Class II Phosphoinositide 3-Kinases Contribute to Endothelial Cells Morphogenesis

PMCID: PMC3539993This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

EMG-Driven inverse dynamic analysis of knee contact forces during gait and cycling using OpenSim

Joint contact forces determine the loading experienced by cartilage tissue and, thus, may be used to predict risk of cartilage tissue damage and osteoarthritis (OA). Participating in low impact and/or non-weight bearing activities such as cycling may help reduce knee OA risk by limiting forces exerted during exercise [1]. Cycling is a common recommendation for rehabilitative or fitness sustainment exercise for select patients [1]. Although knee joint contact forces have been directly measured in gait and cycling using instrumented knee implants [2,3] and calculated in gait using EMG-driven analysis [4]; they have not been calculated in cycling using EMG-driven analysis. The long-term goal of this study is to identify weight control exercises for overweight (OW) and obese (OB) subjects that minimize OA risk. This current study tests the hypothesis that knee joint contact forces are significantly lower during cycling than gait. The objectives are to: (1) conduct motion analysis experiments and EMG-driven OpenSim analyses for gait and cycling, (2) compare predicted tibiofemoral (TF) contact forces to published values, and (3) test for significant differences in maximum TF compressive forces in gait and cycling

Diet quality in late midlife is associated with faster walking speed in later life in women, but not men: findings from a prospective British birth cohort

Healthy diet has been linked to better age-related physical functioning, but evidence on the relationship of overall diet quality in late midlife and clinically relevant measures of physical functioning in later life is limited. Research on potential sex differences in this relationship is scarce. The aim was to investigate the prospective association between overall diet quality, as assessed by the Healthy Eating Index-2015 at age 60-64y and measures of walking speed seven years later, among men and women from the Insight46, a neuroscience sub-study of the Medical Research Council National Survey of Health and Development. Diet was assessed at age 60-64y using five-day food diaries, from which total HEI-2015 was calculated. At age 69-71y, walking speed was estimated during four 10-meter walks at self-selected pace, using inertial measurement units. Multivariable linear regression models with sex as modifier, controlling for age, follow-up, lifestyle, health, social variables and physical performance were used. The final sample was 164 women and 167 men (n=331). Women had higher HEI-2015 scores and slower walking speed than men. A 10 point increase in HEI-2015 was associated with faster walking speed seven years later among women (B: 0.024, 95% CI: 0.006, 0.043), but not men. The association remained significant in the multivariable model (B: 0.021, 95% CI: 0.003, 0.040). In women in late midlife higher diet quality is associated with faster walking speed. A healthy diet in late midlife is likely to contribute towards better age-related physical capability and sex differences are likely to affect this relationship

Diet quality in late midlife is associated with faster walking speed in later life in women, but not men

Healthy diet has been linked to better age-related physical functioning, but evidence on the relationship of overall diet quality in late midlife and clinically relevant measures of physical functioning in later life is limited. Research on potential sex differences in this relationship is scarce. The aim was to investigate the prospective association between overall diet quality, as assessed by the Healthy Eating Index-2015 at age 60-64y and measures of walking speed seven years later, among men and women from the Insight46, a neuroscience sub-study of the Medical Research Council National Survey of Health and Development. Diet was assessed at age 60-64y using five-day food diaries, from which total HEI-2015 was calculated. At age 69-71y, walking speed was estimated during four 10-meter walks at self-selected pace, using inertial measurement units. Multivariable linear regression models with sex as modifier, controlling for age, follow-up, lifestyle, health, social variables and physical performance were used. The final sample was 164 women and 167 men (n=331). Women had higher HEI-2015 scores and slower walking speed than men. A 10 point increase in HEI-2015 was associated with faster walking speed seven years later among women (B: 0.024, 95% CI: 0.006, 0.043), but not men. The association remained significant in the multivariable model (B: 0.021, 95% CI: 0.003, 0.040). In women in late midlife higher diet quality is associated with faster walking speed. A healthy diet in late midlife is likely to contribute towards better age-related physical capability and sex differences are likely to affect this relationship

Deliberative multiattribute valuation of ecosystem services across a range of regional land-use, socioeconomic, and climate scenarios for the upper Merrimack River watershed, New Hampshire, USA

We evaluate the relative desirability of alternative futures for the upper Merrimack River watershed in New Hampshire, USA based on the value of ecosystem services at the end of the 21st century as gauged by its present-day inhabitants. This evaluation is accomplished by integrating land-use and socioeconomic scenarios, downscaled climate projections, biogeophysical simulation models, and the results of a citizen-stakeholder deliberative multicriteria evaluation. We find that although there are some trade-offs between alternative plausible futures, for the most part, it can be expected that future inhabitants of the watershed will be most satisfied if land-use planning in the intervening years prioritizes water supply and flood protection as well as maintenance of existing farmland and forest cover. With respect to climate change, it is expected that future watershed inhabitants will be more negatively affected by the projected loss of snow cover than the anticipated increase in hot summer days. More important than the specific results for the upper Merrimack River watershed, this integrative assessment demonstrates the complex yet ultimately informative potential to link stakeholder engagement with scenario generation, ecosystem models, and multiattribute evaluation for informing regional-scale planning and decision making

