718 research outputs found
Perturbations to the IGF1 growth pathway and adult energy homeostasis following disruption of mouse chromosome 12 imprinting
AIM: Disruption to insulin-like growth factor (IGF) signalling pathways during early life causes growth retardation and defects of developing metabolic organs that can alter set points of energy homeostasis for a lifetime. Inheritance of two maternal copies of human chromosome 14q32.2 (Temple syndrome) causes severe foetal growth retardation and post-natal failure to thrive. Disruption of imprinted gene dosage in the orthologous region on mouse chromosome 12 also affects growth. Here, we investigated whether altering chromosome 12-imprinted gene dosage can affect IGF signalling. METHODS: We investigated mice with a transgene insertion at the imprinted domain of chromosome 12. This lesion causes misexpression of neighbouring genes such that the expression of non-coding RNAs is elevated, and levels of delta-like homologue 1 (Dlk1), retrotransposon-like 1 (Rtl1) and deiodinase 3 (Dio3) transcripts are reduced. RESULTS: We observed three key phenotypes in these mice: (i) embryonic growth retardation associated with altered expression of IGF1 binding proteins, (ii) peri-natal failure to thrive accompanied by hypothyroidism and low serum IGF1. Unexpectedly this phenotype was growth hormone independent. (iii) Adult animals had reduced glucose tolerance as a result of endocrine pancreatic insufficiency. CONCLUSIONS: We propose that all of these phenotypes are attributable to impaired IGF action and show for the first time that the chromosome 12 cluster in the mouse is an imprinted locus that modulates the IGF signalling pathway. We propose that growth retardation observed in human Temple syndrome might have a similar cause
TRANSPORTE PĂBLICO
INTRODUĂĂOO projeto serĂĄ atravĂ©s de um relatĂłrio, com um artigo em anexo, que serĂĄ entregue ao SETERB â Serviço AutĂŽnomo Municipal de TrĂąnsito e Transportes de Blumenau, sendo esse projeto criado devido Ă crise do transporte pĂșblico da cidade de Blumenau, SC, vivenciada entre 2015 e 2016.O objetivo Ă© levar ao ĂłrgĂŁo sugestĂ”es e ideias recolhidas de outras cidades e em consulta popular no grupo do Facebook Coletivo Blumenau, para o contrato oficial do transporte pĂșblico na cidade, sendo o documento publicado em outros meios, como o site do IFC â Campus Blumenau e no Coletivo Blumenau. MATERIAIS E MĂTODOSReunindo informaçÔes de sistemas de transporte pĂșblico de diversos lugares do Brasil e em consulta popular em redes sociais, no caso foi utilizado o Facebook, foi desenvolvido este trabalho.Algumas sugestĂ”es foram desenvolvidas pelos autores do projeto, como o item IBRTS do trabalho, que Ă© algo que nĂŁo existe atualmente, mas pode ser dito como a uniĂŁo de vĂĄrios aspectos dos SITs (Sistemas Integrados de Transporte) e dos sistemas BRT (Bus Rapid Transit) em uma Ășnica modalidade de sistemas de transporte pĂșblico.Outras sugestĂ”es foram de sugestĂŁo popular, vindos do grupo Coletivo Blumenau e vindos de pesquisa de sistemas de transporte pĂșblico de outras cidades.Ainda serĂŁo recolhidas sugestĂ”es durante a realização do evento, dos dias 27 a 28 de Outubro, atravĂ©s de um espaço no feedback que o pĂșblico poderĂĄ preencher apĂłs a apresentação do projeto. RESULTADOS E DISCUSSĂOO resultado atĂ© o momento foi a reuniĂŁo de vĂĄrias sugestĂ”es e ideias para o relatĂłrio que, jĂĄ que o mesmo ainda estava em fase de montagem quando foi escrito este documento no dia 03 de Outubro de 2016. Os resultados possĂveis desse relatĂłrio Ă© a aceitação de vĂĄrios itens que serĂŁo apresentados no mesmo, o que leve ao melhoramento do transporte pĂșblico da cidade alvo do projeto, alĂ©m de lançar uma nova modalidade de sistema de transporte pĂșblico.Entre as sugestĂ”es incluĂdas estĂŁo diversos itens, sendo que ainda podem ser adicionados mais itens apĂłs a realização do evento, mas entre alguns deles estĂŁo novas linhas, criação de plataformas que auxiliem a fiscalização do sistema de transporte pĂșblico, uma nova modalidade de transporte pĂșblico, o IBRTS, podendo ser chamado tambĂ©m de Mini-BRT e integração entre modais.Ainda hĂĄ a possibilidade de se fazer outro documento para o SETERB, se caso surgir outras sugestĂ”es, que forem entregues apĂłs a entrega do relatĂłrio ao ĂłrgĂŁo citado e se for realmente viĂĄvel para se realizar a elaboração de outro documento a nĂvel do construĂdo.Os documentos serĂŁo nĂŁo sĂł entregues ao SETERB, mas serĂŁo publicados em outros meios, como o site do