Employment status and health after privatisation in white collar civil servants: prospective cohort study

Objectives To determine whether employment status after job loss due to privatisation influences health and use of health services and whether financial strain, psychosocial measures, or health related behaviours can explain any findings.Design Data collected before and 18 months after privatisation.Setting One department of the civil service that was sold to the private sector,Participants 666 employees during baseline screening in the department to be privatised.Main outcome measures Health and health service outcomes associated with insecure re-employment, permanent exit from paid employment, and unemployment after privatisation compared with outcomes associated with secure re-employmentResults Insecure re-employment and unemployment were associated with relative increases in minor psychiatric morbidity (mean difference 1.56 (95% confidence intervals interval 1.0 to 2.2) and 1.25 (0.6 to 2.0) respectively) and having four or more consultations with a general practitioner in the past year (odds ratio 2.04 (1.1 to 3.8) and 2.39 (1.3 to 4.7) respectively). Health outcomes for respondents permanently out of paid employment closely resembled those in secure re-employment, except for a substantial relative increase in longstanding illness (2.25; 1.1 to 4.4), Financial strain and change in psychosocial measures and health related behaviours accounted for little of the observed associations. Adjustment for change in minor psychiatric morbidity attenuated the association between insecure re-employment or unemployment and general practitioner consultations by 26% and 27%, respectively.Conclusions Insecure re-employment and unemployment after privatisation result in increases in minor psychiatric morbidity and consultations with a general practitioner, which are possibly due to the increased minor psychiatric morbidity

The MemProtMD database : a resource for membrane-embedded protein structures and their lipid interactions

Integral membrane proteins fulfil important roles in many crucial biological processes, including cell signalling, molecular transport and bioenergetic processes. Advancements in experimental techniques are revealing high resolution structures for an increasing number of membrane proteins. Yet, these structures are rarely resolved in complex with membrane lipids. In 2015, the MemProtMD pipeline was developed to allow the automated lipid bilayer assembly around new membrane protein structures, released from the Protein Data Bank (PDB). To make these data available to the scientific community, a web database (http://memprotmd.bioch.ox.ac.uk) has been developed. Simulations and the results of subsequent analysis can be viewed using a web browser, including interactive 3D visualizations of the assembled bilayer and 2D visualizations of lipid contact data and membrane protein topology. In addition, ensemble analyses are performed to detail conserved lipid interaction information across proteins, families and for the entire database of 3506 PDB entries. Proteins may be searched using keywords, PDB or Uniprot identifier, or browsed using classification systems, such as Pfam, Gene Ontology annotation, mpstruc or the Transporter Classification Database. All files required to run further molecular simulations of proteins in the database are provided

The energetics of protein-lipid interactions as viewed by molecular simulations

Membranes are formed from a bilayer containing diverse lipid species with which membrane proteins interact. Thus, integral membrane proteins are embedded in a bilayer, where they interact with lipids from their surroundings, whilst peripheral membrane proteins bind to lipids at the surface of membranes. Lipid interactions can influence the function of membrane proteins, either directly or allosterically. Both experimental (structural) and computational approaches can reveal lipid binding sites on membrane proteins. It is therefore important to understand the free energies of these interactions. This affords a more complete view of the engagement of a particular protein with the biological membrane surrounding it. Here, we describe a number of computational approaches currently in use for this purpose, including recent advances using both free energy and unbiased simulation methods. In particular we focus on interactions of integral membrane proteins with cholesterol, and with anionic lipids such as phosphatidylinositol 4,5-bisphosphate and cardiolipin. Peripheral membrane proteins are exemplified via interactions of PH domains with phosphoinositide-containing membranes. We summarise the current state of the field and provide an outlook on likely future directions of investigation

Atomistic mechanism of transmembrane helix association

Transmembrane helix association is a fundamental step in the folding of helical membrane proteins. The prototypical example of this association is formation of the glycophorin dimer. While its structure and stability have been well-characterized experimentally, the detailed assembly mechanism is harder to obtain. Here, we use all-atom simulations within phospholipid membrane to study glycophorin association. We find that initial association results in the formation of a non-native intermediate, separated by a significant free energy barrier from the dimer with a native binding interface. We have used transition-path sampling to determine the association mechanism. We find that the mechanism of the initial bimolecular association to form the intermediate state can be mediated by many possible contacts, but seems to be particularly favoured by formation of non-native contacts between the C-termini of the two helices. On the other hand, the contacts which are key to determining progression from the intermediate to the native state are those which define the native binding interface, reminiscent of the role played by native contacts in determining folding of globular proteins. As a check on the simulations, we have computed association and dissociation rates from the transition-path sampling. We obtain results in reasonable accord with available experimental data, after correcting for differences in native state stability. Our results yield an atomistic description of the mechanism for a simple prototype of helical membrane protein folding

Factors associated with first return to work and sick leave durations in workers with common mental disorders

Background: Associations are examined between socio-demographic, medical, work-related and organizational factors and the moment of first return to work (RTW) (within or after 6 weeks of sick leave) and total sick leave duration in sick leave spells due to common mental disorders. Methods: Data are derived from a Dutch database, build to provide reference data for sick leave duration for various medical conditions. The cases in this study were entered in 2004 and 2005 by specially trained occupational health physicians, based on the physician's assessment of medical and other factors. Odds ratios for first RTW and sick leave durations are calculated in logistic regression models. Results: Burnout, depression and anxiety disorder are associated with longer sick leave duration. Similar, but weaker associations were found for female sex, being a teacher, small company size and moderate or high psychosocial hazard. Distress is associated with shorter sick leave duration. Medical factors, psychosocial hazard and company size are also and analogously associated with first RTW. Part-time work is associated with delayed first RTW. The strength of the associations varies for various factors and for different sick leave durations. Conclusion: The medical diagnosis has a strong relation with the moment of first RTW and the duration of sick leave spells in mental disorders, but the influence of demographic and work-related factors should not be neglected

