Transition path dynamics of a nanoparticle in a bistable optical trap

Many processes in chemistry, physics, and biology involve rare events in which the system escapes from a metastable state by surmounting an activation barrier. Examples range from chemical reactions, protein folding, and nucleation events to the catastrophic failure of bridges. A challenge in understanding the underlying mechanisms is that the most interesting information is contained within the rare transition paths, the exceedingly short periods when the barrier is crossed. To establish a model process that enables access to all relevant timescales, although highly disparate, we probe the dynamics of single dielectric particles in a bistable optical trap in solution. Precise localization by high-speed tracking enables us to resolve the transition paths and relate them to the detailed properties of the 3D potential within which the particle diffuses. By varying the barrier height and shape, the experiments provide a stringent benchmark of current theories of transition path dynamics

Role of Serine/Threonine Kinase 11 (STK11) or liver kinase B1 (LKB1) Gene in Peutz-Jeghers Syndrome

Peutz-Jeghers syndrome (PJS) is a well-described inherited syndrome, characterized by the development of gastrointestinal polyps and characteristic mucocutaneous freckling. PJS is an autosomal prevailing disease, due to genetic mutation on chromosome 19p, manifested by restricted mucocutaneous melanosis in association with gastrointestinal (GI) polyposis. The gene for PJS has recently been shown to be a serine/threonine kinase, known as LKB1 or STK11, which maps to chromosome subband 19p13.3. This gene has a putative coding region of 1302 bp, divided into nine exons, and acts as a tumor suppressor in the hamartomatous polyps of PJS patients and in the other neoplasms that develop in PJS patients. It is probable that these neoplasms develop from hamartomas, but it remains possible that the LKB1 or STK11 locus plays a role in a different genetic pathway of tumor growth in the cancers of PJS patients. This article focuses on the role of LKB1 or STK11 gene expression in PJS and related cancers

Recent Advances in Anticancer Activity of Novel Plant Extracts and Compounds from Curcuma longa in Hepatocellular Carcinoma

PURPOSE: Among all forms of cancers, hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. There are several treatment options for HCC ranging from loco-regional therapy to surgical treatment. Yet, there is high morbidity and mortality. Recent research focus has shifted towards more effective and less toxic cancer treatment options. Curcumin, the active ingredient in the Curcuma longa plant, has gained widespread attention in recent years because of its multifunctional properties as an antioxidant, anti-inflammatory, antimicrobial, and anticancer agent. METHODS: A systematic search of PubMed, Embase and Google Scholar was performed for studies reporting incidence of HCC, risk factors associated with cirrhosis and experimental use of curcumin as an anti-cancer agent. RESULTS: This review exclusively encompasses the anti-cancer properties of curcumin in HCC globally and it’s postulated molecular targets of curcumin when used against liver cancers. CONCLUSIONS: This review is concluded by presenting the current challenges and future perspectives of novel plant extracts derived from C. longa and the treatment options against cancers

Understanding structural transitions and dynamics in biomolecules at a single molecule level

Transition paths are fleeting events when a molecule crosses a barrier separating stable configurational basins. Recent advances in single molecule experiments, including optical tweezers-based force spectroscopy and FRET-based techniques, and data analysis methods have allowed detection of various statistical properties of transition paths. These observations have highlighted an important limitation in their current theoretical interpretation – a model of diffusive dynamics of the reaction coordinate along a one-dimensional free energy landscape is often unable to account for measurements of transition path time distributions in single molecule experiments. Here, we report similar observations in a long all-atom simulation of a small fast folding protein that exhibits multiple folding and unfolding transitions. Specifically, we discovered that the distribution of transition path times in this case is much broader than the prediction of the one-dimensional diffusion model. Moreover, direct analysis of the dynamics of the reaction coordinate in this simulation as well as in several other polypeptide simulations revealed that those dynamics are not diffusive, but subdiffusive. To explain these observations, we developed and tested several non-Markovian models, which include memory effects in the dynamics of the reaction coordinate in the form of time-dependent transport coefficients. We invented a novel technique, based on an overdamped generalized Langevin equation, to extract conformational memory directly from one-dimensional trajectories in single molecule experiments and simulations. Finally, we tested our theories on loop formation kinetics in intrinsically disordered proteins and found that, while mean first passage times to loop closure are well described by both one-dimensional diffusion and generalized Langevin equation, neither of them can capture long-time tails observed in distributions of transition path times in all-atom simulations.Cellular and Molecular Biolog

