Free Brick1 Is a Trimeric Precursor in the Assembly of a Functional Wave Complex

Background: The Wave complex activates the Arp2/3 complex, inducing actin polymerization in lamellipodia and membrane ruffles. The Wave complex is composed of five subunits, the smallest of which, Brick1/Hspc300 (Brk1), is the least characterized. We previously reported that, unlike the other subunits, Brk1 also exists as a free form. Principal Findings: Here we report that this free form of Brk1 is composed of homotrimers. Using a novel assay in which purified free Brk1 is electroporated into HeLa cells, we were able to follow its biochemical fate in cells and to show that free Brk1 becomes incorporated into the Wave complex. Importantly, incorporation of free Brk1 into the Wave complex was blocked upon inhibition of protein synthesis and incorporated Brk1 was found to associate preferentially with neosynthesized subunits. Brk1 depleted HeLa cells were found to bleb, as were Nap1, Wave2 or ARPC2 depleted cells, suggesting that this blebbing phenotype of Brk1 depleted cells is due to an impairment of the Wave complex function rather than a specific function of free Brk1. Blebs of Brk1 depleted cells were emitted at sites where lamellipodia and membrane ruffles were normally emitted. In Brk1 depleted cells, the electroporation of free Brk1 was sufficient to restore Wave complex assembly and to rescue the blebbing phenotype. Conclusion: Together these results establish that the free form of Brk1 is an essential precursor in the assembly of

Activity pacing for osteoarthritis symptom management: study design and methodology of a randomized trial testing a tailored clinical approach using accelerometers for veterans and non-veterans

<p>Abstract</p> <p>Background</p> <p>Osteoarthritis (OA) is a prevalent chronic disease and a leading cause of disability in adults. For people with knee and hip OA, symptoms (e.g., pain and fatigue) can interfere with mobility and physical activity. Whereas symptom management is a cornerstone of treatment for knee and hip OA, limited evidence exists for behavioral interventions delivered by rehabilitation professionals within the context of clinical care that address how symptoms affect participation in daily activities. Activity pacing, a strategy in which people learn to preplan rest breaks to avoid symptom exacerbations, has been effective as part of multi-component interventions, but hasn't been tested as a stand-alone intervention in OA or as a tailored treatment using accelerometers. In a pilot study, we found that participants who underwent a tailored activity pacing intervention had reduced fatigue interference with daily activities. We are now conducting a full-scale trial.</p> <p>Methods/Design</p> <p>This paper provides a description of our methods and rationale for a trial that evaluates a tailored activity pacing intervention led by occupational therapists for adults with knee and hip OA. The intervention uses a wrist accelerometer worn during the baseline home monitoring period to glean recent symptom and physical activity patterns and to tailor activity pacing instruction based on how symptoms relate to physical activity. At 10 weeks and 6 months post baseline, we will examine the effectiveness of a tailored activity pacing intervention on fatigue, pain, and physical function compared to general activity pacing and usual care groups. We will also evaluate the effect of tailored activity pacing on physical activity (PA).</p> <p>Discussion</p> <p>Managing OA symptoms during daily life activity performance can be challenging to people with knee and hip OA, yet few clinical interventions address this issue. The activity pacing intervention tested in this trial is designed to help people modulate their activity levels and reduce symptom flares caused by too much or too little activity. As a result of this trial, we will be able to determine if activity pacing is more effective than usual care, and among the intervention groups, if an individually tailored approach improves fatigue and pain more than a general activity pacing approach.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01192516">NCT01192516</a></p

The interest of gait markers in the identification of subgroups among fibromyalgia patients

<p>Abstract</p> <p>Background</p> <p>Fibromyalgia (FM) is a heterogeneous syndrome and its classification into subgroups calls for broad-based discussion. FM subgrouping, which aims to adapt treatment according to different subgroups, relies in part, on psychological and cognitive dysfunctions. Since motor control of gait is closely related to cognitive function, we hypothesized that gait markers could be of interest in the identification of FM patients' subgroups. This controlled study aimed at characterizing gait disorders in FM, and subgrouping FM patients according to gait markers such as stride frequency (SF), stride regularity (SR), and cranio-caudal power (CCP) which measures kinesia.</p> <p>Methods</p> <p>A multicentre, observational open trial enrolled patients with primary FM (44.1 ± 8.1 y), and matched controls (44.1 ± 7.3 y). Outcome measurements and gait analyses were available for 52 pairs. A 3-step statistical analysis was carried out. A preliminary single blind analysis using k-means cluster was performed as an initial validation of gait markers. Then in order to quantify FM patients according to psychometric and gait variables an open descriptive analysis comparing patients and controls were made, and correlations between gait variables and main outcomes were calculated. Finally using cluster analysis, we described subgroups for each gait variable and looked for significant differences in self-reported assessments.</p> <p>Results</p> <p>SF was the most discriminating gait variable (73% of patients and controls). SF, SR, and CCP were different between patients and controls. There was a non-significant association between SF, FIQ and physical components from Short-Form 36 (p = 0.06). SR was correlated to FIQ (p = 0.01) and catastrophizing (p = 0.05) while CCP was correlated to pain (p = 0.01). The SF cluster identified 3 subgroups with a particular one characterized by normal SF, low pain, high activity and hyperkinesia. The SR cluster identified 2 distinct subgroups: the one with a reduced SR was distinguished by high FIQ, poor coping and altered affective status.</p> <p>Conclusion</p> <p>Gait analysis may provide additional information in the identification of subgroups among fibromyalgia patients. Gait analysis provided relevant information about physical and cognitive status, and pain behavior. Further studies are needed to better understand gait analysis implications in FM.</p

Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities

Background Epidermal growth factor receptor inhibitors (EGFRI) produce various dermatologic side effects in the majority of patients, and guidelines are crucial for the prevention and treatment of these untoward events. The purpose of this panel was to develop evidence-based recommendations for EGFRI-associated dermatologic toxicities. Methods A multinational, interdisciplinary panel of experts in supportive care in cancer reviewed pertinent studies using established criteria in order to develop first-generation recommendations for EGFRI-associated dermatologic toxicities. Results Prophylactic and reactive recommendations for papulopustular (acneiform) rash, hair changes, radiation dermatitis, pruritus, mucositis, xerosis/fissures, and paronychia are presented, as well as general dermatologic recommendations when possible. Conclusion Prevention and management of EGFRI-related dermatologic toxicities is critical to maintain patients’ health-related quality of life and dose intensity of antineoplastic regimens. More rigorous investigation of these toxicities is warranted to improve preventive and treatment strategies

Interaction for Immersive Analytics

International audienceIn this chapter, we briefly review the development of natural user interfaces and discuss their role in providing human-computer interaction that is immersive in various ways. Then we examine some opportunities for how these technologies might be used to better support data analysis tasks. Specifically, we review and suggest some interaction design guidelines for immersive analytics. We also review some hardware setups for data visualization that are already archetypal. Finally, we look at some emerging system designs that suggest future directions

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead