Understanding the effects of oxytocin receptor variants on OXT-OXT receptor binding: A mathematical model.

Approximately half of U.S. women giving birth annually receive Pitocin, the synthetic form of oxytocin (OXT), yet its effective dose can vary significantly. This variability presents safety concerns due to unpredictable responses, which may lead to adverse outcomes for both mother and baby. To address the need for improved dosing, we developed a data-driven mathematical model to predict OXT receptor (OXTR) binding. Our study focuses on five prevalent OXTR variants (V45L, P108A, L206V, V281M, and E339K) and their impact on OXT-OXTR binding dynamics in two distinct cell types: human embryonic kidney cells (HEK293T), commonly used in experimental systems, and human myometrial smooth muscle cells, containing endogenous OXTR. We parameterized the model with cell-specific OXTR surface localization measurements. To strengthen the robustness of our study, we conducted a comprehensive meta-analysis of OXT- OXTR binding, enabling parameterization of our model with cell-specific OXT-OXTR binding kinetics (myometrial OXT-OXTR K d = 1.6 nM, kon = 6.8 × 10 5 M -1 min -1 , and koff = 0.0011 min -1 ). Our meta-analysis revealed significant homogeneity in OXT-OXTR affinity across experiments and species with a K d = 0.52 - 9.32 nM and mean K d = 1.48 ± 0.36 nM. Our model achieves several valuable insights into designing dosage strategies. First, we predicted that the OXTR complex reaches maximum occupancy at 10 nM OXT in myometrial cells and at 1 µM in HEK293T cells. This information is pivotal for guiding experimental design and data interpretation when working with these distinct cell types, emphasizing the need to consider effects for specific cell types when choosing OXTR-transfected cell lines. Second, our model recapitulated the significant effects of genetic variants for both experimental and physiologically relevant systems, with V281M and E339K substantially compromising OXT-OXTR binding capacity. These findings suggest the need for personalized oxytocin dosing based on individual genetic profiles to enhance therapeutic efficacy and reduce risks, especially in the context of labor and delivery. Third, we demonstrated the potential for rescuing the attenuated cell response observed in V281M and E339K variants by increasing the OXT dosage at specific, early time points. Cellular responses to OXT, including Ca 2+ release, manifest within minutes. Our model indicates that providing V281M- and E339K-expressing cells with doubled OXT dose during the initial minute of binding can elevate OXT-OXTR complex formation to levels comparable to wild-type OXTR. In summary, our study provides a computational framework for precision oxytocin dosing strategies, paving the way for personalized medicine.

Rates of SARS-CoV-2 transmission between and into California state prisons.

Correctional institutions are a crucial hotspot amplifying SARS-CoV-2 spread and disease disparity in the U.S. In the California state prison system, multiple massive outbreaks have been caused by transmission between prisons. Correctional staff are a likely vector for transmission into the prison system from surrounding communities. We used publicly available data to estimate the magnitude of flows to and between California state prisons, estimating rates of transmission from communities to prison staff and residents, among and between residents and staff within facilities, and between staff and residents of distinct facilities in the state's 34 prisons through March 22, 2021. We use a mechanistic model, the Hawkes process, reflecting the dynamics of SARS-CoV-2 transmission, for joint estimation of transmission rates. Using nested models for hypothesis testing, we compared the results to simplified models (i) without transmission between prisons, and (ii) with no distinction between prison staff and residents. We estimated that transmission between different facilities' staff is a significant cause of disease spread, and that staff are a vector of transmission between resident populations and outside communities. While increased screening and vaccination of correctional staff may help reduce introductions, large-scale decarceration remains crucially needed as more limited measures are not likely to prevent large-scale disease spread.

Comparative transcriptome profiling reveals the reprogramming of gene networks under arsenic stress in Indian mustard.

