The absence of SigX may result in a nutritional stress response in Pseudomonas aeruginosa

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The Temperature-Regulation of Pseudomonas aeruginosa cmaX-cfrX-cmpX Operon Reveals an Intriguing Molecular Network Involving the Sigma Factors AlgU and SigX

Pseudomonas aeruginosa is a highly adaptable Gram-negative opportunistic pathogen, notably due to its large number of transcription regulators. The extracytoplasmic sigma factor (ECFσ) AlgU, responsible for alginate biosynthesis, is also involved in responses to cell wall stress and heat shock via the RpoH alternative σ factor. The SigX ECFσ emerged as a major regulator involved in the envelope stress response via membrane remodeling, virulence and biofilm formation. However, their functional interactions to coordinate the envelope homeostasis in response to environmental variations remain to be determined. The regulation of the putative cmaX-cfrX-cmpX operon located directly upstream sigX was investigated by applying sudden temperature shifts from 37°C. We identified a SigX- and an AlgU- dependent promoter region upstream of cfrX and cmaX, respectively. We show that cmaX expression is increased upon heat shock through an AlgU-dependent but RpoH independent mechanism. In addition, the ECFσ SigX is activated in response to valinomycin, an agent altering the membrane structure, and up-regulates cfrX-cmpX transcription in response to cold shock. Altogether, these data provide new insights into the regulation exerted by SigX and networks that are involved in maintaining envelope homeostasis

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Rôles du facteur sigma à fonction extracytoplasmique SigX dans l'adaptation, la formation de biofilm et la réponse à des stress de l'enveloppe chez Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a major opportunistic pathogen causing many infectious diseases in immunocompromised patients. Widely studied because of its involvement in lung infections of cysticfibrosis suffering patients, this bacterium is a major public health challenge. P. aeruginosa persistence is largely due to its ability to adopt a multicellular lifestyle called biofilm. P. aeruginosa genome encodes numerous genes predicted to be involved in signal transduction allowing this bacterium to adapt to many environments. Among these systems, the extracytoplasmic function sigma factors, which are transitory subunits of the RNA polymerase, are of major importance for stress resistance and adaptation. SigX is an ECF sigma factor that has been involved in virulence, biofilm formation and in short chain fatty acidsbiosynthesis. This work led to precise the cellular functions of SigX. We have shown that SigX is of major importance for membrane homeostasis, including composition, fluidity and permeability. As a consequence, SigX was shown to be involved in P. aeruginosa metabolism. SigX activity is enhanced in conditions leading to a cell wall stress, as the lack of the major outer membrane porin OprF, high concentrations of sucrose or sublethal concentration of tobramycin, suggesting that this ECF, as AlgU,is a new cell wall stress responsive sigma factor. Remarkably, some alterations could induce biofilm formation, a phenotype involving at least partially SigX. The molecular mechanisms leading to SigX activity should now be deciphered and the role of this ECF in biofilm formation should be precised.Pseudomonas aeruginosa est un pathogène opportuniste de l’Homme responsable de nombreuses infections des voies pulmonaires et urinaires chez des patients immunodéprimés. Largement étudié pour son implication dans la sévérité des symptômes liés à la mucoviscidose, le« bacille pyocyanique » constitue un enjeu majeur en termes de sécurité sanitaire puisqu’il représente après Escherichia coli et Staphylococcus aureus la 3ème cause d’infections nosocomiales en France (INVS, Enquête nationale de prévalence des infections nosocomiales en France, 2012). La persistance de P. aeruginosa notamment dans le cadre médical, est largement due à sa grande capacité à s’adapter et à se développer en communauté organisée au sein de biofilm. Le génome de P. aeruginosa contient de nombreux gènes codant des systèmes de régulation dont la majorité est impliquée dans des mécanismes de perception-transduction de signaux, conférant à la bactérie son fort pouvoir d’adaptation. Parmi ces systèmes, les facteurs sigma à fonction extracytoplasmique (ECF), des sous-unités transitoires de l’ARN polymérase, jouent un rôle fondamental dans la résistance et l’adaptation aux stress. SigX est un facteur sigma ECF, impliqué dans la virulence et la formation de biofilms, ainsi que dans la production des acides gras à courte chaine. Au cours de cette étude, les fonctions cellulaires de SigX ont été précisées, Nous avons montré que SigX joue un rôle important dans la composition, la fluidité et la perméabilité membranaires, et par conséquent dans le métabolisme de la cellule. L’activation de SigX en réponse à des conditions entrainant un stress de l’enveloppe, telles que la perte de la porine majoritaire OprF, la présence d’une concentration de sucrose dans le milieu de culture ou d’une concentration sub-inhibitrice de tobramycine, suggère que cet ECF, comme AlgU, pourrait appartenir à la classe des ECF de type RpoE.De manière remarquable, certaines altérations de l’enveloppe pourraient induire la formation de biofilm, un phénotype impliquant au moins partiellement SigX. Il conviendra à présent de caractériser les mécanismes moléculaires conduisant à l’activation de SigX et de préciser le rôle de ce facteur sigma dans la formation de biofilm

