PROS1 novel splice-site variant decreases protein S expression in patients from two families with thrombotic disease

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Staphylococcus saprophyticus from clinical and environmental origins have distinct biofilm composition

Biofilm formation has been shown to be critical to the success of uropathogens. Although Staphylococcus saprophyticus is a common cause of urinary tract infections, its biofilm production capacity, composition, genetic basis, and origin are poorly understood. We investigated biofilm formation in a large and diverse collection of S. saprophyticus (n = 422). Biofilm matrix composition was assessed in representative strains (n = 63) belonging to two main S. saprophyticus lineages (G and S) recovered from human infection, colonization, and food-related environment using biofilm detachment approach. To identify factors that could be associated with biofilm formation and structure variation, we used a pangenome-wide association study approach. Almost all the isolates (91%; n = 384/422) produced biofilm. Among the 63 representative strains, we identified eight biofilm matrix phenotypes, but the most common were composed of protein or protein-extracellular DNA (eDNA)-polysaccharides (38%, 24/63 each). Biofilms containing protein-eDNA-polysaccharides were linked to lineage G and environmental isolates, whereas protein-based biofilms were produced by lineage S and infection isolates (p < 0.05). Putative biofilm-associated genes, namely, aas, atl, ebpS, uafA, sasF, sasD, sdrH, splE, sdrE, sdrC, sraP, and ica genes, were found with different frequencies (3-100%), but there was no correlation between their presence and biofilm production or matrix types. Notably, icaC_1 was ubiquitous in the collection, while icaR was lineage G-associated, and only four strains carried a complete ica gene cluster (icaADBCR) except one that was without icaR. We provided evidence, using a comparative genomic approach, that the complete icaADBCR cluster was acquired multiple times by S. saprophyticus and originated from other coagulase-negative staphylococci. Overall, the composition of S. saprophyticus biofilms was distinct in environmental and clinical isolates, suggesting that modulation of biofilm structure could be a key step in the pathogenicity of these bacteria. Moreover, biofilm production in S. saprophyticus is ica-independent, and the complete icaADBCR was acquired from other staphylococci

Escherichia coli α-Hemolysin Counteracts the Anti-Virulence Innate Immune Response Triggered by the Rho GTPase Activating Toxin CNF1 during Bacteremia

International audienceThe detection of the activities of pathogen-encoded virulence factors by the innate immune system has emerged as a new paradigm of pathogen recognition. Much remains to be determined with regard to the molecular and cellular components contributing to this defense mechanism in mammals and importance during infection. Here, we reveal the central role of the IL-1 beta signaling axis and Gr1+ cells in controlling the Escherichia coli burden in the blood in response to the sensing of the Rho GTPase-activating toxin CNF1. Consistently, this innate immune response is abrogated in caspase-1/11-impaired mice or following the treatment of infected mice with an IL-1 beta antagonist. In vitro experiments further revealed the synergistic effects of CNF1 and LPS in promoting the maturation/secretion of IL-1 beta and establishing the roles of Rac, ASC and caspase-1 in this pathway. Furthermore, we found that the Phi-hemolysin toxin inhibits IL-1 beta secretion without affecting the recruitment of Gr1+ cells. Here, we report the first example of anti-virulence-triggered immunity counteracted by a pore-forming toxin during bacteremia

The male and female complete mitochondrial genomes of the threatened freshwater pearl mussel Margaritifera margaritifera (Linnaeus, 1758) (Bivalvia: Margaritiferidae)