Arsenic is a widespread toxic metalloid that is classified as a class I carcinogen known to cause adverse health effects in humans. In the present study, we investigated arsenic accumulation potential and comparative gene expression in Indian mustard. The amount of arsenic accumulated in shoots varied in the range of 15.99-1138.70 mg/kg on a dry weight basis among five cultivars. Comparative expression analysis revealed 10 870 significantly differentially expressed genes mostly belonging to response to stress, metabolic processes, signal transduction, transporter activity, and transcription regulator activity to be up-regulated, while most of the genes involved in photosynthesis, developmental processes, and cell growth were found to be down-regulated in arsenic-treated tissues. Further, pathway analysis using the KEGG Automated Annotation server (KAAS) revealed a large-scale reprogramming of genes involved in genetic and environmental information processing pathways. Top pathways with maximum KEGG orthology hits included carbon metabolism (2.5%), biosynthesis of amino acids (2.1%), plant hormone signal transduction (1.4%), and glutathione metabolism (0.6%). A transcriptomic investigation to understand the arsenic accumulation and detoxification in Indian mustard will not only help to improve its phytoremediation efficiency but also add to the control measures required to check bioaccumulation of arsenic in the food chain.

Acceptability of Mental Health Facilities and De-addiction Centers in India.

Not much is known about disease prevalence, treatment outcomes, trained manpower, programs, and patients' awareness of diseases from South Asia, compared with the Western world. While other aspects are improving, the quantitative evaluation of awareness of diseases is lagging. Compared with other diseases, the situation for mental health disorders and addiction is worse. While no single study can fully quantify all aspects of awareness, a good starting point is to understand if increasing the number of mental health facilities is beneficial by understanding people's perception toward the likelihood of contracting various diseases, their preferred approach to treatment, and their perception of whether there are enough current facilities. We surveyed over 8000 families across several states of India and asked if they would treat a particular problem at home, visit a local healer, seek religious council, or go to a modern hospital for treatment. Our questions also included non-medical options to assess how likely people are to avoid trained medical help. We also asked people about their perceived likelihood of a family member ever suffering from (1) diarrhea, (2) high fever, (3) alcoholism, and (4) schizophrenia and other mental health problems. We reversed the order of diseases in our questions for a fraction of the population to evaluate the effect of order of questioning. Finally, we asked, if people feel they have enough local healers, religious places, general hospitals, de-addiction centers, and mental health facilities. Despite the taboo around mental health, many people claimed that their family members were unlikely to contract mental health or addiction problems, people recognized the severe paucity of mental health facilities and de-addiction centers. This raises hope for improving the mental health situation in India. We also found a significant relation between education levels and choices people make, underscoring the positive role education has in improving mental health.

A randomized, proof-of-concept clinical trial on repurposing chlorcyclizine for the treatment of chronic hepatitis C.

BACKGROUND & AIMS: Chlorcyclizine HCl (CCZ) is a piperazine-class antihistamine with anti-hepatitis C virus (HCV) activity in vitro and in vivo. In a first-in-humans study for HCV, we evaluated the antiviral effects and safety of CCZ±ribavirin (RBV), characterized pharmacokinetic (PK) and viral kinetic (VK) patterns, and provide insights into CCZs mode of action against HCV. METHODS: Chronic HCV patients were randomized to CCZ (75 mg twice daily) or CCZ+weight-based RBV (1000/1200 mg daily) for 28 days. Therapy started with a loading dose of CCZ 150 mg ± RBV. Serial assessments of safety, liver tests, PK and VK markers were obtained. RESULTS: 24 HCV patients were treated; 54% male, median age 56 years, median HCV RNA 6.30 log IU/ml, without baseline differences between groups. At the end of therapy, subjects treated with CCZ monotherapy did not show any significant or sustained reduction in viremia (p = 0.69), whereas 7/12 (58%) subjects treated with CCZ+RBV had a >3-fold decline in HCV RNA. Subjects who responded demonstrated monophasic (n = 2), biphasic (n = 2) and triphasic (n = 3) VK responses. Contrary to historical RBV monotherapy response, CCZ+RBV demonstrated a continued viral decline suggesting a possible synergistic effect of CCZ+RBV. Mathematical modeling predicts a median effectiveness of CCZ+RBV in blocking viral production (ε) of 59% (Interquartile range, IQR: 50%) and blocking infection (η) of 78% (IQR: 23%). Adverse events (AEs) were mild-moderate without treatment discontinuations for AEs. CONCLUSIONS: In this human pilot study, CCZ demonstrated some anti-HCV effects, mostly in combination with RBV. More potent CCZ derivatives with optimal PK features may be more suitable for future therapeutic development. ClinicalTrials.gov number: NCT02118012.