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Fetal genome

Eric Courchesne, Tiziano Pramparo, Vahid H Gazestani, Michael V Lombardo, Karen Pierce, Nathan E Lewis
Autism spectrum disorder (ASD) has captured the attention of scientists, clinicians and the lay public because of its uncertain origins and striking and unexplained clinical heterogeneity. Here we review genetic, genomic, cellular, postmortem, animal model, and cell model evidence that shows ASD begins in the womb. This evidence leads to a new theory that ASD is a multistage, progressive disorder of brain development, spanning nearly all of prenatal life. ASD can begin as early as the 1st and 2nd trimester with disruption of cell proliferation and differentiation...
June 22, 2018: Molecular Psychiatry
Nicholas B Larson, Chen Wang, Jie Na, Ross A Rowsey, William Edward Highsmith, Nicole L Hoppman, Jean-Pierre Kocher, Eric W Klee
The recent advances in next-generation sequencing (NGS) technologies have enabled the development of effective high-throughput noninvasive prenatal screening (NIPS) assays for fetal genetic abnormalities using maternal circulating cell-free DNA (ccfDNA). An important NIPS quality assurance is quantifying the fetal proportion of the sampled ccfDNA. For methods using allelic read count ratios from targeted sequencing of single-nucleotide polymorphisms (SNPs), systematic biases and errors may reduce accuracy and diminish assay performance...
June 22, 2018: Journal of Computational Biology: a Journal of Computational Molecular Cell Biology
Leen J Luyten, Nelly D Saenen, Bram G Janssen, Karen Vrijens, Michelle Plusquin, Harry A Roels, Florence Debacq-Chainiaux, Tim S Nawrot
BACKGROUND: Fetal development is a crucial window of susceptibility in which exposure-related alterations can be induced on the molecular level, leading to potential changes in metabolism and development. The placenta serves as a gatekeeper between mother and fetus, and is in contact with environmental stressors throughout pregnancy. This makes the placenta as a temporary organ an informative non-invasive matrix suitable to investigate omics-related aberrations in association with in utero exposures such as ambient air pollution...
June 13, 2018: Environmental Research
Cornelis J Boogerd, Xiaoming Zhu, Ivy Aneas, Noboru J Sakabe, Lunfeng Zhang, Debora R Sobreira, Lindsey E Montefiori, Julius Bogomolovas, Amelia C Joslin, Bin Zhou, Ju Chen, Marcelo Nobrega, Sylvia M Evans
<u>Rationale:</u> Mutations in the transcription factor TBX20 are associated with congenital heart disease. Germline ablation of Tbx20 results in abnormal heart development and embryonic lethality by E9.5. As Tbx20 is expressed in multiple cell lineages required for myocardial development, including pharyngeal endoderm, cardiogenic mesoderm, endocardium, and myocardium, the cell type specific requirement for Tbx20 in early myocardial development remains to be explored. <u>Objective:</u> Here, we investigated roles of Tbx20 in mid-gestation cardiomyocytes for heart development...
June 14, 2018: Circulation Research
Ketil Størdal, Harry J McArdle, Helen Hayes, German Tapia, Marte K Viken, Nicolai A Lund-Blix, Margaretha Haugen, Geir Joner, Torild Skrivarhaug, Karl Mårild, Pål R Njølstad, Merete Eggesbø, Siddhartha Mandal, Christian M Page, Stephanie J London, Benedicte A Lie, Lars C Stene
Iron overload due to environmental or genetic causes have been associated diabetes. We hypothesized that prenatal iron exposure is associated with higher risk of childhood type 1 diabetes. In the Norwegian Mother and Child cohort study (n = 94,209 pregnancies, n = 373 developed type 1 diabetes) the incidence of type 1 diabetes was higher in children exposed to maternal iron supplementation than unexposed (36.8/100,000/year compared to 28.6/100,000/year, adjusted hazard ratio 1.33, 95%CI: 1.06-1.67)...
June 13, 2018: Scientific Reports
Max Gerlach, Theresia Kraft, Bernhard Brenner, Björn Petersen, Heiner Niemann, Judith Montag
During CRISPR/Cas9 mediated genome editing, site-specific double strand breaks are introduced and repaired either unspecific by non-homologous end joining (NHEJ) or sequence dependent by homology directed repair (HDR). Whereas NHEJ-based generation of gene knock-out is widely performed, the HDR-based knock-in of specific mutations remains a bottleneck. Especially in primary cell lines that are essential for the generation of cell culture and animal models of inherited human diseases, knock-in efficacy is insufficient and needs significant improvement...
