Mycobacterium tuberculosis in vivo-expressed genes detection during active pulmonary tuberculosis

Indexación: Web of Science; ScieloEl estudio de la expresión génica de Mycobacterium tuberculosis ha involucrado la experimentación "in vitro ", "ex vivo " e "in vivo " (modelos animales), pero aún sin el éxito esperado. Proponemos que revelar los factores clave de la tuberculosis humana requiere investigar la expresión génica de M. tuberculosis dentro del ser humano ("in vivo "). Para ello, aislamos el mRNA total de M. tuberculosis, desde muestras clínicas respiratorias de pacientes con diagnóstico de tuberculosis pulmonar; posteriormente, sintetizamos el dscDNA y lo analizamos mediante RT-PCR cualitativo. Detectamos la expresión de la secuencia de inserción IS6110 y de los genes "housekeeping " 16SrRNA y sigA en M. tuberculosis creciendo in vivo (tuberculosis pulmonar) así como cultivado in vitro. La expresión de los genes mprA y mprB, que codifican el sistema de transducción de señales MprAB, sólo se detectó en M. tuberculosis crecido in vitro. Con nuestros resultados damos el primer paso hacia la implementación de un método no invasivo para el estudio del transcriptoma de M. tuberculosis, dentro de su único hospedero natural, con el fin de analizar la regulación "in vivo" de los determinantes genéticos requeridos para su virulencia y patogénesis.Mycobacterium tuberculosis gene expression studies have involved "in vitro", "ex vivo" and "in vivo" experiments (animal models), but without the expected success. We propose that key features of human tuberculosis could be discovered by studying the M. tuberculosis gene expression within the human host. Therefore, we isolated totalM. tuberculosis mRNA from human clinical respiratory specimens of patients diagnosed with pulmonary tuberculosis; after this, we synthesized the dscDNA and tested it by qualitative RT-PCR assays. We detected the expression of IS6110 insertion sequence and of the "housekeeping" genes 16SrRNA andsigA in M. tuberculosis grown in vivo (pulmonary tuberculosis) as well as grown in vitro M. tuberculosis. mprA and mprB genes expression, which code the MprAB signal transduction system, were only detected in M. tuberculosis grown in vitro. Our results provide the first step towards a non invasive methodfor the study of the transcriptome of M. tuberculosis within its native host, to analyze "in vivo" regulation of the genetic determinants required for virulence and pathogenesis.http://www.scielo.cl/pdf/rcher/v28n4/art04.pd

Effects of copy number variations on brain structure and risk for psychiatric illness: large-scale studies from the ENIGMA working groups on CNVs

