A Noncanonical Binding Site in the EVH1 Domain of Vasodilator-Stimulated Phosphoprotein Regulates Its Interactions with the Proline Rich Region of Zyxin

Vasodilator-stimulated phosphoprotein (VASP) is a processive actin polymerase with roles in the control of cell shape and cell migration. Through interaction with the cytoskeletal adaptor protein Zyxin, VASP can localize to damaged stress fibers where it serves to repair and reinforce these structures. VASP localization is mediated by its N-terminal Ena/VASP homology (EVH1) domain, which binds to the (W/F)Px phi P motif (most commonly occurring as FPPPP) found in cytoskeletal proteins such as vinculin, lamellipodin, and Zyxin. Sequentially close clusters of four or five of these motifs frequently occur, as in the proline rich region of Zyxin with four such motifs. This suggests that tetrameric VASP might bind very tightly to Zyxin through avidity, with all four EVH1 domains binding to a single Zyxin molecule. Here, quantitative nuclear magnetic resonance titration analysis reveals a dominant bivalent 1:1 (Zyxin:EVH1)interaction between the Zyxin proline rich region and the VASP EVH1 domain that utilizes the EVH1 canonical binding site and a novel secondary binding site on the opposite face of the EVH1 domain. We further show that binding to the secondary binding site is specifically inhibited by mutation of VASP EVH1 domain residue Y39 to E, which mimics Abl-induced phosphorylation of Y39. On the basis of these findings, we propose a model in which phosphorylation of Y39 acts as a stoichiometry switch that governs binding partner selection by the constitutive VASP tetramer. These results have broader implications for other multivalent VASP EVH1 domain binding partners and for furthering our understanding of the role of Y39 phosphorylation in regulating VASP localization and cellular function

Offloading devices for the prevention of heel pressure ulcers: a realist evaluation

Background Heel pressure ulcers can cause pain, reduce mobility, lead to longer hospital stays and in severe cases can lead to sepsis, amputation, and death. Offloading boots are marketed as heel pressure ulcer prevention devices, working by removing pressure to the heel, yet there is little good quality evidence about their clinical effectiveness. Given that evidence is not guiding use of these devices, this study aims to explore, how, when, and why these devices are used in hospital settings. Objective To explore how offloading devices are used to prevent heel pressure ulcers, for whom and in what circumstances. Methods A realist evaluation was undertaken to explore the contexts, mechanisms, and outcomes that might influence how offloading devices are implemented and used in clinical practice for the prevention of heel pressure ulcers in hospitals. Eight Tissue Viability Nurse Specialists from across the UK (England, Wales, and Northern Ireland) were interviewed. Questions sought to elicit whether, and in what ways, initial theories about the use of heel pressure ulcers fitted with interviewee's experiences. Results Thirteen initial theories were refined into three programme theories about how offloading devices are used by nurses ‘proactively’ to prevent heel pressure ulcers, ‘reactively’ to treat and minimise deterioration of early-stage pressure ulcers, and patient factors that influence how these devices are used. Conclusions Offloading devices were used in clinical practice by all the interviewees. It was viewed that they were not suitable to be used by every patient, at every point in their inpatient journey, nor was it financially viable. However, the interviewees thought that identifying suitable ‘at risk’ patient groups that can maintain use of the devices could lead to proactive and cost-effective use of the devices. This understanding of the contexts and mechanisms that influence the effective use of offloading devices has implications for clinical practice and design of clinical trials of offloading devices. Tweetable abstract How, for whom, and in what circumstances do offloading devices work to prevent heel pressure ulcers? Tissue viability nurses' perspectives

Comparative effectiveness of heel-specific medical devices for the prevention of heel pressure ulcers: a systematic review

