Recruitment of the Arp2/3 complex to vinculin: coupling membrane protrusion to matrix adhesion

Cell migration involves many steps, including membrane protrusion and the development of new adhesions. Here we have investigated whether there is a link between actin polymerization and integrin engagement. In response to signals that trigger membrane protrusion, the actin-related protein (Arp)2/3 complex transiently binds to vinculin, an integrin-associated protein. The interaction is regulated, requiring phosphatidylinositol-4,5-bisphosphate and Rac1 activation, and is sufficient to recruit the Arp2/3 complex to new sites of integrin aggregation. Binding of the Arp2/3 complex to vinculin is direct and does not depend on the ability of vinculin to associate with actin. We have mapped the binding site for the Arp2/3 complex to the hinge region of vinculin, and a point mutation in this region selectively blocks binding to the Arp2/3 complex. Compared with WT vinculin, expression of this mutant in vinculin-null cells results in diminished lamellipodial protrusion and spreading on fibronectin. The recruitment of the Arp2/3 complex to vinculin may be one mechanism through which actin polymerization and membrane protrusion are coupled to integrin-mediated adhesion

Search for exotic baryons in double radiative capture on pionic hydrogen

We report a search for low-lying exotic baryons via double radiative capture on pionic hydrogen. The data were collected at the TRIUMF cyclotron using the RMC spectrometer by detecting gamma-ray pairs from pion stops in liquid hydrogen. No evidence was found to support an earlier claim for exotic baryons of masses 1004 and 1044 MeV/$c^2$. We obtain upper limits on the branching ratios for double radiative capture via these exotic states of $< 3 \times 10^{-6}$ and $< 4 \times 10^{-6}$ respectively.Comment: 13 pages, 4 figure

Nitrogen Production in Starburst Galaxies Detected by GALEX

We investigate the production of nitrogen in star-forming galaxies with ultraviolet (UV) radiation detected by the Galaxy Evolution Explorer Satellite (GALEX). We use a sample of 8745 GALEX emission-line galaxies matched to the Sloan Digital Sky Survey (SDSS) spectroscopic sample. We derive both gas-phase oxygen and nitrogen abundances for the sample and apply stellar population synthesis models to derive stellar masses and star formation histories of the galaxies. We compare oxygen abundances derived using three different diagnostics. We derive the specific star formation rates of the galaxies by modeling the seven-band GALEX+SDSS photometry. We find that galaxies that have log (SFR/M_*) ≳ − 10.0 typically have values of log (N/O) ~ 0.05 dex less than galaxies with log (SFR/M_*) ≾ − 10.0 and similar oxygen abundances

Lifestyle, exercise and activity package for people living with progressive Multiple Sclerosis (LEAP-MS): adaptions during the COVID-19 pandemic and remote delivery for improved efficiency

The LEAP-MS (Lifestyle, Exercise and Activity Package for People living with Progressive Multiple Sclerosis) study has developed an individualised supported self-management approach for physical activity for people with progressive multiple sclerosis (MS) and severe disability. The intervention has been evaluated in a single-arm feasibility study with embedded process evaluation. The feasibility study was due to open to recruitment during the COVID-19 2020–2021 pandemic, 1 month into the first UK-wide lockdown. We worked rapidly to implement adaptions to the trial procedures and intervention delivery that we believe are applicable to randomised controlled trials. Recruitment became predominantly via self-referral. Electronic consent was employed, with consent discussions occurring over the telephone. Registration, consent, eligibility assessment and data collection as well as the intervention (online physical activity tool) were via a secure, encrypted multi-user web-based platform for participants, physiotherapists and researchers accessible via various hardware. Physiotherapy consultations, as well as the process evaluation, were conducted remotely using video conferencing software or the telephone. A remote training package for physiotherapists and site initiations was also developed and electronic site files employed. Our adaptions are extremely topical given the COVID-19 situation, and whilst not what we had originally planned, have enabled successful delivery of the feasibility study and are relevant to conducting randomised controlled trials and meeting the needs of people with MS who are far more isolated than ever before

