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1. La protéine NF-Y contrôle la fidelité de l'initiation de la transcription aux promoteurs de gènes à travers la maintenance de région déplétée en nucléosome

Author

Raja Jothi, Telmo Henriques, Christopher A. Lavender, Dhirendra Kumar, Senthilkumar Cinghu, Karen Adelman, Andrew J. Oldfield, Brian D. Bennett, Adam B. Burkholder, Pengyi Yang, Damien Paulet, Benjamin S. Scruggs, Eric Rivals, Epigenetics and Stem Cell Biology Laboratory [Durham] (ESCBL-NIEHS-NIH), National Institute of Environmental Health Sciences [Durham] (NIEHS-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Harvard Medical School [Boston] (HMS), Maharishi Valmiki Hospital, Méthodes et Algorithmes pour la Bioinformatique (MAB), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Computationnelle (IBC), Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Marquette University, National Institutes of Health [Bethesda] (NIH), ATGC bioinformatics platform Montpellier. the Institut de Biologie Computationnelle (ANR-11-BINF-0002) Institut Français de Bioinformatique (ANR-11-INBS-0013)GEM Flagship project funded from Labex NUMEV (ANR-10-LABX-0020)France Génomique., ANR-10-LABX-0020/10-LABX-0020,NUMEV,Digital and Hardware Solutions and Modeling for the Environement and Life Sciences(2010), ANR-11-INBS-0013/11-INBS-0013,ReNaBi-IFB,Institut français de bioinformatique(2011), ANR-11-BINF-0002,IBC,Institut de Biologie Computationnelle de Montpellier(2011), ANR-10-INBS-09-01/10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), Marquette University [Milwaukee], ANR-10-LABX-0020,NUMEV,Digital and Hardware Solutions and Modeling for the Environement and Life Sciences(2010), ANR-11-INBS-0013,IFB (ex Renabi-IFB),Institut français de bioinformatique(2011), ANR-11-BINF-0002,IBC,Institut de biologie Computationnelle(2011), and ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010)

Subjects
0301 basic medicine, General Physics and Astronomy, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], 02 engineering and technology, Mice, 0302 clinical medicine, Transcription (biology), Gene expression, Gene Knockdown Techniques, RNA, Small Interfering, Promoter Regions, Genetic, lcsh:Science, Transcription Initiation, Genetic, 0303 health sciences, Multidisciplinary, 021001 nanoscience & nanotechnology, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Chromatin, Nucleosomes, 3. Good health, Cell biology, Transcription Initiation Site, 0210 nano-technology, Transcription, Science, Protein domain, Site Transcription Initiation, Genomics, Biology, Small Interfering, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, Promoter Regions, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals, Nucleosome, Transcription factor, Embryonic Stem Cells, 030304 developmental biology, Promoter, General Chemistry, Metabolism, 030104 developmental biology, CCAAT-Binding Factor, RNA, lcsh:Q, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], 030217 neurology & neurosurgery
Abstract

Faithful transcription initiation is critical for accurate gene expression, yet the mechanisms underlying specific transcription start site (TSS) selection in mammals remain unclear. Here, we show that the histone-fold domain protein NF-Y, a ubiquitously expressed transcription factor, controls the fidelity of transcription initiation at gene promoters in mouse embryonic stem cells. We report that NF-Y maintains the region upstream of TSSs in a nucleosome-depleted state while simultaneously protecting this accessible region against aberrant and/or ectopic transcription initiation. We find that loss of NF-Y binding in mammalian cells disrupts the promoter chromatin landscape, leading to nucleosomal encroachment over the canonical TSS. Importantly, this chromatin rearrangement is accompanied by upstream relocation of the transcription pre-initiation complex and ectopic transcription initiation. Further, this phenomenon generates aberrant extended transcripts that undergo translation, disrupting gene expression profiles. These results suggest NF-Y is a central player in TSS selection in metazoans and highlight the deleterious consequences of inaccurate transcription initiation., The mechanisms underlying specific TSS selection in mammals remain unclear. Here the authors show that the ubiquitously expressed transcription factor NF-Y regulate fidelity of transcription initiation at gene promoters, maintaining the region upstream of TSSs in a nucleosome-depleted state, while protecting this region from ectopic transcription initiation.