The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype-phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This "genotype-first" approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior.Funding information: European Union's Horizon2020 Research and Innovation Programme, Grant/Award Number: CoMorMent project; Grant #847776; KG Jebsen Stiftelsen; National Institutes of Health, Grant/Award Number: U54 EB020403; Norges Forskningsråd, Grant/Award Number: #223273; South-Eastern Norway Regional Health Authority, Grant/Award Number: #2020060ACKNOWLEDGMENTS: The ENIGMA Consortium is supported by the NIH Big Data to Knowledge (BD2K) program under consortium grant number U54 EB020403 (PI: Thompson). OAA is supported by the Research Council of Norway, South East Norway Health Authority, KG Jebsen Stiftelsen, EU H2020. C. A. has been funded by the Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/ 024), co-financed by ERDF Funds from the European Commission, “A way of making Europe”, CIBERSAM; Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds; European Union Seventh Framework Program under grant agreements FP7-4-HEALTH-2009-2.2.1-2-241,909 (Project EU-GEI), FP7- HEALTH-2013-2.2.1-2-603,196 (Project PSYSCAN) and FP7- HEALTH-2013- 2.2.1-2-602,478 (Project METSY); and European Union H2020 Program under the Innovative Medicines Initiative two Joint Undertaking (grant agreement No 115916, Project PRISM, and grant agreement No 777394, Project AIMS-2-TRIALS), Fundación Familia Alonso and Fundación Alicia Koplowitz. R. A-A is funded by a Miguel Servet contract from the Carlos III Health Institute (CP18/00003). G. B. is supported by the Dutch Organization for Health Research and Development ZonMw (grants 91112002 & 91712394). A. S. B. is supported by the Dalglish Family Chair in 22q11.2 Deletion Syndrome, Canadian Institutes of Health Research (CIHR) grants MOP-79518, MOP89066, MOP-97800 and MOP-111238, and NIMH grant number U01 MH101723–01(3/5). C. E. B. is also supported by the National Institute of Mental Health: RO1 MH085953, R01 MH100900 and 1U01MH119736. N. E. B. is granted the KNAW Academy Professor Award (PAH/6635). V. D. C. is supported by NIH R01 MH094524. S. C. is supported by the European Union's Horizon 2020 Framework Programme for Research and Innovation under the Specific Grant Agreement No. 945539 (Human Brain Project SGA3); Helmholtz Initiative and Networking Fund. C. R. K. C. is supported by NIA T32AG058507. E. W. C. C. is supported by the Canadian Institutes of Health Research, Ontario Mental Health Foundation grant MOP-74631 and NIMH grant U01MH101723–01(3/5). S. Ci. has received funding from the European Union's Horizon 2020 Framework Programme for Research and Innovation under the Specific Grant Agreement No. 945539 (Human Brain Project SGA3). M. C. C. is supported by the Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. N. A. C. is supported by Agencia Nacional de Investigación y Desarrollo (ANID Chile) PIA ACT192064. GId. Z. is supported by the NHMRC. J. L. D. and D. E. J. L. are supported by the Wellcome Trust. T. B. C. is supported by NICHD grant PO1-HD070454, NIH grant UO1-MH191719, and NIMH grant R01 MH087636-01A1. AMD is supported by U24DA041147. B. D. is supported by the Swiss National Science Foundation (NCCR Synapsy, project grant numbers 32003B_135679, 32003B_159780, 324730_192755 and CRSK3_190185), the Leenaards Foundation and the Roger De Spoelberch Foundation. SE is supported by the NARSAD-Young Investigator Grant “Epigenetic Regulation of Intermediate Phenotypes in Schizophrenia”. B. E. S. is supported by the NIH (NIMH). D. C. G. is supported by NIH grant numbers MH078143, MH083824, AG058464. W. R. K. is supported by NIH/MH R0106824. R. E. G. is supported by NIH/NIMH grant numbers MH087626, MH119737. DMMcD-McG is supported by National Institutes of Mental Health (NIMH), grant numbers MH119737-02; MH191719; and MH087636-01A1. S. E. M. is supported by NHMRC grants APP1103623; APP1158127; APP1172917. TM is supported by Research Council of Norway - grant number 273345. D. G. M. is supported by the National Institute for Health Research Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London and S (European Autism Interventions)/EU AIMS-2-TRIALS, a European Innovative Medicines Initiative Joint Undertaking under grant agreements 115300 and 777394. T. N. was supported by Stiftelsen KG Jebsen under grant number SKGJ-MED-021. R. A. O. is supported by NIMH R01 MH090553. S. Y. S. has been funded by the Canadain Institutes of Health Research. M. J. O. is supported by MRC Centre grant MR/L010305/1 and Wellcome Trust grant 100,202/Z/12/Z; Dr. Owen has received research support from Takeda. Z. P. is supported by CIHR, CFI, HSFC. B. G. P. is supported by CIHR FDN 143290 and CAIP Chair. G. M. R. is supported by Fondecyt-Chile #1171014 and ANID-Chile ACT192064. A. Re. was supported by a grant from the Swiss National Science Foundation (31003A_182632). DRR is supported by R01 MH120174 (PI: Roalf). This report represents independent research funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London (to J. J. R). PSS is supported by NHMRC (Australia) program grant 1093083. J. E. S. is supported by NIH K01-ES026840. S. M. S. is supported by the Epilepsy Society. T. J. S. is supported by NIH grants R01MH107108, R01HD042794, and HDU54079125. I. E. S. is supported by South-Eastern Norway Regional Health Authority (#2020060), European Union's Horizon2020 Research and Innovation Programme (CoMorMent project; grant #847776) and the KG Jebsen Foundation (SKGJ-MED-021). V. M. S. is supported by Research Council of Norway (CoE funding scheme, grant number 223273). D. J. S. is supported by the SA MRC. C. K. T. is supported by Research Council of Norway (#230345, #288083, #223273) and South-Eastern Norway Regional Health Authority (#2019069, #2021070, #500189). D. T.