Atypical brain structures as a function of gray matter volume (GMV) and gray matter density (GMD) in young adults relating to autism spectrum traits

Individuals with autistic traits are those who present in the normal population with characteristics of social, communication, personality, and cognitive impairments but do not meet the clinical threshold for autism spectrum disorder (ASD). Most studies have focused on the abnormalities in ASD patients rather than on individuals with autistic traits. In this study, we focused on the behaviors of a large sample (N = 401) of Chinese individuals with different levels of autistic traits, measured using the Autism Spectrum Quotient, and applied voxel-based morphometry (VBM) to determine their association to differences in brain structure. The results mainly showed that the correlation between gray matter volume (GMV) and gray matter density of the brain and the Autism Spectrum Quotient was significant in these regions: the right middle frontal gyrus, which are involved in social processing and social reasoning; the left parahippocampal gyrus, which is involved in socioemotional behaviors and unconscious relational memory encoding; and the right superior parietal lobule, which are involved in cognitive control and the ability to show attention to detail. These findings reveal that people with autistic traits in the normal population have atypical development in GMV and gray matter density, which may affect their social functioning and communication ability

Cosmic Structure Formation with Topological Defects

Topological defects are ubiquitous in physics. Whenever a symmetry breaking phase transition occurs, topological defects may form. The best known examples are vortex lines in type II super conductors or in liquid Helium, and declination lines in liquid crystals. In an adiabatically expanding universe which cools down from a very hot initial state, it is quite natural to postulate that topological defects may have emerged during a phase transition in the early universe and that they may have played the role of initial inhomogeneities seeding the formation of cosmic structure. This basic idea goes back to Kibble (1976). In this report we summarize the progress made in the investigation of Kibble's idea during the last 25 years. Our understanding of the formation and evolution of topological defects is reported almost completely in the beautiful book by Vilenkin & Shellard or the excellent Review by Hindmarsh & Kibble, and we shall hence be rather short on that topic. Nevertheless, in order to be self contained, we have included a short chapter on spontaneous symmetry breaking and defect formation. Our main topic is however the calculation of structure formation with defects, results which are not included in the above references.Comment: Review for Physics Reports, 133 pages 29 figures. Updated to match published version. Better quality and color figures are available at http://mpej.unige.ch/~durre

Preeclampsia and COVID-19: results from the INTERCOVID prospective longitudinal study

Background: It is unclear whether the suggested link between COVID-19 during pregnancy and preeclampsia is an independent association or if these are caused by common risk factors. Objective: This study aimed to quantify any independent association between COVID-19 during pregnancy and preeclampsia and to determine the effect of these variables on maternal and neonatal morbidity and mortality. Study Design: This was a large, longitudinal, prospective, unmatched diagnosed and not-diagnosed observational study assessing the effect of COVID-19 during pregnancy on mothers and neonates. Two consecutive not-diagnosed women were concomitantly enrolled immediately after each diagnosed woman was identified, at any stage during pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed until hospital discharge using the standardized INTERGROWTH-21st protocols and electronic data management system. A total of 43 institutions in 18 countries contributed to the study sample. The independent association between the 2 entities was quantified with the risk factors known to be associated with preeclampsia analyzed in each group. The outcomes were compared among women with COVID-19 alone, preeclampsia alone, both conditions, and those without either of the 2 conditions. Results: We enrolled 2184 pregnant women; of these, 725 (33.2%) were enrolled in the COVID-19 diagnosed and 1459 (66.8%) in the COVID-19 not-diagnosed groups. Of these women, 123 had preeclampsia of which 59 of 725 (8.1%) were in the COVID-19 diagnosed group and 64 of 1459 (4.4%) were in the not-diagnosed group (risk ratio, 1.86; 95% confidence interval, 1.32–2.61). After adjustment for sociodemographic factors and conditions associated with both COVID-19 and preeclampsia, the risk ratio for preeclampsia remained significant among all women (risk ratio, 1.77; 95% confidence interval, 1.25–2.52) and nulliparous women specifically (risk ratio, 1.89; 95% confidence interval, 1.17–3.05). There was a trend but no statistical significance among parous women (risk ratio, 1.64; 95% confidence interval, 0.99–2.73). The risk ratio for preterm birth for all women diagnosed with COVID-19 and preeclampsia was 4.05 (95% confidence interval, 2.99–5.49) and 6.26 (95% confidence interval, 4.35–9.00) for nulliparous women. Compared with women with neither condition diagnosed, the composite adverse perinatal outcome showed a stepwise increase in the risk ratio for COVID-19 without preeclampsia, preeclampsia without COVID-19, and COVID-19 with preeclampsia (risk ratio, 2.16; 95% confidence interval, 1.63–2.86; risk ratio, 2.53; 95% confidence interval, 1.44–4.45; and risk ratio, 2.84; 95% confidence interval, 1.67–4.82, respectively). Similar findings were found for the composite adverse maternal outcome with risk ratios of 1.76 (95% confidence interval, 1.32–2.35), 2.07 (95% confidence interval, 1.20–3.57), and 2.77 (95% confidence interval, 1.66–4.63). The association between COVID-19 and gestational hypertension and the direction of the effects on preterm birth and adverse perinatal and maternal outcomes, were similar to preeclampsia, but confined to nulliparous women with lower risk ratios. Conclusion: COVID-19 during pregnancy is strongly associated with preeclampsia, especially among nulliparous women. This association is independent of any risk factors and preexisting conditions. COVID-19 severity does not seem to be a factor in this association. Both conditions are associated independently of and in an additive fashion with preterm birth, severe perinatal morbidity and mortality, and adverse maternal outcomes. Women with preeclampsia should be considered a particularly vulnerable group with regard to the risks posed by COVID-19

