Management of sodium disorders during continuous haemofiltration

In patients with acute kidney injury and concomitant severe hyponatraemia or hypernatraemia, rapid correction of the serum Na+ concentration needs to be avoided. The present paper outlines the principles of how to adjust the Na+ concentration in the replacement fluid during continuous renal replacement therapy to prevent rapid changes of the serum Na+ concentration

Calcium puffs are generic InsP₃-activated elementary calcium signals and are downregulated by prolonged hormonal stimulation to inhibit cellular calcium responses

Elementary Ca2+ signals, such as "Ca2+ puffs", which arise from the activation of inositol 1,4,5-trisphosphate receptors, are building blocks for local and global Ca2+ signalling. We characterized Ca2+ puffs in six cell types that expressed differing ratios of the three inositol 1,4,5-trisphosphate receptor isoforms. The amplitudes, spatial spreads and kinetics of the events were similar in each of the cell types. The resemblance of Ca2+ puffs in these cell types suggests that they are a generic elementary Ca2+ signal and, furthermore, that the different inositol 1,4,5-trisphosphate isoforms are functionally redundant at the level of subcellular Ca2+ signalling. Hormonal stimulation of SH-SY5Y neuroblastoma cells and HeLa cells for several hours downregulated inositol 1,4,5-trisphosphate expression and concomitantly altered the properties of the Ca2+ puffs. The amplitude and duration of Ca2+ puffs were substantially reduced. In addition, the number of Ca2+ puff sites active during the onset of a Ca2+ wave declined. The consequence of the changes in Ca2+ puff properties was that cells displayed a lower propensity to trigger regenerative Ca2+ waves. Therefore, Ca2+ puffs underlie inositol 1,4,5-trisphosphate signalling in diverse cell types and are focal points for regulation of cellular responses

Environmental effects on emergent strategy in micro-scale multi-agent reinforcement learning

Multi-Agent Reinforcement Learning (MARL) is a promising candidate for realizing efficient control of microscopic particles, of which micro-robots are a subset. However, the microscopic particles' environment presents unique challenges, such as Brownian motion at sufficiently small length-scales. In this work, we explore the role of temperature in the emergence and efficacy of strategies in MARL systems using particle-based Langevin molecular dynamics simulations as a realistic representation of micro-scale environments. To this end, we perform experiments on two different multi-agent tasks in microscopic environments at different temperatures, detecting the source of a concentration gradient and rotation of a rod. We find that at higher temperatures, the RL agents identify new strategies for achieving these tasks, highlighting the importance of understanding this regime and providing insight into optimal training strategies for bridging the generalization gap between simulation and reality. We also introduce a novel Python package for studying microscopic agents using reinforcement learning (RL) to accompany our results.Comment: 12 pages, 5 figure

Phosphorylated c-Src in the nucleus is associated with improved patient outcome in ER-positive breast cancer

Elevated c-Src protein expression has been shown in breast cancer and <i>in vitro</i> evidence suggests a role in endocrine resistance. To investigate whether c-Src is involved in endocrine resistance, we examined the expression of both total and activated c-Src in human breast cancer specimens from a cohort of oestrogen receptor (ER)-positive tamoxifen-treated breast cancer patients. Tissue microarray technology was employed to analyse 262 tumour specimens taken before tamoxifen treatment. Immunohistochemistry using total c-Src and activated c-Src antibodies was performed. Kaplan–Meier survival curves were constructed and log-rank test were performed. High level of nuclear activated Src was significantly associated with improved overall survival (<i>P</i>=0.047) and lower recurrence rates on tamoxifen (<i>P</i>=0.02). Improved patient outcome was only seen with activated Src in the nucleus. Nuclear activated Src expression was significantly associated with node-negative disease and a lower NPI (<i>P</i><0.05). On subgroup analysis, only ER-positive/progesterone receptor (PgR)-positive tumours were associated with improved survival (<i>P</i>=0.004). This shows that c-Src activity is increased in breast cancer and that activated Src within the nucleus of ER-positive tumours predicts an improved outcome. In ER/PgR-positive disease, activated Src kinase does not appear to be involved in <i>de novo</i> endocrine resistance. Further study is required in ER-negative breast cancer as this may represent a cohort in which it is associated with poor outcome

N/P ratio in the PEI2-GNP-DNA complex affects transgene delivery in the human cornea in vitro

Recently, we discovered that polyethylenimine-conjugated gold nanoparticles (PEI2- GNP) could be used as gene therapy vector for the cornea. It was hypothesized that DNA concentration, incubation timing and PEI monomer amount in transfection solution affect gene transfer efficiency and toxicity. The aims of this study were to test whether molar ratio of PEI2 nitrogen (N) and phosphate (P) of DNA in PEI2-GNP transfection solution regulates transgene delivery in human corneal fibroblasts in vitro, and examine PEI2-GNP toxicity, uptake and clearance for the cornea in vivo."National Eye Institute, NIH, Bethesda for RO1EY017294 (RRM), Diversity (RRM) and Veteran Health Affairs Merit (RRM) grants and Unrestricted grant from Research to Prevent Blindness, New York

Enhancing the usability of systematic reviews by improving the consideration and description of interventions

The importance of adequate intervention descriptions in minimising research waste and improving research usability and reproducibility has gained attention in the past few years. Nearly all focus to date has been on intervention reporting in randomised trials. Yet clinicians are encouraged to use systematic reviews, whenever available, rather than single trials to inform their practice. This article explores the problem and implications of incomplete intervention details during the planning, conduct, and reporting of systematic reviews and makes recommendations for review authors, peer reviewers, and journal editors

Evidence Synthesis International (ESI): Position Statement

This paper is the initial Position Statement of Evidence Synthesis International, a new partnership of organizations that produce, support and use evidence synthesis around the world. The paper (i) argues for the importance of synthesis as a research exercise to clarify what is known from research evidence to inform policy, practice and personal decision making; (ii) discusses core issues for research synthesis such as the role of research evidence in decision making, the role of perspectives, participation and democracy in research and synthesis as a core component of evidence ecosystems; (iii) argues for 9 core principles for ESI on the nature and role of research synthesis; and (iv) lists the 5 main goals of ESI as a coordinating partnership for promoting and enabling the production and use of research synthesis