A negative feedback loop mediated by the Bcl6-cullin 3 complex limits Tfh cell differentiation

Induction of Bcl6 (B cell lymphoma 6) is essential for T follicular helper (Tfh) cell differentiation of antigen-stimulated CD4(+) T cells. Intriguingly, we found that Bcl6 was also highly and transiently expressed during the CD4(+)CD8(+) (double positive [DP]) stage of T cell development, in association with the E3 ligase cullin 3 (Cul3), a novel binding partner of Bcl6 which ubiquitinates histone proteins. DP stage-specific deletion of the E3 ligase Cul3, or of Bcl6, induced the derepression of the Bcl6 target genes Batf (basic leucine zipper transcription factor, ATF-like) and Bcl6, in part through epigenetic modifications of CD4(+) single-positive thymocytes. Although they maintained an apparently normal phenotype after emigration, they expressed increased amounts of Batf and Bcl6 at basal state and produced explosive and prolonged Tfh responses upon subsequent antigen encounter. Ablation of Cul3 in mature CD4(+) splenocytes also resulted in dramatically exaggerated Tfh responses. Thus, although previous studies have emphasized the essential role of Bcl6 in inducing Tfh responses, our findings reveal that Bcl6-Cul3 complexes also provide essential negative feedback regulation during both thymocyte development and T cell activation to restrain excessive Tfh responses

HIV medication adherence, substance use, sexual risk behaviors and psychological distress among younger black men who have sex with men and transgender women: Preliminary findings

Background: In the United Sates, young Black men who have sex with men and transgender women (YBMSM/TW) ages 16 to 29 bear the highest burden of new HIV infections. HIV medication adherence is critical for maintaining the quality of life for infected persons, supporting secondary prevention efforts and reducing community viral loads. However, few studies have examined the relationship between medication adherence and health related factors such as substance use, sexual risk behaviors and psychological distress symptoms among YBMSM/TW. This represents the primary focus of this exploratory study. Methods: Baseline data is from Project nGage, a RCT that enrolled 86 newly diagnosed YBMSM/TW (ages 18-29). Measures on medication adherence, substance use, sexual risks behaviors and psychological distress symptoms were assessed. Results: Study findings indicated that medication adherence was related to less alcohol use, alcohol desire, alcohol compulsion, and having a partner who used marijuana as a sex drug. Findings also indicated that medication adherence was related to decreased feelings of psychological distress. Study findings did not indicate any relationship between medication adherence and group or unprotected anal sex. Conclusion: Our study findings indicated that HIV medication adherence, among YBMSM/TW was a significant correlate of lower substance use and psychological distress, and that service providers may enhance such gains by promoting medication adherence

Low-dose aspirin and racial disparities in spontaneous preterm delivery in low-risk individuals

Preterm birth is a leading cause of perinatal morbidity and mortality. There are significant racial disparities in the rates of preterm delivery in the United States, with Black individuals at disproportionately higher risk than their White counterparts. Although low-dose aspirin is currently under investigation for reducing the rates of preterm delivery, limited data are available on how the use of low-dose aspirin might affect racial and ethnic disparities in the rates of preterm delivery. Our group and others have shown that low-dose aspirin decreases spontaneous preterm delivery in low-risk parturients. This study aimed to examine whether the relationship between low-dose aspirin and the risk of spontaneous preterm delivery is modified by race and ethnicity. This was a secondary analysis of a randomized clinical trial examining low-dose aspirin for preeclampsia prevention in low-risk nulliparous individuals. The parent trial defined low risk as the absence of preexisting hypertension or other medical comorbidities. Participants received 60-mg aspirin or placebo between 13 and 25 weeks of gestation. Here, multiple pregnancies, fetal anomalies, terminations or abortions at <20 weeks of gestation, and participants with previous miscarriages were excluded. Our exposure, race and ethnicity, was self-reported in the parent trial and categorized as non-Hispanic White, Hispanic, non-Hispanic Black, and other. The primary outcome was spontaneous preterm delivery at <34 weeks of gestation; the secondary outcomes included spontaneous preterm delivery at <37 weeks of gestation and all preterm deliveries at <34 and <37 weeks of gestation. Fit logistic regression models were used to examine how the use of low-dose aspirin modified the relationship between race and ethnicity and preterm delivery, adjusting for confounders. Furthermore, sensitivity analyses were performed to compare the rates of preterm delivery by race and ethnicity. Of note, 2528 of 3171 parent study participants were included in this analysis. Of the participants, 425 (16.8%) were White, 819 (32.4%) were Hispanic, 1265 (50%) were Black, and 19 (0.8%) were other. The baseline characteristics differed among racial and ethnic groups, including maternal age, body mass index, education level, marital status, tobacco and alcohol use, and pregnancy loss. The rate of spontaneous preterm delivery at <34 weeks of gestation was significantly higher in Black participants (2.8%) than in White (1.2%) and Hispanic (1.2%) participants (P=.04). Logistical regression analysis showed that Black race was no longer an independent risk factor for spontaneous preterm delivery at <34 weeks of gestation when controlling for low-dose aspirin (adjusted odds ratio, 1.71; 95% confidence interval, 0.67-4.40). A similar pattern was found for spontaneous preterm delivery at <37 weeks of gestation and preterm delivery at <34 and <37 weeks of gestation. In our sensitivity analyses, spontaneous preterm delivery at <34 weeks of gestation differed by race and ethnicity in the placebo group (P=.01) but did not differ in the low-dose aspirin group (P=.90). The use of low-dose aspirin mitigated racial disparities in spontaneous preterm delivery at <34 weeks of gestation. Additional investigation is warranted to assess the reproducibility of our findings