campus e em sites especializados sobre o tema (exemplo: o site Ănibus Brasil) alĂ©m do grupo do Facebook, Coletivo Blumenau, onde foi inclusive realizada a pesquisa popular de sugestĂ”es para o relatĂłrio. CONCLUSĂOO projeto obteve resultados no nĂvel de pesquisa de sugestĂ”es e ideias para o relatĂłrio, mas se pode concluir tambĂ©m que o mesmo tem grande potencial para conseguir resultados concretos, a partir de aceitação de sugestĂ”es apresentadas no documento, para melhorar o transporte coletivo da cidade de Blumenau, ainda havendo a possibilidade de se lançar outro documento que irĂĄ ter o mesmo destino do relatĂłrio e artigo entregues ao SETERB e publicados em outros meios de comunicação, porĂ©m ainda no inĂcio do novo contrato oficial do transporte coletivo de Blumenau, sendo os documentos podendo servir de referĂȘncia para cidades que ainda estĂŁo desenvolvendo um sistema de transporte coletivo e que procuram tĂȘ-lo com qualidade e com mĂnimo de problemas que possam ocorrer ao sistema dessas cidades, como o caso de TimbĂł, SC e de outras cidades Brasil afora.
Loss of Hierarchical Imprinting Regulation at the Prader-Willi/Angelman Syndrome Locus in Human iPSCs
The human chr15q11-q13 imprinted cluster is linked to several disorders, including Prader-Willi (PWS) and Angelman (AS) syndromes. Recently, disease modeling approaches based on induced pluripotent stem cells (iPSCs) have been used to study these syndromes. A concern regarding the use of these cells for imprinted disease modeling is the numerous imprinting defects found in many iPSCs. Here, by reprogramming skin fibroblasts from a control and AS individuals, we generated several iPSC lines and addressed the stability of imprinting status across the PWS/AS domain. We focused on three important regulatory DNA elements which are all differentially methylated regions (DMRs), methylated on the maternal allele: the PWS imprinting center (PWS-IC), which is a germline DMR and the somatic NDN and MKRN3 DMRs, hierarchically controlled by PWS-IC. Normal PWS-IC methylation pattern was maintained in most iPSC lines; however, loss of maternal methylation in one out of five control iPSC lines resulted in a monoallelic to biallelic switch for many imprinted genes in this domain. Surprisingly, MKRN3 DMR was found aberrantly hypermethylated in all control and AS iPSCs, regardless of the methylation status of the PWS-IC master regulator. This suggests a loss of hierarchical control of imprinting at PWS/AS region. We confirmed these results in established iPSC lines derived using different reprogramming procedures. Overall, we show that hierarchy of imprinting control in donor cells might not apply to iPSCs, accounting for their spectrum of imprinting alterations. Such differences in imprinting regulation should be taken into consideration for the use of iPSCs in disease modeling.info:eu-repo/semantics/publishedVersio
The IG-DMR and the MEG3-DMR at Human Chromosome 14q32.2: Hierarchical Interaction and Distinct Functional Properties as Imprinting Control Centers
Human chromosome 14q32.2 harbors the germline-derived primary DLK1-MEG3 intergenic differentially methylated region (IG-DMR) and the postfertilization-derived secondary MEG3-DMR, together with multiple imprinted genes. Although previous studies in cases with microdeletions and epimutations affecting both DMRs and paternal/maternal uniparental disomy 14-like phenotypes argue for a critical regulatory function of the two DMRs for the 14q32.2 imprinted region, the precise role of the individual DMR remains to be clarified. We studied an infant with upd(14)pat body and placental phenotypes and a heterozygous microdeletion involving the IG-DMR alone (patient 1) and a neonate with upd(14)pat body, but no placental phenotype and a heterozygous microdeletion involving the MEG3-DMR alone (patient 2). The results generated from the analysis of these two patients imply that the IG-DMR and the MEG3-DMR function as imprinting control centers in the placenta and the body, respectively, with a hierarchical interaction for the methylation pattern in the body governed by the IG-DMR. To our knowledge, this is the first study demonstrating an essential long-range imprinting regulatory function for the secondary DMR
The roles of vicariance and isolation by distance in shaping biotic diversification across an ancient archipelago: evidence from a Seychelles caecilian amphibian
© 2020 The Authors. Published by BMC. This is an open access article available under a Creative Commons licence.
