55 research outputs found

    Broken replication forks trigger heritable DNA breaks in the terminus of a circular chromosome

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    <p><u>(A) Circular map of the <i>E</i>. <i>coli</i> chromosome</u>: <i>oriC</i>, <i>dif</i> and <i>terD</i> to <i>terB</i> sites are indicated. Numbers refer to the chromosome coordinates (in kb) of MG1655. (<u>B) Linear map of the terminus region:</u> chromosome coordinates are shown increasing from left to right, as in the marker frequency panels (see Figure 1C for example), therefore in the opposite direction to the circular map. In addition to <i>dif</i> and <i>ter</i> sites, the positions of the <i>parS</i><sub>pMT1</sub> sites used for microscopy experiments are indicated. (<u>C) MFA analysis of terminus DNA loss in the <i>recB</i> mutant</u>: sequence read frequencies of exponential phase cells normalized to the total number of reads were calculated for each strain. Ratios of normalized reads in isogenic wild-type and <i>recB</i> mutant are plotted against chromosomal coordinates (in kb). The profile ratio of the terminus region is enlarged and the profile of the corresponding entire chromosomes is shown in inset. Original normalized profiles used to calculate ratios are shown in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1007256#pgen.1007256.s005" target="_blank">S1 Fig</a>. The position of <i>dif</i> is indicated by a red arrow. The <i>ter</i> sites that arrest clockwise forks (<i>terC</i>, <i>terB</i>, green arrow) and counter-clockwise forks (<i>terA</i>, <i>terD</i>, blue arrow) are shown. <u>(D) Schematic representation of focus loss in the <i>recB</i> mutant:</u> Time-lapse microscopy experiments showed that loss of a focus in the <i>recB</i> mutant occurs concomitantly with cell division in one of two daughter cells, and that the cell that keeps the focus then generates a focus-less cell at each generation. The percentage of initial events was calculated as the percentage of cell divisions that generate a focus-less cell, not counting the following generations. In this schematic representation, two initial events occurred (generations #2 and #7) out of 9 generations, and focus loss at generation #2 is heritable. Panels shown in this figure were previously published in [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1007256#pgen.1007256.ref019" target="_blank">19</a>] and are reproduced here to introduce the phenomenon.</p

    Study of predictive genetic factors of postoperative natural history of Crohn's disease

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    La maladie de Crohn est prĂ©sente principalement dans les pays industrialisĂ©s. En France, elle touche 1 personne sur 1000. L’incidence est de 5 pour 100000 habitants par an. A l’heure actuelle sa pathogĂ©nie reste mal expliquĂ©e et de nombreux facteurs interviennent (facteurs gĂ©nĂ©tiques, immunologiques et environnementaux). Il semble donc essentiel de mieux comprendre la pathogĂ©nie de la maladie de Crohn afin d’identifier des cibles thĂ©rapeutiques permettant d’amĂ©liorer sa prise en charge et d’identifier des facteurs prĂ©dictifs de la rĂ©cidive post-opĂ©ratoire et des complications post-opĂ©ratoires afin de personnaliser la prise en charge de chaque patient. Dans ce travail nous avons montrĂ© qu'un variant gĂ©nĂ©tique de CARD8 (rs2043211) est un facteur de risque de rĂ©cidive post-opĂ©ratoire. Cette association n’est pas influencĂ©e par les autres facteurs de risque connus comme le tabagisme actif. L’identification de CARD8 comme un facteur de risque gĂ©nĂ©tique de risque de rĂ©cidive chirurgicale est d’un intĂ©rĂȘt particulier puisqu’il pourrait devenir une nouvelle cible thĂ©rapeutique pour le traitement de la maladie de Crohn dans la pĂ©riode post-opĂ©ratoire. Notre travail a Ă©galement montrĂ© qu'un variant gĂ©nĂ©tique de NOD2 (rs5743289) est un facteur de risque de complications intra-abdominales infectieuses post-opĂ©ratoires (CIIP) aprĂšs chirurgie dans la maladie de Crohn. L’identification de NOD2 comme un gĂšne Ă  risque pour la survenue de CIIP pourrait permettre d’établir une stratification prĂ©coce des patients Ă  haut risque de CIIP chez qui la chirurgie devra ĂȘtre planifiĂ©e et prĂ©dire les patients Ă  haut risque de CIIP. Des Ă©tudes sur larges effectifs avec cohorte de rĂ©plication restent encore nĂ©cessaires avant que les patients puissent bĂ©nĂ©ficier des retombĂ©es de ces outils en pratique couranteCrohn's disease occurs mainly in industrialized countries. In France it affects 1 person in 1000. The incidence is 5 per 100,000 persons per year. At present its pathogenesis remains poorly explained and many factors are involved (genetic, immunological and environmental). It seems essential to better understand Crohn's disease pathogenesis in order to identify therapeutic targets to improve its management and to identify predictors of postoperative recurrence and postoperative complications to customize the care of each patient. In this work we showed that a genetic variant of CARD8 (rs2043211) is a risk factor for postoperative recurrence. This combination is not influenced by the other known risk factors such as active smoking. Identifying CARD8 as a genetic risk factor for risk of surgical recurrence is of particular interest since it may become a novel therapeutic target for the treatment of Crohn's disease in the post-operative period. Our work has also shown that a genetic variant of NOD2 (rs5743289) is a risk factor for postoperative intraabdominal infectious complications (CIIP) after surgery in Crohn's disease. The identification of NOD2 gene as a risk factor for the occurrence of CIIP could establish an early stratification of patients at high risk for CIIP in whom surgery should be planned and predict patients at high risk for CIIP. Studies with large numbers replication cohort are still necessary before patients can enjoy the benefits of these tools in clinical practic

