or secondary infection, using both systemic and mucosal models of infection. IL-22 is also not required for the protection of LM infected spleens and livers from organ damage. Collectively, these data indicate that IL-22 produced during LM infection must play a role other than clearance of LM or protection of tissues from pathogen- or immune-mediated damage.

To assess reliability and reproducibility of a recently instituted anesthesiology resident applicant interview scoring system at our own institution. Retrospective evaluation of 2 years of interview data with a newly implemented scoring system using randomly assigned interviewing faculty. Interview scoring evaluations were completed as standard practice in a large academic anesthesiology department. All anesthesiology resident applicants interviewed over the 2013/14 and 2014/15 seasons by a stable cohort of faculty interviewers. Data collection blinded for both interviewers and interviewees. None for purposes of study – collation of blinded data already used as standard practice during interview process and analysis. None specific to study. Good inter-rater faculty reliability of interview scoring (day-of) and excellent inter-faculty reliability of application review (pre-interview). Development of a department-specific interview scoring system including many elements beyond traditional standardized tests shows good-excellent reliability of faculty scoring of both the interview itself (including non-technical skills) and the application resume. •Evaluation of anesthesiology resident applicants is challenging.•We describe our departmental review process for the file application and interview.•Objective scoring is done by 2 randomly assigned faculty.•Inter-rater reproducibility was excellent between faculty.•Reliability and reproducibility of our scoring system are reassuring.