The published version can be accessed at the following link on the publisherâs website: https://doi.org/10.1186/s12862-020-01673-wBackground
Island systems offer excellent opportunities for studying the evolutionary histories of species by virtue of their restricted size and easily identifiable barriers to gene flow. However, most studies investigating evolutionary patterns and processes shaping biotic diversification have focused on more recent (emergent) rather than ancient oceanic archipelagos. Here, we focus on the granitic islands of the Seychelles, which are unusual among island systems because they have been isolated for a long time and are home to a monophyletic radiation of caecilian amphibians that has been separated from its extant sister lineage for ca. 65â62âMa. We selected the most widespread Seychelles caecilian species, Hypogeophis rostratus, to investigate intraspecific morphological and genetic (mitochondrial and nuclear) variation across the archipelago (782 samples from nine islands) to identify patterns and test processes that shaped their evolutionary history within the Seychelles.
Results
Overall a signal of strong geographic structuring with distinct northern- and southern-island clusters were identified across all datasets. We suggest that these distinct groups have been isolated for ca. 1.26âMaâyears without subsequent migration between them. Populations from the somewhat geographically isolated island of FrĂ©gate showed contrasting relationships to other islands based on genetic and morphological data, clustering alternatively with northern-island (genetic) and southern-island (morphological) populations.
Conclusions
Although variation in H. rostratus across the Seychelles is explained more by isolation-by-distance than by adaptation, the genetic-morphological incongruence for affinities of FrĂ©gate H. rostratus might be caused by local adaptation over-riding the signal from their vicariant history. Our findings highlight the need of integrative approaches to investigate fine-scale geographic structuring to uncover underlying diversity and to better understand evolutionary processes on ancient, continental islands.Funding for this research was provided by two grants from the National Science Foundation (BSR 88â17453, BSR 90â24505) [funding for fieldwork and lab work], two grants from the National Geographic Society (Grants 1977: 1633, 1743) [funding for fieldwork], three grants from the University of Michigan Office of the Vice President for Research, and a Research Partnership Award from the University of Michigan to RAN [morphology work]; a joint NHM-UCL IMPACT studentship [to fund STMâs PhD, lab work and fieldwork], Mohamed Bin Zayed Species Conservation Fund [funding for fieldwork] and Systematics Research Fund [funding for fieldwork] to STM; an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under Grant #P20GM103408 to LL [funding for lab work]; a NERC/BBSRC SynTax grant [funding for fieldwork and collaboration], and Darwin Initiative (grant 19â002) [funding for fieldwork, lab work and capacity building] with partners Bristol University, Islands Conservation Society, Seychelles Islands Foundation, Seychelles Ministry of Environment, Seychelles National Parks Authority, Seychelles Natural History Museum, University of Kent, Zoological Society of London to MW, DJG, JJD. The funding bodies played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.Published onlin
The critical influence of nocturnal breathing complaints on the quality of sleep after stroke: the Pittsburgh Sleep Quality Index and STOP-BANG
Fetus-derived DLK1 is required for maternal metabolic adaptations to pregnancy and is associated with fetal growth restriction.
