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Trans-silencing effect of the 3′RR immunoglobulin heavy chain enhancer on Igκtranscription at the pro-B cell stage

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Cellular & Molecular Immunology 2019年第7期16卷 668-670页

作者： Nour Ghazzaui Hussein Issaoui Ophélie Alyssa Martin Alexis Saintamand Jeanne Cook-Moreau Yves Denizot François Boyer CNRS uMR 7276 Inserm U1262Universitéde LimogesLimogesFrance Present address:inserm u1236 UniversitéRennes 1RennesFrance

Due to their impact on nuclear organization,enhancers are master regulators of cell fate.1,2 The immunoglobulin heavy chain(IgH)locus undergoes numerous changes(such as transcription,accessibility,DNA breaks,and mutations)throughout B-cell *** of these events are controlled by the IgH 3′regulatory region(3′RR).The 3′RR is the master control element of mature B-cell IgH transcription,3 somatic hypermutation(SHM),4,5 conventional class switch recombination(CSR),4,6–10 and locus suicide recombination(LSR).11 In contrast,the 3′RR is expected to be dispensable for V(D)J recombination.12,13 During Bcell development,the heavy and light chain loci are poised for their VDJ and VJ rearrangements,*** IgH locus rearranges first,with D-J joining at the pro-B-cell stages,followed by V-DJ joining at the pre-B-cell *** Igk locus is poised for VJ rearrangements at the pre-B cell stage.

关键词： effect joining recombination

Spinal cord injury reprograms muscle fibroadipogenic progenitors to form heterotopic bones within muscles

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Bone Research 2022年第2期10卷 310-325页

作者： Hsu-Wen Tseng Dorothée Girard Kylie A.Alexander Susan M.Millard Frédéric Torossian Adrienne Anginot Whitney Fleming Jules Gueguen Marie-Emmanuelle Goriot Denis Clay Beulah Jose Bianca Nowlan Allison R.Pettit Marjorie Salga François Genêt Marie-Caroline Le Bousse-Kerdilès Sébastien Banzet Jean-Pierre Lévesque Mater Research Institute-The university of Queensland WoolloongabbaQLDAustralia Institut de Recherche Biomédicale des Armées(IRBA) INSERM UMRS-MD1197 ClamartFrance inserm uMRS-MD 1197 Universitéde Paris-SaclayHôpital Paul BrousseVillejuifFrance inserm uMS-44 Universitéde Paris-SaclayHôpital Paul BrousseVillejuifFrance uPOH(unitéPéri Opératoire du Handicap Perioperative Disability Unit)Physical and Rehabilitation Medicine departmentRaymond-PoincaréHospitalAssistance Publique-Hôpitaux de Paris(AP-HP)GarchesFrance universitéde Versailles Saint Quentin en Yvelines UFR Simone Veil-SantéEND:ICAP INSERM U1179Montigny le BretonneuxFrance

The cells of origin of neurogenic heterotopic ossifications(NHOs), which develop frequently in the periarticular muscles following spinal cord injuries(SCIs) and traumatic brain injuries, remain unclear because skeletal muscle harbors two progenitor cell populations: satellite cells(SCs), which are myogenic, and fibroadipogenic progenitors(FAPs), which are mesenchymal. Lineage-tracing experiments using the Cre recombinase/Lox P system were performed in two mouse strains with the fluorescent protein Zs Green specifically expressed in either SCs or FAPs in skeletal muscles under the control of the Pax7 or Prrx1 gene promoter, respectively. These experiments demonstrate that following muscle injury, SCI causes the upregulation of PDGFRα expression on FAPs but not SCs and the failure of SCs to regenerate myofibers in the injured muscle, with reduced apoptosis and continued proliferation of muscle resident FAPs enabling their osteogenic differentiation into NHOs. No cells expressing Zs Green under the Prrx1 promoter were detected in the blood after injury, suggesting that the cells of origin of NHOs are locally derived from the injured muscle. We validated these findings using human NHO biopsies. PDGFRα+mesenchymal cells isolated from the muscle surrounding NHO biopsies could develop ectopic human bones when transplanted into immunocompromised mice, whereas CD56+myogenic cells had a much lower potential. Therefore, NHO is a pathology of the injured muscle in which SCI reprograms FAPs to undergo uncontrolled proliferation and differentiation into osteoblasts.

关键词： progenitor injuries muscles

Light-controlled phosphorylation in the TrkA-Y785 site by photosensitive uAAs activates the MAPK/ERK signaling pathway

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BIOCELL 2023年第6期47卷 1377-1388页

作者： SHu ZHAO SHIXIN YE School of Life Sciences Nantong UniversityNantong226019China Institute National de la Sante et de la Recherche Medicale(inserm)u1195 Bicetre HospitalParis-Saclay UniversityLe Kremlin-Bicêtre94276France

Background:This paper aims to establish a light-controlled phosphorylation detection method at the Y785 site of tropomyosin receptor kinase A(TrkA)receptor in mammalian cells by using genetic code expansion technology and detecting the effects of optical activation of this site on the downstream MAPK/ERK *** study is based on the current situation that the regulatory mechanism of TrkA phosphorylation has not been fully ***:Two photosensitive unnatural amino acids,p-azido-L-phenylalanine(AzF)and photo-caged tyrosine(ONB)were introduced into the TrkA-Y785 site by genetic code expansion technology and site-directed *** blotting and laser confocal imaging were conducted to analyze the effects of this site on activating the MAPK/ERK pathway and nerve cell differentiation before and after ***:Our results supplemented the light-controlled results of the TrkA-Y785 site based on our previous research and verified that Y785 also makes important contributions in regulating the MAPK/ERK ***:This study demonstrated the significant contributions of the TrkAY785 site in regulating the ERK pathway by precisely controlling the phosphorylation state of a single tyrosine site.

关键词： Tropomyosin receptor kinase A Genetic code expansion Y785 P-azido-L-phenylalanine Photo-caged tyrosine

Bladder-colon chronic cross-sensitization involves neuro-glial pathways in male mice

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World Journal of Gastroenterology 2022年第48期28卷 6935-6949页

作者： Karim Atmani Fabien Wuestenberghs Maximilien Baron Illona Bouleté Charlène Guérin Wafa Bahlouli David Vaudry Jean Claude do Rego Jean-Nicolas Cornu Anne-Marie Leroi Moïse Coëffier Mathieu Meleine Guillaume Gourcerol Nutrition Gut and Brain Unit(Inserm U1073)Institute for Research and Innovation in BiomedicineUniversitéde Rouen NormandieRouen 76000France Department of Gastroenterology and Hepatology UniversitéCatholique de LouvainCHU UCL NamurYvoir 5530Belgium Department of Physiology CHU RouenUniversitéde Rouen NormandieRouen 76031France Department of urology CHU RouenUniversitéde Rouen NormandieRouen 76000France inserm UMR 1245Team Epigenetics and Pathophysiology of Neurodevelopmental DisordersUniversitéde Rouen NormandieRouen 76000France Behavioural Analysis Platform(SCAC) HeRacLeS Inserm US51-CNRS UAR2026Institute for Research and Innovation in BiomedicineUniversitéde Rouen NormandieRouen 76000France Department of Nutrition CHU RouenUniversitéde Rouen NormandieRouen 76000France inserm u1107 NeuroDolClermont Auvergne UniversityClermont-Ferrand 63000France

BACKGROuND Irritable bowel syndrome and bladder pain syndrome often overlap and are both characterized by visceral *** pelvic organs share common sensory pathways,it is likely that those syndromes involve a cross-sensitization of the bladder and the *** precise pathophysiology remains poorly *** To develop a model of chronic bladder-colon cross-sensitization and to investigate the mechanisms *** Chronic cross-organ visceral sensitization was obtained in C57BL/6 mice using ultrasound-guided intravesical injections of acetic acid under brief isoflurane *** sensitivity was assessed in conscious mice by measuring intracolonic pressure during isobaric colorectal ***,used as a marker of colorectal inflammation,was measured in the colon,and colorectal permeability was measured using chambers.c-Fos protein expression,used as a marker of neuronal activation,was assessed in the spinal cord(L6-S1 level)using *** fluorescent protein on the fractalkine receptor-positive mice were used to identify and count microglia cells in the L6-S1 dorsal horn of the spinal *** expression of NK1 receptors and MAPK-p38 were quantified in the spinal cord using western *** Visceral hypersensitivity to colorectal distension was observed after the intravesical injection of acetic acid vs saline(Pup to 7 d *** increased permeability or inflammation was shown in the bladder or colon 7 d *** hypersensitivity was associated with the increased expression of c-Fos protein in the spinal cord(Puorescent protein on the fractalkine receptor-positive mice,intravesical acetic acid injection resulted in an increased number of microglia cells in the L6-S1 dorsal horn of the spinal cord(Pup to 7 d after

关键词： Cross-organ sensitization MAPK-p38 Microglia NK1 receptor Pain Visceral hypersensitivity

Effect of Bifidobacterium longum 35624 on disease severity and quality of life in patients with irritable bowel syndrome

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World Journal of Gastroenterology 2022年第7期28卷 732-744页

作者： Jean-Marc Sabaté Franck Iglicki Department of Gastroenterology Hôpital AvicenneAP-HPSorbonne Paris NordBobigny 93000France inserm u-987 Pathophysiology and Clinical Pharmacology of PainAmbroise ParéHospitalBoulogne-Billancourt 92100France allée Léon Gambetta Clichy 92110France

BACKGROuND Bifidobacterium longum 35624 has shown efficacy in improving irritable bowel syndrome(IBS)symptoms compared with placebo in double-blind randomized ***,few data are available from real-life clinical practice or from studies that used Rome IV criteria to diagnose *** To assess the effect of *** 35624 on IBS severity and quality of life in a reallife *** From November 2018 to January 2020,278 patients with IBS(according to Rome IV criteria)were enrolled in a prospective,open-label,multicenter observational study by private practice gastroenterologists to received one capsule of *** 35624(10^(9) colony-forming units)per day for 30 *** in the study was independently proposed to patients during spontaneous *** severity(assessed by the IBS severity scoring system)and patient quality of life(assessed by the IBS quality of life questionnaire)were compared between the inclusion visit(baseline)and the visit at the end of 30 d of *** characteristics of patients were described at *** variables comparisons between inclusion and end-of-treatment visits were performed using the t-test and Kruskal-Wallis *** variables comparisons were performed using theχ^(2) *** total of 233 patients,with a mean age of 51.4 years and composed of 71.2%women,were included in the *** these patients,48.1%had moderate IBS and 46.4%had severe *** a 30-d treatment period with one *** 35624 capsule per day,a significant decrease in IBS severity was observed compared to baseline(mean±SD,IBS severity scoring system scores:208±104 vs 303±81,Puality of life of patients was also improved by the treatment(IBS Quality of Life questionnaire score:68.8±20.9 vs 60.2±20.5;P<0.001)and 63.8%of patients were satisfied with the *** Thirty days of treatment with *** 35624

关键词： Irritable bowel syndrome Probiotics Bifidobacterium longum Quality of life Severity of illness index Abdominal pain

uracil-DNA glycosylase is not implicated in the choice of the DNA repair pathway during B-cell class switch recombination

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Cellular & Molecular Immunology 2019年第1期16卷 93-95页

作者： Nour Ghazzaui Hussein Issaoui Alexis Saintamand Yves Denizot François Boyer uMR CNRS 7276 INSERM U1262University of LimogesCBRSrue Pr.Descottes87025 LimogesFrance inserm u1236 Rennes 1 UniversityRennesFrance

Mature B-cells express membrane IgM and IgD(of same specificity)through alternative splicing of a pre-mRNA encompassing constant(C)μand Cδ*** encountering antigen,Bcells undergo class switch recombination(CSR)that substitutes the Cμgene with Cγ,Cε,or Cα,thereby generating IgG,IgE,and IgA antibodies with the same antigenic specificity but new effector ***-editing enzyme activation-induced deaminase(AID)is essential for CSR by targeting switch(S)regions preceding Cμ(namely,the Sμdonor region)and the Cγ,Cε,and Cαgenes(namely,the Sγ,ε,αacceptor regions).1,2 CSR is controlled in cis by IgH locus super-enhancers3 and in trans by a wide spectrum of enzymes and proteins.1,2 Among them,the role of the uracil DNA glycosylase(uNG)remains *** is a key enzyme of base excision repair,which carries out faithful *** authors estimate that during CSR,the uNG enzymatic activity removes the AID-induced dC to du converted base of singlestrand DNA,generating abasic sites and leading to DNA strand breaks.1 For other authors,the role of uNG is to stabilize the S–S synapse and to recruit DNA repair factors that facilitate the endjoining process.4,5 Thus,the classical non-homogenous end joining pathway would be increased over the alternative end joining(A-EJ)pathway in uNG-deficient mice,4 suggesting an intriguing role of uNG in promoting the A-EJ pathway.

