The SITLESS project: Exercise referral schemes enhanced by self-management strategies to battle sedentary behaviour in older adults: Study protocol for a randomised controlled trial

Abstract Background Older adults are the fastest growing segment of the world‘s population. Recent evidence indicates that excessive sitting time is harmful to health, independent of meeting the recommended moderate to vigorous physical activity (PA) guidelines. The SITLESS project aims to determine whether exercise referral schemes (ERS) can be enhanced by self-management strategies (SMSs) to reduce sedentary behaviour (SB), increase PA and improve health, quality of life and function in the long term, as well as psychosocial outcomes in community-dwelling older European citizens from four countries, within a three-armed pragmatic randomised controlled trial, compared with ERS alone and also with general recommendations about PA. Methods A total of 1338 older adults will be included in this study, recruited from four European countries through different existing primary prevention pathways. Participants will be randomly allocated into an ERS of 16 weeks (32 sessions, 45–60 min per session), ERS enhanced by seven sessions of SMSs and four telephone prompts, or a control group. Outcomes will be assessed at baseline, month 4 (end of ERS intervention), month 16 (12 months post intervention) and month 22 (18 months post intervention). Primary outcomes will include measures of SB (time spent sedentary) and PA (counts per minute). Secondary outcomes will include muscle and physical function, health economics’ related outcomes, anthropometry, quality of life, social networks, anxiety and depressive symptoms, disability, fear of falling, executive function and fatigue. A process evaluation will be conducted throughout the trial. The full analysis set will follow an intention-to-treat principle and will include all randomised participants for whom a baseline assessment is conducted. The study hypothesis will be tested with mixed linear models with repeated measures, to assess changes in the main outcomes (SB and PA) over time (baseline to month 22) and between study arms. Discussion The findings of this study may help inform the design and implementation of more effective interventions to reduce SB and increase PA levels, and hence improve long-term health outcomes in the older adult population. SITLESS aims to support policy-makers in deciding how or whether ERS should be further implemented or restructured in order to increase its adherence, impact and cost-effectiveness. Trial registration ClinicalTrials.gov, NCT02629666 . Registered 19 November 2015

Covid-19: la malinterpretación de los datos de la pandemia daña la confianza del público

Dos cartas publicadas en The Lancet y The Lancet Public Health en los últimos meses defienden la necesidad de evaluar de forma independiente la respuesta española ante la covid-19. Estamos de acuerdo, pero nos gustaría complementarlas con tres puntos que nos acercan a la ciencia abierta. Nos referimos a la confusión terminológica, la calidad de los datos y su disponibilidad

Cognate RNA-Binding Modes by the Alternative-Splicing Regulator MBNL1 Inferred from Molecular Dynamics

The muscleblind-like protein family (MBNL) plays a prominent role in the regulation of alternative splicing. Consequently, the loss of MBNL function resulting from sequestration by RNA hairpins triggers the development of a neuromuscular disease called myotonic dystrophy (DM). Despite the sequence and structural similarities between the four zinc-finger domains that form MBNL1, recent studies have revealed that the four binding domains have differentiated splicing activity. The dynamic behaviors of MBNL1 ZnFs were simulated using conventional molecular dynamics (cMD) and steered molecular dynamics (sMD) simulations of a structural model of MBNL1 protein to provide insights into the binding selectivity of the four zinc-finger (ZnF) domains toward the GpC steps in YGCY RNA sequence. In accordance with previous studies, our results suggest that both global and local residue fluctuations on each domain have great impacts on triggering alternative splicing, indicating that local motions in RNA-binding domains could modulate their affinity and specificity. In addition, all four ZnF domains provide a distinct RNA-binding environment in terms of structural sampling and mobility that may be involved in the differentiated MBNL1 splicing events reported in the literature

Devolution in the United Kingdom and its perspectives

<p>(A) Optimized distance dependent force constant (γ). Closest nodes are weighted by 12 (arbitrary units), and the weighting decays exponentially down to 25 Å. (B) Overlap between the top six PCA modes and the softest six NMA modes. The second softest ANM mode exhibits the highest overlap with PC1. (C) All-atom representation of (CUG)₃ fragment and PC1 normal mode vectors. U-U pairs are represented in red. Normal mode vectors (in green) show the structural variations along this mode. (D) Representation of the dispersion of the examined PDB structures along the PC1 and ANM2.</p

Percentage of captured variance (%σ²), collectivity (κ) and cumulative overlap (CO) extracted from the first three PCs of models with 2, 6 and 12 CUG repeats.

<p>Cumulative overlap was calculated for the 20 softest normal modes.</p

Atomic global fluctuations extracted from the <i>reference</i> structures, and the cMD and aMD ensembles.

<p>Only P, C2’, C4 and N3 atoms are considered. Computed fluctuations for the P atoms only are plotted in the box in the top right corner of the figure.</p

Structural analysis of the cMD and aMD simulations.