Cryoglobulinemic vasculitis in primary Sj\uf6gren's Syndrome: Clinical presentation, association with lymphoma and comparison with Hepatitis C-related disease

Objective: To describe the clinical spectrum of cryoglobulinemic vasculitis (CV) in primary Sj\uf6gren's syndrome (pSS), investigate its relation to lymphoma and identify the differences with hepatitis C virus (HCV) related CV. Methods: From a multicentre study population of consecutive pSS patients, those who had been evaluated for cryoglobulins and fulfilled the 2011 classification criteria for CV were identified retrospectively. pSS-CV patients were matched with pSS patients without cryoglobulins (1:2) and HCV-CV patients (1:1). Clinical, laboratory and outcome features were analyzed. A data driven logistic regression model was applied for pSS-CV patients and their pSS cryoglobulin negative controls to identify independent features associated with lymphoma. Results: 1083 pSS patients were tested for cryoglobulins. 115 (10.6%) had cryoglobulinemia and 71 (6.5%) fulfilled the classification criteria for CV. pSS-CV patients had higher frequency of extraglandular manifestations and lymphoma (OR=9.87, 95% CI: 4.7\u201320.9) compared to pSS patients without cryoglobulins. Purpura was the commonest vasculitic manifestation (90%), presenting at disease onset in 39% of patients. One third of pSS-CV patients developed B-cell lymphoma within the first 5 years of CV course, with cryoglobulinemia being the strongest independent lymphoma associated feature. Compared to HCV-CV patients, pSS-CV individuals displayed more frequently lymphadenopathy, type II IgMk cryoglobulins and lymphoma (OR = 6.12, 95% CI: 2.7\u201314.4) and less frequently C4 hypocomplementemia and peripheral neuropathy. Conclusion: pSS-CV has a severe clinical course, overshadowing the typical clinical manifestations of pSS and higher risk for early lymphoma development compared to HCV related CV. Though infrequent, pSS-CV constitutes a distinct severe clinical phenotype of pSS

SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response.

SF3B1 hotspot mutations are associated with a poor prognosis in several tumor types and lead to global disruption of canonical splicing. Through synthetic lethal drug screens, we identify that SF3B1 mutant (SF3B1MUT) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1MUT cells display a defective response to PARPi-induced replication stress that occurs via downregulation of the cyclin-dependent kinase 2 interacting protein (CINP), leading to increased replication fork origin firing and loss of phosphorylated CHK1 (pCHK1; S317) induction. This results in subsequent failure to resolve DNA replication intermediates and G2/M cell cycle arrest. These defects are rescued through CINP overexpression, or further targeted by a combination of ataxia-telangiectasia mutated and PARP inhibition. In vivo, PARPi produce profound antitumor effects in multiple SF3B1MUT cancer models and eliminate distant metastases. These data provide the rationale for testing the clinical efficacy of PARPi in a biomarker-driven, homologous recombination proficient, patient population

The effect of breaking sitting time with physical activity breaks on cognitive performance in young people with cerebral palsy : an exposure response cross-over feasibility design

Objectives. To assess the feasibility of methods and estimate the potential effect of interrupting sedentary behaviour, with intermittent or continuous physical activity breaks, on cognitive performance in young people with Cerebral Palsy. Methods. A randomised three-arm exposure response cross-over design with process evaluation. Participants were recruited throughout the Thames Valley, UK between 01/11/2018 to 31/03/2020. The three 2 h activity exposure visits included: (i) sitting only (controls), (ii) sitting plus 20 min of moderate-to-vigorous activity burst, or (iii) 4×5 min of moderate-to-vigorous activity bursts, during a 2.5 h sedentary session. Measures of feasibility were sought. Cognitive performance outcomes (using the Eriksen Flanker task and Forward and Backward Digit Span) were delivered before and after the 2 h testing period. Results. 36 participants were randomised (age 13.2±2.7, Gross-Motor Functional Classification System 1–3). Study retention was 83 % across all three interventions and overall missing data for measures was 4 %. A small intervention effect was found in reaction time in the 4×5 min physical activity exposure session compared to the sedentary control condition (0.42; 95 % CI 0.40 to 0.79). There were two research-related minor adverse effects, an allergic reaction to the FreeStyle Libre and feeling faint and vomiting after consumption of glucose solution. Both events were resolved and participants continued with the study. Conclusions. The study design and intervention implementing short bursts of physical activity was feasible and indicated a potential effect on reaction time as a measure of cognitive performance in young people with cerebral palsy