Published
2019

2. NF-Y controls fidelity of transcription initiation at gene promoters through maintenance of the nucleosome-depleted region

Author

Oldfield, Andrew, Henriques, Telmo, Kumar, Dhirendra, Burkholder, Adam, Cinghu, Senthilkumar, Paulet, Damien, Bennett, Brian, Yang, Pengyi, Scruggs, Benjamin, Lavender, Christopher, Rivals, Eric, Adelman, Karen, Jothi, Raja, Epigenetics and Stem Cell Biology Laboratory [Durham] (ESCBL-NIEHS-NIH), National Institute of Environmental Health Sciences [Durham] (NIEHS-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Harvard Medical School [Boston] (HMS), Maharishi Valmiki Hospital, Méthodes et Algorithmes pour la Bioinformatique (MAB), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Computationnelle (IBC), Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Marquette University, National Institutes of Health [Bethesda] (NIH), ATGC bioinformatics platform Montpellier. the Institut de Biologie Computationnelle (ANR-11-BINF-0002) Institut Français de Bioinformatique (ANR-11-INBS-0013)GEM Flagship project funded from Labex NUMEV (ANR-10-LABX-0020)France Génomique., ANR-10-LABX-0020/10-LABX-0020,NUMEV,Digital and Hardware Solutions and Modeling for the Environement and Life Sciences(2010), ANR-11-INBS-0013/11-INBS-0013,ReNaBi-IFB,Institut français de bioinformatique(2011), ANR-11-BINF-0002,IBC,Institut de Biologie Computationnelle de Montpellier(2011), ANR-10-INBS-09-01/10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), Marquette University [Milwaukee], ANR-10-LABX-0020,NUMEV,Digital and Hardware Solutions and Modeling for the Environement and Life Sciences(2010), ANR-11-INBS-0013,IFB (ex Renabi-IFB),Institut français de bioinformatique(2011), ANR-11-BINF-0002,IBC,Institut de biologie Computationnelle(2011), and ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010)

Subjects
Site Transcription Initiation, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Small Interfering, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Chromatin, Nucleosomes, Promoter Regions, Mice, Metabolism, CCAAT-Binding Factor, Gene Knockdown Techniques, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], RNA, Transcription Initiation Site, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Embryonic Stem Cells
Abstract

International audience; Faithful transcription initiation is critical for accurate gene expression, yet the mechanisms underlying specific transcription start site (TSS) selection in mammals remain unclear. Here, we show that the histone-fold domain protein NF-Y, a ubiquitously expressed transcription factor, controls the fidelity of transcription initiation at gene promoters in mouse embryonic stem cells. We report that NF-Y maintains the region upstream of TSSs in a nucleosome-depleted state while simultaneously protecting this accessible region against aberrant and/or ectopic transcription initiation. We find that loss of NF-Y binding in mammalian cells disrupts the promoter chromatin landscape, leading to nucleosomal encroachment over the canonical TSS. Importantly, this chromatin rearrangement is accompanied by upstream relocation of the transcription pre-initiation complex and ectopic transcription initiation. Further, this phenomenon generates aberrant extended transcripts that undergo translation, disrupting gene expression profiles. These results suggest NF-Y is a central player in TSS selection in metazoans and highlight the deleterious consequences of inaccurate transcription initiation.

