Gating-induced large aqueous volumetric remodeling and aspartate tolerance in the voltage sensor domain of Shaker K+ channels

Indexación: Scopus.ACKNOWLEDGMENTS. We thank Chris Lingle and Yu Zhou (Washington University) for critical reading of the manuscript and Victoria Prado for Xenopus care and oocyte preparation. We also thank Millennium Scientific Initiative P029-022-F. This work was supported by Fondecyt Postdoctoral Grants 3170599 (to I.D.-F.) and 3160321 (to H.M.).Neurons encode electrical signals with critically tuned voltage-gated ion channels and enzymes. Dedicated voltage sensor domains (VSDs) in these membrane proteins activate coordinately with an unresolved structural change. Such change conveys the transmembrane translocation of four positively charged arginine side chains, the voltage-sensing residues (VSRs; R1–R4). Countercharges and lipid phosphohead groups likely stabilize these VSRs within the low-dielectric core of the protein. However, the role of hydration, a sign-independent charge stabilizer, remains unclear. We replaced all VSRs and their neighboring residues with negatively charged aspartates in a voltage-gated potassium channel. The ensuing mild functional effects indicate that hydration is also important in VSR stabilization. The voltage dependency of the VSR aspartate variants approached the expected arithmetic summation of charges at VSR positions, as if negative and positive side chains faced similar pathways. In contrast, aspartates introduced between R2 and R3 did not affect voltage dependence as if the side chains moved outside the electric field or together with it, undergoing a large displacement and volumetric remodeling. Accordingly, VSR performed osmotic work at both internal and external aqueous interfaces. Individual VSR contributions to volumetric works approached arithmetical additivity but were largely dissimilar. While R1 and R4 displaced small volumes, R2 and R3 volumetric works were massive and vectorially opposed, favoring large aqueous remodeling during VSD activation. These diverse volumetric works are, at least for R2 and R3, not compatible with VSR translocation across a unique stationary charge transfer center. Instead, VSRs may follow separated pathways across a fluctuating low-dielectric septum. © National Academy of Sciences. All rights reserved.https://www.pnas.org/content/115/32/820

Primary care healthcare policy impelmentation in the eastern Mediterranean region; experience of six countries: part ii

Background: Primary healthcare (PHC) is the cornerstone of health systems for the rightful access and cost-effective. It is a key factor in the global strategy for universal health coverage (UHC). Implementing PHC requires an understanding of health system under prevailing circumstances essential to implement PHC, but data are unavailable. Objectives: This paper describes and analyses the health systems of Algeria, Kuwait, Morocco, Saudi Arabia, Jordan and Iraq and PHC status. Methods: Data were collected during a Workshop at 2018 WONCA East Mediterranean Regional Conference in Kuwait. Academic family physicians (FP) and general practitioners (GP) presented their country reports using the WONCA framework of 11 PowerPoint slides. WHO EMRO reflected on how countries’ experiences can contribute to their Frameworks on Integrated People-Centered Health Services and UHC.. Results: The six countries had achieved a great improvement in populations’ health, but currently face challenges of health financing, small number of certified family physicians, difficulties to access service and bureaucratic process. Main concerns were the absence of a family practice model, brain drain and immigration of FPs. Countries differed in building a coherent policy. Conclusion: Priorities should be focused on: developing PHC model in Eastern Mediterranean Region with advocacy for community-based PHC to policymakers: capacity building for strengthening PHC-oriented health systems with FP specialty training and restrict practicing to fully trained FPs; engage communities to improve understanding of PHC; adopt quality and accreditation policies for better services; validation of the referral and follow-up process; and, develop public-private partnership mechanisms to enhance PHC for UHC

APOBEC mutagenesis in drug resistance and immune escape in HIV and cancer evolution

The APOBEC mutational signature has only recently been detected in a multitude of cancers through next-generation sequencing. In contrast, APOBEC has been a focus of virology research for over a decade. Many lessons learnt regarding APOBEC within virology are likely to be applicable to cancer. In this review, we explore the parallels between the role of APOBEC enzymes in HIV and cancer evolution. We discuss data supporting the role of APOBEC mutagenesis in creating HIV genome heterogeneity, drug resistance, and immune escape variants. We hypothesize similar functions of APOBEC will also hold true in cancer

Differential binding affinity of mutated peptides for MHC class I is a predictor of survival in advanced lung cancer and melanoma

Background: Cancer mutations generate novel (neo-)peptides recognised by T cells, but the determinants of recognition are not well characterised. The difference in predicted class I major histocompatibility complex (MHC-I) binding affinity between wild-type and corresponding mutant peptides (differential agretopicity index; DAI) may reflect clinically relevant cancer peptide immunogenicity. Our aim was to explore the relationship between DAI, measures of immune infiltration and patient outcomes in advanced cancer. Patients and methods: Cohorts of patients with advanced non-small-cell lung cancer (NSCLC; LUAD, n = 66) and melanoma (SKCM, n = 72) were obtained from The Cancer Genome Atlas. Three additional cohorts of immunotherapy treated patients with advanced melanoma (total n = 131) and NSCLC (n = 31) were analysed. Neopeptides and their clonal status were defined using genomic data. MHC-I binding affinity was predicted for each neopeptide and DAI values summarised as the sample mean DAI. Correlations between mean DAI and markers of immune activity were evaluated using measures of lymphocyte infiltration and immune gene expression. Results: In univariate and multivariate analyses, mean DAI significantly correlated with overall survival in 3/5 cohorts, with evidence of superiority over nonsynonymous mutational and neoantigen burden. In these cohorts, the effect was seen for mean DAI of clonal but not subclonal peptides. In SKCM, the association between mean DAI and survival bordered significance (P = 0.068), reaching significance in an immunotherapy-treated melanoma cohort (P = 0.003). Mean DAI but not mutational nor neoantigen burden was positively correlated with independently derived markers of immune infiltration in both SKCM (P = 0.027) and LUAD (P = 0.024). Conclusions: The association between mean DAI, survival and measures of immune activity support the hypothesis that DAI is a determinant of cancer peptide immunogenicity. Investigation of DAI as a marker of immunologically relevant peptides in further datasets and future clinical studies of neoantigen based immunotherapies is warranted