关键词： generating joining specificity

Locoregional therapies and their effects on the tumoral microenvironment of pancreatic ductal adenocarcinoma

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World Journal of Gastroenterology 2022年第13期28卷 1288-1303页

作者： Thomas Lambin Cyril Lafon Robert Andrew Drainville Mathieu Pioche Frédéric Prat LabTAu INSERMCentre Léon BérardUniversitéLyon 1Univ LyonLyon 69003France Department of Gastroenterology Hospices Civils de LyonEdouard Herriot HospitalLyon 69008France Service d’Endoscopie Digestive Hôpital BeaujonAssistance Publique-Hôpitaux de ParisClichy 92110France inserm u1016 Institut CochinUniversitéde ParisParis 75014France

Pancreatic ductal adenocarcinoma(PDAC) is expected to become the second leading cause of death from cancer by 2030. Despite intensive research in the field of therapeutics, the 5-year overall survival is approximately 8%, with only 20% of patients eligible for surgery at the time of diagnosis. The tumoral microenvironment(TME) of the PDAC is one of the main causes for resistance to antitumoral treatments due to the presence of tumor vasculature, stroma, and a modified immune response. The TME of PDAC is characterized by high stiffness due to fibrosis, with hypo microvascular perfusion, along with an immunosuppressive environment that constitutes a barrier to effective antitumoral treatment. While systemic therapies often produce severe side effects that can alter patients’ quality of life, locoregional therapies have gained attention since their action is localized to the pancreas and can thus alleviate some of the barriers to effective antitumoral treatment due to their physical effects. Local hyperthermia using radiofrequency ablation and radiation therapy-most commonly using a local high single dose-are the two main modalities holding promise for clinical efficacy. Recently, irreversible electroporation and focused ultrasound-derived cavitation have gained increasing attention. To date, most of the data are limited to preclinical studies, but ongoing clinical trials may help better define the role of these locoregional therapies in the management of PDAC patients.

关键词： Pancreatic ductal adenocarcinoma Tumoral microenvironment Stroma Hyperthermia Radiation therapy High-intensity focused ultrasound

High-throughput sequencing reveals similar molecular signatures for class switch recombination junctions for theγandαisotypes

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Cellular & Molecular Immunology 2019年第1期16卷 90-92页

作者： ussein Issaoui Nour Ghazzaui Alexis Saintamand Yves Denizot François Boyer uMR CNRS 7276 INSERM U1262CBRSLimoges Universityrue Pr.DescottesLimoges 87025France inserm u1236 Rennes 1 UniversityRennesFrance

INTRODuCTION After encountering an antigen,B cells undergo class switch recombination(CSR),which substitutes the Cμgene with Cγ,Cε,or Cαto generate IgG,IgE,and IgA antibodies with the same antigenic specificity but new effector functions.1 The DNAediting enzyme activation-induced deaminase(AID)is essential for CSR by targeting switch(S)regions preceding Cμ(namely,the Sμdonor region)and the Cγ,Cε,and Cαgenes(namely,the Sγ,ε,αacceptor regions).1 Cis-and trans-controlled DNA double strand beaks are generated during this process.2–6 Recruitment of DNA repair factors that facilitate the end-joining process is a crucial step of class switch *** pathways are implicated in this end *** classical non-homogenous end joining(c-NHEJ)pathway ligates DNA ends with no or little *** contrast,the alternative end joining(A-EJ)pathways is used to ligate DNA ends that have microhomology.

关键词： functions. process. joining

Development of novel Gemini-cholesterol analogues for retinoid-related orphan receptors

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Organic Chemistry Frontiers 2022年第6期9卷 1522-1530页

作者： uxía Gómez-Bouzó Alioune Fall Judit Osz Yagamare Fall ORCID logo Natacha Rochel Hugo Santalla Departamento de Química Orgánica Facultade de QuímicaUniversity of VigoCampus Lagoas de Marcosende36310 VigoSpain Department of Integrative Structural Biology IGBMC-CNRS UMR7104-Inserm U9641rue Laurent Fries67400 IllkirchFrance

Retinoic-acid-related Orphan Receptors (RORs) regulate the maintenance of the circadian rhythm and immune response among others and are involved in increasing numbers of pathologies including autoimmune diseases, cancer and neurological disorders leading to huge interest in the development of ROR ligands. Here, we describe the synthesis of six novel Gemini cholesterol analogues and the binding mode of one of them to RORγ.

关键词： analogues synthesis numbers