Protein kinase A-mediated CREB phosphorylation is an oxidant-induced survival pathway in alveolar type II cells

Oxidant stress plays a role in the pathogenesis of pulmonary diseases, including fibrotic lung disease and cancer. We previously found that hydrogen peroxide (H2O2) initiates an increase in Ca2+/cAMP-response element binding protein (CREB) phosphorylation in C10 alveolar type II cells that requires activation of extracellular regulated kinases 1/2 (ERK1/2). Here, we investigated the role of crosstalk between protein kinase A (PKA) and epidermal growth factor receptor (EGFR) in oxidant-induced signaling to ERK1/2 and CREB in C10 cells. Application of H2O2 increased nuclear accumulation of PKA, and inhibition of PKA with H89 reduced oxidant-mediated phosphorylation of both CREB and ERK1/2. Single cell measurements of cAMP and redox status, using a FRET-based biosensor and a redox-sensitive GFP, respectively, indicated that H2O2 increases production of cAMP that correlates with redox state. Inhibition of EGFR activity decreased both H2O2-induced CREB phosphorylation and translocation of PKA to the nucleus, suggesting that crosstalk between PKA and EGFR underlies the oxidant-induced CREB response. Furthermore, knockdown of CREB expression using siRNA led to a decrease in bcl-2 and an increase in oxidant-induced apoptosis. Together these data reveal a novel role for crosstalk between PKA, ERK1/2 and CREB that mediates cell survival during oxidant stress

CKI isoforms α and ε regulate Star–PAP target messages by controlling Star–PAP poly(A) polymerase activity and phosphoinositide stimulation

Star–PAP is a non-canonical, nuclear poly(A) polymerase (PAP) that is regulated by the lipid signaling molecule phosphatidylinositol 4,5 bisphosphate (PI4,5P2), and is required for the expression of a select set of mRNAs. It was previously reported that a PI4,5P2 sensitive CKI isoform, CKIα associates with and phosphorylates Star–PAP in its catalytic domain. Here, we show that the oxidative stress-induced by tBHQ treatment stimulates the CKI mediated phosphorylation of Star–PAP, which is critical for both its polyadenylation activity and stimulation by PI4,5P2. CKI activity was required for the expression and efficient 3′-end processing of its target mRNAs in vivo as well as the polyadenylation activity of Star–PAP in vitro. Specific CKI activity inhibitors (IC261 and CKI7) block in vivo Star–PAP activity, but the knockdown of CKIα did not equivalently inhibit the expression of Star–PAP targets. We show that in addition to CKIα, Star–PAP associates with another CKI isoform, CKIε in the Star–PAP complex that phosphorylates Star–PAP and complements the loss of CKIα. Knockdown of both CKI isoforms (α and ε) resulted in the loss of expression and the 3′-end processing of Star–PAP targets similar to the CKI activity inhibitors. Our results demonstrate that CKI isoforms α and ε modulate Star–PAP activity and regulates Star–PAP target messages

Effectiveness and cost-effectiveness of a personalised self-management intervention for living with long COVID: protocol for the LISTEN randomised controlled trial

Background: Individuals living with long COVID experience multiple, interacting and fluctuating symptoms which can have a dramatic impact on daily living. The aim of the Long Covid Personalised Self-managemenT support EvaluatioN (LISTEN) trial is to evaluate effects of the LISTEN co-designed self-management support intervention for non-hospitalised people living with long COVID on participation in routine activities, social participation, emotional well-being, quality of life, fatigue, and self-efficacy. Cost-effectiveness will also be evaluated, and a detailed process evaluation carried out to understand how LISTEN is implemented. Methods: The study is a pragmatic randomised effectiveness and cost-effectiveness trial in which a total of 558 non-hospitalised people with long COVID will be randomised to either the LISTEN intervention or usual care. Recruitment strategies have been developed with input from the LISTEN Patient and Public Involvement and Engagement (PPIE) advisory group and a social enterprise, Diversity and Ability, to ensure inclusivity. Eligible participants can self-refer into the trial via a website or be referred by long COVID services. All participants complete a range of self-reported outcome measures, online, at baseline, 6 weeks, and 3 months post randomisation (the trial primary end point). Those randomised to the LISTEN intervention are offered up to six one-to-one sessions with LISTEN-trained intervention practitioners and given a co-designed digital resource and paper-based book. A detailed process evaluation will be conducted alongside the trial to inform implementation approaches should the LISTEN intervention be found effective and cost-effective. Discussion: The LISTEN trial is evaluating a co-designed, personalised self-management support intervention (the LISTEN intervention) for non-hospitalised people living with long COVID. The design has incorporated extensive strategies to minimise participant burden and maximise access. Whilst the duration of follow-up is limited, all participants are approached to consent for long-term follow-up (subject to additional funding being secured)