The complete mitogenomes of one (M-)ale (North America), one Hermaphroditic (Europe), and two (F-)emale (North America and Europe) individuals of the freshwater pearl mussel Margaritifera margaritifera were sequenced. The M-type and F-type (Female and Hermaphroditic) mitogenomes have 17,421 and 16,122 nucleotides, respectively. All with the same content: 13 protein-coding genes, 22 transfer RNA, two ribosomal RNA genes, and one sex-related ORF. The M-type is highly divergent (37.6% uncorrected p-distance) from the F-type mitogenomes. North American and European F-type mitogenomes exhibit low genetic divergence (68 nt substitutions), and the Female and Hermaphroditic European mitogenomes are almost identical, and matching sex-related ORFs.This work was supported by Portuguese Foundation for Science and Technology (FCT) [grant number SFRH/BD/115728/2016 (MLL), grant number SFRH/BD/137935/2018 (AGS)]; Russian Foundation for Basic Research [grant number 18-34-20033 (IVV)]; Dawson Fellowship at St. Catharine's College, Cambridge (DCA); Life Margal Ulla [number LIFE09 NAT/ES/000514 (RA and PO)]; COMPETE 2020, Portugal 2020 and the European Union through the ERDF, and by Portuguese Foundation for Science and Technology (FCT) through national funds [UID/Multi/04423/2019] under project ConBiomics: the missing approach for the Conservation of freshwater Bivalves Project, and [project number NORTE-01-0145-FEDER-030286]; Federal Agency for Scientific Organizations under Grants [grant number 0409-2015-0143 (INB and IVV)

Diversity, biogeography, evolutionary relationships, and conservation of Eastern Mediterranean freshwater mussels (Bivalvia: Unionidae)

Located at the junction between Europe, Africa, and Asia, with distinct evolutionary origins and varied ecological and geographical settings, together with a marked history of changes in orogeny and configuration of the main river basins, turned the Eastern Mediterranean into a region of high diversity and endemism of freshwater taxa. Freshwater mussels (Bivalvia, Unionidae) from the Western Palearctic have been widely studied in their European range, but little attention has been dedicated to these taxa in the Eastern Mediterranean region and their diversity and phylogeography are still poorly understood. The present study aims to resolve the diversity, biogeography, and evolutionary relationships of the Eastern Mediterranean freshwater mussels. To that end, we performed multiple field surveys, phylogenetic analyses, and a thorough taxonomic revaluation. We reassessed the systematics of all Unionidae species in the region, including newly collected specimens across Turkey, Israel, and Iran, combining COI+16S+28S phylogenies with molecular species delineation methods. Phylogeographical patterns were characterized based on published molecular data, newly sequenced specimens, and species distribution data, as well as ancestral range estimations. We reveal that Unionidae species richness in the Eastern Mediterranean is over 70% higher than previously assumed, counting 19 species within two subfamilies, the Unioninae (14) and Gonideinae (5). We propose two new species, Anodonta seddoni sp. nov. and Leguminaia anatolica sp. nov. Six additional taxa, Unio delicatus stat. rev., Unio eucirrus stat. rev., Unio hueti stat. rev., Unio sesirmensis stat. rev., Unio terminalis stat. rev. removed from the synonymy of Unio tigridis, as well as Unio damascensis stat. rev. removed from the synonymy of Unio crassus, are re-described. The nominal taxa Unio rothi var. komarowi O. Boettger, 1880 and Unio armeniacus Kobelt, 1911 are proposed as new synonyms of Unio bruguierianus, and Anodonta cyrea Drouët, 1881 and Anodonta cilicica Kobelt & Rolle, 1895 as new synonyms of Anodonta anatina. Also, the presence of Unio tumidus in the Maritza River is confirmed. The phylogeographic patterns described here are interpreted concerning major past geological events. Conservation needs and implications are presented, together with populations and species conservation priorities

Behavioral response to headache: a comparison between migraine and tension-type headache.