Background Pressure ulcers (PUs) impact on patient's quality of life and are costly for healthcare providers. Heels are a particular concern due to specific risk factors. Relative effectiveness of medical devices, e.g., dressings, off-loading devices, heel cushioning devices, to reduce PU development is unknown. Methods Systematic review of the effectiveness of heel-specific medical devices for the prevention of heel PU (HPU)s. Database searches were performed from inception to June 2021 for RCTs. The primary outcome was incidence of new HPUs. Trials were assessed for risk of bias and data analysed with risk ratios, mean difference or hazard ratios as appropriate. Results Fifteen RCTs (4724 participants) were identified. Dressings, as constant low pressure (CLP) devices vs standard care: eight trials (very low quality) showed no-significant difference in effectiveness (RR 0.31, 95%CI 0.10 to 1.01). Off-loading devices vs standard care: three trials (low quality), showed significant reduction in development of Category≥1 HPUs (RR 0.20, 95%CI 0.05 to 0.80) two trials (medium quality), showed significant reduction in development of Category≥2 HPUs (RR 0.08, 95%CI 0.01 to 0.67). Comparisons between off-loading devices: two trials (low quality) showed no clear difference in HPU incidence. In a paediatric post-surgical population, one trial of off-loading device and one of a dressing (CLP device), both versus standard care, showed no clear difference in HPU incidence (RR 0.19 95%CI 0.02 to 1.55 and RR 0.89 95%CI 0.56 to 1.42 respectively). Conclusions Off-loading devices may reduce HPU incidence, from low-quality evidence. There is insufficient evidence to suggest that dressings reduce HPU incidence

Potential zoonotic sources of SARS‐CoV‐2 infections

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causing coronavirus disease-2019 (COVID-19) likely has evolutionary origins in other animals than humans based on genetically related viruses existing in rhinolophid bats and pangolins. Similar to other animal coronaviruses, SARS-CoV-2 contains a functional furin cleavage site in its spike protein, which may broaden the SARS-CoV-2 host range and affect pathogenesis. Whether ongoing zoonotic infections are possible in addition to efficient human-to-human transmission remains unclear. In contrast, human-to-animal transmission can occur based on evidence provided from natural and experimental settings. Carnivores, including domestic cats, ferrets and minks, appear to be particularly susceptible to SARS-CoV-2 in contrast to poultry and other animals reared as livestock such as cattle and swine. Epidemiologic evidence supported by genomic sequencing corroborated mink-to-human transmission events in farm settings. Airborne transmission of SARS-CoV-2 between experimentally infected cats additionally substantiates the possibility of cat-to-human transmission. To evaluate the COVID-19 risk represented by domestic and farmed carnivores, experimental assessments should include surveillance and health assessment of domestic and farmed carnivores, characterization of the immune interplay between SARS-CoV-2 and carnivore coronaviruses, determination of the SARS-CoV-2 host range beyond carnivores and identification of human risk groups such as veterinarians and farm workers. Strategies to mitigate the risk of zoonotic SARS-CoV-2 infections may have to be developed in a One Health framework and non-pharmaceutical interventions may have to consider free-roaming animals and the animal farming industry

Charge migration induced by attosecond pulses in bio-relevant molecules

After sudden ionization of a large molecule, the positive charge can migrate throughout the system on a sub-femtosecond time scale, purely guided by electronic coherences. The possibility to actively explore the role of the electron dynamics in the photo-chemistry of bio-relevant molecules is of fundamental interest for understanding, and perhaps ultimately controlling, the processes leading to damage, mutation and, more generally, to the alteration of the biological functions of the macromolecule. Attosecond laser sources can provide the extreme time resolution required to follow this ultrafast charge flow. In this review we will present recent advances in attosecond molecular science: after a brief description of the results obtained for small molecules, recent experimental and theoretical findings on charge migration in bio-relevant molecules will be discussed

