Insulin-dependent diabetes mellitus (IDDM) is thought to be an immunologically mediated disease resulting in the complete destruction of the insulin-producing islets of Langerhans. It has become increasingly clear that autoreactive T cells play a major role in the development and progression of this disease. In this study, we examined the role of the CD28/B7 costimulation pathway in the development and progression of autoimmune diabetes in the nonobese diabetic (NOD) mouse model. Female NOD mice treated at the onset of insulitis (2-4 wk of age) with CTLA4Ig immunoglobulin (Ig) (a soluble CD28 antagonist) or a monoclonal antibody (mAb) specific for B7-2 (a CD28 ligand) did not develop diabetes. However, neither of these treatments altered the disease process when administered late, at > 10 wk of age. Histological examination of islets from the various treatment groups showed that while CTLA4Ig and anti-B7-2 mAb treatment blocked the development of diabetes, these reagents had little effect on the development or severity of insulitis. Together these results suggest that blockade of costimulatory signals by CTLA4Ig or anti-B7-2 acts early in disease development, after insulitis but before the onset of frank diabetes. NOD mice were also treated with mAbs to another CD28 ligand, B7-1. In contrast to the previous results, the anti-B7-1 treatment significantly accelerated the development of disease in female mice and, most interestingly, induced diabetes in normally resistant male mice. A combination of anti-B7-1 and anti-B7-2 mAbs also resulted in an accelerated onset of diabetes, similar to that observed with anti-B7-1 mAb treatment alone, suggesting that anti-B7-1 mAb's effect was dominant. Furthermore, treatment with anti-B7-1 mAbs resulted in a more rapid and severe infiltrate. Finally, T cells isolated from the pancreas of these anti-B7-1-treated animals exhibited a more activated phenotype than T cells isolated from any of the other treatment groups. These studies demonstrate that costimulatory signals play an important role in the autoimmune process, and that different members of the B7 family have distinct regulatory functions during the development of autoimmune diabetes.

Bacterial vaginosis (BV) is a common vaginal syndrome associated with altered microflora that increases the risk of preterm delivery and acquisition of sexually transmitted diseases. The cause of BV is unknown although toll-like receptors (TLRs), that are central to innate immune responses, may be important. We evaluated associations between TLR SNPs and BV among HIV-1 infected and uninfected African women. Logistic regression was used to assess associations between SNPs (N=99) in TLRs 2-4, 7-9 and BV (as classified by Nugent's criteria). Among HIV-1 uninfected women, TLR7 rs5743737 and TLR7 rs1634323 were associated with a decreased risk of BV, whereas TLR7 rs179012 was associated with an increased risk. TLR2 SNP rs3804099 was associated with a decreased risk of BV among HIV-1 infected women. Our findings indicate that there may be differences in TLR association with BV among HIV-1 infected and HIV-1 uninfected women.

Youth represent a large proportion of new HIV infections worldwide, yet their utilization of HIV testing and counseling (HTC) remains low. Using the post-intervention, cross-sectional, population-based household survey done in 2011 as part of HPTN 043/NIMH Project Accept, a cluster-randomized trial of community mobilization and mobile HTC in South Africa (Soweto and KwaZulu Natal), Zimbabwe, Tanzania and Thailand, we evaluated age-related differences among socio-demographic and behavioral determinants of HTC in study participants by study arm, site, and gender. A multivariate logistic regression model was developed using complete individual data from 13,755 participants with recent HIV testing (prior 12 months) as the outcome. Youth (18-24 years) was not predictive of recent HTC, except for high-risk youth with multiple concurrent partners, who were less likely (aOR 0.75; 95% CI 0.61-0.92) to have recently been tested than youth reporting a single partner. Importantly, the intervention was successful in reaching men with site specific success ranging from aOR 1.27 (95% CI 1.05-1.53) in South Africa to aOR 2.30 in Thailand (95% CI 1.85-2.84). Finally, across a diverse range of settings, higher education (aOR 1.67; 95% CI 1.42, 1.96), higher socio-economic status (aOR 1.21; 95% CI 1.08-1.36), and marriage (aOR 1.55; 95% CI 1.37-1.75) were all predictive of recent HTC, which did not significantly vary across study arm, site, gender or age category (18-24 vs. 25-32 years).

The breast is a dynamic organ whose response to physiological and pathophysiological conditions alters its disease susceptibility, yet the specific effects of these clinical variables on cell state remain poorly annotated. We present a unified, high-resolution breast atlas by integrating single-cell RNA-seq, mass cytometry, and cyclic immunofluorescence, encompassing a myriad of states. We define cell subtypes within the alveolar, hormone-sensing, and basal epithelial lineages, delineating associations of several subtypes with cancer risk factors, including age, parity, and BRCA2 germline mutation. Of particular interest is a subset of alveolar cells termed basal-luminal (BL) cells, which exhibit poor transcriptional lineage fidelity, accumulate with age, and carry a gene signature associated with basal-like breast cancer. We further utilize a medium-depletion approach to identify molecular factors regulating cell-subtype proportion in organoids. Together, these data are a rich resource to elucidate diverse mammary cell states.

Airborne transmission of SARS-CoV-2 aerosol remains contentious. Importantly, whether cough or breath-generated bioaerosols can harbor viable and replicating virus remains largely unclarified. We performed size-fractionated aerosol sampling (Andersen cascade impactor) and evaluated viral culturability in human cell lines (infectiousness), viral genetics, and host immunity in ambulatory participants with COVID-19. Sixty-one percent (27/44) and 50% (22/44) of participants emitted variant-specific culture-positive aerosols <10μm and <5μm, respectively, for up to 9 days after symptom onset. Aerosol culturability is significantly associated with lower neutralizing antibody titers, and suppression of transcriptomic pathways related to innate immunity and the humoral response. A nasopharyngeal Ct <17 rules-in ~40% of aerosol culture-positives and identifies those who are probably highly infectious. A parsimonious three transcript blood-based biosignature is highly predictive of infectious aerosol generation (PPV > 95%). There is considerable heterogeneity in potential infectiousness i.e., only 29% of participants were probably highly infectious (produced culture-positive aerosols <5μm at ~6 days after symptom onset). These data, which comprehensively confirm variant-specific culturable SARS-CoV-2 in aerosol, inform the targeting of transmission-related interventions and public health containment strategies emphasizing improved ventilation.