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      Age-related transcriptional modules and TF-miRNA-mRNA interactions in neonatal and infant human thymus

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          Abstract

          The human thymus suffers a transient neonatal involution, recovers and then starts a process of decline between the 1 st and 2 nd years of life. Age-related morphological changes in thymus were extensively investigated, but the genomic mechanisms underlying this process remain largely unknown. Through Weighted Gene Co-expression Network Analysis (WGCNA) and TF-miRNA-mRNA integrative analysis we studied the transcriptome of neonate and infant thymic tissues grouped by age: 0–30 days (A); 31days-6 months (B); 7–12 months (C); 13–18 months (D); 19-31months (E). Age-related transcriptional modules, hubs and high gene significance (HGS) genes were identified, as well as TF-miRNA-hub/HGS co-expression correlations. Three transcriptional modules were correlated with A and/or E groups. Hubs were mostly related to cellular/metabolic processes; few were differentially expressed (DE) or related to T-cell development. Inversely, HGS genes in groups A and E were mostly DE. In A (neonate) one third of the hyper-expressed HGS genes were related to T-cell development, against one-twentieth in E, what may correlate with the early neonatal depletion and recovery of thymic T-cell populations. This genomic mechanism is tightly regulated by TF-miRNA-hub/HGS interactions that differentially govern cellular and molecular processes involved in the functioning of the neonate thymus and in the beginning of thymic decline.

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          Systems Biology of Seasonal Influenza Vaccination in Humans

          We used a systems biological approach to study innate and adaptive responses to influenza vaccination in humans, during 3 consecutive influenza seasons. Healthy adults were vaccinated with inactivated (TIV) or live attenuated (LAIV) influenza vaccines. TIV induced greater antibody titers and enhanced numbers of plasmablasts than LAIV. In TIV vaccinees, early molecular signatures correlated with, and accurately predicted, later antibody titers in two independent trials. Interestingly, the expression of Calcium/calmodulin-dependent kinase IV (CamkIV) at day 3 was inversely correlated with later antibody titers. Vaccination of CamkIV −/− mice with TIV induced enhanced antigen-specific antibody titers, demonstrating an unappreciated role for CaMKIV in the regulation of antibody responses. Thus systems approaches can predict immunogenicity, and reveal new mechanistic insights about vaccines.
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            Systems scale interactive exploration reveals quantitative and qualitative differences in response to influenza and pneumococcal vaccines.

            Systems immunology approaches were employed to investigate innate and adaptive immune responses to influenza and pneumococcal vaccines. These two non-live vaccines show different magnitudes of transcriptional responses at different time points after vaccination. Software solutions were developed to explore correlates of vaccine efficacy measured as antibody titers at day 28. These enabled a further dissection of transcriptional responses. Thus, the innate response, measured within hours in the peripheral blood, was dominated by an interferon transcriptional signature after influenza vaccination and by an inflammation signature after pneumococcal vaccination. Day 7 plasmablast responses induced by both vaccines was more pronounced after pneumococcal vaccination. Together, these results suggest that comparing global immune responses elicited by different vaccines will be critical to our understanding of the immune mechanisms underpinning successful vaccination. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Activation of the Hypothalamic-Pituitary-Gonadal Axis in Infancy: Minipuberty

              The hypothalamic-pituitary-gonadal (HPG) axis is active in the midgestational foetus but silenced towards term because of the negative feedback effects mediated by the placental hormones. This restraint is removed at birth, leading to reactivation of the axis and an increase in gonadotrophin levels. Gonadotrophin levels are high during the first 3 months of life but decrease towards the age of 6 months except for FSH levels in girls that remain elevated until 3-4 years of age. After this, the HPG axis remains quiescent until puberty. The postnatal gonadotrophin surge results in gonadal activation in both sexes. In boys, testosterone levels rise to a peak at 1-3 months of age and then decline following LH levels. Postnatal HPG axis activation is associated with penile and testicular growth and therefore considered important for the development of male genitalia. In girls, elevated gonadotrophin levels result in the maturation of ovarian follicles and in an increase in oestradiol levels. Biological significance and possible long-term consequences of this minipuberty remain elusive, as do the mechanisms that silence the HPG axis until puberty. However, the first months of life provide a ‘window of opportunity' for functional studies of the HPG axis prior to pubertal development.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Investigation
                Role: Resources
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: Project administrationRole: ResourcesRole: Writing – review & editing
                Role: Funding acquisitionRole: Project administrationRole: Resources
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: ResourcesRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                15 April 2020
                2020
                : 15
                : 4
                : e0227547
                Affiliations
                [1 ] Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
                [2 ] Instituto Dante Pazzanese de Cardiologia, São Paulo, SP, Brazil
                [3 ] Department of Pathology, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
                University of Pittsburgh, UNITED STATES
                Author notes

                Competing Interests: The authors declare no competing interests.

                Author information
                http://orcid.org/0000-0002-3675-1362
                http://orcid.org/0000-0003-3433-4714
                Article
                PONE-D-19-27724
                10.1371/journal.pone.0227547
                7159188
                32294112
                f2f22b47-cfde-43a5-8f7c-590c6fbad33e
                © 2020 Bertonha et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 3 October 2019
                : 18 December 2019
                Page count
                Figures: 5, Tables: 2, Pages: 20
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001807, Fundação de Amparo à Pesquisa do Estado de São Paulo;
                Award ID: 2015/22308-2
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001807, Fundação de Amparo à Pesquisa do Estado de São Paulo;
                Award ID: 2014/50489-9
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100003593, Conselho Nacional de Desenvolvimento Científico e Tecnológico;
                Award ID: 306893/2018-5
                Award Recipient :
                The work was funded by grants awarded to VHH from FRAM - High North Research Centre for Climate and the Environment through the Flagship MIKON (Project RConnected; https://www.framcentre.com/) and the Arctic Belmont Forum Arctic Observing and Research for Sustainability (Project CONNECT; https://www.belmontforum.org/). The Norwegian collaboration was financed by Norwegian Research Council grant 247474 ( https://www.forskningsradet.no/en). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and life sciences
                Biochemistry
                Nucleic acids
                RNA
                Non-coding RNA
                Natural antisense transcripts
                MicroRNAs
                Biology and life sciences
                Genetics
                Gene expression
                Gene regulation
                MicroRNAs
                People and Places
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                Cell Biology
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                Immune Receptors
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                Biochemistry
                Proteins
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                Biology and Life Sciences
                Immunology
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                Thymus
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                Immune System
                Thymus
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                Custom metadata
                All relevant data are within the paper and its Supporting Information files. Additional datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Microarray data were deposited in GEO under accession number GSE131242 (Reference Series).

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