DNA Supercoiling Drives a Transition between Collective Modes of Gene Synthesis.

Transcription of genes can be affected by both biochemical and mechanical factors. Recent experiments suggested that the mechanical stress associated with transcription-induced DNA supercoiling is responsible for the transition from cooperative to antagonistic group dynamics of RNA polymerases (RNAPs) upon promoter repression. To underpin the mechanism behind this drastic transition, we developed a continuum deterministic model for transcription under torsion. In our model, the speed of an RNAP is affected by the local DNA supercoiling, as well as two global factors: (i) the number of RNAPs on the gene affecting the torsional stress experienced by individual RNAPs and (ii) transcription factors blocking the diffusion of DNA supercoils. Our minimal model can successfully reproduce the experimental findings and helps elucidate the interplay of mechanical and biological factors in the collective dynamics of molecular machines involved in gene expression.

Field-theoretic model for chemotaxis in run and tumble particles.

In this paper, we develop a field-theoretic description for run and tumble chemotaxis, based on a density-functional description of crystalline materials modified to capture orientational ordering. We show that this framework, with its in-built multiparticle interactions, soft-core repulsion, and elasticity, is ideal for describing continuum collective phases with particle resolution, but on diffusive timescales. We show that our model exhibits particle aggregation in an externally imposed constant attractant field, as is observed for phototactic or thermotactic agents. We also show that this model captures particle aggregation through self-chemotaxis, an important mechanism that aids quorum-dependent cellular interactions.

Implementation of HIV care in Western Kenya during corona virus disease 2019 response.

: To ensure the continuity of high-quality HIV care in Kisumu County, Kenya during the corona virus disease 2019 pandemic, the Ministry of Health implemented a strategy to promote physical distancing and corona virus disease 2019 case detection. A total of 23 262 (84.2%) of the 27 641 patients eligible for early refill received an extra 3-month supply of antiretrovirals. Across 60 Ministry of Health clinics, average attendance decreased from 1298 to 640 patients per day postintervention, representing a 50.7% reduction.

Testing a Real-Time Tenofovir Urine Adherence Assay for Monitoring and Providing Feedback to Preexposure Prophylaxis in Kenya (PUMA): Protocol for a Pilot Randomized Controlled Trial.

BACKGROUND: The worldwide expansion of preexposure prophylaxis (PrEP) with oral tenofovir-disoproxil-fumarate/emtricitabine will be critical to ending the HIV epidemic. However, maintaining daily adherence to PrEP can be difficult, and the accuracy of self-reported adherence is often limited by social desirability bias. Pharmacologic adherence monitoring (measuring drug levels in a biomatrix) has been critical to interpreting PrEP trials, but testing usually requires expensive equipment and skilled personnel. We have recently developed a point-of-care (POC) immunoassay to measure tenofovir in urine, allowing real-time adherence monitoring for the first time. OBJECTIVE: The goal of this study is to examine a point-of-care adherence metric in PrEP to support and increase adherence via a randomized controlled trial. METHODS: The paper describes the protocol for a pilot randomized controlled trial to test the acceptability, feasibility, and impact on long-term adherence of implementing a POC urine test to provide real-time adherence feedback among women on PrEP. Eligible women (n=100) will be HIV-negative, ≥18 years old, and recruited from a clinic in Kenya that provides PrEP. Participants will be randomized 1:1 to the intervention of providing real-time feedback via the assay versus standard of care adherence counseling. Acceptability by participants will be assessed by a quantitative survey, as well as by qualitative data collected via in-depth interviews (n=20) and focus group discussions (n=4 groups, 5-10 women each). Feasibility will be assessed by the proportion of women retained in the study, the mean number of missed visits, the proportion of planned urine assessments completed, and messages delivered, while in-depth interviews with providers (n=8) will explore the ease of administering the urine test. Tenofovir levels in hair will serve as long-term adherence metrics. A linear mixed-effects model will estimate the effect of the intervention versus standard of care on logarithmically transformed levels of tenofovir in hair. RESULTS: This study has been funded by the National Institute of Health, approved by the Kenya Medical Research Institute Institutional Review Board, and will commence in June 2020. CONCLUSIONS: A novel urine assay to measure and deliver information on adherence to PrEP in real-time will be tested for the first time in this trial planned among women on PrEP in Kenya. Study findings will inform a larger-scale trial assessing the impact of real-time adherence monitoring/feedback on HIV prevention. Improving adherence to PrEP will have long-term implications for efforts to end the HIV epidemic worldwide. TRIAL REGISTRATION: ClinicalTrials.gov NCT03935464; https://clinicaltrials.gov/ct2/show/NCT03935464. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/15029.

