95038 research outputs found
Sort by
Molecular mechanisms of inverse agonism via κ-opioid receptor–G protein complexes
Get PDFOpioid receptors, a subfamily of G protein-coupled receptors (GPCRs), are key therapeutic targets. In the canonical GPCR activation model, agonist binding is required for receptor–G protein complex formation, while antagonists prevent G protein coupling. However, many GPCRs exhibit basal activity, allowing G protein association without an agonist. The pharmacological impact of agonist-free receptor–G protein complexes is poorly understood. Here we present biochemical evidence that certain κ-opioid receptor (KOR) inverse agonists can act via KOR–Gi protein complexes. To investigate this phenomenon, we determined cryo-EM structures of KOR–Gi protein complexes with three inverse agonists: JDTic, norBNI and GB18, corresponding to structures of inverse agonist-bound GPCR–G protein complexes. Remarkably, the orthosteric binding pocket resembles the G protein-free ‘inactive’ receptor conformation, while the receptor remains coupled to the G protein. In summary, our work challenges the canonical model of receptor antagonism and offers crucial insights into GPCR pharmacology
Lifetime of ground conformational state determines the activity of structured RNA
Get PDFBiomolecules continually sample alternative conformations. Consequently, even the most energetically favored ground conformational state has a finite lifetime. Here, we show that, in addition to the three-dimensional (3D) structure, the lifetime of a ground conformational state determines its biological activity. Using hydrogen–deuterium exchange nuclear magnetic resonance spectroscopy, we found that Zika virus exoribonuclease-resistant RNA (xrRNA) encodes a ground conformational state with a lifetime that is ~105–107 longer than that of canonical base pairs. Mutations that shorten the apparent lifetime of the ground state without affecting its 3D structure decreased exoribonuclease resistance in vitro and impaired virus replication in cells. Additionally, we observed this exceptionally long-lived ground state in xrRNAs from diverse infectious mosquito-borne flaviviruses. These results demonstrate the biological importance of the lifetime of a preorganized ground state and further suggest that elucidating the lifetimes of dominant 3D structures of biomolecules may be crucial for understanding their behaviors and functions
Psychedelic compounds directly excite 5-HT2A layer V medial prefrontal cortex neurons through 5-HT2A Gq activation
Get PDFPsilocybin, and its active metabolite psilocin, have seen renewed interest due to studies suggesting potential therapeutic utility. 5-Hydroxytryptamine2A receptors (5-HT2ARs) are primary mediators of the psychoactive effects of psychedelics in animals and humans, but the underlying neurobiological mechanisms remain poorly understood. Functional magnetic resonance imaging identified significant psilocin-induced increases in medial prefrontal cortex (mPFC) activity, a site of enriched 5-HT2AR expression. We identified a population of 5-HT2AR neurons in the prelimbic/anterior cingulate mPFC. Psilocin and the 5-HT2AR-selective compound 25-CN-NBOH increased excitability, and stimulated firing across a range of current injections in these neurons that was both 5-HT2AR and Gαq dependent. Similar effects were observed with a novel, non-hallucinogenic psychedelic compound. These findings provide valuable insight into the specific role of 5-HT2AR-containing neurons in psychedelic-associated plasticity in mPFC regions that are likely implicated in the clinical effects of psychedelics and further identify membrane-bound 5-HT2ARs and subsequent intracellular Gαq signaling as therapeutic targets
Variational Autoencoder-based Model Improves Polygenic Prediction in Blood Cell Traits
Get PDFGenetic prediction of complex traits, enabled by large-scale genomic studies, has created new measures to understand individual genetic predisposition. Polygenic Risk Scores (PRS) offer a way to aggregate information across the genome, enabling personalized risk prediction for complex traits and diseases. However, conventional PRS calculation methods that rely on linear models are limited in their ability to capture complex patterns and interaction effects in high-dimensional genomic data. In this study, we seek to improve the predictive power of PRS through applying advanced deep learning techniques. We show that the Variational AutoEncoder-based model for PRS construction (VAE-PRS) outperforms currently state-of-the-art methods for biobank-level data in 14 out of 16 blood cell traits, while being computationally efficient. Through comprehensive experiments, we found that the VAE-PRS model offers the ability to capture interaction effects in high-dimensional data and shows robust performance across different pre-screened variant sets. Furthermore, VAE-PRS is easily interpretable via assessing the contribution of each individual marker to the final prediction score through the SHapley Additive exPlanations (SHAP) method, providing potential new insights in identifying trait-associated genetic variants. In summary, VAE-PRS presents a measure to genetic risk prediction for blood cell traits by harnessing the power of deep learning methods given appropriate training sample size, which could further facilitate the development of personalized medicine and genetic research