    Étude des facteurs gĂ©nĂ©tiques prĂ©dictifs de l’histoire naturelle postopĂ©ratoire de la maladie de Crohn

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    Crohn's disease occurs mainly in industrialized countries. In France it affects 1 person in 1000. The incidence is 5 per 100,000 persons per year. At present its pathogenesis remains poorly explained and many factors are involved (genetic, immunological and environmental). It seems essential to better understand Crohn's disease pathogenesis in order to identify therapeutic targets to improve its management and to identify predictors of postoperative recurrence and postoperative complications to customize the care of each patient. In this work we showed that a genetic variant of CARD8 (rs2043211) is a risk factor for postoperative recurrence. This combination is not influenced by the other known risk factors such as active smoking. Identifying CARD8 as a genetic risk factor for risk of surgical recurrence is of particular interest since it may become a novel therapeutic target for the treatment of Crohn's disease in the post-operative period. Our work has also shown that a genetic variant of NOD2 (rs5743289) is a risk factor for postoperative intraabdominal infectious complications (CIIP) after surgery in Crohn's disease. The identification of NOD2 gene as a risk factor for the occurrence of CIIP could establish an early stratification of patients at high risk for CIIP in whom surgery should be planned and predict patients at high risk for CIIP. Studies with large numbers replication cohort are still necessary before patients can enjoy the benefits of these tools in clinical practiceLa maladie de Crohn est prĂ©sente principalement dans les pays industrialisĂ©s. En France, elle touche 1 personne sur 1000. L’incidence est de 5 pour 100000 habitants par an. A l’heure actuelle sa pathogĂ©nie reste mal expliquĂ©e et de nombreux facteurs interviennent (facteurs gĂ©nĂ©tiques, immunologiques et environnementaux). Il semble donc essentiel de mieux comprendre la pathogĂ©nie de la maladie de Crohn afin d’identifier des cibles thĂ©rapeutiques permettant d’amĂ©liorer sa prise en charge et d’identifier des facteurs prĂ©dictifs de la rĂ©cidive post-opĂ©ratoire et des complications post-opĂ©ratoires afin de personnaliser la prise en charge de chaque patient. Dans ce travail nous avons montrĂ© qu'un variant gĂ©nĂ©tique de CARD8 (rs2043211) est un facteur de risque de rĂ©cidive post-opĂ©ratoire. Cette association n’est pas influencĂ©e par les autres facteurs de risque connus comme le tabagisme actif. L’identification de CARD8 comme un facteur de risque gĂ©nĂ©tique de risque de rĂ©cidive chirurgicale est d’un intĂ©rĂȘt particulier puisqu’il pourrait devenir une nouvelle cible thĂ©rapeutique pour le traitement de la maladie de Crohn dans la pĂ©riode post-opĂ©ratoire. Notre travail a Ă©galement montrĂ© qu'un variant gĂ©nĂ©tique de NOD2 (rs5743289) est un facteur de risque de complications intra-abdominales infectieuses post-opĂ©ratoires (CIIP) aprĂšs chirurgie dans la maladie de Crohn. L’identification de NOD2 comme un gĂšne Ă  risque pour la survenue de CIIP pourrait permettre d’établir une stratification prĂ©coce des patients Ă  haut risque de CIIP chez qui la chirurgie devra ĂȘtre planifiĂ©e et prĂ©dire les patients Ă  haut risque de CIIP. Des Ă©tudes sur larges effectifs avec cohorte de rĂ©plication restent encore nĂ©cessaires avant que les patients puissent bĂ©nĂ©ficier des retombĂ©es de ces outils en pratique courant

    Mate-choice copying in Drosophila melanogaster: Impact of demonstration conditions and male–male competition

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    International audienceIndividuals of many species, including invertebrates, have been shown to use social information in mate choice, notably by extracting information from the mating performance of opposite sex conspecifics, a process called “mate-choice copying” (MCC). Here, we performed four experiments with Drosophila melanogaster to investigate two aspects of MCC methodology: whether providing positive and negative social information simultaneously or sequentially during the demonstration phase of the protocol, and male–male competition during the mate-choice test, affect MCC. We found that the simultaneous provision of positive and negative information during demonstrations hampered female MCC performance, compared to the sequential provision of information. This can be interpreted in two alternative, yet not exclusive, ways: attentional mechanisms may restrict the focus of the brain to one source of information at a time, and/or the shorter duration of demonstrations in the simultaneous protocol may have not permit full social learning use and may explain the non-detection of MCC in that protocol. Moreover, we did not detect any significant effect of male–male competition on female choice. This study thus provides further evidence for MCC in D. melanogaster and expands on the necessary methodology for detailed studies

    Is Hartmann’s Pouch an Option in the Management of Acute Severe Ulcerative Colitis?