Insights into membrane protein–lipid interactions from free energy calculations

Integral membrane proteins are regulated by specific interactions with lipids from the surrounding bilayer. The structures of protein–lipid complexes can be determined through a combination of experimental and computational approaches, but the energetic basis of these interactions is difficult to resolve. Molecular dynamics simulations provide the primary computational technique to estimate the free energies of these interactions. We demonstrate that the energetics of protein–lipid interactions may be reliably and reproducibly calculated using three simulation-based approaches: potential of mean force calculations, alchemical free energy perturbation, and well-tempered metadynamics. We employ these techniques within the framework of a coarse-grained force field and apply them to both bacterial and mammalian membrane protein–lipid systems. We demonstrate good agreement between the different techniques, providing a robust framework for their automated implementation within a pipeline for annotation of newly determined membrane protein structures

The process of establishing implementing and maintaining a social support infant feeding programme

Objective To describe the process of establishing and implementing a social support infant feeding intervention. Design This paper outlines the initial stages of a randomised controlled trial which assessed the effectiveness of a social support intervention on a range of infant feeding outcomes. Details are presented of the processes involved in recruiting, training and supporting a group of volunteers who provided support to the study sample. Setting Camden and Islington, London, UK. Results Initial networking with local agencies and organisations provided invaluable information and contacts. Employing a dedicated volunteer co-ordinator is vitally important in the recruitment, training and support of volunteers. Providing child care and travel expenses is an essential incentive for volunteers with young children. Advertisements placed in local newspapers were the most successful means of recruiting volunteers. Appropriate training is needed to equip volunteers with the necessary knowledge and skills to provide effective support. Particular emphasis in the training focused upon developing the necessary interpersonal skills and self-confidence. The evaluation of the training programme demonstrated that it improved volunteers’ knowledge and reported confidence. The provision of ongoing support is also essential to maintain volunteers’ interest and enthusiasm. The retention of volunteers is, however, a key challenge. Conclusions The processes outlined in this paper have demonstrated the feasibility of successfully establishing, implementing and maintaining a community-based social support infant feeding programme. The experiences described provide useful insights into the practical issues that need to be addressed in setting up a social support intervention

The Association Between Informal Caregiving and Exit From Employment Among Older Workers: Prospective Findings From the UK Household Longitudinal Study

OBJECTIVE: This study investigated associations between informal caregiving and exit from paid employment among older workers in the United Kingdom. METHOD: Information on caregiving and work status for 8,473 older workers (aged 50-75 years) was drawn from five waves of Understanding Society (2009-2014). We used discrete-time survival models to estimate the associations of caring intensity and type on the probability of exiting paid work (from >0 to 0 hours/week) in the following year. Models were stratified by sex and working hours, and adjusted for age, self-rated health, long-standing illness, occupation, and partner's employment status. RESULTS: No association was found between caregiving intensity and exit from paid work. Full-time employees who provided care within the household (women and men) or cared for a partner/spouse (women only) more likely to stop working, compared to those not providing care. Women who entered a caregiving role (more than 10 hours/week) were between 2.64 (95% confidence interval [CI]: 1.46, 4.79) and 4.46 (95% CI: 2.53, 7.88) times more likely to exit work (for part-time and full-time workers, respectively), compared to women providing no care. DISCUSSION: This study highlights the onset of caregiving as a key period for older workers. Ensuring that caregiving responsibilities are adequately recognized and supported may help extend working life

Structural basis for membrane attack complex inhibition by CD59

CD59 is an abundant immuno-regulatory receptor that protects human cells from damage during complement activation. Here we show how the receptor binds complement proteins C8 and C9 at the membrane to prevent insertion and polymerization of membrane attack complex (MAC) pores. We present cryo-electron microscopy structures of two inhibited MAC precursors known as C5b8 and C5b9. We discover that in both complexes, CD59 binds the pore-forming β-hairpins of C8 to form an intermolecular β-sheet that prevents membrane perforation. While bound to C8, CD59 deflects the cascading C9 β-hairpins, rerouting their trajectory into the membrane. Preventing insertion of C9 restricts structural transitions of subsequent monomers and indirectly halts MAC polymerization. We combine our structural data with cellular assays and molecular dynamics simulations to explain how the membrane environment impacts the dual roles of CD59 in controlling pore formation of MAC, and as a target of bacterial virulence factors which hijack CD59 to lyse human cells

A lipid gating mechanism for the channel-forming O antigen ABC transporter

Extracellular glycan biosynthesis is a widespread microbial protection mechanism. In Gram-negative bacteria, the O antigen polysaccharide represents the variable region of outer membrane lipopolysaccharides. Fully assembled lipid-linked O antigens are translocated across the inner membrane by the WzmWzt ABC transporter for ligation to the lipopolysaccharide core, with the transporter forming a continuous transmembrane channel in a nucleotide-free state. Here, we report its structure in an ATP-bound conformation. Large structural changes within the nucleotide-binding and transmembrane regions push conserved hydrophobic residues at the substrate entry site towards the periplasm and provide a model for polysaccharide translocation. With ATP bound, the transporter forms a large transmembrane channel with openings toward the membrane and periplasm. The channel’s periplasmic exit is sealed by detergent molecules that block solvent permeation. Molecular dynamics simulation data suggest that, in a biological membrane, lipid molecules occupy this periplasmic exit and prevent water flux in the transporter’s resting state