T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription

T helper type 1 (Th1) development is facilitated by interrelated changes in key intracellular factors, particularly signal transducer and activator of transcription (STAT)4, T-bet, and GATA-3. Here we show that CD4+ cells from T-bet−/− mice are skewed toward Th2 differentiation by high endogenous GATA-3 levels but exhibit virtually normal Th1 differentiation provided that GATA-3 levels are regulated at an early stage by anti–interleukin (IL)-4 blockade of IL-4 receptor (R) signaling. In addition, under these conditions, Th1 cells from T-bet−/− mice manifest IFNG promotor accessibility as detected by histone acetylation and deoxyribonuclease I hypersensitivity. In related studies, we show that the negative effect of GATA-3 on Th1 differentiation in T-bet−/− cells arises from its ability to suppress STAT4 levels, because if this is prevented by a STAT4-expressing retrovirus, normal Th1 differentiation is observed. Finally, we show that retroviral T-bet expression in developing and established Th2 cells leads to down-regulation of GATA-3 levels. These findings lead to a model of T cell differentiation that holds that naive T cells tend toward Th2 differentiation through induction of GATA-3 and subsequent down-regulation of STAT4/IL-12Rβ2 chain unless GATA-3 levels or function is regulated by T-bet. Thus, the principal function of T-bet in developing Th1 cells is to negatively regulate GATA-3 rather than to positively regulate the IFNG gene

Track A Basic Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138319/1/jia218438.pd

LILRB2 Interaction with HLA Class I Correlates with Control of HIV-1 Infection.

Natural progression of HIV-1 infection depends on genetic variation in the human major histocompatibility complex (MHC) class I locus, and the CD8+ T cell response is thought to be a primary mechanism of this effect. However, polymorphism within the MHC may also alter innate immune activity against human immunodeficiency virus type 1 (HIV-1) by changing interactions of human leukocyte antigen (HLA) class I molecules with leukocyte immunoglobulin-like receptors (LILR), a group of immunoregulatory receptors mainly expressed on myelomonocytic cells including dendritic cells (DCs). We used previously characterized HLA allotype-specific binding capacities of LILRB1 and LILRB2 as well as data from a large cohort of HIV-1-infected individuals (N = 5126) to test whether LILR-HLA class I interactions influence viral load in HIV-1 infection. Our analyses in persons of European descent, the largest ethnic group examined, show that the effect of HLA-B alleles on HIV-1 control correlates with the binding strength between corresponding HLA-B allotypes and LILRB2 (p = 10-2). Moreover, overall binding strength of LILRB2 to classical HLA class I allotypes, defined by the HLA-A/B/C genotypes in each patient, positively associates with viral replication in the absence of therapy in patients of both European (p = 10-11-10-9) and African (p = 10-5-10-3) descent. This effect appears to be driven by variations in LILRB2 binding affinities to HLA-B and is independent of individual class I allelic effects that are not related to the LILRB2 function. Correspondingly, in vitro experiments suggest that strong LILRB2-HLA binding negatively affects antigen-presenting properties of DCs. Thus, we propose an impact of LILRB2 on HIV-1 disease outcomes through altered regulation of DCs by LILRB2-HLA engagement

Elevated protein concentrations in newborn blood and the risks of autism spectrum disorder, and of social impairment, at age 10 years among infants born before the 28th week of gestation

Among the 1 of 10 children who are born preterm annually in the United States, 6% are born before the third trimester. Among children who survive birth before the 28th week of gestation, the risks of autism spectrum disorder (ASD) and non-autistic social impairment are severalfold higher than in the general population. We examined the relationship between top quartile inflammation-related protein concentrations among children born extremely preterm and ASD or, separately, a high score on the Social Responsiveness Scale (SRS total score ≥65) among those who did not meet ASD criteria, using information only from the subset of children whose DAS-II verbal or non-verbal IQ was ≥70, who were assessed for ASD, and who had proteins measured in blood collected on ≥2 days (N = 763). ASD (N = 36) assessed at age 10 years is associated with recurrent top quartile concentrations of inflammation-related proteins during the first post-natal month (e.g., SAA odds ratio (OR); 95% confidence interval (CI): 2.5; 1.2–5.3) and IL-6 (OR; 95% CI: 2.6; 1.03–6.4)). Top quartile concentrations of neurotrophic proteins appear to moderate the increased risk of ASD associated with repeated top quartile concentrations of inflammation-related proteins. High (top quartile) concentrations of SAA are associated with elevated risk of ASD (2.8; 1.2–6.7) when Ang-1 concentrations are below the top quartile, but not when Ang-1 concentrations are high (1.3; 0.3–5.8). Similarly, high concentrations of TNF-α are associated with heightened risk of SRS-defined social impairment (N = 130) (2.0; 1.1–3.8) when ANG-1 concentrations are not high, but not when ANG-1 concentrations are elevated (0.5; 0.1–4.2)

