c-di-GMP Arms an Anti-σ to Control Progression of Multicellular Differentiation in Streptomyces.

Streptomyces are our primary source of antibiotics, produced concomitantly with the transition from vegetative growth to sporulation in a complex developmental life cycle. We previously showed that the signaling molecule c-di-GMP binds BldD, a master repressor, to control initiation of development. Here we demonstrate that c-di-GMP also intervenes later in development to control differentiation of the reproductive hyphae into spores by arming a novel anti-σ (RsiG) to bind and sequester a sporulation-specific σ factor (σWhiG). We present the structure of the RsiG-(c-di-GMP)2-σWhiG complex, revealing an unusual, partially intercalated c-di-GMP dimer bound at the RsiG-σWhiG interface. RsiG binds c-di-GMP in the absence of σWhiG, employing a novel E(X)3S(X)2R(X)3Q(X)3D motif repeated on each helix of a coiled coil. Further studies demonstrate that c-di-GMP is essential for RsiG to inhibit σWhiG. These findings reveal a newly described control mechanism for σ-anti-σ complex formation and establish c-di-GMP as the central integrator of Streptomyces development.

Evolution of a σ-(c-di-GMP)-anti-σ switch.

Filamentous actinobacteria of the genus Streptomyces have a complex lifecycle involving the differentiation of reproductive aerial hyphae into spores. We recently showed c-di-GMP controls this transition by arming a unique anti-σ, RsiG, to bind the sporulation-specific σ, WhiG. The Streptomyces venezuelae RsiG-(c-di-GMP)2-WhiG structure revealed that a monomeric RsiG binds c-di-GMP via two E(X)3S(X)2R(X)3Q(X)3D repeat motifs, one on each helix of an antiparallel coiled-coil. Here we show that RsiG homologs are found scattered throughout the Actinobacteria. Strikingly, RsiGs from unicellular bacteria descending from the most basal branch of the Actinobacteria are small proteins containing only one c-di-GMP binding motif, yet still bind their WhiG partners. Our structure of a Rubrobacter radiotolerans (RsiG)2-(c-di-GMP)2-WhiG complex revealed that these single-motif RsiGs are able to form an antiparallel coiled-coil through homodimerization, thereby allowing them to bind c-di-GMP similar to the monomeric twin-motif RsiGs. Further data show that in the unicellular actinobacterium R. radiotolerans, the (RsiG)2-(c-di-GMP)2-WhiG regulatory switch controls type IV pilus expression. Phylogenetic analysis indicates the single-motif RsiGs likely represent the ancestral state and an internal gene-duplication event gave rise to the twin-motif RsiGs inherited elsewhere in the Actinobacteria. Thus, these studies show how the anti-σ RsiG has evolved through an intragenic duplication event from a small protein carrying a single c-di-GMP binding motif, which functions as a homodimer, to a larger protein carrying two c-di-GMP binding motifs, which functions as a monomer. Consistent with this, our structures reveal potential selective advantages of the monomeric twin-motif anti-σ factors.

Mental illness and suicide among physicians.

The COVID-19 pandemic has heightened interest in how physician mental health can be protected and optimised, but uncertainty and misinformation remain about some key issues. In this Review, we discuss the current literature, which shows that despite what might be inferred during training, physicians are not immune to mental illness, with between a quarter and a third reporting increased symptoms of mental ill health. Physicians, particularly female physicians, are at an increased risk of suicide. An emerging consensus exists that some aspects of physician training, working conditions, and organisational support are unacceptable. Changes in medical training and health systems, and the additional strain of working through a pandemic, might have amplified these problems. A new evidence-informed framework for how individual and organisational interventions can be used in an integrated manner in medical schools, in health-care settings, and by professional colleagues is proposed. New initiatives are required at each of these levels, with an urgent need for organisational-level interventions, to better protect the mental health and wellbeing of physicians.

Structures of MERS1, the 5' processing enzyme of mitochondrial mRNAs in Trypanosoma brucei.