Pregnancy is a state of high metabolic demand. Fasting diverts metabolism to fatty acid oxidation, and the fasted response occurs much more rapidly in pregnant women than in non-pregnant women. The product of the imprinted DLK1 gene (delta-like homolog 1) is an endocrine signaling molecule that reaches a high concentration in the maternal circulation during late pregnancy. By using mouse models with deleted Dlk1, we show that the fetus is the source of maternal circulating DLK1. In the absence of fetally derived DLK1, the maternal fasting response is impaired. Furthermore, we found that maternal circulating DLK1 levels predict embryonic mass in mice and can differentiate healthy small-for-gestational-age (SGA) infants from pathologically small infants in a human cohort. Therefore, measurement of DLK1 concentration in maternal blood may be a valuable method for diagnosing human disorders associated with impaired DLK1 expression and to predict poor intrauterine growth and complications of pregnancy.M.A.M.C. was supported by a PhD studentship from the Cambridge Centre for Trophoblast Research. Research was supported by grants from the MRC (MR/J001597/1 and MR/L002345/1), the Medical College of Saint Bartholomew's Hospital Trust, a Wellcome Trust Investigator Award, EpigeneSys (FP7 Health-257082), EpiHealth (FP7 Health-278414), a Herchel Smith Fellowship (N.T.) and NIH grant RO1 DK89989. The contents are the authors' sole responsibility and do not necessarily represent official NIH views. We thank G. Burton for invaluable support, and M. ConstĂąncia and I. Sandovici (University of Cambridge) for the Meox2-cre mice. We are extremely grateful to all of the participants in the Pregnancy Outcome Prediction study. This work was supported by the NIHR Cambridge Comprehensive Biomedical Research Centre (Women's Health theme) and project grants from the MRC (G1100221) and Sands (Stillbirth and Neonatal Death Charity). The study was also supported by GE Healthcare (donation of two Voluson i ultrasound systems for this study) and by the NIHR Cambridge Clinical Research Facility, where all research visits took place.This is the author accepted manuscript. The final version is available from Nature Publishing Group via https://doi.org/10.1038/ng.369
Spatial Dimensions of Dengue Virus Transmission across Interepidemic and Epidemic Periods in Iquitos, Peru (1999â2003)
To target prevention and control strategies for dengue fever, it is essential to understand how the virus travels through the city. We report spatial analyses of dengue infections from a study monitoring school children and adult family members for dengue infection at six-month intervals from 1999â2003, in the Amazonian city of Iquitos, Peru. At the beginning of the study, only DENV serotypes 1 and 2 were circulating. Clusters of infections of these two viruses were concentrated in the northern region of the city, where mosquito indices and previous DENV infection were both high. In 2002, DENV-3 invaded the city, replacing DENV-1 and -2 as the dominant strain. During the invasion process, the virus spread rapidly across the city, at low levels. After this initial phase, clusters of infection appeared first in the northern region of the city, where clusters of DENV-1 and DENV-2 had occurred in prior years. Most of the clusters we identified had radii >100 meters, indicating that targeted or reactive treatment of these high-risk areas might be an effective proactive intervention strategy. Our results also help explain why vector control within 100 m of a dengue case is often not successful for large-scale disease prevention
Observation of associated near-side and away-side long-range correlations in âsNN=5.02ââTeV proton-lead collisions with the ATLAS detector
Two-particle correlations in relative azimuthal angle (ÎÏ) and pseudorapidity (Îη) are measured in âsNN=5.02ââTeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1ââÎŒb-1 of data as a function of transverse momentum (pT) and the transverse energy (ÎŁETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Îη|<5) ânear-sideâ (ÎÏâŒ0) correlation that grows rapidly with increasing ÎŁETPb. A long-range âaway-sideâ (ÎÏâŒÏ) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ÎŁETPb, is found to match the near-side correlation in magnitude, shape (in Îη and ÎÏ) and ÎŁETPb dependence. The resultant ÎÏ correlation is approximately symmetric about Ï/2, and is consistent with a dominant cosâĄ2ÎÏ modulation for all ÎŁETPb ranges and particle pT
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