An engineered protein antagonist of K-Ras/B-Raf interaction

Ras is at the hub of signal transduction pathways controlling cell proliferation and survival. Its mutants, present in about 30% of human cancers, are major drivers of oncogenesis and render tumors unresponsive to standard therapies. Here we report the engineering of a protein scaffold for preferential binding to K-Ras G12D. This is the first reported inhibitor to achieve nanomolar affinity while exhibiting specificity for mutant over wild type (WT) K-Ras. Crystal structures of the protein R11.1.6 in complex with K-Ras WT and K-Ras G12D offer insight into the structural basis for specificity, highlighting differences in the switch I conformation as the major defining element in the higher affinity interaction. R11.1.6 directly blocks interaction with Raf and reduces signaling through the Raf/MEK/ERK pathway. Our results support greater consideration of the state of switch I and provide a novel tool to study Ras biology. Most importantly, this work makes an unprecedented contribution to Ras research in inhibitor development strategy by revealing details of a targetable binding surface. Unlike the polar interfaces found for Ras/effector interactions, the K-Ras/R11.1.6 complex reveals an extensive hydrophobic interface that can serve as a template to advance the development of high affinity, non-covalent inhibitors of K-Ras oncogenic mutants.National Institutes of Health (U.S.) (Grant 5-R01-CA096504-15

Psychometric testing of the British‐English perceived workplace support scale, work accommodations, benefits, policies and practices scale, and work transitions index in four rheumatic and musculoskeletal conditions

Objective The aims were to validate linguistically British-English versions of the Perceived Workplace Support Scale (PWSS), Work Accommodations, Benefits, Policies and Practices Scale (WABPPS), and Work Transitions Index (WTI) in rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), osteoarthritis (OA) and fibromyalgia (FM). Methods The three scales were adapted into British-English and reviewed by an expert panel prior to cognitive debriefing interviews. Participants completed postal questionnaires. Construct validity for the PWSS was assessed using Rasch analysis. Concurrent validity included testing between the three scales and work, job strain and work-life balance scales. Two weeks later, participants were mailed a second questionnaire to measure test-retest reliability. Results The questionnaire was completed by 831 employed participants: 68% women, 53.50 (SD 8.9) years of age, with condition duration 7.70 (SD 8.00) years. The PWSS satisfied Rasch model requirements. Concurrent validity was mostly as hypothesised, that is, weak to moderate negative correlations for the PWSS (rs = 0.07 to −0.61), and weak to moderate positive correlations for the WABPPS and WTI (rs = 0.20–0.52). Some correlations were stronger, mostly in axSpA. Internal consistency (Cronbach's alpha) for all three scales was consistent with group use in all conditions. Test-retest reliability was generally excellent, with intraclass coefficients (2,1) of 0.80–0.93 for the three scales in the four conditions. Discussion Reliable, valid versions of the British-English PWSS, WABPPS, and WTI are now available for use in research, organisational level studies and vocational rehabilitation

Muscle-specific ablation of glucose transporter 1 (GLUT1) does not impair basal or overload-stimulated skeletal muscle glucose uptake

Glucose transporter 1 (GLUT1) is believed to solely mediate basal (insulin-independent) glucose uptake in skeletal muscle; yet recent work has demonstrated that mechanical overload, a model of resistance exercise training, increases muscle GLUT1 levels. The primary objective of this study was to determine if GLUT1 is necessary for basal or overload-stimulated muscle glucose uptake. Muscle-specific GLUT1 knockout (mGLUT1KO) mice were generated and examined for changes in body weight, body composition, metabolism, systemic glucose regulation, muscle glucose transporters, and muscle

Novel appeasing pheromones to minimize stress during metapopulation management of African wild dogs

In the last century, human persecution and increased habitat fragmentation has reduced African wild dog populations from around 500,000 to 6,600 individuals, with the population continuing to decline. In South Africa, metapopulation management has been instrumental to the survival of populations across fragmented habitats, and entails the translocation and artificial new pack formation of animals to reinforce populations, maximize genetic dispersal and reintroduce animals into their former range. However, temporary captivity during such conservation interventions regularly cause chronic stress in African wild dogs, and can result in increased aggression, disrupted pack hierarchy, injury and occasionally mortality. Pheromones are naturally occurring chemicals that can moderate behaviours and physiology in conspecifics. Appeasing pheromones identified in domestic dogs (DAP) are known to reduce stress and aggression. When applied to African wild dog packs, we showed DAP treatment decreased faecal androgen metabolite concentrations and shifted dominance behaviour from contact to non-contact compared to controls (Van den Berghe et al. PLoS ONE 14(3): e0212551). However, because pheromones are largely species-specific, an African wild dog-specific appeasing pheromone (AWDAP) should elicit a stronger beneficial physiological and behavioural effect during conservation interventions. In this project, AWDAP will be isolated and applied to packs undergoing translocation in South Africa. Using a combination of behaviour, faecal hormone metabolites and antibodies, animals will be monitored for reduced stress and aggression, improved immune function and greater social cohesion, all of which should ultimately confer a survival advantage to the pack upon release into the wild

Psychometric testing of the British‐English long‐term conditions job strain scale, long‐term conditions work spillover scale and work‐health‐personal life perceptions Scale in four rheumatic and musculoskeletal conditions