Most mitochondrial mRNAs are transcribed as polycistronic precursors that are cleaved by endonucleases to produce mature mRNA transcripts. However, recent studies have shown that mitochondrial transcripts in the kinetoplastid protozoan, Trypanosoma brucei, are transcribed individually. Also unlike most mitochondrial mRNAs, the 5' end of these transcripts harbor a triphosphate that is hydrolyzed. This modification is carried out by a putative Nudix hydrolase called MERS1. The Nudix motif in MERS1 is degenerate, lacking a conserved glutamic acid, thus it is unclear how it may bind its substrates and whether it contains a Nudix fold. To obtain insight into this unusual hydrolase, we determined structures of apo, GTP-bound and RNA-bound T. brucei MERS1 to 2.30 Å, 2.45 Å, and 2.60 Å, respectively. The MERS1 structure has a unique fold that indeed contains a Nudix motif. The nucleotide bound structures combined with binding studies reveal that MERS1 shows preference for RNA sequences with a central guanine repeat which it binds in a single-stranded conformation. The apo MERS1 structure indicates that a significant portion of its nucleotide binding site folds upon substrate binding. Finally, a potential interaction region for a binding partner, MERS2, that activates MERS1 was identified. The MERS2-like peptide inserts a glutamate near the missing Nudix acidic residue in the RNA binding pocket, suggesting how the enzyme may be activated. Thus, the combined studies reveal insight into the structure and enzyme properties of MERS1 and its substrate-binding activities.

Structures of maintenance of carboxysome distribution Walker-box McdA and McdB adaptor homologs.

Carboxysomes, protein-coated organelles in cyanobacteria, are important in global carbon fixation. However, these organelles are present at low copy in each cell and hence must be segregated to ensure transmission from one generation to the next. Recent studies revealed that a DNA partition-like ParA-ParB system mediates carboxysome maintenance, called McdA-McdB. Here, we describe the first McdA and McdB homolog structures. McdA is similar to partition ParA Walker-box proteins, but lacks the P-loop signature lysine involved in ATP binding. Strikingly, a McdA-ATP structure shows that a lysine distant from the P-loop and conserved in McdA homologs, enables ATP-dependent nucleotide sandwich dimer formation. Similar to partition ParA proteins this ATP-bound form binds nonspecific-DNA. McdB, which we show directly binds McdA, harbors a unique fold and appears to form higher-order oligomers like partition ParB proteins. Thus, our data reveal a new signature motif that enables McdA dimer formation and indicates that, similar to DNA segregation, carboxysome maintenance systems employ Walker-box proteins as DNA-binding motors while McdB proteins form higher order oligomers, which could function as adaptors to link carboxysomes and provide for stable transport by the McdA proteins.

Correction to: Cervical and breast cancer screening uptake among women with serious mental illness: a data linkage study.

Following publication of the original article [1], the authors notified us of an error in the reported percentages in Table 3.

NIPSA: a new scale for measuring non-illness predictors of sickness absence.

OBJECTIVES: We describe the development and initial validation of a new scale for measuring non-illness factors that are important in predicting occupational outcomes, called the NIPSA (non-illness predictors of sickness absence) scale. METHODS: Forty-two questions were developed which covered a broad range of potential non-illness-related risk factors for sickness absence. 682 participants in the South East London Community Health study answered these questions and a range of questions regarding both short-term and long-term sickness absence. Factor analysis was conducted prior to examining the links between each identified factor and sickness absence outcomes. RESULTS: Exploratory factor analysis using the oblique rotation method suggested the questionnaire should contain 26 questions and extracted four factors with eigenvalues greater than 1: perception of psychosocial work environment (factor 1), perceived vulnerability (factor 2), rest-focused attitude towards recovery (factor 3) and attitudes towards work (factor 4). Three of these factors (factors 1, 2 and 3) showed significant associations with long-term sickness absence measures (p<0.05), meaning a final questionnaire that included 20 questions with three subscales. CONCLUSIONS: The NIPSA is a new tool that will hopefully allow clinicians to quickly assess for the presence of non-illness factors that may be important in predicting occupational outcomes and tailor treatments and interventions to address the barriers identified. To the best of our knowledge, this is the first time that a scale focused on transdiagnostic, non-illness-related predictors of sickness absence has been developed.

A framework to create more mentally healthy workplaces: A viewpoint.

Mental illness is now the leading cause of long-term sickness absence among Australian workers, with significant costs to the individual, their employers and society more broadly. However, to date, there has been little evidence-informed guidance as to what workplaces should be doing to enhance their employees' mental health and wellbeing. In this article, we present a framework outlining the key strategies employers can implement to create more mentally healthy workplaces. The five key strategies outlined are as follows: (1) designing work to minimise harm, (2) building organisational resilience through good management, (3) enhancing personal resilience, (4) promoting early help-seeking and (5) supporting recovery and return to work. A narrative review is utilised to outline the theoretical evidence for this framework and to describe the available research evidence for a number of key example interventions for each of the five strategies. While each workplace needs to develop tailored solutions, the five strategy framework proposed in this review will hopefully provide a simple framework for employers and those advising them to use when judging the adequacy of existing services and considering opportunities for further enhancements.

