Connecting the dots: combined control of endocytic recycling and degradation.

Endocytosis is an essential process where proteins and lipids are internalised from the plasma membrane in membrane-bound carriers, such as clathrin-coated vesicles. Once internalised into the cell these vesicles fuse with the endocytic network where their contents are sorted towards degradation in the lysosome or recycling to their origin. Initially, it was thought that cargo recycling is a passive process, but in recent years the identification and characterisation of specialised recycling complexes has established a hitherto unthought-of level of complexity that actively opposes degradation. This review will summarise recent developments regarding the composition and regulation of the recycling machineries and their relationship with the degradative pathways of the endosome.

Occupation and risk of severe COVID-19: prospective cohort study of 120 075 UK Biobank participants.

OBJECTIVES: To investigate severe COVID-19 risk by occupational group. METHODS: Baseline UK Biobank data (2006-10) for England were linked to SARS-CoV-2 test results from Public Health England (16 March to 26 July 2020). Included participants were employed or self-employed at baseline, alive and aged <65 years in 2020. Poisson regression models were adjusted sequentially for baseline demographic, socioeconomic, work-related, health, and lifestyle-related risk factors to assess risk ratios (RRs) for testing positive in hospital or death due to COVID-19 by three occupational classification schemes (including Standard Occupation Classification (SOC) 2000). RESULTS: Of 120 075 participants, 271 had severe COVID-19. Relative to non-essential workers, healthcare workers (RR 7.43, 95% CI 5.52 to 10.00), social and education workers (RR 1.84, 95% CI 1.21 to 2.82) and other essential workers (RR 1.60, 95% CI 1.05 to 2.45) had a higher risk of severe COVID-19. Using more detailed groupings, medical support staff (RR 8.70, 95% CI 4.87 to 15.55), social care (RR 2.46, 95% CI 1.47 to 4.14) and transport workers (RR 2.20, 95% CI 1.21 to 4.00) had the highest risk within the broader groups. Compared with white non-essential workers, non-white non-essential workers had a higher risk (RR 3.27, 95% CI 1.90 to 5.62) and non-white essential workers had the highest risk (RR 8.34, 95% CI 5.17 to 13.47). Using SOC 2000 major groups, associate professional and technical occupations, personal service occupations and plant and machine operatives had a higher risk, compared with managers and senior officials. CONCLUSIONS: Essential workers have a higher risk of severe COVID-19. These findings underscore the need for national and organisational policies and practices that protect and support workers with an elevated risk of severe COVID-19.

Conservation geopolitics.

We reviewed recent work concerning the impact of geopolitics on wildlife conservation (and vice versa) and identified future priorities in conservation geopolitics research. Geopolitics is understood as both an analytical focus on geopolitical practices (especially concerning the behavior) of countries with respect to territory and national security and a set of theories developed to explain and predict those behaviors. We developed a typology of core geopolitical practices of relevance to conservation: territorial practices of colonization and the management of migrations and borders, and security practices relating to military, economic, and environmental security. We identified research that considers how these practices affect conservation situations and outcomes, noting the recent emergence of conceptual developments such as "environmental geopolitics" and "geopolitical ecology" that draw on multiple fields within the social sciences to theorize the links between geopolitics and environmental management. We defined a "geopolitical perspective" as a focus on geopolitical practices combined with an explicit engagement with geopolitical theory and identified conservation situations where this perspective could contribute to analytical clarity. We suggest the most pressing questions in conservation research to which the geopolitical perspective might contribute are how political and economic differences between countries affect biodiversity outcomes, how geopolitical practices to address those differences facilitate or frustrate conservation efforts, how national borders and human and wildlife movements can be better managed for the benefit of both, and how the most effective conservation strategies can be best selected to suit existing (and future) geopolitical realities.