Restrained Th17 response and myeloid cell infiltration into the central nervous system by human decidua-derived mesenchymal stem cells during experimental autoimmune encephalomyelitis

Background: Multiple sclerosis is a widespread inflammatory demyelinating disease. Several immunomodulatory therapies are available, including interferon-β, glatiramer acetate, natalizumab, fingolimod, and mitoxantrone. Although useful to delay disease progression, they do not provide a definitive cure and are associated with some undesirable side-effects. Accordingly, the search for new therapeutic methods constitutes an active investigation field. The use of mesenchymal stem cells (MSCs) to modify the disease course is currently the subject of intense interest. Decidua-derived MSCs (DMSCs) are a cell population obtained from human placental extraembryonic membranes able to differentiate into the three germ layers. This study explores the therapeutic potential of DMSCs. Methods: We used the experimental autoimmune encephalomyelitis (EAE) animal model to evaluate the effect of DMSCs on clinical signs of the disease and on the presence of inflammatory infiltrates in the central nervous system. We also compared the inflammatory profile of spleen T cells from DMSC-treated mice with that of EAE control animals, and the influence of DMSCs on the in vitro definition of the Th17 phenotype. Furthermore, we analyzed the effects on the presence of some critical cell types in central nervous system infiltrates. Results: Preventive intraperitoneal injection of DMSCs resulted in a significant delay of external signs of EAE. In addition, treatment of animals already presenting with moderate symptoms resulted in mild EAE with reduced disease scores. Besides decreased inflammatory infiltration, diminished percentages of CD4+IL17+, CD11b+Ly6G+ and CD11b+Ly6C+ cells were found in infiltrates of treated animals. Early immune response was mitigated, with spleen cells of DMSC-treated mice displaying low proliferative response to antigen, decreased production of interleukin (IL)-17, and increased production of the anti-inflammatory cytokines IL-4 and IL-10. Moreover, lower RORγT and higher GATA-3 expression levels were detected in DMSC-treated mice. DMSCs also showed a detrimental influence on the in vitro definition of the Th17 phenotype. Conclusions: DMSCs modulated the clinical course of EAE, modified the frequency and cell composition of the central nervous system infiltrates during the disease, and mediated an impairment of Th17 phenotype establishment in favor of the Th2 subtype. These results suggest that DMSCs might provide a new cell-based therapy for the control of multiple sclerosis.This work was sponsored by grants from Acción Estratégica en Salud (PI13/00297 and PI11/00581), the Neurosciences and Aging Foundation, the Francisco Soria Melguizo Foundation, Octopharma, and Parkinson Madrid (PI2012/0032).S

How effective is low vision service provision? A systematic review

Visual impairment is a large and growing socioeconomic problem. Good evidence on rehabilitation outcomes is required to guide service development and improve the lives of people with sight loss. Of the 478 potentially relevant articles identified, only 58 studies met our liberal inclusion criteria, and of these only 7 were randomized controlled trials. Although the literature is sufficient to confirm that rehabilitation services result in improved clinical and functional ability outcomes, the effects on mood, vision-related quality of life (QoL) and health-related QoL are less clear. There are some good data on the performance of particular types of intervention, but almost no useful data about outcomes in children, those of working age, and other groups. There were no reports on cost effectiveness. Overall, the number of well-designed and adequately reported studies is pitifully small; visual rehabilitation research needs higher quality research. We highlight study design and reporting considerations and suggest a future research agenda