OBJECTIVE: To compare patients with migraine and tension-type headache in their behavior during the attacks and the maneuvers used to relieve the pain. BACKGROUND: Patients with headache often perform nonpharmacological measures to relieve the pain, but it is not known if these behaviors vary with the diagnosis, clinical features, and pathogenesis. METHODS: One hundred consecutive patients with either migraine (n = 72 ) or tension-type headache (n = 28) were questioned (including the use of a checklist) concerning their usual behavior during the attacks and nonpharmacological maneuvers performed to relieve the pain. The results of the two types of headache were compared. RESULTS: Patients with migraine tended to perform more maneuvers than individuals with tension-type headache (mean, 6.2 versus 3). These maneuvers included pressing and applying cold stimuli to the painful site, trying to sleep, changing posture, sitting or reclining in bed (using more pillows than usual to lay down), isolating themselves, using symptomatic medication, inducing vomiting, changing diet, and becoming immobile during the attacks. The only measure predominantly reported by patients with tension-type headache was scalp massage. However, the benefit derived from these measures was not significantly different between the two groups (except for a significantly better response to isolation, local pressure, local cold stimulation, and symptomatic medication in migraineurs). CONCLUSIONS: The behavior of patients during headache attacks varies with the diagnosis. Measures that do not always result in pain relief are performed to prevent its worsening or to improve associated symptoms. These behavioral differences may be due to the different pathogenesis of the attacks or to different styles of dealing with the pain. They can also aid the differential diagnosis between headaches in doubtful cases

Helix movement is coupled to displacement of the second extracellular loop in rhodopsin activation

The second extracellular loop (EL2) of rhodopsin forms a cap over the binding site of its photoreactive 11-cis retinylidene chromophore. A crucial question has been whether EL2 forms a reversible gate that opens upon activation or acts as a rigid barrier. Distance measurements using solid-state 13C NMR spectroscopy between the retinal chromophore and the β4 strand of EL2 show that the loop is displaced from the retinal binding site upon activation, and there is a rearrangement in the hydrogen-bonding networks connecting EL2 with the extracellular ends of transmembrane helices H4, H5 and H6. NMR measurements further reveal that structural changes in EL2 are coupled to the motion of helix H5 and breaking of the ionic lock that regulates activation. These results provide a comprehensive view of how retinal isomerization triggers helix motion and activation in this prototypical G protein-coupled receptor. © 2009 Nature America, Inc. All rights reserved

Thousands of Rab GTPases for the Cell Biologist

Rab proteins are small GTPases that act as essential regulators of vesicular trafficking. 44 subfamilies are known in humans, performing specific sets of functions at distinct subcellular localisations and tissues. Rab function is conserved even amongst distant orthologs. Hence, the annotation of Rabs yields functional predictions about the cell biology of trafficking. So far, annotating Rabs has been a laborious manual task not feasible for current and future genomic output of deep sequencing technologies. We developed, validated and benchmarked the Rabifier, an automated bioinformatic pipeline for the identification and classification of Rabs, which achieves up to 90% classification accuracy. We cataloged roughly 8.000 Rabs from 247 genomes covering the entire eukaryotic tree. The full Rab database and a web tool implementing the pipeline are publicly available at www.RabDB.org. For the first time, we describe and analyse the evolution of Rabs in a dataset covering the whole eukaryotic phylogeny. We found a highly dynamic family undergoing frequent taxon-specific expansions and losses. We dated the origin of human subfamilies using phylogenetic profiling, which enlarged the Rab repertoire of the Last Eukaryotic Common Ancestor with Rab14, 32 and RabL4. Furthermore, a detailed analysis of the Choanoflagellate Monosiga brevicollis Rab family pinpointed the changes that accompanied the emergence of Metazoan multicellularity, mainly an important expansion and specialisation of the secretory pathway. Lastly, we experimentally establish tissue specificity in expression of mouse Rabs and show that neo-functionalisation best explains the emergence of new human Rab subfamilies. With the Rabifier and RabDB, we provide tools that easily allows non-bioinformaticians to integrate thousands of Rabs in their analyses. RabDB is designed to enable the cell biology community to keep pace with the increasing number of fully-sequenced genomes and change the scale at which we perform comparative analysis in cell biology

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)