Cervical and breast cancer screening uptake among women with serious mental illness: a data linkage study.

BACKGROUND: Breast and cancer screening uptake has been found to be lower among women with serious mental illness (SMI). This study aims to corroborate these findings in the UK and to identify variation in screening uptake by illness/treatment factors, and primary care consultation frequency. METHODS: Linked population-based primary and secondary care data from the London borough of Lambeth (UK) were used to compare breast and cervical screening receipt among linked eligible SMI patients (n = 625 and n = 1393), to those without SMI known only to primary care (n = 106,554 and n = 25,385) using logistic regression models adjusted first for socio-demographic factors and second, additionally for primary care consultation frequency. RESULTS: Eligible SMI patients were less likely to have received breast (adjusted odds ratio (OR) 0.69, 95 % confidence interval (CI), 0.57 - 0.84, p < 0.001) or cervical screening (adjusted OR 0.72, CI: 0.60 - 0.85, p < 0.001). Schizophrenia diagnosis, depot injectable antipsychotic prescription, and illness severity and risk were associated with the lowest odds of uptake of breast (adjusted ORs 0.46 to 0.59, all p < 0.001) and cervical screening (adjusted ORs 0.48 - 0.65, all p < 0.001). Adjustments for consultation frequency further reduced effect sizes for all subgroups of SMI patient, in particular for cervical screening. CONCLUSIONS: Women with SMI are less likely to receive breast and cervical cancer screening than comparable women without SMI. Higher primary care consultation rates among SMI patients is likely a mediating factor between SMI status and uptake, particularly for cervical screening - a service organised in primary care. To tackle health disparities linked to SMI, efforts at increasing screening uptake are key and should be targeted at women with other markers of illness severity or risk, beyond SMI status alone.

Seeking informal and formal help for mental health problems in the community: a secondary analysis from a psychiatric morbidity survey in South London.

BackgroundOnly 30-35% of people with mental health problems seek help from professionals. Informal help, usually from friends, family and religious leaders, is often sought but is under-researched. This study aimed to contrast patterns of informal and formal help-seeking using data from a community psychiatric morbidity survey (n=1692) (South East London Community Health (SELCOH) Study).MethodsPatterns of help-seeking were analysed by clinical, sociodemographic and socioeconomic indicators. Factors associated with informal and formal help-seeking were investigated using logistic regression. Cross-tabulations examined informal help-seeking patterns from different sources.Results`Cases¿ (n = 386) were participants who had scores of ¿ 12 on the Revised Clinical Interview Schedule (CIS-R), indicating a common mental disorder. Of these, 40.1% had sought formal help, (of whom three-quarters (29%) had also sought informal help), 33.6% had sought informal help only and only 26.3% had sought no help. When controlling for non-clinical variables, severity, depression, suicidal ideas, functioning and longstanding illnesses were associated with formal rather than informal help-seeking. Age and ethnic group influenced sources of informal help used. Younger people most frequently sought informal help only whereas older people tended to seek help from their family. There were ethnic group differences in whether help was sought from friends, family or religious leaders.ConclusionsThis study has shown how frequently informal help is used, whether in conjunction with formal help or not. Among the `cases¿, over 60% had sought informal help, whether on its own or together with formal help. Severity was associated with formal help-seeking. Patterns of informal help use have been found. The use and effectiveness of informal help merit urgent research.

Medical student depression, anxiety and distress outside North America: a systematic review.