<p>(A) Average and standard deviation for each helical parameter (base pair opening, buckle, propeller and helical twist). cMD and aMD results are colored in blue and green respectively. Structures were aligned to all heavy atoms and represented with PyMOL. Notice that the 3’-end from the aMD simulation yields significant deviation from the cMD. (B) Cartoon representation of two clustered structures from the cMD simulation and opening effect (σ) of the U-U pair. The two main principal motions observed along the simulation correspond to the backbone expansion-compression (opening and closing of the major groove) and the base pair opening of the uridines. (C) Cartoon representation of the first and second CUG fragments from the aMD simulation. The main distortions are observed in the 3’-end, as stated by the helical parameter values.</p

El Diario de Pontevedra : periódico liberal: Ano XXVI Número 7581 - 1909 agosto 19

<div><p>Myotonic dystrophy type 1 (DM1) is a rare multisystemic disorder associated with an expansion of CUG repeats in mutant <i>DMPK</i> (dystrophia myotonica protein kinase) transcripts; the main effect of these expansions is the induction of pre-mRNA splicing defects by sequestering muscleblind-like family proteins (e.g. MBNL1). Disruption of the CUG repeats and the MBNL1 protein complex has been established as the best therapeutic approach for DM1, hence two main strategies have been proposed: targeted degradation of mutant <i>DMPK</i> transcripts and the development of CUG-binding molecules that prevent MBNL1 sequestration. Herein, suitable CUG-binding small molecules were selected using in silico approaches such as scaffold analysis, similarity searching, and druggability analysis. We used polarization assays to confirm the CUG repeat binding in vitro for a number of candidate compounds, and went on to evaluate the biological activity of the two with the strongest affinity for CUG repeats (which we refer to as compounds <b>1</b>–<b>2</b> and <b>2</b>–<b>5</b>) in DM1 mutant cells and Drosophila DM1 models with an impaired locomotion phenotype. In particular, <b>1</b>–<b>2</b> and <b>2</b>–<b>5</b> enhanced the levels of free MBNL1 in patient-derived myoblasts in vitro and greatly improved DM1 fly locomotion in climbing assays. This work provides new computational approaches for rational large-scale virtual screens of molecules that selectively recognize CUG structures. Moreover, it contributes valuable knowledge regarding two compounds with desirable biological activity in DM1 models.</p></div

In silico discovery of substituted pyrido[2,3-<i>d</i>]pyrimidines and pentamidine-like compounds with biological activity in myotonic dystrophy models - Fig 5

<p>(A) Schematic representation of the r(CUG)₃ model system. (B) Druggability analysis description of the <b>S1</b> and <b>S2</b> model systems. RNA is shown as a surface representation with C•G and G•C pairs in white and U-U pairs in green; three druggability solutions were obtained per system. Each druggable region, or hotspot, is represented by a colored sphere (red to blue, from lowest to highest binding-energy, respectively). Notice that the druggable sites in model <b>S1</b> are distributed along the major groove but are mainly located in the U-U pairs. Model <b>S2</b> had a stacking interaction pattern caused by the imidazole fragment, which stacks via one U-U pair and forms an H-bond with the O4 atom of U14 (3.0 Å). Some features can also be observed along the minor groove.</p

Metabolic, mitochondrial, renal and hepatic safety of enfuvirtide and raltegravir antiretroviral administration: Randomized crossover clinical trial in healthy volunteers

Context: Classical antiretroviral agents may acutely impact on metabolic, mitochondrial, renal and hepatic function in HIV-infected and uninfected persons. Fusion and integrase inhibitors are supposed to be safer, but have been scarcely investigated. To avoid any interference with HIV or other antiretrovirals, we assessed markers of these toxicities in healthy adult volunteers treated with Enfuvirtide (T20) or Raltegravir (RAL). Methods: Twenty-six healthy participants were randomized to T20/90mg vs. placebo (n = 12) or RAL/400mg vs. placebo (n = 14) every 12h in two 7-day periods separated by a 4-week washout period. Major end-points were changes in lipid profile (total cholesterol, high-density-lipoprotein (HDL)-cholesterol, low-density-lipoprotein (LDL)-cholesterol, triglycerides), insulin resistance (glucose) and mitochondrial toxicity (mitochondrial DNA content-mtDNA-in peripheral blood mononuclear cells). Renal and hepatic toxicity (creatinine, alanine transaminase (AST), alanine aminotransferase (ALT), bilirubin and total plasma proteins) and overall safety were also analysed. Effect of period, treatment, and basal measures were evaluated for each end-point. Results: Neither T20-administration nor RAL-administration yielded to any statistic significant change in the markers of metabolic, mitochondrial, renal or hepatic toxicity assessed. No symptoms indicative of drug toxicity were neither found in any subject. Conclusions: In absence of HIV infection, or concomitant treatment, short-term exposure to T20 or RAL in healthy adult volunteers did not lead to any indicative changes in toxicity markers thus presuming the safe profile of both drugs