Sex-dependent responses in mice to indomethacin-induced organ injury and gut microbiome-targeted alleviation
Get PDFNonsteroidal anti-inflammatory drugs (NSAIDs) are used widely but produce gastrointestinal (GI) toxicities in both short- and long-term users. Previous studies have shown that the intestinal microbiota play an important role in gut damage and that gut microbial β-glucuronidase (GUS) inhibitors can alleviate NSAID-induced injury in male mice by blocking the GI reactivation of NSAID-glucuronides. Here, in both male and female C57BL/6 mice, we examine the effects of indomethacin alone and with the GUS inhibitor UNC10201652. Oral delivery of 5 mg/kg body weight indomethacin over 5 days decreased body weight, induced colonic and hepatic inflammatory cytokine gene expression, and enlarged the spleens of both male and female mice. However, sex-specific inflammatory responses to indomethacin were observed, with males demonstrating more colonic injury while females presented greater splenic and hepatic toxic responses. Females also showed a unique indomethacin-induced bloom of fecal Verrucomicrobia as measured by 16S rRNA metagenomic sequencing. UNC10201652 alleviated aspects of these indomethacin-induced toxicities, including features of the male-specific colonic damage and the female-specific compositional changes and spleen and liver toxicities. Thus, GI and non-GI tissues in male and female mice respond distinctly to indomethacin-induced damage. These findings advance our understanding of how sex impacts systemic responses to xenobiotic exposure and may lead to improved therapeutic outcomes with these widely used drugs
The association between childhood exposure to local wealth inequality and intergenerational income mobility in the United States
Get PDFPrevious research has documented that income inequality is negatively associated with intergenerational income mobility. Beyond income, wealth is also distributed unequally. However, a lack of comprehensive wealth data has meant that the link between wealth inequality and upward mobility in income remains unclear. This study examines this association using a recently published database of local wealth inequality estimates (GEOWEALTH-US) as well as upward mobility estimates published by Opportunity Insights. Results from linear models estimated by OLS reveal a negative association between childhood exposure to local wealth inequality at the commuting zone level (N = 724) and mobility outcomes later in life. Static simulations show that local wealth inequality is more strongly associated with upward income mobility than income inequality itself. One channel through which local wealth inequality may be associated with lower upward mobility is its correlation with reduced educational attainment among children from families with a low income
Mental healthcare practices from entry to release across Southeastern jails
Get PDFBackground Individuals with mental illnesses are disproportionately incarcerated in jails, which have become de facto mental health institutions across the US. Yet there is limited research describing mental healthcare practices from entry to release among multiple jails and states. Methods We conducted 34 semi-structured interviews with jail healthcare personnel across five Southeastern states and used the Framework Method to guide analyses. Results We report results on challenges and practices related to mental health staffing, screening, additional evaluations and services, and discharge planning in jails. Initial mental health screenings were often restricted to the detection of suicidality and history of treatment and medications as opposed to current mental health symptoms. Use of validated mental health screening forms was uncommon. We found delays in care between the initial health screening and being evaluated by a mental health professional. Most jails reported primary responsibilities for mental healthcare as preventing suicides and managing psychiatric medications. Jails reported mental healthcare as challenging to manage, with high volumes of individuals with mental health needs, yet limited resources, especially regarding staffing. Discharge planning was limited despite reports of poor continuity of mental health services. Conclusions Jails have a constitutional duty to provide adequate healthcare to individuals with mental illnesses, yet practices are insufficient and resources are limited across jails. Based on our findings, we recommend 1) greater adoption and revisions of jail health standards 2) system improvement that expands identification of mental illnesses and quicker, less variable follow-up mental health evaluations, 3) improved linkages and supports for community resources that prevent incarceration of this population
