Dynamical model of DNA-protein interaction: effect of protein charge distribution and mechanical properties

The mechanical model based on beads and springs, which we recently proposed to study non-specific DNA-protein interactions [J. Chem. Phys. 130, 015103 (2009)], was improved by describing proteins as sets of interconnected beads instead of single beads. In this paper, we first compare the results obtained with the updated model with those of the original one and then use it to investigate several aspects of the dynamics of DNA sampling, which could not be accounted for by the original model. These aspects include the effect on the speed of DNA sampling of the regularity and/or randomness of the protein charge distribution, the charge and location of the search site, and the shape and deformability of the protein. We also discuss the efficiency of facilitated diffusion, that is, the extent to which the combination of 1D sliding along the DNA and 3D diffusion in the cell can lead to faster sampling than pure 3D diffusion of the protein.Comment: accepted in JC

Free energy landscape and characteristic forces for the initiation of DNA unzipping

DNA unzipping, the separation of its double helix into single strands, is crucial in modulating a host of genetic processes. Although the large-scale separation of double-stranded DNA has been studied with a variety of theoretical and experimental techniques, the minute details of the very first steps of unzipping are still unclear. Here, we use atomistic molecular dynamics (MD) simulations, coarse-grained simulations and a statistical-mechanical model to study the initiation of DNA unzipping by an external force. The calculation of the potential of mean force profiles for the initial separation of the first few terminal base pairs in a DNA oligomer reveal that forces ranging between 130 and 230 pN are needed to disrupt the first base pair, values of an order of magnitude larger than those needed to disrupt base pairs in partially unzipped DNA. The force peak has an "echo," of approximately 50 pN, at the distance that unzips the second base pair. We show that the high peak needed to initiate unzipping derives from a free energy basin that is distinct from the basins of subsequent base pairs because of entropic contributions and we highlight the microscopic origin of the peak. Our results suggest a new window of exploration for single molecule experiments.Comment: 25 pages, 6 figures , Accepted for publication in Biophysical Journa

Digital Commons and Management towards Sustainability, Equity and Resilience

This Research in Progress paper is a literature review on management activities and processes that take place within the digital commons, through the lenses of three pillars: sustainability, equity and resilience. The aim is to examine previous studies, in order to be able to answer the following question: how can the environmental sustainability, equity and resilience of digital commons be improved? Initial research shows few results on this topic. But, more than answers, this literature review highlights three avenues of research

Description of non-specific DNA-protein interaction and facilitated diffusion with a dynamical model

We propose a dynamical model for non-specific DNA-protein interaction, which is based on the 'bead-spring' model previously developed by other groups, and investigate its properties using Brownian Dynamics simulations. We show that the model successfully reproduces some of the observed properties of real systems and predictions of kinetic models. For example, sampling of the DNA sequence by the protein proceeds via a succession of 3d motion in the solvent, 1d sliding along the sequence, short hops between neighboring sites, and intersegmental transfers. Moreover, facilitated diffusion takes place in a certain range of values of the protein effective charge, that is, the combination of 1d sliding and 3d motion leads to faster DNA sampling than pure 3d motion. At last, the number of base pairs visited during a sliding event is comparable to the values deduced from single-molecule experiments. We also point out and discuss some discrepancies between the predictions of this model and some recent experimental results as well as some hypotheses and predictions of kinetic models

UK Nutrition Research Partnership (NRP) workshop:Forum on advancing dietary intake assessment

The development of better and more robust measures of dietary intake in free living situations was identified as a priority for advancing nutrition research by the Office of Strategic Coordination for Health Research (OSCHR) Review of Nutrition and Human Health Research in 2017. The UK Nutrition Research Partnership (NRP) sponsored a workshop on Dietary Intake Assessment methodology alongside its series of ‘Hot Topic’ workshops designed to accelerate progress in nutrition research by bringing together people from a range of different disciplines. The workshop on Dietary Intake Assessment methodology took place via Zoom over two half‐days in January 2021 and included 50 scientists from a wide range of disciplines. The problems with current methods of dietary assessment and how emerging technologies might address them were set out in pre‐recorded presentations and explored in panel discussions. Participants then worked in breakout groups to discuss and prioritise the research questions that should be addressed to best further the field and lead to improvements in dietary assessment methodology. Five priority research questions were selected. Participants were asked to brainstorm potential approaches for addressing them and were then asked to focus on one approach and develop it further. At the end of these sessions, participants presented their project ideas to the rest of the workshop and these will be reported back to the Medical Research Council. It is hoped that potential collaborative projects arising from these discussions will be taken forward in response to future funding calls

Endoscopic treatment in carpal tunnel syndrome: a case study in Bucharest – Romania

Background. Carpal tunnel syndrome is currently the most common peripheral nerve compression neuropathy that affects approximately 1% of the population. The incidence of CTS seems to be increasing. The diagnosis is based on clinical symptoms and electrodiagnostic studies. The purpose of this study is to analyze the effects of the endoscopic technique on patients with carpal tunnel syndrome. In addition, we want to demonstrate if this condition occurs more in men than in women. Methods. In a group of 53 patients we used the endoscopic technique for the treatment of carpal syndrome, and as a measure of its effectiveness we used the Phalen, Durken and Tinel tests. Also, for the qualitative analysis of the data, the clinical and demographic characteristics of the patients were taken into account. Results. We identified statistically significant differences between men and women regarding the occurrence of carpal syndrome, women having significantly lower results than men in the Phalen, Durken and Tinel tests (X2Phalen(2) =17.33, X2Durken(2) =15.94, X2Tinel(2) =10.76, p<0.05). There are statistically significant differences between the results of the Phalen, Durken and Tinel tests before and after surgery (WPhalen=111.24, WDurken=139.91, WTinel=102.46, p<0.05)

Dynamical versus statistical mesoscopic models for DNA denaturation

We recently proposed a dynamical mesoscopic model for DNA, which is based, like statistical ones, on site-dependent finite stacking and pairing enthalpies. In the present article, we first describe how the parameters of this model are varied to get predictions in better agreement with experimental results that were not addressed up to now, like mechanical unzipping, the evolution of the critical temperature with sequence length, and temperature resolution. We show that the model with the new parameters provides results that are in quantitative agreement with those obtained from statistical models. Investigation of the critical properties of the dynamical model suggests that DNA denaturation looks like a first-order phase transition in a broad temperature interval, but that there necessarily exists, very close to the critical temperature, a crossover to another regime. The exact nature of the melting dynamics in this second regime still has to be elucidated. We finally point out that the descriptions of the physics of the melting transition inferred from statistical and dynamical models are not completely identical and discuss the relevance of our model from the biological point of view

Applications of Corticosteroid Therapy in Inflammatory Rheumatic Diseases

Corticosteroids still remain the anchor drugs in therapy strategies for patients with inflammatory rheumatic diseases even though new drugs such as biologic or targeted synthetic molecules have emerged in the past years, being the most commonly prescribed medicines in the world due to their powerful immune-modulating properties. In this chapter, we aim to discuss the main characteristics of the glucocorticoids, their mechanism of action and effects on the immune system given the fact that they reduce the activation, proliferation, differentiation and survival of inflammatory cells such as macrophages and lymphocytes. Nevertheless, of great importance are the indications and tapering regimens, but also the adverse effects and various methods of monitoring the corticosteroid therapy