Published
2019

3. Genomic insights into the 2016–2017 cholera epidemic in Yemen

Author

Dhirendra Kumar, Abdullah M. Assiri, Naresh Chand Sharma, Joseph F. Wamala, Samuel Kariuki, Caroline Seguin, Thérèse E. Malliavin, Abdullrahman A. Almesbahi, Nicholas R. Thomson, Samuel M. C. Njoroge, Thandavarayan Ramamurthy, Mona Naji, Daryl Domman, Elisabeth Njamkepo, Samar Saeed Nasher, Jane Y. Carter, Abdinasir Abubakar, Bita Bakhshi, Jean Rauzier, Andrew S. Azman, Christiane Bouchier, John Kiiru, Francisco J. Luquero, François-Xavier Weill, Hayder H.N. Abulmaali, Marie Laure Quilici, Mohammad Reza Pourshafie, Ankur Rakesh, Mamunur Rahman Malik, Bactéries pathogènes entériques (BPE), Institut Pasteur [Paris] (IP), The Wellcome Trust Sanger Institute [Cambridge], Los Alamos National Laboratory (LANL), Ministry of Public Health [Yemen], Epicentre [Paris] [Médecins Sans Frontières], Ministry of Health [Saudi Arabia], Kenya Medical Research Institute (KEMRI), Institut Pasteur d'Iran, Réseau International des Instituts Pasteur (RIIP), WHO - Regional Office for the Eastern Mediterranean [Cairo, Egypt] (EMRO), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Amref Health Africa [Kenya], African Medical and Research Foundation (AMREF), Médecins Sans Frontières [Dubai], Génomique (Plate-Forme) - Genomics Platform, Bioinformatique structurale - Structural Bioinformatics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Tarbiat Modares University [Tehran], Ministry of Health [Iraq], Maharishi Valmiki Hospital, Translational Health Science and Technology Institute [Faridabad] (THSTI), Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU), London School of Hygiene and Tropical Medicine (LSHTM), This study was supported by the Institut Pasteur, Santé publique France, the French government’s Investissement d’Avenir programme, Laboratoire d’Excellence ‘Integrative Biology of Emerging Infectious Diseases’ (grant number ANR-10-LABX-62-IBEID), the Wellcome Trust through grant 098051 to the Sanger Institute and the Department of Biotechnology of India. The Institut Pasteur Genomics Platform is a member of the France Génomique consortium (ANR10-INBS-09-08)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Institut Pasteur [Paris], Regional Office for the Eastern Mediterranean [Cairo] (EMRO), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Serotype, Yemen, 030106 microbiology, Context (language use), Biology, medicine.disease_cause, El Tor, 03 medical and health sciences, Antibiotic resistance, Cholera, Pandemic, medicine, Humans, Vibrio cholerae, Phylogeny, Multidisciplinary, Outbreak, Genomics, biology.organism_classification, medicine.disease, Virology, 3. Good health, 030104 developmental biology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Genome, Bacterial
Abstract

International audience; Yemen is currently experiencing, to our knowledge, the largest cholera epidemic in recent history. The first cases were declared in September 2016, and over 1.1 million cases and 2,300 deaths have since been reported1. Here we investigate the phylogenetic relationships, pathogenesis and determinants of antimicrobial resistance by sequencing the genomes of Vibrio cholerae isolates from the epidemic in Yemen and recent isolates from neighbouring regions. These 116 genomic sequences were placed within the phylogenetic context of a global collection of 1,087 isolates of the seventh pandemic V. cholerae serogroups O1 and O139 biotype El Tor2-4. We show that the isolates from Yemen that were collected during the two epidemiological waves of the epidemic1-the first between 28 September 2016 and 23 April 2017 (25,839 suspected cases) and the second beginning on 24 April 2017 (more than 1 million suspected cases)-are V. cholerae serotype Ogawa isolates from a single sublineage of the seventh pandemic V. cholerae O1 El Tor (7PET) lineage. Using genomic approaches, we link the epidemic in Yemen to global radiations of pandemic V. cholerae and show that this sublineage originated from South Asia and that it caused outbreaks in East Africa before appearing in Yemen. Furthermore, we show that the isolates from Yemen are susceptible to several antibiotics that are commonly used to treat cholera and to polymyxin B, resistance to which is used as a marker of the El Tor biotype.

Published
2019

4. A Whole Spine MRI Based Study of the Prevalence, Associated Disc Degeneration and Anatomical Correlations of Lumbosacral Transitional Vertebra.

Author

Bhagchandani C, Murugan C, Jakkepally S, Shetty AP, Kanna RM, and Rajasekaran S

Abstract

Study Design: Retrospective cohort study., Objective: Lumbosacral transitional vertebra (LSTV) results in numerical alterations of the lumbar and sacral segments. Literature concerning true prevalence, associated disc degeneration, and variation in numerous anatomical landmarks concerning LSTV is lacking., Methods: This is a retrospective cohort study. The prevalence of LSTV was determined in whole spine MRIs of 2011 poly-trauma patients. LSTV was identified as sacralization (LSTV-S) or lumbarization (LSTV-L) and further sub-classified into Castellvi's and O'Driscoll's type respectively. Disc degeneration was evaluated using Pfirmann grading. Variation in important anatomical landmarks was also analysed., Results: Prevalence of LSTV was 11.6% with 82% having LSTV-S . Castellvi's type 2A and O'Driscoll type 4 were the commonest sub-types. LSTV patients demonstrated considerably advanced disc degeneration. The median termination level of conus medullaris (TLCM) in non- LSTV and LSTV-L groups was at middle L1 (48.1% and 40.2%) while in the LSTV-S group, it was at upper L1 (47.2%). The median level of right renal artery (RRA) in non- LSTV patients was at middle L1 in 40.0% of individuals while in the LSTV-L and LSTV-S groups, it was at upper L1 level in 35.2% and 56.2% respectively. The median level of abdominal aortic bifurcation (AA) in non-LSTV and LSTV-S patients was at middle L4 in 83.3% and 52.04% respectively. However, in the LSTV-L group, the most common level was middle L5 (53.6%)., Conclusion: The overall prevalence of LSTV was 11.6%, with sacralization accounting for more than 80%. LSTV is associated with disc degeneration and a variation in the levels of important anatomical landmarks., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Published
2024
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5. Re-exposure animal bite management among incident animal bite cases in a secondary care Hospital in Delhi, India.

Author

Basu S, Mariam W, Santra S, Garg S, and Singhal R

Subjects
Adolescent, Adult, Child, Child, Preschool, Cross-Sectional Studies, Documentation, Female, Humans, India, Male, Medical Overuse prevention & control, Practice Guidelines as Topic, Secondary Care, Bites and Stings drug therapy, Medical Overuse statistics & numerical data, Post-Exposure Prophylaxis statistics & numerical data, Rabies prevention & control, Rabies Vaccines administration & dosage
Abstract

Complete postexposure prophylaxis with 4 doses of anti-rabies vaccine (ARV) in a previously vaccinated (nonnaïve) individual results in administration of two extra ARV doses resulting in wastages of precious resources comprising vaccine logistics, human resources, physician, and patient time. This cross-sectional study conducted in a secondary care hospital in Delhi among 175 incident animal bite cases observed 39 (22.3%) had an animal-bite history within the previous 5 years. A total of 19 (10.8%) cases reported a history of complete ARV vaccination during a previous animal-bite exposure. However, in the absence of supportive patient medical documentation, all the animal bite cases without exception were prescribed a full course of ARV irrespective of their previous exposure status. Rabies immunoglobulins (anti rabies serum) were also re-administered in 13 (81.2%) cases. National guidelines for rabies prophylaxis should, therefore, consider the inclusion of an explicit decision-making algorithmic mechanism when the health-care provider is confronted with this situation carrying the potential for hidden vaccine wastage., Competing Interests: None

Published
2020
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6. Knowledge and Attitude of Adolescent Girls and Their Mothers Regarding Cervical Cancer: A Community-Based Cross-Sectional Study.

Author

Ahlawat P, Batra N, Sharma P, Kumar S, and Kumar A

Abstract

Background: Cervical cancer is the second most commonly diagnosed cancer in India. The mother's awareness about the symptoms and risk factors has a large impact on the daughter's knowledge and attitude. Mother and adolescent daughter duos were selected as the sample as they are the target population at risk for suffering from carcinoma cervix. Mothers are the prime information providers and in an excellent position to aware their adolescent daughters about cervical cancer., Objectives: The aim of this study is to determine knowledge and attitude of adolescent girls and their mothers regarding cervical cancer and to find the association between the education of the mothers and their knowledge about risk factors., Materials and Methods: A community-based cross-sectional study was conducted among 100 duos of adolescent daughters along with their mothers residing in Balmiki Basti (Delhi), using a predesigned, pretested, semi-structured interview schedule. The collected data were analyzed using SPSS-22 version., Results: Only 61% of mothers and 52% of daughters have heard about cervical cancer. Inter-menstrual bleeding was the most common symptom recognized by the mother (50%) and daughter (44%) duos followed by postmenopausal bleeding (47% of mothers and 33% of daughters). Most common risk factors recognized by mothers and their daughters were promiscuity and tobacco and smoking. About 81% of mothers and 68% of daughters have a positive attitude toward internal examination by a gynecologist at least once in 3 years. Human papillomavirus infection was recognized as a risk factor by 13 among which 8 were educated till graduation ( P < 0.05)., Conclusions: Study revealed a low-level knowledge about cervical cancer among adolescent daughters and their mothers. Therefore, there is an urgent need to empower the women by educating them on this issue. Furthermore, there is a need to encourage the mothers to communicate the right information to their adolescent daughters., Competing Interests: There are no conflicts of interest.

Published
2018
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8. Primary total elbow arthroplasty.

Author

Kumar S and Mahanta S

Abstract

Background: Primary total elbow arthroplasty (TEA) is a challenging procedure for orthopedic surgeons. It is not performed as frequently as compared to hip or knee arthroplasty. The elbow is a nonweight-bearing joint; however, static loading can create forces up to three times the body weight and dynamic loading up to six times. For elderly patients with deformity and ankylosis of the elbow due to posttraumatic arthritis or rheumatoid arthritis or comminuted fracture distal humerus, arthroplasty is one of the option. The aim of this study is to analyze the role of primary total elbow arthroplasty in cases of crippling deformity of elbow., Materials and Methods: We analyzed 11 cases of TEA, between December 2002 and September 2012. There were 8 females and 3 males. The average age was 40 years (range 30-69 years). The indications for TEA were rheumatoid arthritis, comminuted fracture distal humerus with intraarticular extension, and posttraumatic bony ankylosis of elbow joint. The Baksi sloppy (semi constrained) hinge elbow prosthesis was used. Clinico-radiological followup was done at 1 month, 3 months, 6 months, 1 year, and then yearly basis., Results: In the present study, average supination was 70° (range 60-80°) and average pronation was 70° (range 60-80°). Average flexion was 135° (range 130-135°). However, in 5 cases, there was loss of 15 to 35° (average 25°) of extension (45°) out of 11 cases. The mean Mayo elbow performance score was 95.4 points (range 70-100). Arm length discrepancy was only in four patients which was 36% out of 11 cases. Clinico-radiologically all the elbows were stable except in one case and no immediate postoperative complication was noted. Radiolucency or loosening of ulnar stem was seen in 2 cases (18%) out of 11 cases, in 1 case it was noted after 5 years and in another after 10 years. In second case, revision arthroplasty was done, in which only ulnar hinge section, hinge screw and lock screw with hexagonal head were replaced., Conclusion: Elbow arthroplasty remains a valuable option for deformed and ankylosed elbows especially in the demanding patients with crippling deformity of the elbow.

Published
2013
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