Role of the Extracytoplasmic function sigma factor SigX in biofilm formation and response to antimicrobials in Pseudomonas aeruginosa

Pseudomonas aeruginosa est un pathogène opportuniste de l’Homme responsable de nombreuses infections des voies pulmonaires et urinaires chez des patients immunodéprimés. Largement étudié pour son implication dans la sévérité des symptômes liés à la mucoviscidose, le« bacille pyocyanique » constitue un enjeu majeur en termes de sécurité sanitaire puisqu’il représente après Escherichia coli et Staphylococcus aureus la 3ème cause d’infections nosocomiales en France (INVS, Enquête nationale de prévalence des infections nosocomiales en France, 2012). La persistance de P. aeruginosa notamment dans le cadre médical, est largement due à sa grande capacité à s’adapter et à se développer en communauté organisée au sein de biofilm. Le génome de P. aeruginosa contient de nombreux gènes codant des systèmes de régulation dont la majorité est impliquée dans des mécanismes de perception-transduction de signaux, conférant à la bactérie son fort pouvoir d’adaptation. Parmi ces systèmes, les facteurs sigma à fonction extracytoplasmique (ECF), des sous-unités transitoires de l’ARN polymérase, jouent un rôle fondamental dans la résistance et l’adaptation aux stress. SigX est un facteur sigma ECF, impliqué dans la virulence et la formation de biofilms, ainsi que dans la production des acides gras à courte chaine. Au cours de cette étude, les fonctions cellulaires de SigX ont été précisées, Nous avons montré que SigX joue un rôle important dans la composition, la fluidité et la perméabilité membranaires, et par conséquent dans le métabolisme de la cellule. L’activation de SigX en réponse à des conditions entrainant un stress de l’enveloppe, telles que la perte de la porine majoritaire OprF, la présence d’une concentration de sucrose dans le milieu de culture ou d’une concentration sub-inhibitrice de tobramycine, suggère que cet ECF, comme AlgU, pourrait appartenir à la classe des ECF de type RpoE.De manière remarquable, certaines altérations de l’enveloppe pourraient induire la formation de biofilm, un phénotype impliquant au moins partiellement SigX. Il conviendra à présent de caractériser les mécanismes moléculaires conduisant à l’activation de SigX et de préciser le rôle de ce facteur sigma dans la formation de biofilm.Pseudomonas aeruginosa is a major opportunistic pathogen causing many infectious diseases in immunocompromised patients. Widely studied because of its involvement in lung infections of cysticfibrosis suffering patients, this bacterium is a major public health challenge. P. aeruginosa persistence is largely due to its ability to adopt a multicellular lifestyle called biofilm. P. aeruginosa genome encodes numerous genes predicted to be involved in signal transduction allowing this bacterium to adapt to many environments. Among these systems, the extracytoplasmic function sigma factors, which are transitory subunits of the RNA polymerase, are of major importance for stress resistance and adaptation. SigX is an ECF sigma factor that has been involved in virulence, biofilm formation and in short chain fatty acidsbiosynthesis. This work led to precise the cellular functions of SigX. We have shown that SigX is of major importance for membrane homeostasis, including composition, fluidity and permeability. As a consequence, SigX was shown to be involved in P. aeruginosa metabolism. SigX activity is enhanced in conditions leading to a cell wall stress, as the lack of the major outer membrane porin OprF, high concentrations of sucrose or sublethal concentration of tobramycin, suggesting that this ECF, as AlgU,is a new cell wall stress responsive sigma factor. Remarkably, some alterations could induce biofilm formation, a phenotype involving at least partially SigX. The molecular mechanisms leading to SigX activity should now be deciphered and the role of this ECF in biofilm formation should be precised