CONTEXT: North American medical students are more depressed and anxious than their peers. In the UK, the regulator now has responsibility for medical students, which may potentially increase scrutiny of their health. This may either help or hinder medical students in accessing appropriate care. The prevalences of anxiety, depression and psychological distress in medical students outside North America are not clear. A better understanding of the prevalence of, risk factors for and results of psychological distress will guide the configuration of support services, increasingly available for doctors, for medical students too. OBJECTIVES: The aim of this study was to examine the prevalences of depression, anxiety and psychological distress in students in medical schools in the UK, Europe and elsewhere in the English-speaking world outside North America. METHODS: A systematic review was conducted using search terms encompassing psychological distress amongst medical students. OvidSP was used to search the following databases: Ovid MEDLINE (R) from 1948 to October 2013; PsycINFO from 1806 to October 2013, and EMBASE from 1980 to October 2013. Results were restricted to medical schools in Europe and the English-speaking world outside North America, and were evaluated against a set of inclusion criteria including the use of validated assessment tools. RESULTS: The searches identified 29 eligible studies. Prevalences of 7.7-65.5% for anxiety, 6.0-66.5% for depression and 12.2-96.7% for psychological distress were recorded. The wide range of results reflects the variable quality of the studies. Almost all were cross-sectional and many did not mention ethical approval. Better-quality studies found lower prevalences. There was little information on the causes or consequences of depression or anxiety. CONCLUSIONS: Prevalences of psychological distress amongst medical students outside North America are substantial. Future research should move on from simple cross-sectional studies to better-quality longitudinal work which can identify both predictors for and outcomes of poor mental health in medical students.

Shame among long-term sickness absentees: correlates and impact on subsequent sickness absence.

AIMS: The contribution of general psychological aspects, such as emotions, has received little focus in research on sickness absence. We wanted to study the relationship between shame and sickness absence, which factors that explained differences in levels of shame, and if shame predicted subsequent sickness absence. METHODS: We employed a Swedish population-based cohort of current sickness absentees (19-64 years old), responding to a mailed questionnaire in 2008. Data was linked to national registries on sickness absence. RESULTS: The young, those born outside the Nordic countries, those on lower incomes and those with higher level of education reported being more ashamed of their sickness absence. Those with more sickness absence in the past were also more likely to report higher levels of shame. Level of shame was not associated with gender or occupational class. Compared to those absent for a somatic cause, mental or co-morbid illness was associated with higher levels of shame. Those reporting high level of shame were more likely to have prolonged sickness absence the following year. Symptoms of depression at baseline only partly explained these associations. CONCLUSIONS: Our results suggest that shame might prolong sickness absence. Increased understanding of the impact of social and emotional aspects around sickness absence could be an important source for improved quality of rehabilitation.

Patterns of physical co-/multi-morbidity among patients with serious mental illness: a London borough-based cross-sectional study.

BACKGROUND: Serious mental illness (SMI) is associated with elevated mortality compared to the general population; the majority of this excess is attributable to co-occurring common physical health conditions. There may be variation within the SMI group in the distribution of physical co/multi-morbidity. This study aims to a) compare the pattern of physical co- and multi-morbidity between patients with and without SMI within a South London primary care population; and, b) to explore socio-demographic and health risk factors associated with excess physical morbidity among the SMI group. METHODS: Data were obtained from Lambeth DataNet, a database of electronic patient records derived from general practices in the London borough of Lambeth. The pattern of 12 co-morbid common physical conditions was compared by SMI status. Multivariate ordinal and logistic regression analyses were conducted to assess the strength of association between each condition and SMI status; adjustments were made for potentially confounding socio-demographic characteristics and for potentially mediating health risk factors. RESULTS: While SMI patients were more frequently recorded with all 12 physical conditions than non-SMI patients, the pattern of co-/multi-morbidity was similar between the two groups. Adjustment for socio-demographic characteristics - in particular age and, to a lesser extent ethnicity, considerably reduced effect sizes and accounted for some of the associations, though several conditions remained strongly associated with SMI status. Evidence for mediation by health risk factors, in particular BMI, was supported. CONCLUSIONS: SMI patients are at an elevated risk of a range of physical health conditions than non-SMI patients but they do not appear to experience a different pattern of co-/multimorbidity among those conditions considered. Socio-demographic differences between the two groups account for some of the excess in morbidity and known health risk factors are likely to mediate the association. Further work to examine a wider range of conditions and health risk factors would help determine the extent of excess mortality attributable to these factors.

Impact of psychotic disorder on transplant eligibility and outcomes.

PURPOSE OF REVIEW: Organ transplantation decisions are complex, and psychosocial assessment is an important part of the process. The impact of pretransplant psychotic disorder on posttransplant outcomes is unclear, but some guidelines cite psychosis as a relative contraindication to organ transplantation because of concerns about medication adherence and poor postoperative outcomes. This review explores the evidence for poorer solid organ transplant outcomes for people with preexisting psychotic disorders and discusses future directions for how research can contribute to a better understanding of how organ transplantation outcomes are affected by psychotic illness. RECENT FINDINGS: When added to the existing small body of literature, recent findings show a continuing insufficient evidence base to suggest that the presence of psychotic disorder increases risk of poorer adherence and outcomes. The evidence points to social isolation being a key factor in poorer adherence posttransplant. SUMMARY: Further research is needed to determine the impact of psychotic disorder on transplant outcomes, but based on current evidence a diagnosis of psychotic disorder should not preclude consideration for organ transplantation.