Are you ready for change? Farsight for construction: Exploratory scenarios for Queensland’s construction industry to 2036

The future of work and employment is a global hot topic with interconnected and powerful forces shaping jobs, industries and entire economies. Farsight, prepared in partnership with Construction Skills Queensland, examines the future of construction work in the state. Specifically, the report discusses critical trends and alternative scenarios for the future of Queensland’s construction workforce. Eighty leading experts across the state contributed to this future through a range of thinking and participation in interviews and workshops – where they considered what the industry could look like in 2036, and how job profiles and skills requirements might change to align with that future. A comprehensive scan of trends impacting the industry was undertaken, 25 of which are discussed in this report. This industry input and trends scan culminated in the development of four scenarios (Figure 1) that capture key areas of uncertainty and impact for jobs and skills in the industry. Each scenario is possible and takes the reader down an evidence-based journey about a plausible future. Because the future is not exact, there are multiple paths leading to multiple scenarios. Our scenarios describe a range of futures – some we would like to happen or others we would like to avoid. The aim in scenario planning is to be objective and inform decision-makers to identify, select and implement optimal strategies to achieve a better future – for all involved. Farsight was designed to help the industry understand what could happen in the future, and to identify what future(s) the industry wants and what steps could be taken to move toward desired futures. The scenarios were defined using a strategic foresight process that involves the identification of two spectrums that capture a range of plausible outcomes. The end points are extreme possibilities, with each relatively independent of the other. The outcomes of Farsight rests upon a set of trends compiled and synthesised by the research team. Crossing the axes defines the scenario space and the four scenarios which detail the tools we will need to keep stay nimble, relevant and effective in a global marke

Patient-initiated second medical consultations: patient characteristics and motivating factors, impact on care and satisfaction: A systematic review

Objectives: To review the characteristics and motivations of patients seeking second opinions, and the impact of such opinions on patient management, satisfaction, and cost-effectiveness. Data sources: Embase, Medline, PsycINFO and HMIC databases. Study design: A systematic literature search was performed for terms related to second opinion and patient characteristics. Study quality was assessed using the National Institutes of Health (NIH) Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Data collection / Extraction methods: We included articles focused on patient-initiated second opinions, which provided quantitative data on their impact on diagnosis, treatment, prognosis or patient satisfaction, described the characteristics or motivating factors of patients who initiated a second opinion, or the cost-effectiveness of patient-initiated second opinions. Principal findings: Thirty-one articles were included in the review. 27 studies considered patient characteristics, 18 patient motivating factors, 10 patient satisfaction, and 17 clinical agreement between the first and second opinion. Seeking a second opinion was more common in women, middle age patients, more educated patients; and in people having a chronic condition, with higher income or socioeconomic status or living in central urban areas. Patients seeking a second opinion sought to gain more information or reassurance about their diagnosis or treatment. While many second opinions confirm the original diagnosis or treatment, discrepancies in opinions had a potential major impact on patient outcomes in up to 58% of cases. No studies reporting on the cost-effectiveness of patient initiated second opinions. Conclusions: Seeking a second opinion was more common in women, middle-age patients, and more educated patients, and in people having a chronic condition, with higher income or socioeconomic status or living in central urban areas. Patients seeking a second opinion sought to gain more information or reassurance about their diagnosis or treatment

Novel, bilateral, two-bellied muscles span the extensor forearm, thenar eminence to insert on the proximal phalanx of the thumb: clinical and embryological significance

Muscle and tendon variations in the forearm, wrist and hand are commonly reported in the anatomical and surgical literature. They are frequently the source of inflammatory conditions such as de Quervain’s tenosynovitis or carpal tunnel syndrome. During academic dissection, a cadaver presented with bilateral, additional muscles running parallel to the abductor pollicis longus muscles (APL) in the extensor compartment of the forearm. Both additional muscles had two bellies, one proximal and one distal, with an intervening tendon. The proximal bellies were separate and distinct from the adjacent APLs. The tendons traversed the first dorsal compartments with the tendons of the APLs and the extensor pollicis brevis muscles (EPB). The distal bellies lay adjacent to the abductor pollicis brevis (APB) muscles in the thenar compartments, and inserted onto the volar base of the proximal phalanges of the thumbs. Following a thorough search of the literature, we determined that these additional muscles constitute a previously unreported variation. This report details the variation, compares it with other reported variations, presents the related embryology, and reviews the significance of this variation as it relates to inflammatory conditions and surgical procedures