Nonequilibrium carrier dynamics and gain in semiconductor quantum wells

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Primary care providers' perceptions of mobile store-and-forward teledermatology

Introduction: Although teledermatology offers promise as a tool to increase access to care, adoption has been limited. Understanding the perspectives and experiences of key stakeholders, such as primary care providers (PCPs) and patients, is important to identify opportunities to reduce barriers to adoption and to improve teledermatology programs. Although many studies have examined patients’ experiences and satisfaction with teledermatology, few have examined referring PCPs’ perspectives.Objective: To identify PCPs’ perceptions on the strengths and limitations of teledermatology in order to identify opportunities to improve teledermatology programs.Methods: We distributed an anonymous, web-based survey to 30 PCPs involved in a two-year study evaluating a mobile app-based teledermatology platform.Results: 100% (18/18) agreed or strongly agreed that teledermatology increases access to dermatologic care, improves patient care, and is acceptable to patients. 100% (18/18) agreed or strongly agreed that teledermatology provides educational benefit to the PCP. Only 6% (1/18) agreed that teledermatology increases medical liability and 11% (2/18) agreed that it increases risk of a breach in privacy or confidentiality.Conclusions: Our findings highlight that PCPs are highly satisfied with mobile app-based, store-and-forward teledermatology and that they believe teledermatology offers synergistic educational benefit. We hope these results will help guide the development of teledermatology programs to increase access to timely, cost-effective care

Primary care providers' perceptions of mobile store-and-forward teledermatology

Introduction: Although teledermatology offers promise as a tool to increase access to care, adoption has been limited. Understanding the perspectives and experiences of key stakeholders, such as primary care providers (PCPs) and patients, is important to identify opportunities to reduce barriers to adoption and to improve teledermatology programs. Although many studies have examined patients’ experiences and satisfaction with teledermatology, few have examined referring PCPs’ perspectives.Objective: To identify PCPs’ perceptions on the strengths and limitations of teledermatology in order to identify opportunities to improve teledermatology programs.Methods: We distributed an anonymous, web-based survey to 30 PCPs involved in a two-year study evaluating a mobile app-based teledermatology platform.Results: 100% (18/18) agreed or strongly agreed that teledermatology increases access to dermatologic care, improves patient care, and is acceptable to patients. 100% (18/18) agreed or strongly agreed that teledermatology provides educational benefit to the PCP. Only 6% (1/18) agreed that teledermatology increases medical liability and 11% (2/18) agreed that it increases risk of a breach in privacy or confidentiality.Conclusions: Our findings highlight that PCPs are highly satisfied with mobile app-based, store-and-forward teledermatology and that they believe teledermatology offers synergistic educational benefit. We hope these results will help guide the development of teledermatology programs to increase access to timely, cost-effective care

Whole exome sequencing and the clinician: we need clinical skills and functional validation in variant filtering

- Introduction - The problems of reuse in polymer composites - Plastic waste disposal into other materials - Mechanical recycling of polymeric matrix composites - Recovery techniques - Properties of recovered fibres - Future strategies for making polymer matrix composites more recyclable - Conclusions - Sources of further information and advice - References - Appendix: abbreviation

Data on serologic inflammatory biomarkers assessed using multiplex assays and host characteristics in the Multicenter AIDS Cohort Study (MACS)

This article contains data on the associations between fixed and modifiable host characteristics and twenty-three biomarkers of inflammation and immune activation measured longitudinally in a cohort of 250 HIV-uninfected men from the Multicenter AIDS Cohort Study (1984–2009) after adjusting for age, study site, and blood draw time of day using generalized gamma regression. This article also presents associations between each biomarker and each host characteristic in a sample restricted to 2001–2009. These data are supplemental to our original research article entitled “Host factors associated with serologic inflammatory markers assessed using multiplex assays” (McKay, S. Heather, Bream, H. Jay, Margolick, B. Joseph, Martínez-Maza, Otoniel, Phair, P. John, Rinaldo, R. Charles, Abraham, G. Alison, L.P. Jacobson, 2016) [1]