Long-term health conditions and UK labour market outcomes during the COVID-19 pandemic.

BACKGROUND: Long-term health conditions can affect labour market outcomes. COVID-19 may have increased labour market inequalities, e.g. due to restricted opportunities for clinically vulnerable people. Evaluating COVID-19's impact could help target support. AIM: To quantify the effect of several long-term conditions on UK labour market outcomes during the COVID-19 pandemic and compare them to pre-pandemic outcomes. METHODS: The Understanding Society COVID-19 survey collected responses from around 20,000 UK residents in nine waves from April 2020-September 2021. Participants employed in January/February 2020 with a variety of long-term conditions were matched with people without the condition but with similar baseline characteristics. Models estimated probability of employment, hours worked and earnings. We compared these results with results from a two-year pre-pandemic period. We also modelled probability of furlough and home-working frequency during COVID-19. RESULTS: Most conditions (asthma, arthritis, emotional/nervous/psychiatric problems, vascular/pulmonary/liver conditions, epilepsy) were associated with reduced employment probability and/or hours worked during COVID-19, but not pre-pandemic. Furlough was more likely for people with pulmonary conditions. People with arthritis and cancer were slower to return to in-person working. Few effects were seen for earnings. CONCLUSION: COVID-19 had a disproportionate impact on people with long-term conditions' labour market outcomes.

Allosteric regulation of glycogen breakdown by the second messenger cyclic di-GMP.

Streptomyces are our principal source of antibiotics, which they generate concomitant with a complex developmental transition from vegetative hyphae to spores. c-di-GMP acts as a linchpin in this transition by binding and regulating the key developmental regulators, BldD and WhiG. Here we show that c-di-GMP also binds the glycogen-debranching-enzyme, GlgX, uncovering a direct link between c-di-GMP and glycogen metabolism in bacteria. Further, we show c-di-GMP binding is required for GlgX activity. We describe structures of apo and c-di-GMP-bound GlgX and, strikingly, their comparison shows c-di-GMP induces long-range conformational changes, reorganizing the catalytic pocket to an active state. Glycogen is an important glucose storage compound that enables animals to cope with starvation and stress. Our in vivo studies reveal the important biological role of GlgX in Streptomyces glucose availability control. Overall, we identify a function of c-di-GMP in controlling energy storage metabolism in bacteria, which is widespread in Actinobacteria.

Long-term sickness absence among patients with chronic fatigue syndrome.

Chronic fatigue syndrome is associated with high levels of occupational disability. Consecutive out-patients at a chronic fatigue syndrome treatment service were studied for associations between occupational status, symptom severity and cognitive and behavioural responses to symptoms. All patients had high symptom levels; however, those on long-term sickness absence had significantly more physical fatigue (ß = 0.098, P<0.05) and worse sleep (ß = 0.075, P<0.05). Patients with long-term sickness absence also demonstrated more embarrassment avoidance cognitions (ß = 0.086, P<0.05) and avoidance resting behavioural responses (ß = 0.078, P<0.05). Identifying and addressing avoidance behaviours and cognitions regarding embarrassment in interventions may enhance the chances of individuals returning to work.

Psychiatric disorder in early adulthood and risk of premature mortality in the 1946 British Birth Cohort.

BACKGROUND: Few studies of the association between psychiatric disorder and premature death have adjusted for key confounders and used structured psychiatric interviews. We aimed to investigate if psychiatric disorder was associated with a higher risk of mortality and whether any excess mortality was due to suicide, or explained by other health or socioeconomic risk factors. METHODS: We used data from the MRC National Survey of Health and Development, a nationally representative UK birth cohort. 3283 men and women completed the Present State Examination at age 36. The main outcome measure was all-cause mortality before age 60. RESULTS: Those with psychiatric disorder at age 36 had a higher risk of death even after adjusting for potential confounders (Hazard ratio = 1.84, 95% C.I. 1.22-2.78). Censoring violent deaths and suicides led to similar results. CONCLUSIONS: Psychiatric disorder was associated with excess premature mortality not explained by suicide or other health or socioeconomic risk factors.