Neurocognitive disorders, depression, and associated factors in younger and older adults from an urban‐marginalized area of Peru
Get PDFINTRODUCTION: In urban-marginalized areas of low-to-middle-income countries (LMICs), neurocognitive disorders (NCDs) and depression present significant public health issues, exacerbated by socioeconomic disparities. METHODS: This study explores the prevalence and risk factors of NCDs and depression among 1064 community-dwelling adults in an urban-marginalized district of Lima, Peru. Structured questionnaires collected demographic, health, and socioeconomic data; neurocognitive assessments and depression screening were conducted. RESULTS: Mean age was 50.5 years, with 71% female, and a mean of 9.1 years of education. Among older adults, 32% had mild NCD and 4.2% had major NCD; 21.1% of younger adults had any NCD. Nearly 40% of the cohort was depressed. Risk factors for MCI and NCD included lower education, hypertension, and non-Spanish native language, while depression was associated with female sex, lower education, overcrowding, and chronic diseases. DISCUSSION: The study emphasizes the need for targeted interventions to address NCDs and mental health in urban-marginalized areas of LMICs. HIGHLIGHTS: Among older adults, 32% had mild neurocognitive disorder (NCD) and 4.2% had major NCD; 21.1% of younger adults had any NCD. Nearly 40% of the cohort was depressed. Risk factors for mild cognitive impairment (MCI) and NCD included lower education, hypertension, and non-Spanish native language, while depression was associated with female sex, lower education, overcrowding, and chronic diseases
[Community Classroom] Behind the Numbers - Falling Overdose Rates and Drug Supply Changes
No full textBehind the Numbers: Falling Overdose Rates and Drug Supply Changes
Nabarun (Nab) Dasgupta, MPH, Ph.D., Senior Scientist, UNC Injury Prevention Research Center, Innovation Fellow, UNC Gillings School of Global Public Health
Thursday, October 23, 2025 | 6:30 – 8:00 PM
Drug overdose deaths have devastated communities for decades, but innovative work at UNC is helping turn the tide. Join Dr. Nabarun Dasgupta, a national leader in overdose prevention, for an eye-opening look at how science and community partnerships are saving lives. Dr. Dasgupta directs the UNC Street Drug Analysis Lab, a groundbreaking public service that tests the street drug supply with atomic precision. On October 8, Dr. Dasgupta was recognized for his work, receiving a 2025 MacArthur Fellowship award from the John D. and Catherine T. MacArthur Foundation.
Learn more about Falling Overdose Rates and Drug Supply Change
Impact of mouse tracheal basal cell expansion medium on formation and metabolic characteristics of tracheospheres
Get PDFBackground Airway basal cells have been shown to play important roles in lung disease, prompting their use in research involving 3-dimensional (3D) organoid culture. Mouse tracheal basal cells (MTBC) represent a key model in understanding the differentiation of airway basal cells in normal development and diseased states. The isolation, expansion, and culture media of basal cells can affect their capacity to maintain stemness and properly differentiate, thereby introducing unknown experimental variables. As MTBC use in 3D organoid culture proceeds, there is an increasing need for comparative studies to identify unknown experimental variables. In this study, we examined the effects of MTBC expansion media on the differentiation and tracheosphere-forming ability in 3D culture. Methods MTBC were isolated from mouse tracheas, and three commonly used airway basal cell media were compared during MTBC expansion in cell culture (hereafter referred to as Media 1, 2, and 3). Following expansion, MTBC were cultured identically in 3D conditions to analyze tracheosphere-forming capability. Image analyses were performed to characterize tracheosphere count, size, and morphology, while metabolic and transcriptomic signatures were analyzed to assess MTBC differentiation in 3D culture. Results Expansion of MTBC in the three distinct media resulted in subsequent 3D tracheospheres that displayed unique metabolite and gene expression profiles, accompanied by overall changes in tracheosphere count and size. MTBC expanded in Medium 1 displayed lower levels of TCA cycle intermediates, along with lowered expression of differentiation markers Foxj1 and Scgb1a1, compared to MTBC expanded in Media 2 or 3. Pathway analysis showed an upregulation of idiopathic pulmonary fibrosis signaling pathways in tracheospheres cultured from MTBC expanded in Media 2 or 3. Conclusion This study identified several key differences in tracheosphere-forming ability of MTBC resulting from MTBC expansion media and highlights the importance of transparency in cell culture protocols, particularly those involving stem cells or 3D culture. Supplementary Information The online version contains supplementary material available at 10.1186/s12860-025-00554-8