Objective: The aims were to validate linguistically British‐English versions of the Long‐Term Conditions Job Strain Scale (LTCJSS), Long‐Term Conditions Work Spillover Scale (LTCWSS) and Work‐Health‐Personal Life Perceptions Scale (WHPLPS) in rheumatoid arthritis, axial spondyloarthritis, osteoarthritis and fibromyalgia (FM). Methods: The three scales were forward translated and reviewed by an expert panel prior to cognitive debriefing interviews. Participants completed a postal questionnaire. Construct validity was assessed using Rasch analysis. Concurrent validity included testing between the three scales and work (e.g., Workplace Activity Limitations Scale [WALS]) and condition‐specific health scales. Two weeks later, participants were mailed a second questionnaire to measure test‐retest reliability. Results: The questionnaire was completed by 831 employed participants: 68% women, 53.5 (SD 8.9) years of age, with condition duration 7.7 (SD 8.0) years. The LTCJSS, LTCWSS and WHPLPS Parts 1 and 2 satisfied Rasch model requirements, but Part 3 did not. A Rasch transformation scale and Reference Metric equating scales with the WALS were created. Concurrent validity was generally good (r s = 0.41–0.85) for the three scales, except the WHPLPS Part 3. Internal consistency (Person Separation Index values) was consistent with group use in all conditions, and individual use except for the LTCWSS and WHPLSP Parts 1 and 2 in FM. Test‐retest reliability was excellent, with intraclass coefficients (2,1) of 0.80–0.96 for the three scales in the four conditions. Discussion: Reliable, valid versions of the British‐English LTCJSS, LTCWSS and WHPLPS Parts 1 and 2 are now available for use in the UK

Psychometric testing of the British‐English Long‐Term Conditions Job Strain Scale, Long‐Term Conditions Work Spillover Scale and Work‐Health‐Personal Life Perceptions Scale in four rheumatic and musculoskeletal conditions

Objective: The aims were to validate linguistically British-English versions of the Long-Term Conditions Job Strain Scale (LTCJSS), Long-Term Conditions Work Spillover Scale (LTCWSS) and Work-Health-Personal Life Perceptions Scale (WHPLPS) in rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), osteoarthritis (OA) and fibromyalgia (FM). Methods: The three scales were forward translated and reviewed by an expert panel prior to cognitive debriefing interviews. Participants completed a postal questionnaire. Construct validity was assessed using Rasch analysis. Concurrent validity included testing between the three scales and work (e.g., Workplace Activity Limitations Scale (WALS)) and condition-specific health scales. Two weeks later, participants were mailed a second questionnaire to measure test-retest reliability. Results: The questionnaire was completed by 831 employed participants: 68% women; 53.5 (SD 8.9) years of age; with condition duration 7.7 (SD 8.0) years. The LTCJSS, LTCWSS and WHPLPS Parts 1 and 2 satisfied Rasch model requirements, but Part 3 did not. A Rasch transformation scale, and a Reference Metric equating scales with the WALS, were created. Concurrent validity was generally good (rs =0.41-0.85) for the three scales, except the WHPLPS Part 3. Internal consistency (Person Separation Index values) was consistent with group use in all conditions, and individual use except for the LTCWSS and WHPLSP Parts 1 and 2 in FM. Test-retest reliability was excellent, with intraclass coefficients (2,1) of 0.80 – 0.96 for the three scales in the four conditions. Discussion: Reliable, valid versions of the British-English LTCJSS, LTCWSS and WHPLPS Parts 1 and 2 are now available for use in the UK

Psychometric testing of the British‐English Perceived Workplace Support Scale, Work Accommodations, Benefits, Policies and Practices Scale, and Work Transitions Index in four rheumatic and musculoskeletal conditions

Objective: The aims were to validate linguistically British‐English versions of the Perceived Workplace Support Scale (PWSS), Work Accommodations, Benefits, Policies and Practices Scale (WABPPS), and Work Transitions Index (WTI) in rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), osteoarthritis (OA) and fibromyalgia (FM). Methods: The three scales were adapted into British‐English and reviewed by an expert panel prior to cognitive debriefing interviews. Participants completed postal questionnaires. Construct validity for the PWSS was assessed using Rasch analysis. Concurrent validity included testing between the three scales and work, job strain and work‐life balance scales. Two weeks later, participants were mailed a second questionnaire to measure test‐retest reliability. Results: The questionnaire was completed by 831 employed participants: 68% women, 53.50 (SD 8.9) years of age, with condition duration 7.70 (SD 8.00) years. The PWSS satisfied Rasch model requirements. Concurrent validity was mostly as hypothesised, that is, weak to moderate negative correlations for the PWSS (rs = 0.07 to −0.61), and weak to moderate positive correlations for the WABPPS and WTI (rs = 0.20–0.52). Some correlations were stronger, mostly in axSpA. Internal consistency (Cronbach's alpha) for all three scales was consistent with group use in all conditions. Test‐retest reliability was generally excellent, with intraclass coefficients (2,1) of 0.80–0.93 for the three scales in the four conditions. Discussion: Reliable, valid versions of the British‐English PWSS, WABPPS, and WTI are now available for use in research, organisational level studies and vocational rehabilitation

Efficacy of an Adapted HIV and Sexually Transmitted Infection Prevention Intervention for Incarcerated Women: A Randomized Controlled Trial

Objectives. We tested the efficacy of an adapted evidence-based HIV–sexually transmitted infection (STI) behavioral intervention (Providing Opportunities for Women’s Empowerment, Risk-Reduction, and Relationships, or POWER) among incarcerated women