Implementation research for public sector mental health care scale-up (SMART-DAPPER): a sequential multiple, assignment randomized trial (SMART) of non-specialist-delivered psychotherapy and/or medication for major depressive disorder and posttraumatic stress disorder (DAPPER) integrated with outpatient care clinics at a county hospital in Kenya.

BACKGROUND: Mental disorders are a leading cause of global disability, driven primarily by depression and anxiety. Most of the disease burden is in Low and Middle Income Countries (LMICs), where 75% of adults with mental disorders have no service access. Our research team has worked in western Kenya for nearly ten years. Primary care populations in Kenya have high prevalence of Major Depressive Disorder (MDD) and Posttraumatic Stress Disorder (PTSD). To address these treatment needs with a sustainable, scalable mental health care strategy, we are partnering with local and national mental health stakeholders in Kenya and Uganda to identify 1) evidence-based strategies for first-line and second-line treatment delivered by non-specialists integrated with primary care, 2) investigate presumed mediators of treatment outcome and 3) determine patient-level moderators of treatment effect to inform personalized, resource-efficient, non-specialist treatments and sequencing, with costing analyses. Our implementation approach is guided by the Exploration, Preparation, Implementation, Sustainment (EPIS) framework. METHODS/DESIGN: We will use a Sequential, Multiple Assignment Randomized Trial (SMART) to randomize 2710 patients from the outpatient clinics at Kisumu County Hospital (KCH) who have MDD, PTSD or both to either 12 weekly sessions of non-specialist-delivered Interpersonal Psychotherapy (IPT) or to 6 months of fluoxetine prescribed by a nurse or clinical officer. Participants who are not in remission at the conclusion of treatment will be re-randomized to receive the other treatment (IPT receives fluoxetine and vice versa) or to combination treatment (IPT and fluoxetine). The SMART-DAPPER Implementation Resource Team, (IRT) will drive the application of the EPIS model and adaptations during the course of the study to optimize the relevance of the data for generalizability and scale -up. DISCUSSION: The results of this research will be significant in three ways: 1) they will determine the effectiveness of non-specialist delivered first- and second-line treatment for MDD and/or PTSD, 2) they will investigate key mechanisms of action for each treatment and 3) they will produce tailored adaptive treatment strategies essential for optimal sequencing of treatment for MDD and/or PTSD in low resource settings with associated cost information - a critical gap for addressing a leading global cause of disability. TRIAL REGISTRATION: ClinicalTrials.gov NCT03466346, registered March 15, 2018.

Three-body interactions drive the transition to polar order in a simple flocking model.

A large class of mesoscopic or macroscopic flocking theories are coarse-grained from microscopic models that feature binary interactions as the chief aligning mechanism. However, while such theories seemingly predict the existence of polar order with just binary interactions, actomyosin motility assay experiments show that binary interactions are insufficient to obtain polar order, especially at high densities. To resolve this paradox, here we introduce a solvable one-dimensional flocking model and derive its stochastic hydrodynamics. We show that two-body interactions are insufficient to generate polar order unless the noise is non-Gaussian. We show that noisy three-body interactions in the microscopic theory allow us to capture all essential dynamical features of the flocking transition, in systems that achieve orientational order above a critical density.

Mechanism of apoptosis induction in human breast cancer MCF-7 cell by Ruviprase, a small peptide from Daboia russelii russelii venom.

Ruviprase, a 4.4 kDa peptide isolated from Daboia russelii russelii venom demonstrated antiproliferative activity against EMT6/AR1, U-87MG, HeLa and MCF-7 cancer cells with an IC50 value of 23.0, 8.8, 5.8 and 4.0 µg ml(-1), respectively. However, it was nontoxic to non-cancerous human embryonic kidney cell and human peripheral blood lymphocytes. Flow-cytometric analysis confirmed the apoptosis induction in MCF-7 cells by Ruviprase where it induced DNA condensation but did not cause mitotic blockage or chromosomal aberration in treated-cells. Immunofluorescence microscopic analysis indicated Ruviprase induced apoptosis in MCF-7 cells through p53 and p21-mediated pathways. Ruviprase generated reactive oxygen species (ROS), altered the mitochondrial transmembrane potential, and significantly decreased the cellular glutathione (GSH) content of MCF-7 cells. Immunoblotting and quantitative real-time PCR (qRT-PCR) analyses suggested that Ruviprase down-regulated the expression of anti-apoptotic protein Bcl-2, increased cleavage of poly (ADP-ribose) polymerase (PARP) protein, and up-regulated the expression of pro-apoptotic protein Bax, as well as executer protein caspase-7 to induced apoptosis in MCF-7 cells via intrinsic pathway. This is the first report on the characterization of the anticancer potential of a small, non-toxic and anticoagulant peptide purified from Russell's viper venom.