Renal Association Clinical Practice Guideline on Haemodialysis

© The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.This guideline is written primarily for doctors and nurses working in dialysis units and related areas of medicine in the UK, and is an update of a previous version written in 2009. It aims to provide guidance on how to look after patients and how to run dialysis units, and provides standards which units should in general aim to achieve. We would not advise patients to interpret the guideline as a rulebook, but perhaps to answer the question: "what does good quality haemodialysis look like?"The guideline is split into sections: each begins with a few statements which are graded by strength (1 is a firm recommendation, 2 is more like a sensible suggestion), and the type of research available to back up the statement, ranging from A (good quality trials so we are pretty sure this is right) to D (more like the opinion of experts than known for sure). After the statements there is a short summary explaining why we think this, often including a discussion of some of the most helpful research. There is then a list of the most important medical articles so that you can read further if you want to - most of this is freely available online, at least in summary form.A few notes on the individual sections: 1. This section is about how much dialysis a patient should have. The effectiveness of dialysis varies between patients because of differences in body size and age etc., so different people need different amounts, and this section gives guidance on what defines "enough" dialysis and how to make sure each person is getting that. Quite a bit of this section is very technical, for example, the term "eKt/V" is often used: this is a calculation based on blood tests before and after dialysis, which measures the effectiveness of a single dialysis session in a particular patient. 2. This section deals with "non-standard" dialysis, which basically means anything other than 3 times per week. For example, a few people need 4 or more sessions per week to keep healthy, and some people are fine with only 2 sessions per week - this is usually people who are older, or those who have only just started dialysis. Special considerations for children and pregnant patients are also covered here. 3. This section deals with membranes (the type of "filter" used in the dialysis machine) and "HDF" (haemodiafiltration) which is a more complex kind of dialysis which some doctors think is better. Studies are still being done, but at the moment we think it's as good as but not better than regular dialysis. 4. This section deals with fluid removal during dialysis sessions: how to remove enough fluid without causing cramps and low blood pressure. Amongst other recommendations we advise close collaboration with patients over this. 5. This section deals with dialysate, which is the fluid used to "pull" toxins out of the blood (it is sometimes called the "bath"). The level of things like potassium in the dialysate is important, otherwise too much or too little may be removed. There is a section on dialysate buffer (bicarbonate) and also a section on phosphate, which occasionally needs to be added into the dialysate. 6. This section is about anticoagulation (blood thinning) which is needed to stop the circuit from clotting, but sometimes causes side effects. 7. This section is about certain safety aspects of dialysis, not seeking to replace well-established local protocols, but focussing on just a few where we thought some national-level guidance would be useful. 8. This section draws together a few aspects of dialysis which don't easily fit elsewhere, and which impact on how dialysis feels to patients, rather than the medical outcome, though of course these are linked. This is where home haemodialysis and exercise are covered. There is an appendix at the end which covers a few aspects in more detail, especially the mathematical ideas. Several aspects of dialysis are not included in this guideline since they are covered elsewhere, often because they are aspects which affect non-dialysis patients too. This includes: anaemia, calcium and bone health, high blood pressure, nutrition, infection control, vascular access, transplant planning, and when dialysis should be started.Peer reviewe

Quantitative photo-crosslinking mass spectrometry revealing protein structure response to environmental changes

Protein structures respond to changes in their chemical and physical environment. However, studying such conformational changes is notoriously difficult, as many structural biology techniques are also affected by these parameters. Here, the use of photo-crosslinking, coupled with quantitative crosslinking mass spectrometry (QCLMS), offers an opportunity, since the reactivity of photo-crosslinkers is unaffected by changes in environmental parameters. In this study, we introduce a workflow combining photo-crosslinking using sulfosuccinimidyl 4,4′-azipentanoate (sulfo-SDA) with our recently developed data-independent acquisition (DIA)-QCLMS. This novel photo-DIA-QCLMS approach is then used to quantify pH-dependent conformational changes in human serum albumin (HSA) and cytochrome C by monitoring crosslink abundances as a function of pH. Both proteins show pH-dependent conformational changes resulting in acidic and alkaline transitions. 93% and 95% of unique residue pairs (URP) were quantifiable across triplicates for HSA and cytochrome C, respectively. Abundance changes of URPs and hence conformational changes of both proteins were visualized using hierarchical clustering. For HSA we distinguished the N–F and the N–B form from the native conformation. In addition, we observed for cytochrome C acidic and basic conformations. In conclusion, our photo-DIA-QCLMS approach distinguished pH-dependent conformers of both proteins

Reaching Hard-to-Reach Individuals: Nonselective Versus Targeted Outbreak Response Vaccination for Measles

Current mass vaccination campaigns in measles outbreak response are nonselective with respect to the immune status of individuals. However, the heterogeneity in immunity, due to previous vaccination coverage or infection, may lead to potential bias of such campaigns toward those with previous high access to vaccination and may result in a lower-than-expected effective impact. During the 2010 measles outbreak in Malawi, only 3 of the 8 districts where vaccination occurred achieved a measureable effective campaign impact (i.e., a reduction in measles cases in the targeted age groups greater than that observed in nonvaccinated districts). Simulation models suggest that selective campaigns targeting hard-to-reach individuals are of greater benefit, particularly in highly vaccinated populations, even for low target coverage and with late implementation. However, the choice between targeted and nonselective campaigns should be context specific, achieving a reasonable balance of feasibility, cost, and expected impact. In addition, it is critical to develop operational strategies to identify and target hard-to-reach individuals