Identification d'une nouvelle protéine eucaryote essentielle pour la localisation membranaire de la toxine ExoU de Pseudomonas aeruginosa

Pseudomonas aeruginosa is an opportunistic Gram-negative bacterium, responsible for different types of infection, in particular for nosocomial diseases. The acute infections caused by this pathogen are promoted by a broad panel of virulence factors; the most aggressive one being the Type III Secretion System. Among the four effectors injected by this system into the cytoplasm of target cells, ExoU is the most cytotoxic one. ExoU+ strains are associated with the most severe pathologies and to higher multiresistance to antibiotics. The toxin possesses a phospholipase activity inducing cell necrosis upon plasma membrane rupture. However, the trafficking of the toxin in host cells to reach the plasma membrane is unknown.In this study, I aimed at identifying ExoU host partners, using a genome-wide screen employing the CRISPR-Cas9 system. Likewise, I identified the gene encoding a co-chaperone protein, named DNAJC5. This protein, located at the surface of late endosomes, is involved in an unconventional secretion pathway required for the release of misfolded cytosolic proteins. Using human cellular models, as well as Drosophila, we demonstrate that lack of DNAJC5 confers resistance to ExoU+ strain infection. In the host cytoplasm, the toxin localizes at the surface of DNAJC5+ vesicles. Mutations in DNAJC5 gene, preventing vesicle trafficking to the plasma membrane, also impede ExoU targeting to the plasma membrane and inhibit its cytotoxicity. We conclude that, once delivered into the host cell cytoplasm, ExoU uses DNAJC5+ vesicles to be transported to the plasma membrane, a process strictly required for ExoU-induced cell necrosis.Pseudomonas aeruginosa est une bactérie Gram-négative opportuniste, responsable de différents types d'infections, et notamment de maladies nosocomiales. Les infections aiguës causées par ce pathogène sont dues à un large panel de facteurs de virulence, dont le plus agressif est un système de sécrétion de type III. Parmi les quatre effecteurs injectés par ce système dans le cytoplasme des cellules cibles, ExoU est le plus cytotoxique. Les souches ExoU+ sont associées aux pathologies les plus sévères et à une multirésistance aux antibiotiques plus élevée. La toxine possède une activité phospholipase qui induit une nécrose cellulaire après rupture de la membrane plasmique. Cependant, le trafic de la toxine dans les cellules hôtes pour atteindre la membrane plasmique n’est pas connu.Dans ce travail, j’ai recherché des partenaires eucaryotes d’ExoU en réalisant un criblage génétique sur l’ensemble du génome humain, mettant en oeuvre le système CRISPR-Cas9. J’ai ainsi identifié le gène codant pour une protéine co-chaperone appelée DNAJC5. Cette protéine, localisée à la surface des endosomes tardifs, est impliquée dans un système de sécrétion non-conventionnel permettant le relargage de protéines cytosoliques mal repliées. Nous démontrons dans des modèles cellulaires et chez la drosophile, que l'absence de DNAJC5 confère une résistance à la nécrose induite par des souches ExoU+. Dans le cytoplasme, la toxine est localisée à la membrane des vésicules DNAJC5+. Des mutations dans le gène DNAJC5, empêchant le trafic des endosomes tardifs DNAJC5+ vers la membrane plasmique, entravent également la localisation d’ExoU à ce niveau et inhibent sa cytotoxicité. Nous concluons, qu'une fois administrée dans le cytoplasme de la cellule hôte, ExoU utilise des vésicules DNAJC5+, pour être transportée à la membrane plasmique, un processus strictement nécessaire à la nécrose cellulaire induite par la toxine