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    Background: The surgical management of remnant rectosigmoid after subtotal colectomy with end ileostomy for acute severe ulcerative colitis remains controversial with respect to the need to perform sigmoidostomy or Hartmann’s pouch. The aim of this retrospective study was to investigate whether Hartmann’s pouch may be a safe option. Methods: Thirty-eight Hartmann’s pouches were performed between January 2003 and December 2015. We looked at morbidity (with a focus on the occurrence of pelvic sepsis and leakage of the rectal stump) and the rate of restored intestinal continuity. Results: Nineteen patients had surgical complications. Seven had an intra-abdominal collection, only one of which was in the pelvis, and the patient had to be reoperated. Only one patient had a reopening of the rectal stump, which was revealed by rectal bleeding. Twenty-six patients (68.4%) underwent further proctectomy with ileal J-pouch anal anastomosis with no difficulty in localizing or mobilizing the rectal stump and no major surgical complications. Conclusions: Hartmann’s pouch may be considered in patients with acute severe ulcerative colitis, with low rates of morbidity and pelvic sepsis. The restoration of intestinal continuity is possible after this procedure without any special difficulty

    Long-term Outcomes of Robot-assisted Laparoscopic Rectopexy for Rectal Prolapse

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    International audienceBACKGROUND: Robot-assisted laparoscopic rectopexy for total rectal prolapse is safe and feasible. Small series proved clinical and functional short-term results comparable with conventional laparoscopy. No long-term results have been reported yet.OBJECTIVE: The primary objective of the study was to evaluate long-term functional and anatomic results of robot-assisted laparoscopic rectopexy. The secondary objective was to evaluate the learning curve of this procedure.DESIGN: Monocentric study data, both preoperative and perioperative, were collected prospectively, and follow-up data were assessed by a telephone questionnaire.SETTINGS: The study was performed in an academic center by 3 different surgeons.PATIENTS: We evaluated all of the consecutive patients who underwent a robot-assisted laparoscopic rectopexy between June 2002 and August 2010.INTERVENTION: Rectopexy was performed with 2 anterolateral meshes or with 1 ventral mesh, and in 9 patients a sigmoidectomy was associated with rectopexy.MAIN OUTCOME MEASURES: The actuarial recurrence rate was evaluated using the Kaplan-Meier method.RESULTS: During the study period, 77 patients underwent a robot-assisted laparoscopic rectopexy, and the mean age was 59.9 years (range, 23–90 y). Average operating time was 223 minutes (range, 100–390 min); the learning curve was completed after 18 patients were seen. Two patients died of causes unrelated to surgery at 5 and 24 months. There were 5 conversions (6%) to open procedure. Overall morbidity was low and concerned only 8 patients (10.4%). Mean follow-up time was 52.5 months (range, 12–115 mo). Recurrences have been observed in 9 patients (12.8%). Preoperatively, 24 (34%) of the patients had constipation. Postoperatively, constipation disappeared for 12 (50%) of 24 and constipation appeared for 11 (24%) of 46 patients. Fecal incontinence decreased after surgery from Wexner score 10.5 to 5.1 of 20.LIMITATIONS: There was a lack of standardization of the surgical procedure. The study was monocentric. Seven patients (9%) were lost to follow-up.CONCLUSIONS: Long-term results of robot-assisted laparoscopic rectopexy are satisfying. Further studies comparing robot-assisted and conventional laparoscopy, including cost-effectiveness, are needed

    Whole-Exome Sequencing of Bronchial Epithelial Cells Reveals a Genetic Print of Airway Remodelling in COPD

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    International audienceThe remodelling of the airways is a hallmark of chronic obstructive pulmonary disease, but it is highly heterogeneous and erratically distributed in the airways. To assess the genetic print of remodelling in chronic obstructive pulmonary disease (COPD), we performed a comparative whole-exome sequencing analysis on microdissected bronchial epithelia. Lung resections from four non-COPD and three COPD subjects (ex-smokers and current smokers) were formalin-fixed paraffin-embedded (FFPE). Non-remodelled and remodelled bronchial epithelia were isolated by laser microdissection. Genomic DNA was captured and sequenced. The comparative quantitative analysis identified a list of 109 genes as having variants in remodelled epithelia and 160 genes as having copy number alterations in remodelled epithelia, mainly in COPD patients. The functional analysis highlighted cilia-associated processes. Therefore, bronchial-remodelled epithelia appeared genetically more altered than non-remodelled epithelia. Characterizing the unique molecular print of airway remodelling in respiratory diseases may help uncover additional factors contributing to epithelial dysfunctions, ultimately providing additional targetable proteins to correct epithelial remodelling and improve lung function
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