Localized Tensional Forces on PECAM-1 Elicit a Global Mechanotransduction Response via the Integrin-RhoA Pathway

SummaryBackgroundMechanical forces regulate cell behavior and function during development, differentiation, and tissue morphogenesis. In the vascular system, forces produced by blood flow are critical determinants not only of morphogenesis and function, but also of pathological states such as atherosclerosis. Endothelial cells (ECs) have numerous mechanotransducers, including platelet endothelial cell adhesion molecule-1 (PECAM-1) at cell-cell junctions and integrins at cell-matrix adhesions. However, the processes by which forces are transduced to biochemical signals and subsequently translated into downstream effects are poorly understood.ResultsHere, we examine mechanochemical signaling in response to direct force application on PECAM-1. We demonstrate that localized tensional forces on PECAM-1 result in, surprisingly, global signaling responses. Specifically, force-dependent activation of phosphatidylinositol 3-kinase (PI3K) downstream of PECAM-1 promotes cell-wide activation of integrins and the small GTPase RhoA. These signaling events facilitate changes in cytoskeletal architecture, including growth of focal adhesions and adaptive cytoskeletal stiffening.ConclusionsTaken together, our work provides the first evidence of a global signaling event in response to a localized mechanical stress. In addition, these data provide a possible mechanism for the differential stiffness of vessels exposed to distinct hemodynamic force patterns in vivo

Localized Tensional Forces on PECAM-1 Elicit a Global Mechanotransduction Response via the Integrin-RhoA Pathway

Mechanical forces regulate cell behavior and function during development, differentiation, and tissue morphogenesis. In the vascular system, forces produced by blood flow are critical determinants not only of morphogenesis and function, but also pathological states such as atherosclerosis. Endothelial cells (ECs) have numerous mechanotransducers, including platelet endothelial cell adhesion molecule-1 (PECAM-1) at cell-cell junctions and integrins at cell-matrix adhesions. However, the processes by which forces are transduced to biochemical signals and subsequently translated into downstream effects are poorly understood

Veloce Rosso: Australia's new precision radial velocity spectrograph

Veloce is an ultra-stable fibre-fed R4 echelle spectrograph for the 3.9 m Anglo-Australian Telescope. The first channel to be commissioned, Veloce ‘Rosso’, utilises multiple low-cost design innovations to obtain Doppler velocities for sun-like and M-dwarf stars at 75,000 spectra over a 580-930 nm range for the Rosso channel. Simultaneous calibration is provided by a single-mode pulsed laser frequency comb in tandem with a traditional arc lamp. A bundle of 19 object fibres ensures full sampling of stellar targets from the AAT site. Veloce is housed in dual environmental enclosures that maintain positive air pressure at a stability of ±0.3 mbar, with a thermal stability of ±0.01 K on the optical bench. We present a technical overview and early performance data from Australia's next major spectroscopic machine

Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

A scoping review of the use of co-design methods with culturally and linguistically diverse communities to improve or adapt mental health services

Mental health services are increasingly encouraged to use co-design methodologies to engage individuals and families affected by mental health problems in service design and improvement. This scoping review aimed to identify research that used co-design methods with Culturally and Linguistically Diverse (CALD) communities in mental health services, and to identify methodological considerations for working with this population. In October 2019, we searched five electronic databases (CINAHL, PsycINFO, EMBASE, MEDLINE, Web of Science) to identify papers published in which people from CALD backgrounds were engaged in the co-design of a mental health service or program. Searches were limited to peer-reviewed articles published in English in the last 25 years (1993–2019). The search identified nine articles that matched the inclusion criteria. Using a scoping review methodology, the first author charted the data using extraction fields and then used qualitative synthesis methods to identify themes. Data were grouped into themes relevant to the research question. The two key themes relate first, to improving the experience for CALD communities when engaging in co-design research and second, to the development of co-design methods themselves. These findings support the need for further research into the transferability of co-design tools with CALD communities, particularly if co-design is to become a best practice method for service design and improvement. This scoping review identified methodological and practical consideration for researchers looking to use co-design with CALD communities for mental health service design, re-design or quality improvement initiatives. Further research is required to explore experiences of co-design methods, including documented protocols such as experience-based co-design, with CALD communities. This review indicates that explanatory models of mental health, community and co-design impact partnerships with CALD communities, and need to be understood to optimise the quality of these relationships when using co-design methods

Characteristics of endemic areas and clusters for gonorrhoea, England: 2012 and 2013.

<p>Characteristics of endemic areas and clusters for gonorrhoea, England: 2012 and 2013.</p

Quarterly gonorrhoea diagnosis rate with regions grouped by Local Authority (LA), England: 2013.

<p>Regions are compared to the English average (12.6/100,000 people) as higher, similar or lower. Similar regions were denoted as those within 20% above or below the English average (12.6–15.1 and 10.1–12.6/100,000 people, respectively).</p

Patients attending GUM clinics and diagnoses of gonorrhoea, England: 2012 to 2013.

<p>Patients attending GUM clinics and diagnoses of gonorrhoea, England: 2012 to 2013.</p

Gonorrhoea endemic regions and outbreak clusters, England: 2012 & 2013.

<p>Brighton, London, Birmingham and Manchester were endemic for gonorrhoea by persistently arising in clusters every six months for two years. The London area is enlarged to the top right to better illustrate endemic areas and clusters. Circles denote 33 clusters across 21 aggregate regions (1,137 MSOAs). Numbers next to clusters correspond to region names listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0195178#pone.0195178.s006" target="_blank">S1 Table</a>. All outbreak clusters are interpreted as significant at <i>p</i><0.05. Age, gender, ethnicity, and IMD were included covariates.</p