-G. was supported by the Instituto de Salud Carlos III (PI14/00639 and PI14/00918) and Fundación Instituto de Investigación Marqués de Valdecilla (NCT0235832 and NCT02534363). Dvd. M. is supported by Research Council of Norway #276082. F. V. R. is supported by the Michael Smith Foundation for Health Research Scholar Award. deCODE genetics has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreements' no. 115008 (NEWMEDS) and no. 115300 (EUAIMS), of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (EU-FP7/ 2007–2013). L. T. W. is supported by Research Council of Norway, European Research Council. The IDIVAL neuroimage unit is supported by Instituto de Salud Carlos III PI020499, research funding SCIII-INT13/0014, MICINN research funding SAF2010-20840-C02- 02, SAF2013-46292-R. The TOP/NORMENT study are supported by the Research Council of Norway (#223273). The GOBS study data collection was supported in part by the National Institutes of Health (NIH) grants: R01 MH078143, R01 MH078111, and R01 MH083824 with work conducted in part in facilities constructed under the support of NIH grant number C06 RR020547. The Sydney Memory and Ageing Study has been funded by three National Health & Medical Research Council (NHMRC) Program Grants (ID No. ID350833, ID568969, and APP1093083). We thank the participants and their informants for their time and generosity in contributing to this research. We also acknowledge the MAS research team: https://cheba.unsw.edu.au/researchprojects/sydney-memory-and-ageing-study. We acknowledge the contribution of the OATS research team (https://cheba.unsw.edu.au/ project/older-australian-twins-study) to this study. The OATS study has been funded by a National Health & Medical Research Council (NHMRC) and Australian Research Council (ARC) Strategic Award Grant of the Aging Well, Aging Productively Program (ID No. 401162); NHMRC Project (seed) Grants (ID No. 1024224 and 1025243); NHMRC Project Grants (ID No. 1045325 and 1085606); and NHMRC Program Grants (ID No. 568969 and 1093083). We thank the participants for their time and generosity in contributing to this research. This research was facilitated through access to Twins Research Australia, a national resource supported by a Centre of Research Excellence Grant (ID No. 1079102) from the National Health and Medical Research Council. The NCNG sample collection was supported by grants from the Bergen Research Foundation and the University of Bergen, the Dr Einar Martens Fund, the KG Jebsen Foundation, the Research Council of Norway, to S. L. H., V. M. S., A. J. L., and T. E. The authors thank Dr. Eike Wehling for recruiting participants in Bergen, and Professor Jonn-Terje Geitung and Haraldplass Deaconess Hospital for access to the MRI facility. Additional support by RCN grants 177458/V50 and 231286/F20. The Betula study was supported by a Wallenberg Scholar Grant (KAW). The HUNT Study is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU—Norwegian University of Science and Technology), Nord-Trøndelag County Council, Central Norway Health Authority, and the Norwegian Institute of Public Health. HUNT-MRI was funded by the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology, and the Norwegian National Advisory Unit for functional MRI. Research for the GAP cohort was supported by the Department of Health via the National Institute for Health Research (NIHR) Specialist Biomedical Research Center for Mental Health award to South London and Maudsley NHS Foundation Trust (SLaM) and the Institute of Psychiatry at King's College London, London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. S.J. is supported by Calcul Quebec (http:// www.calculquebec.ca), Compute Canada (http://www.computecanada. ca), the Brain Canada Multi investigator research initiative (MIRI), the Institute of Data Valorization (Canada First Research Excellence Fund), CHIR, Canada Research Chairs and the Jeanne et Jean Louis Levesque Foundation. The NTR cohort was supported by the Netherlands Organization for Scientific Research (NWO), MW904-61-193 (de Geus & Boomsma), MaGWnr: 400-07-080 (van 't Ent), MagW 480-04-004 (Boomsma), NWO/SPI 56-464-14,192 (Boomsma), the European Research Council, ERC-230374 (Boomsma), and Amsterdam Neuroscience. Funding for genotyping was obtained from the National Institutes of Health (NIMH U24 MH068457-06; Grand Opportunity grants 1RC2 MH089951, and 1RC2 MH089995); the Avera Institute for Human Genetics, Sioux Falls, South Dakota (USA). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. The Brainscale study was supported by the Netherlands Organization for Scientific Research MagW 480-04-004 (Boomsma), 51.02.060 (Hilleke Hulshoff Pol), 668.772 (Boomsma & Hulshoff Pol); NWO/SPI 56-464-14192 (Boomsma), the European Research Council (ERC230374) (Boomsma), High Potential Grant Utrecht University (Hulshoff Pol), NWO Brain and Cognition 433-09-220 (Hulshoff Pol). SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide SNP typing in SHIP and MRI scans in SHIP and SHIP-TREND have been supported by a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The ENIGMA-22q11.2 Deletion Syndrome Working Group wishes to acknowledge our dear colleague Dr. Clodagh Murphy, who sadly passed away in April 2020. Open access funding enabled and organized by Projekt DEAL

Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

This work was supported by National Institute of Biomedical Imaging and Bioengineering Grant No. U54EB020403 (to the ENIGMA consortium)

Screening for germline BRCA1, BRCA2, TP53 and CHEK2 mutations in families at-risk for hereditary breast cancer identified in a population-based study from Southern Brazil

Abstract In Brazil, breast cancer is a public health care problem due to its high incidence and mortality rates. In this study, we investigated the prevalence of hereditary breast cancer syndromes (HBCS) in a population-based cohort in Brazils southernmost capital, Porto Alegre. All participants answered a questionnaire about family history (FH) of breast, ovarian and colorectal cancer and those with a positive FH were invited for genetic cancer risk assessment (GCRA). If pedigree analysis was suggestive of HBCS, genetic testing of the BRCA1, BRCA2, TP53, and CHEK2 genes was offered. Of 902 women submitted to GCRA, 214 had pedigrees suggestive of HBCS. Fifty of them underwent genetic testing: 18 and 40 for BRCA1/BRCA2 and TP53 mutation screening, respectively, and 7 for CHEK2 1100delC testing. A deleterious BRCA2 mutation was identified in one of the HBOC probands and the CHEK2 1100delC mutation occurred in one of the HBCC families. No deleterious germline alterations were identified in BRCA1 or TP53. Although strict inclusion criteria and a comprehensive testing approach were used, the suspected genetic risk in these families remains unexplained. Further studies in a larger cohort are necessary to better understand the genetic component of hereditary breast cancer in Southern Brazil

Cortical brain abnormalities in 4474 individuals with schizophrenia and 5098 control subjects via the enhancing neuro Imaging genetics through meta analysis (ENIGMA) Consortium

BACKGROUND: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. METHODS: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide. RESULTS: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. CONCLUSIONS: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia

Strategies to reengage patients lost to follow up in HIV care in high income countries, a scoping review

Background: Despite remarkable achievements in antiretroviral therapy (ART), losses to follow-up (LTFU) might prevent the long-term success of HIV treatment and might delay the achievement of the 90-90-90 objectives. This scoping review is aimed at the description and analysis of the strategies used in high-income countries to reengage LTFU in HIV care, their implementation and impact. Methods: A scoping review was done following Arksey & O'Malley's methodological framework and recommendations from Joanna Briggs Institute. Peer reviewed articles were searched for in Pubmed, Scopus and Web of Science; and grey literature was searched for in Google and other sources of information. Documents were charted according to the information presented on LTFU, the reengagement procedures used in HIV units in high-income countries, published during the last 15 years. In addition, bibliographies of chosen articles were reviewed for additional articles. Results: Twenty-eight documents were finally included, over 80% of them published in the United States later than 2015. Database searches, phone calls and/or mail contacts were the most common strategies used to locate and track LTFU, while motivational interviews and strengths-based techniques were used most often during reengagement visits. Outcomes like tracing activities efficacy, rates of reengagement and viral load reduction were reported as outcome measures. Conclusions: This review shows a recent and growing trend in developing and implementing patient reengagement strategies in HIV care. However, most of these strategies have been implemented in the United States and little information is available for other high-income countries. The procedures used to trace and contact LTFU are similar across reviewed studies, but their impact and sustainability are widely different depending on the country studied

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality