Characterization of an Nmr Homolog That Modulates GATA Factor-Mediated Nitrogen Metabolite Repression in Cryptococcus neoformans

Nitrogen source utilization plays a critical role in fungal development, secondary metabolite production and pathogenesis. In both the Ascomycota and Basidiomycota, GATA transcription factors globally activate the expression of catabolic enzyme-encoding genes required to degrade complex nitrogenous compounds. However, in the presence of preferred nitrogen sources such as ammonium, GATA factor activity is inhibited in some species through interaction with co-repressor Nmr proteins. This regulatory phenomenon, nitrogen metabolite repression, enables preferential utilization of readily assimilated nitrogen sources. In the basidiomycete pathogen Cryptococcus neoformans, the GATA factor Gat1/Are1 has been co-opted into regulating multiple key virulence traits in addition to nitrogen catabolism. Here, we further characterize Gat1/Are1 function and investigate the regulatory role of the predicted Nmr homolog Tar1. While GAT1/ARE1 expression is induced during nitrogen limitation, TAR1 transcription is unaffected by nitrogen availability. Deletion of TAR1 leads to inappropriate derepression of non-preferred nitrogen catabolic pathways in the simultaneous presence of favoured sources. In addition to exhibiting its evolutionary conserved role of inhibiting GATA factor activity under repressing conditions, Tar1 also positively regulates GAT1/ARE1 transcription under non-repressing conditions. The molecular mechanism by which Tar1 modulates nitrogen metabolite repression, however, remains open to speculation. Interaction between Tar1 and Gat1/Are1 was undetectable in a yeast two-hybrid assay, consistent with Tar1 and Gat1/Are1 each lacking the conserved C-terminus regions present in ascomycete Nmr proteins and GATA factors that are known to interact with each other. Importantly, both Tar1 and Gat1/Are1 are suppressors of C. neoformans virulence, reiterating and highlighting the paradigm of nitrogen regulation of pathogenesis

Comorbidity of opioid-related and anxiety-related symptoms and disorders

© 2019 Elsevier Ltd Opioid use disorder and anxiety disorders co-occur at strikingly high rates, and this comorbidity is marked by a more severe clinical presentation and poorer prognosis for treatment. Given the substantial morbidity and mortality associated with these two disorders, it is imperative to understand factors related to the high rates of co-occurrence in order to inform the development of specialized treatments for this population. Several lines of study suggest that simultaneously addressing opioid-related and anxiety-related symptoms and processes, particularly intolerance of distress and pain-related anxiety, may yield improved outcomes for this high risk, vulnerable population. Future work is needed to identify other novel mechanisms as well as develop specialized treatments to augment standard medication-assisted treatment

Pain severity as a predictor of negative affect following a self-guided quit attempt: An ecological momentary assessment study

<p><i>Background</i>: Past work has documented bidirectional associations between pain and cigarette smoking behaviors such that those who smoke evidence greater pain, and those in pain tend to smoke more. However, such work has not focused on the role of pain in relation to negative affect, which plays an important role during cessation attempts. <i>Objective</i>: The current study evaluated pain as a predictor of negative affect as well as level of interference associated with negative affect among individuals undergoing a self-guided quit attempt. <i>Methods</i>: Study variables were assessed via ecological momentary assessment (EMA) during the 2 weeks following a self-guided quit attempt. Participants included 54 daily smokers (33.3% female; <i>M</i>_age = 34.7, <i>SD</i> = 13.9). <i>Results</i>: There were statistically significant within-person associations of pain ratings with negative affect and interference due to negative affect, such that greater pain was associated with higher levels of each dependent variable. Additionally, there was a within-person effect of smoking status (i.e., smoking vs. abstinence, measured via EMA) on negative affect, but not ratings of interference; smoking was associated with greater negative affect. <i>Conclusion</i>: These findings highlight the importance of bodily pain in relation to negative mood following a quit attempt. Clinically, the results suggest a greater focus on the experience of pain during quit attempts may be warranted.</p

Using Social Media for Clinical Research: Recommendations and Examples From the Brown-Lifespan Center for Digital Health

Social media integration into research has increased, and 92% of American social media participants state they would share their data with researchers. Yet, the potential of these data to transform health outcomes has not been fully realized, and the way clinical research is performed has been held back. The use of these technologies in research is dependent on the investigators’ awareness of their potential and their ability to innovate within regulatory and institutional guidelines. The Brown-Lifespan Center for Digital Health has launched an initiative to address these challenges and provide a helpful framework to expand social media use in clinical research

Effect of a peer-led behavioral intervention for emergency department patients at high risk of fatal opioid overdose: a randomized clinical trial.

Importance Fatal and nonfatal opioid overdoses are at record levels, and emergency department (ED) visits may be an opportune time to intervene. Peer-led models of care are increasingly common; however, little is known about their effectiveness. Objective To evaluate the effect of a peer-led behavioral intervention compared with the standard behavioral intervention delivered in the ED on engagement in substance use disorder (SUD) treatment within 30 days after the ED encounter. Design, Setting, and Participants This randomized clinical trial recruited 648 patients from 2 EDs from November 15, 2018, to May 31, 2021. Patients were eligible to participate if they were in the ED for an opioid overdose, receiving treatment related to an opioid use disorder, or identified as having had a recent opioid overdose. Interventions Participants were randomly assigned to receive a behavioral intervention from a certified peer recovery specialist (n = 323) or a standard intervention delivered by a hospital-employed licensed clinical social worker (n = 325). A certified peer recovery specialist was someone with at least 2 years of recovery who completed a 45-hour training program and had 500 hours of supervised work experience. After the ED intervention, the certified peer recovery specialists offered continued contact with participants for up to 90 days. Main Outcomes and Measures The primary outcome was receipt of SUD treatment within 30 days of enrollment, assessed with deterministic linkage of statewide administrative databases. Treatment engagement was defined as admission to a formal, publicly licensed SUD treatment program or receipt of office-based medication for opioid use disorder within 30 days of the initial ED visit. Results Among the 648 participants, the mean (SD) age was 36.9 (10.8) years, and most were male (442 [68.2%]) and White (444 [68.5%]). Receipt of SUD treatment occurred for 103 of 323 participants (32%) in the intervention group vs 98 of 325 participants (30%) in the usual care group within 30 days of the ED visit. Among all participants, the most accessed treatments were outpatient medication for opioid use disorder (buprenorphine, 119 [18.4%]; methadone, 44 [6.8%]) and residential treatment (44 [6.8%]). Conclusions and Relevance Overall, this study found that a substantial proportion of participants in both groups engaged in SUD treatment within 30 days of the ED visit. An ED-based behavioral intervention is likely effective in promoting treatment engagement, but who delivers the intervention may be less influential on short-term outcomes. Further study is required to determine the effects on longer-term engagement in SUD care and other health outcomes (eg, recurrent overdose)