Identification of a new eukaryotic protein essential for the membrane localization of ExoU toxin from Pseudomonas aeruginosa

Pseudomonas aeruginosa est une bactérie Gram-négative opportuniste, responsable de différents types d'infections, et notamment de maladies nosocomiales. Les infections aiguës causées par ce pathogène sont dues à un large panel de facteurs de virulence, dont le plus agressif est un système de sécrétion de type III. Parmi les quatre effecteurs injectés par ce système dans le cytoplasme des cellules cibles, ExoU est le plus cytotoxique. Les souches ExoU+ sont associées aux pathologies les plus sévères et à une multirésistance aux antibiotiques plus élevée. La toxine possède une activité phospholipase qui induit une nécrose cellulaire après rupture de la membrane plasmique. Cependant, le trafic de la toxine dans les cellules hôtes pour atteindre la membrane plasmique n’est pas connu.Dans ce travail, j’ai recherché des partenaires eucaryotes d’ExoU en réalisant un criblage génétique sur l’ensemble du génome humain, mettant en oeuvre le système CRISPR-Cas9. J’ai ainsi identifié le gène codant pour une protéine co-chaperone appelée DNAJC5. Cette protéine, localisée à la surface des endosomes tardifs, est impliquée dans un système de sécrétion non-conventionnel permettant le relargage de protéines cytosoliques mal repliées. Nous démontrons dans des modèles cellulaires et chez la drosophile, que l'absence de DNAJC5 confère une résistance à la nécrose induite par des souches ExoU+. Dans le cytoplasme, la toxine est localisée à la membrane des vésicules DNAJC5+. Des mutations dans le gène DNAJC5, empêchant le trafic des endosomes tardifs DNAJC5+ vers la membrane plasmique, entravent également la localisation d’ExoU à ce niveau et inhibent sa cytotoxicité. Nous concluons, qu'une fois administrée dans le cytoplasme de la cellule hôte, ExoU utilise des vésicules DNAJC5+, pour être transportée à la membrane plasmique, un processus strictement nécessaire à la nécrose cellulaire induite par la toxine.Pseudomonas aeruginosa is an opportunistic Gram-negative bacterium, responsible for different types of infection, in particular for nosocomial diseases. The acute infections caused by this pathogen are promoted by a broad panel of virulence factors; the most aggressive one being the Type III Secretion System. Among the four effectors injected by this system into the cytoplasm of target cells, ExoU is the most cytotoxic one. ExoU+ strains are associated with the most severe pathologies and to higher multiresistance to antibiotics. The toxin possesses a phospholipase activity inducing cell necrosis upon plasma membrane rupture. However, the trafficking of the toxin in host cells to reach the plasma membrane is unknown.In this study, I aimed at identifying ExoU host partners, using a genome-wide screen employing the CRISPR-Cas9 system. Likewise, I identified the gene encoding a co-chaperone protein, named DNAJC5. This protein, located at the surface of late endosomes, is involved in an unconventional secretion pathway required for the release of misfolded cytosolic proteins. Using human cellular models, as well as Drosophila, we demonstrate that lack of DNAJC5 confers resistance to ExoU+ strain infection. In the host cytoplasm, the toxin localizes at the surface of DNAJC5+ vesicles. Mutations in DNAJC5 gene, preventing vesicle trafficking to the plasma membrane, also impede ExoU targeting to the plasma membrane and inhibit its cytotoxicity. We conclude that, once delivered into the host cell cytoplasm, ExoU uses DNAJC5+ vesicles to be transported to the plasma membrane, a process strictly required for ExoU-induced cell necrosis

