Prelamin A Accumulation Attenuates Rac1 Activity and Increases the Intrinsic Migrational Persistence of Aged Vascular Smooth Muscle Cells

Vascular smooth muscle cell (VSMC) motility is essential during both physiological and pathological vessel remodeling. Although ageing has emerged as a major risk factor in the development of cardiovascular disease, our understanding of the impact of ageing on VSMC motility remains limited. Prelamin A accumulation is known to drive VSMC ageing and we show that presenescent VSMCs, that have accumulated prelamin A, display increased focal adhesion dynamics, augmented migrational velocity/persistence and attenuated Rac1 activity. Importantly, prelamin A accumulation in proliferative VSMCs, induced by depletion of the prelamin A processing enzyme FACE1, recapitulated the focal adhesion, migrational persistence and Rac1 phenotypes observed in presenescent VSMCs. Moreover, lamin A/C-depleted VSMCs also display reduced Rac1 activity, suggesting that prelamin A influences Rac1 activity by interfering with lamin A/C function at the nuclear envelope. Taken together, these data demonstrate that lamin A/C maintains Rac1 activity in VSMCs and prelamin A disrupts lamin A/C function to reduce Rac1 activity and induce migrational persistence during VSMC ageing

The UK Healthy Universities Self Review Tool: Whole System Impact

Over recent years, there has been growing interest in Healthy Universities, evidenced by an increased number of national networks and the participation of 375 participants from over 30 countries in the 2015 International Conference on Health Promoting Universities and Colleges, which also saw the launch of the Okanagan Charter. This paper reports on research exploring the use and impact of the UK Healthy Universities Network’s self review tool, specifically examining whether this has supported universities to understand and embed a whole system approach. The research study comprised two stages, the first using an online questionnaire and the second using focus groups. The findings revealed a wide range of perspectives under five overarching themes: motivations; process; outcomes/benefits; challenges/suggested improvements; and future use. In summary, the self review tool was extremely valuable and, when engaged with fully, offered significant benefits to universities seeking to improve the health and wellbeing of their communities. These benefits were felt by institutions at different stages in the journey and spanned outcome and process dimensions: not only did the tool offer an engaging and user-friendly means of undertaking internal benchmarking, generating an easy-to-understand report summarizing strengths and weaknesses; it also proved useful in building understanding of the whole system Healthy Universities approach and served as a catalyst to effective cross-university and cross-sectoral partnership working. Additionally, areas for potential enhancement were identified, offering opportunities to increase the tool’s utility further whilst engaging actively in the development of a global movement for Healthy Universitie

Defects in cell spreading and ERK1/2 activation in fibroblasts with lamin A/C mutations

AbstractIn-frame mutations in nuclear lamin A/C lead to a multitude of tissue-specific degenerative diseases known as the ‘laminopathies’. Previous studies have demonstrated that lamin A/C-null mouse fibroblasts have defects in cell polarisation, suggesting a role for lamin A/C in nucleo-cytoskeletal-cell surface cross-talk. However, this has not been examined in patient fibroblasts expressing modified forms of lamin A/C. Here, we analysed skin fibroblasts from 3 patients with Emery–Dreifuss muscular dystrophy and from 1 with dilated cardiomyopathy. The emerin–lamin A/C interaction was impaired in each mutant cell line. Mutant cells exhibited enhanced cell proliferation, collagen-dependent adhesion, larger numbers of filopodia and smaller cell spread size, compared with control cells. Furthermore, cell migration, speed and polarization were elevated. Mutant cells also showed an enhanced ability to contract collagen gels at early time points, compared with control cells. Phosphotyrosine measurements during cell spreading indicated an initial temporal lag in ERK1/2 activation in our mutant cells, followed by hyper-activation of ERK1/2 at 2 h post cell attachment. Deregulated ERK1/2 activation is linked with cardiomyopathy, cell spreading and proliferation defects. We conclude that a functional emerin–lamin A/C complex is required for cell spreading and proliferation, possibly acting through ERK1/2 signalling

Accelerated competency-based education in primary care (ACE-PC): a 3-year UC Davis and Kaiser permanente partnership to meet California’s primary care physician workforce needs

ProblemOur nation faces an urgent need for more primary care (PC) physicians, yet interest in PC careers is dwindling. Students from underrepresented in medicine (UIM) backgrounds are more likely to choose PC and practice in underserved areas yet their representation has declined. Accelerated PC programs have the potential to address workforce needs, lower educational debt, and diversify the physician workforce to advance health equity.ApproachWith support from Kaiser Permanente Northern California (KPNC) and the American Medical Association's Accelerating Change in Medical Education initiative, University of California School of Medicine (UC Davis) implemented the Accelerated Competency-based Education in Primary Care (ACE-PC) program - a six-year pathway from medical school to residency for students committed to health equity and careers in family medicine or PC-internal medicine. ACE-PC accepts 6-10 students per year using the same holistic admissions process as the 4-year MD program with an additional panel interview that includes affiliated residency program faculty from UC Davis and KPNC. The undergraduate curriculum features: PC continuity clinic with a single preceptor throughout medical school; a 9-month longitudinal integrated clerkship; supportive PC faculty and culture; markedly reduced student debt with full-tuition scholarships; weekly PC didactics; and clinical rotations in affiliated residency programs with the opportunity to match into specific ACE-PC residency tracks.OutcomesSince 2014, 70 students have matriculated to ACE-PC, 71% from UIM groups, 64% are first-generation college students. Of the graduates, 48% have entered residency in family medicine and 52% in PC-internal medicine. In 2020, the first graduates entered the PC workforce; all are practicing in California, including 66% at federally qualified health centers, key providers of underserved care