Geopolítica de la Conservación Resumen Revisamos el trabajo reciente relativo al impacto que tiene la geopolítica sobre la conservación de la vida silvestre (y viceversa) e identificamos prioridades futuras para la investigación de la geopolítica de la conservación. Se define a la geopolítica como un enfoque analítico en las prácticas geopolíticas (especialmente en relación con el comportamiento) de los países con respecto al territorio y a la seguridad nacional y como un conjunto de teorías desarrolladas para explicar y predecir aquellos comportamientos. Desarrollamos una tipología de prácticas nucleares de geopolítica relevantes para la conservación: prácticas territoriales de colonización y el manejo de migraciones y de las fronteras, y prácticas de seguridad relacionadas con la seguridad militar, económica y ambiental. Identificamos las investigaciones que consideran cómo estas prácticas afectan a las situaciones de conservación y sus resultados, tomando en cuenta el surgimiento reciente de desarrollos conceptuales como los de "geopolítica ambiental" y "ecología geopolítica" que parten de múltiples campos de estudio situados dentro de las ciencias sociales para teorizar las conexiones entre la geopolítica y el manejo ambiental. Definimos una perspectiva geopolítica como el enfoque en las prácticas geopolíticas combinada con una participación explícita de la teoría geopolítica e identificamos situaciones de conservación en donde esta perspectiva podría contribuir a la claridad analítica. Sugerimos que las preguntas más urgentes para la investigación en la conservación para las cuales la perspectiva geopolítica podría contribuir son cómo las diferencias políticas y económicas entre los países afectan a los resultados de la biodiversidad, cómo las prácticas geopolíticas abordan esas diferencias facilita o frustra los esfuerzos de conservación, cómo las fronteras nacionales y los movimientos humanos y faunísticos pueden manejarse de mejor manera para el beneficio de ambos, y cómo las estrategias de conservación más efectivas pueden seleccionarse de mejor forma para acoplarse a las realidades geopolíticas existentes (y futuras).

Role of age and health in perceptions of returning to work: a qualitative study.

BACKGROUND: People aged over 50 years form a growing proportion of the working age population, but are at increased risk of unemployment compared to other age groups. It is often difficult to return to work after unemployment, particularly for those with health issues. In this paper, we explored the perceptions, attitudes, and experiences of returning to work after a period of unemployment (hereafter RTW) barriers among unemployed adults aged over 50 years. METHOD: In-depth semi-structured interviews were conducted with a diverse sample of 26 unemployed individuals aged 50-64 years who were engaged with the UK Government's Work Programme. Data were thematically analysed. RESULTS: Age alone was not discussed by participants as a barrier to work; rather their discussions of barriers to work focused on the ways in which age influenced other issues in their lives. For participants reporting chronic health conditions, or disabilities, there was a concern about being unfit to return to their previous employment area, and therefore having to "start again" in a new career, with associated concerns about their health status and managing their treatment burden. Some participants also reported experiencing either direct or indirect ageism (including related to their health status or need to access healthcare) when looking for work. Other issues facing older people included wider socio-political changes, such as the increased pension age, were felt to be unfair in many ways and contradicted existing expectations of social roles (such as acting as a carer for other family members). CONCLUSION: Over-50s experienced multiple and interacting issues, at both the individual and societal level, that created RTW barriers. There is a need for employability interventions that focus on supporting the over-50s who have fallen out of the labour market to take a holistic approach, working across healthcare, employability and the local labour market, providing treatment and skills training for both those out of work and for employers, in order to create an intervention that that helps achieve RTW and its associated health benefit.

Current research priorities for UK occupational physicians and occupational health researchers: a modified Delphi study.

OBJECTIVES: Studies identifying national occupational health (OH) research priorities have been conducted in several countries to establish where OH research should be focused and where funding should be targeted. However, the UK findings are now over 20 years old, and OH practice is continuously evolving. The aim of this study was to identify current research priorities for UK occupational physicians (OPs) and occupational health researchers (OHRs). METHODS: Current research priorities in OH were identified using a modified Delphi technique. This was conducted in two rounds to achieve consensus. Research priorities were rated, and then ranked using questionnaires developed from expert panel discussions, key research topics identified from the medical literature and participant feedback. Overall and intergroup comparisons were completed for the ranking scores. RESULTS: Consensus among OPs and OHRs was high with almost all (9/10) primary domains rated as 'very important' or 'absolutely necessary' by more than 54% of respondents. The research priority areas ranked highest were jointly economic evaluation/cost effectiveness studies and disability management followed by occupational disease/injury/illness. Occupational health policy was ranked lowest after sickness absence management and health promotion. The secondary domain analysis identified priority emphasis on mental health and psychosocial hazards within the workplace and the need to further develop evidence-based guidance for clinical OH practice. CONCLUSIONS: We identified the current research priorities for UK OPs and OHRs. The findings will inform future national OH research strategy and support research that addresses important knowledge gaps within OH and other interdisciplinary specialties.

Differences in opinions of occupational physicians on the required competencies by field of practice: results of an international Delphi study.

BACKGROUND: The activities and work demands of medical professionals, including occupational physicians (OPs), fall into three categories: clinical, academic, and administrative. Work demands of an OP consist of these three categories and additional specialty specific roles and competencies. Research on the core competencies and skills required for OPs have identified high levels of consensus amongst OPs internationally, however these opinions have not been examined between areas of practice specific groups. Furthermore, it has been identified that to a large extent academics are often the group who define the skills required of OPs. The aim of this study is to compare the opinions of OPs grouped by field of practice on the common core competencies required for occupational health (OH) practice using results from an international survey. METHODS: An international modified Delphi study conducted among OPs, completed in two rounds (Rating-Round 1; Ranking-Round 2) using developed questionnaires based on the specialist training syllabus of a number of countries and expert discussions. Respondents were categorised as Physician, Manager/Physician, and Academic/Physician, based on self-reported job titles and place of work. RESULTS: There was good agreement between the Physician and Manager/Physician groups, with the Academic/Physician group deviating the most. The top three and bottom three principle domains (PDs) were in good agreement across all groups. The top three were clinically based and would be considered core OH activities. The PDs with considerable intergroup variance were Environmental Issues Related to Work Practice and Communication Skills, categories which may reflect direct relevance and relative importance to the job tasks of respective groups. CONCLUSION: This study demonstrated general agreement between the three occupational groups. Academic/Physician opinions deviate the most, while good agreement is depicted between the Physician and Manager/Physician groups. The findings of this study can help identify potential gaps in training requirements for OPs and be used as a stepping stone to developing training programmes that are reflective of practice and tailored for those predominantly undertaking these specific roles.

Comparison of competency priorities between UK occupational physicians and occupational health nurses.

OBJECTIVES: The competencies required of occupational physicians (OPs) and occupational health nurses (OHNs) separately have been studied in various countries but little research has made direct comparisons between these two key occupational health (OH) professional groups. The aim of this study was to compare current competency priorities between UK OPs and OHNs. METHODS: A modified Delphi study conducted among professional organisations and networks of UK OPs and OHNs. This formed part of a larger Delphi, including international OPs. It was undertaken in two rounds (round 1-'rating', round 2-'ranking'), using a questionnaire based on available OH competency guidance, the literature, expert panel reviews and conference discussions. RESULTS: In each round (rating/ranking), 57/49 and 48/54 responses were received for OPs and OHNs respectively. The principle domain (PD) competency ranks were very highly correlated (Spearman's r=0.972) with the same PDs featuring in the top four and bottom three positions. OPs and OHNs ranked identically for the top two PDs (good clinical care and general principles of assessment and management of occupational hazards to health). Research methods was ranked lowest by both groups. CONCLUSIONS: This study has observed a high level of agreement among UK OPs and OHNs on current competency priorities. The 'clinically focused' competency priorities likely reflect that although OH practice will broaden in response to various factors, traditional 'core' OH activities will still be required. These mutually identified priorities can serve to strengthen collaboration between these groups, develop joint education/training programmes and identify common professional development opportunities.

USP8 controls the trafficking and sorting of lysosomal enzymes.

The endosomal deubiquitylase USP8 has profound effects on endosomal morphology and organisation. Previous reports have proposed both positive (EGFR, MET) and negative roles in the down-regulation of receptors (Frizzled, Smoothened). Here we report an additional influence of USP8 on the retromer-dependent shuttling of ci-M6PR between the sorting endosome and biosynthetic pathway. Depletion of USP8 leads to a steady state redistribution of ci-M6PR from the Trans-Golgi Network (TGN) to endosomal compartments. Consequently we observe a defect in sorting of lysosomal enzymes, evidenced by increased levels of unprocessed Cathepsin D, which is secreted into the medium. The normal distribution of receptor can be restored by expression of siRNA-resistant USP8 but not by a catalytically inactive mutant or a truncated form, lacking a MIT domain required for endosomal localisation. We suggest that effects of USP8 depletion may reflect the loss of ESCRT-0 components which associate with retromer components Vps35 and SNX1, whilst failure to efficiently deliver lysosomal enzymes may also contribute to the observed block in receptor tyrosine kinase degradation.

International perspective on common core competencies for occupational physicians: a modified Delphi study.

OBJECTIVES: The competencies required of occupational physicians (OPs) have been the subject of peer-reviewed research in Europe and individual countries around the world. In the European Union (EU), there has been development of guidance on training and common competencies, but little research has extended beyond this. The aim of this study was to obtain consensus on and identify the common core competencies required of OPs around the world. METHODS: A modified Delphi study was carried out among representative organisations and networks of OPs in a range of countries around the world. It was conducted in 2 rounds using a questionnaire based on the specialist training syllabus of a number of countries, expert panel reviews and conference discussions. RESULTS: Responses were received from 51 countries around the world, with the majority from Europe (60%; 59%) and North and South America (24%; 32%) in rounds 1 and 2, respectively. General principles of assessment and management of occupational hazards to health and good clinical care were jointly considered most important in ranking when compared with the other topic areas. Assessment of disability and fitness for work, communication skills and legal and ethical issues completed the top five. In both rounds, research methods and teaching and educational supervision were considered least important. CONCLUSIONS: This study has established the current priorities among OPs across 51 countries of the common competencies required for occupational health (OH) practice. These findings can serve as a platform for the development of common core competencies/qualifications within specific geographical regions or internationally. This is particularly pertinent with globalisation of commerce and free movement within the EU.

Priorities for global felid conservation.

Conservation resources are limited, necessitating prioritization of species and locations for action. Most prioritization approaches are based solely on biologically relevant characteristics of taxa or areas and ignore geopolitical realities. Doing so risks a poor return on conservation investment due to nonbiological factors, such as economic or political instability. We considered felids, a taxon which attracts intense conservation attention, to demonstrate a new approach that incorporates both intrinsic species traits and geopolitical characteristics of countries. We developed conservation priority scores for wild felids based on their International Union for Conservation of Nature status, body mass, habitat, range within protected area, evolutionary distinctiveness, and conservation umbrella potential. We used published data on governance, economics and welfare, human population pressures, and conservation policy to assign conservation-likelihood scores to 142 felid-hosting countries. We identified 71 countries as high priorities (above median) for felid conservation. These countries collectively encompassed all 36 felid species and supported an average of 96% of each species' range. Of these countries, 60.6% had below-average conservation-likelihood scores, which indicated these countries are relatively risky conservation investments. Governance was the most common factor limiting conservation likelihood. It was the major contributor to below-median likelihood scores for 62.5% of the 32 felid species occurring in lower-likelihood countries. Governance was followed by economics for which scores were below median for 25% of these species. An average of 58% of species' ranges occurred in 43 higher-priority lower-likelihood countries. Human population pressure was second to governance as a limiting factor when accounting for percentage of species' ranges in each country. As conservation likelihood decreases, it will be increasingly important to identify relevant geopolitical limitations and tailor conservation strategies accordingly. Our analysis provides an objective framework for biodiversity conservation action planning. Our results highlight not only which species most urgently require conservation action and which countries should be prioritized for such action, but also the diverse constraints which must be overcome to maximize long-term success.

Work-health needs of high-altitude mountain guides (Sherpas) in Nepal - a pilot study.

Much of the research in high-altitude medicine has been concerned with non-indigenous travellers; no study has examined the work-related health issues of high altitude mountain guides (Sherpas) in Nepal. This pilot study was performed to investigate the work-related health issues of people working as Sherpas by evaluating their perceptions of their general health and its relation to work. An occupational and general health questionnaire was tailored for the Sherpas following a focus group with five Sherpa workers. 131 Sherpas participated in this study. Respiratory (60%) and musculoskeletal symptoms (55%) were reported significantly more frequently than other health problems (p < .05). 33 Sherpas reported work accident experiences (25%) and 27 (21%) reported eye conditions. This pilot study identified respiratory and musculoskeletal problems as well as accidents as the main work-related health issues of high altitude climbing Sherpas. Another important finding was the high prevalence of reported eye conditions (21%). Better occupational health and safety arrangements including routine recording of accidents or work-related health problems would give better insight into the health needs of Sherpas.

ATP interacts with the CPVT mutation-associated central domain of the cardiac ryanodine receptor.

BACKGROUND: This study was designed to determine whether the cardiac ryanodine receptor (RyR2) central domain, a region associated with catecholamine polymorphic ventricular tachycardia (CPVT) mutations, interacts with the RyR2 regulators, ATP and the FK506-binding protein 12.6 (FKBP12.6). METHODS: Wild-type (WT) RyR2 central domain constructs (G(2236)to G(2491)) and those containing the CPVT mutations P2328S and N2386I, were expressed as recombinant proteins. Folding and stability of the proteins were examined by circular dichroism (CD) spectroscopy and guanidine hydrochloride chemical denaturation. RESULTS: The far-UV CD spectra showed a soluble stably-folded protein with WT and mutant proteins exhibiting a similar secondary structure. Chemical denaturation analysis also confirmed a stable protein for both WT and mutant constructs with similar two-state unfolding. ATP and caffeine binding was measured by fluorescence spectroscopy. Both ATP and caffeine bound with an EC50 of ~200-400µM, and the affinity was the same for WT and mutant constructs. Sequence alignment with other ATP binding proteins indicated the RyR2 central domain contains the signature of an ATP binding pocket. Interaction of the central domain with FKBP12.6 was tested by glutaraldehyde cross-linking and no association was found. CONCLUSIONS: The RyR2 central domain, expressed as a 'correctly' folded recombinant protein, bound ATP in accord with bioinformatics evidence of conserved ATP binding sequence motifs. An interaction with FKBP12.6 was not evident. CPVT mutations did not disrupt the secondary structure nor binding to ATP. GENERAL SIGNIFICANCE: Part of the RyR2 central domain CPVT mutation cluster, can be expressed independently with retention of ATP binding.

Identification of areas in Brazil that optimize conservation of forest carbon, jaguars, and biodiversity.

A major question in global environmental policy is whether schemes to reduce carbon pollution through forest management, such as Reducing Emissions from Deforestation and Degradation (REDD+), can also benefit biodiversity conservation in tropical countries. We identified municipalities in Brazil that are priorities for reducing rates of deforestation and thus preserving carbon stocks that are also conservation targets for the endangered jaguar (Panthera onca) and biodiversity in general. Preliminary statistical analysis showed that municipalities with high biodiversity were positively associated with high forest carbon stocks. We used a multicriteria decision analysis to identify municipalities that offered the best opportunities for the conservation of forest carbon stocks and biodiversity conservation under a range of scenarios with different rates of deforestation and carbon values. We further categorized these areas by their representativeness of the entire country (through measures such as percent forest cover) and an indirect measure of cost (number of municipalities). The municipalities that offered optimal co-benefits for forest carbon stocks and conservation were termed REDDspots (n = 159), and their spatial distribution was compared with the distribution of current and proposed REDD projects (n = 135). We defined REDDspots as the municipalities that offer the best opportunities for co-benefits between the conservation of forest carbon stocks, jaguars, and other wildlife. These areas coincided in 25% (n = 40) of municipalities. We identified a further 95 municipalities that may have the greatest potential to develop additional REDD+ projects while also targeting biodiversity conservation. We concluded that REDD+ strategies could be an efficient tool for biodiversity conservation in key locations, especially in Amazonian and Atlantic Forest biomes.

A review of financial instruments to pay for predator conservation and encourage human-carnivore coexistence.

One of the greatest challenges in biodiversity conservation today is how to facilitate protection of species that are highly valued at a global scale but have little or even negative value at a local scale. Imperiled species such as large predators can impose significant economic costs at a local level, often in poverty-stricken rural areas where households are least able to tolerate such costs, and impede efforts of local people, especially traditional pastoralists, to escape from poverty. Furthermore, the costs and benefits involved in predator conservation often include diverse dimensions, which are hard to quantify and nearly impossible to reconcile with one another. The best chance of effective conservation relies upon translating the global value of carnivores into tangible local benefits large enough to drive conservation "on the ground." Although human-carnivore coexistence involves significant noneconomic values, providing financial incentives to those affected negatively by carnivore presence is a common strategy for encouraging such coexistence, and this can also have important benefits in terms of reducing poverty. Here, we provide a critical overview of such financial instruments, which we term "payments to encourage coexistence"; assess the pitfalls and potentials of these methods, particularly compensation and insurance, revenue-sharing, and conservation payments; and discuss how existing strategies of payment to encourage coexistence could be combined to facilitate carnivore conservation and alleviate local poverty.

Case management training needs to support vocational rehabilitation for case managers and general practitioners: a survey study.

BACKGROUND: The use of the biopsychosocial model of health and case management for effective vocational rehabilitation (VR) has been confirmed for many health conditions. While Case and Condition Managers (CCMPs) use this approach in their everyday work, little is known about their views on training needs. A review of the training curriculum for General Practitioners' (GPs) revealed little training in VR and the biopsychosocial model of care. This study aims to identify Case and Condition Managers and GPs perceptions of their training needs in relation to employability and VR. METHODS: 80 Case and Condition Managers and 304 GPs working in NHS Lanarkshire, providing a comparison group, were invited to participate in this study. A self-completion questionnaire was developed and circulated for online completion with a second round of hardcopy questionnaires distributed. RESULTS: In total 45 responses were obtained from CCMPs, 5 from occupational health nurses (62% response rate) and 60 from GPs (20% response rate). CCMPs and the nursing group expressed a need for training but to a lesser extent than GP's. The GP responses demonstrated a need for high levels of training in case/condition management, the biopsychosocial model, legal and ethical issues associated with employment and VR, and management training. CONCLUSIONS: This survey confirms a need for further training of CCMPs and that respondent GPs in one health board are not fully equipped to deal with patients employability and vocational needs. GPs also reported a lack of understanding about the role of Case and Condition managers. Training for these professional groups and others involved in multidisciplinary VR could improve competencies and mutual understanding among those advising patients on return-to-work.

Direct and indirect control of mitogen-activated protein kinase pathway-associated components, BRAP/IMP E3 ubiquitin ligase and CRAF/RAF1 kinase, by the deubiquitylating enzyme USP15.

The opposing regulators of ubiquitylation status, E3 ligases and deubiquitylases, are often found to be associated in complexes. Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. We map the interaction to the N-terminal DUSP-UBL domain of USP15 and the coiled coil region of BRAP. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15. Importantly, USP15 but not USP4 depletion destabilizes BRAP by promoting its proteasomal degradation, and BRAP-protein levels can be rescued by reintroducing catalytically active but not inactive mutant USP15. Unexpectedly, USP15 depletion results in a decrease in amplitude of MAPK signaling in response to EGF and PDGF. We provide evidence for a model in which the dominant effect of prolonged USP15 depletion upon signal amplitude is due to a decrease in CRAF levels while allowing for the possibility that USP15 may also function to dampen MAPK signaling through direct stabilization of a negative regulator, the E3 ligase BRAP.

3D matrix adhesion feedback controls nuclear force coupling to drive invasive cell migration.

Cell invasion is a multi-step process, initiated by the acquisition of a migratory phenotype and the ability to move through complex 3D extracellular environments. We determine the composition of cell-matrix adhesion complexes of invasive breast cancer cells in 3D matrices and identify an interaction complex required for invasive migration. ßPix and myosin18A (Myo18A) drive polarized recruitment of non-muscle myosin 2A (NM2A) to adhesion complexes at the tips of protrusions. Actomyosin force engagement then displaces the Git1-ßPix complex from paxillin, establishing a feedback loop for adhesion maturation. We observe active force transmission to the nucleus during invasive migration that is needed to pull the nucleus forward. The recruitment of NM2A to adhesions creates a non-muscle myosin isoform gradient, which extends from the protrusion to the nucleus. We postulate that this gradient facilitates coupling of cell-matrix interactions at the protrusive cell front with nuclear movement, enabling effective invasive migration and front-rear cell polarity.