Design of a Toolbox of RNA Thermometers

Biomolecular temperature sensors can be used for efficient control of large-volume bioreactors, for spatiotemporal imaging and control of gene expression, and to engineer robustness to temperature in biomolecular circuit design. Although RNA-based sensors, called “thermometers”, have been investigated in both natural and synthetic contexts, an important challenge is to design diverse responses to temperature differing in sensitivity and threshold. We address this issue by constructing a library of RNA thermometers based on thermodynamic computations and experimentally measuring their activities in cell-free biomolecular “breadboards”. Using free energies of the minimum free energy structures as well as melt profile computations, we estimated that a diverse set of temperature responses were possible. We experimentally found a wide range of responses to temperature in the range 29–37 °C with fold-changes varying over 3-fold around the starting thermometer. The sensitivities of these responses ranged over 10-fold around the starting thermometer. We correlated these measurements with computational expectations, finding that although there was no strong correlation for the individual thermometers, overall trends of diversity, fold-changes, and sensitivities were similar. These results present a toolbox of RNA-based circuit elements with diverse temperature responses

COVID-19: Underpinning Research for Detection, Therapeutics, and Vaccines Development

BACKGROUND:The newly emerged coronavirus SARS-CoV-2, first reported in December 2019, has infected about five and a half million people globally and resulted in nearly 9063264 deaths until the 24th of June 2020. Nevertheless, the highly contagious virus has instigated an unimaginably rapid response from scientific and medical communities. OBJECTIVES:Pioneering research on molecular mechanisms underlying the viral transmission, molecular pathogenicity, and potential treatments will be highlighted in this review. The development of antiviral drugs specific to SARS-CoV-2 is a complicated and tedious process. To accelerate scientific discoveries and advancement, researchers are consolidating available data from associated coronaviruses into a single pipeline, which can be readily made available to vaccine developers. METHODS:In order to find studies evaluating the COVID-19 virus epidemiology, repurposed drugs and potential vaccines, web searches and bibliographical bases have been used with keywords that matches the content of this review. RESULTS:The published results of SARS-CoV-2 structures and interactomics have been used to identify potential therapeutic candidates. We illustrate recent publications on SARS-CoV-2, concerning its molecular, epidemiological, and clinical characteristics, and focus on innovative diagnostics technologies in the production pipeline. This objective of this review is to enhance the comprehension of the unique characteristics of SARS-CoV-2 and strengthen future control measures. Lay Summary:An innovative analysis is evaluating the nature of the COVID-19 pandemic. The aim is to increase knowledge of possible viral detection methods, which highlights several new technology limitations and advantages. We have assessed some drugs currently for patients (Lopinavir, Ritonavir, Anakinra and Interferon beta 1a), as the feasibility of COVID-19 specific antivirals is not presently known. The study explores the race toward vaccine development and highlights some significant trials and candidates in various clinical phases. This research addresses critical knowledge gaps by identifying repurposed drugs currently under clinical trials. Findings will be fed back rapidly to the researchers interested in COVID 19 and support the evidence and potential of possible therapeutics and small molecules with their mode of action

Estimation of tuberculosis incidence at subnational level using three methods to monitor progress towards ending TB in India, 2015–2020

Objectives We verified subnational (state/union territory (UT)/district) claims of achievements in reducing tuberculosis (TB) incidence in 2020 compared with 2015, in India.Design A community-based survey, analysis of programme data and anti-TB drug sales and utilisation data.Setting National TB Elimination Program and private TB treatment settings in 73 districts that had filed a claim to the Central TB Division of India for progress towards TB-free status.Participants Each district was divided into survey units (SU) and one village/ward was randomly selected from each SU. All household members in the selected village were interviewed. Sputum from participants with a history of anti-TB therapy (ATT), those currently experiencing chest symptoms or on ATT were tested using Xpert/Rif/TrueNat. The survey continued until 30 Mycobacterium tuberculosis cases were identified in a district.Outcome measures We calculated a direct estimate of TB incidence based on incident cases identified in the survey. We calculated an under-reporting factor by matching these cases within the TB notification system. The TB notification adjusted for this factor was the estimate by the indirect method. We also calculated TB incidence from drug sale data in the private sector and drug utilisation data in the public sector. We compared the three estimates of TB incidence in 2020 with TB incidence in 2015.Results The estimated direct incidence ranged from 19 (Purba Medinipur, West Bengal) to 1457 (Jaintia Hills, Meghalaya) per 100 000 population. Indirect estimates of incidence ranged between 19 (Diu, Dadra and Nagar Haveli) and 788 (Dumka, Jharkhand) per 100 000 population. The incidence using drug sale data ranged from 19 per 100 000 population in Diu, Dadra and Nagar Haveli to 651 per 100 000 population in Centenary, Maharashtra.Conclusion TB incidence in 1 state, 2 UTs and 35 districts had declined by at least 20% since 2015. Two districts in India were declared TB free in 2020