Time‐lapse photogrammetry reveals hydrological controls of fine‐scale High‐Arctic glacier surface roughness evolution

In a warming Arctic, as glacier snowlines rise, short- to medium-term increases in seasonal bare-ice extent are forecast for the next few decades. These changes will enhance the importance of turbulent energy fluxes for surface ablation and glacier mass balance. Turbulent energy exchanges at the ice surface are conditioned by its topography, or roughness, which has been hypothesized to be controlled by supraglacial hydrology at the glacier scale. However, current understanding of the dynamics in surface topography, and the role of drainage development, remains incomplete, particularly for the transition between seasonal snow cover and well-developed, weathered bare-ice. Using time-lapse photogrammetry, we report a daily timeseries of fine (millimetre)-scale supraglacial topography at a 2 m2 plot on the Lower Foxfonna glacier, Svalbard, over two 9-day periods in 2011. We show traditional kernel-based morphometric descriptions of roughness were ineffective in describing temporal change, but indicated fine-scale albedo feedbacks at depths of ~60 mm contributed to conditioning surface topography. We found profile-based and two-dimensional estimates of roughness revealed temporal change, and the aerodynamic roughness parameter, z0, showed a 22–32% decrease from ~1 mm following the exposure of bare-ice, and a subsequent 72–77% increase. Using geostatistical techniques, we identified ‘hole effect’ properties in the surface elevation semivariograms, and demonstrated that hydrological drivers control the plot-scale topography: degradation of superimposed ice reduces roughness while the inception of braided rills initiates a subsequent development and amplification of topography. Our study presents an analytical framework for future studies that interrogate the coupling between ice surface roughness and hydro-meteorological variables and seek to improve parameterizations of topographically evolving bare-ice areas

Bandage: interactive visualization of de novo genome assemblies.

UNLABELLED: Although de novo assembly graphs contain assembled contigs (nodes), the connections between those contigs (edges) are difficult for users to access. Bandage (a Bioinformatics Application for Navigating De novo Assembly Graphs Easily) is a tool for visualizing assembly graphs with connections. Users can zoom in to specific areas of the graph and interact with it by moving nodes, adding labels, changing colors and extracting sequences. BLAST searches can be performed within the Bandage graphical user interface and the hits are displayed as highlights in the graph. By displaying connections between contigs, Bandage presents new possibilities for analyzing de novo assemblies that are not possible through investigation of contigs alone. AVAILABILITY AND IMPLEMENTATION: Source code and binaries are freely available at https://github.com/rrwick/Bandage. Bandage is implemented in C++ and supported on Linux, OS X and Windows. A full feature list and screenshots are available at http://rrwick.github.io/Bandage. CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online

Prophylactic antibiotic regimens in tumour surgery (PARITY): protocol for a multicentre randomised controlled study.

IntroductionLimb salvage with endoprosthetic reconstruction is the standard of care for the management of lower-extremity bone tumours in skeletally mature patients. The risk of deep postoperative infection in these procedures is high and the outcomes can be devastating. The most effective prophylactic antibiotic regimen remains unknown, and current clinical practice is highly varied. This trial will evaluate the effect of varying postoperative prophylactic antibiotic regimens on the incidence of deep infection following surgical excision and endoprosthetic reconstruction of lower-extremity bone tumours.Methods and analysisThis is a multicentre, blinded, randomised controlled trial, using a parallel two-arm design. 920 patients 15 years of age or older from 12 tertiary care centres across Canada and the USA who are undergoing surgical excision and endoprosthetic reconstruction of a primary bone tumour will receive either short (24 h) or long (5 days) duration postoperative antibiotics. Exclusion criteria include prior surgery or infection within the planned operative field, known colonisation with methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus at enrolment, or allergy to the study antibiotics. The primary outcome will be rates of deep postoperative infections in each arm. Secondary outcomes will include type and frequency of antibiotic-related adverse events, patient functional outcomes and quality-of-life scores, reoperation and mortality. Randomisation will be blocked, with block sizes known only to the methods centre responsible for randomisation, and stratified by location of tumour and study centre. Patients, care givers and a Central Adjudication Committee will be blinded to treatment allocation. The analysis to compare groups will be performed using Cox regression and log-rank tests to compare survival functions at α=0.05.Ethics and disseminationThis study has ethics approval from the McMaster University/Hamilton Health Sciences Research Ethics Board (REB# 12-009). Successful completion will significantly impact on clinical practice and enhance patients' lives. More broadly, this trial will develop a network of collaboration from which further high-quality trials in Orthopaedic Oncology will follow

Pasture, Hay and Silage Crops for East Texas.

28 p