Bacterial Nucleotidyl Cyclases Activated by Calmodulin or Actin in Host Cells: Enzyme Specificities and Cytotoxicity Mechanisms Identified to Date

International audienceMany pathogens manipulate host cell cAMP signaling pathways to promote their survival and proliferation. Bacterial Exoenzyme Y (ExoY) toxins belong to a family of invasive, structurallyrelated bacterial nucleotidyl cyclases (NC). Inactive in bacteria, they use proteins that are uniquely and abundantly present in eukaryotic cells to become potent, unregulated NC enzymes in host cells. Other well-known members of the family include Bacillus anthracis Edema Factor (EF) and Bordetella pertussis CyaA. Once bound to their eukaryotic protein cofactor, they can catalyze supra-physiological levels of various cyclic nucleotide monophosphates in infected cells. Originally identified in Pseudomonas aeruginosa, ExoY-related NC toxins appear now to be more widely distributed among various γ-and β-proteobacteria. ExoY-like toxins represent atypical, poorly characterized members within the NC toxin family. While the NC catalytic domains of EF and CyaA toxins use both calmodulin as cofactor, their counterparts in ExoY-like members from pathogens of the genus Pseudomonas or Vibrio use actin as a potent cofactor, in either its monomeric or polymerized form. This is an original subversion of actin for cytoskeleton-targeting toxins. Here, we review recent advances on the different members of the NC toxin family to highlight their common and distinct functional characteristics at the molecular, cytotoxic and enzymatic levels, and important aspects that need further characterizations

ExlA pore-forming toxin: localization at the bacterial membrane, regulation of secretion by cyclic-Di-GMP, and detection in vivo

International audienceExlA is a highly virulent pore-forming toxin that has been recently discovered in outlier strains from Pseudomonas aeruginosa. ExlA is part of a two-partner secretion system, in which ExlA is the secreted passenger protein and ExlB the transporter embedded in the bacterial outer membrane. In previous work, we observed that ExlA toxicity in a host cell was contact-dependent. Here, we show that ExlA accumulates at specific points of the outer membrane, is likely entrapped within ExlB pore, and is pointing outside. We further demonstrate that ExlA is maintained at the membrane in conditions where the intracellular content of second messenger cyclic-di-GMP is high; lowering c-di-GMP levels enhances ExlB-dependent ExlA secretion. In addition, we set up an ELISA to detect ExlA, and we show that ExlA is poorly secreted in liquid culture, while it is highly detectable in broncho-alveolar lavage fluids of mice infected with an exlA+ strain. We conclude that ExlA translocation is halted at mid-length in the outer membrane and its secretion is regulated by c-di-GMP. In addition, we developed an immunological test able to quantify ExlA in biological samples

A Multicenter Preclinical MRI Study: Definition of Rat Brain Relaxometry Reference Maps

International audienceSimilarly to human population imaging, there are several well-founded motivations for animal population imaging, the most notable being the improvement of the validity of statistical results by pooling a sufficient number of animal data provided by different imaging centers. In this paper, we demonstrate the feasibility of such a multicenter animal study, sharing raw data from forty rats and processing pipelines between four imaging centers. As specific use case, we focused on T1 and T2 mapping of the healthy rat brain at 7T. We quantitatively report about the variability observed across two MR data providers and evaluate the influence of image processing steps on the final maps, using three fitting algorithms from three centers. Finally, to derive relaxation times from different brain areas, two multi-atlas segmentation pipelines from different centers were performed on two different platforms. Differences between the two data providers were 2.21% for T1 and 9.52% for T2. Differences between processing pipelines were 1.04% for T1 and 3.33% for T2. These maps, obtained in healthy conditions, may be used in the future as reference when exploring alterations in animal models of pathology