June 13, 2018: Genes
Yankai Zhang, Alireza Paikari, Pavel Sumazin, Carly C Ginter Summarell, Jacy R Crosby, Eric Boerwinkle, Mitchell J Weiss, Vivien A Sheehan
Induction of red blood cell fetal hemoglobin (HbF, α2γ2) ameliorates the pathophysiology of sickle cell disease (SCD) by reducing the concentration of sickle hemoglobin (HbS, α2βS 2) to inhibit its polymerization. Hydroxyurea (HU), the only FDA-approved drug for SCD, acts in part by inducing HbF, but is not fully effective, reflecting the need for new therapies. Whole exome sequence analysis of rare genetic variants in SCD patients identified FOXO3 as a candidate regulator of RBC HbF. We validated these genomic findings through loss and gain of function studies in normal human CD34+ hematopoietic stem and progenitor cells (HSPCs) induced to undergo erythroid differentiation...
June 8, 2018: Blood
Sriram Bandi, Sanchit Gupta, Tatyana Tchaikovskaya, Sanjeev Gupta
Understanding mechanisms in lineage differentiation is critical for organ development, pathophysiology and oncogenesis. To determine whether microRNAs (miRNA) may serve as drivers or adjuncts in hepatic differentiation, we studied human embryonic stem cell-derived hepatocytes and primary hepatocytes representing fetal or adult stages. Model systems were used for hepatic lineage advancement or regression under culture conditions with molecular assays. Profiles of miRNA in primary fetal and adult hepatocytes shared similarities and distinctions from pluripotent stem cells or stem cell-derived early fetal-like hepatocytes...
June 5, 2018: Experimental Cell Research
Toshiki Aiba, Toshiyuki Saito, Akiko Hayashi, Shinji Sato, Harunobu Yunokawa, Toru Maruyama, Wataru Fujibuchi, Seiichiroh Ohsako
Background: There is still considerable debate about the effects of exposure to bisphenol A (BPA) an endocrine disrupter at low doses. Recently, many studies using animal models have shown that prenatal BPA exposure induces behavioral and neuronal disorders due to epigenetic changes in the brain. However, striking evidence of epigenomic changes has to be shown. Methods: To investigate whether low-dose BPA exposure in the fetal stage can alter CpG methylation levels in the central nervous system, the hippocampus of the inbred C57BL/6 J mouse as the target tissue was collected to detect alterations in CpG methylation levels using a highly sensitive method of genome-wide DNA methylation analysis, methylated site display-amplified fragment length polymorphism (MSD-AFLP)...
2018: Genes and Environment: the Official Journal of the Japanese Environmental Mutagen Society
Emily Lostchuck, Alice Poulton, Jane Halliday, Lisa Hui
OBJECTIVES: To assess trends in ultrasound-indicated prenatal diagnostic testing over the past two decades, in the context of rapidly-changing practices in aneuploidy screening and chromosome analysis. METHODS: Retrospective analysis of ultrasound-indicated amniocenteses and chorionic villus sampling from the Australian state of Victoria from 1994-2016. Ultrasound-indicated prenatal diagnostic testing included those performed for: fetal structural abnormality, fetal death, fetal growth restriction, abnormal amniotic fluid volume, genetic "soft marker", or unspecified ultrasound abnormality...
June 6, 2018: Ultrasound in Obstetrics & Gynecology
Selami Demirci, John F Tisdale
Derivation of functional and mature red blood cells (RBCs) with adult globin expression from renewable source such as induced pluripotent stem cells (iPSCs) is of importance from the clinical point of view. Definitive RBC generation can only be succeeded through production of true hematopoietic stem cells (HSCs). There has been a great effort to obtain definitive engraftable HSCs from iPSCs but the results were mostly unsatisfactory due to low, short-term and linage-biased engraftment in mouse models. Moreover, ex vivo differentiation approaches ended up with RBCs with mostly embryonic and fetal globin expression...
June 7, 2018: Advances in Experimental Medicine and Biology
Patricia B Munroe, Shea Addison, Dominic J Abrams, Neil J Sebire, James Cartwright, Ian Donaldson, Marta M Cohen, Charles Mein, Andrew Tinker, Stephen C Harmer, Qadeer Aziz, Anna Terry, Monika Struebig, Helen R Warren, Bhumita Vadgama, Darren J Fowler, Donald Peebles, Andrew M Taylor, Peter J Lally, Sudhin Thayyil
BACKGROUND: Although stillbirth is a significant health problem worldwide, the definitive cause of death remains elusive in many cases, despite detailed autopsy. In this study of partly explained and unexplained stillbirths, we used next-generation sequencing to examine an extended panel of 35 candidate genes known to be associated with ion channel disorders and sudden cardiac death. METHODS AND RESULTS: We examined tissue from 242 stillbirths (≥22 weeks), including those where no definite cause of death could be confirmed after a full autopsy...
January 2018: Circulation. Genomic and precision medicine
Bianca Vora, Aolin Wang, Idit Kosti, Hongtai Huang, Ishan Paranjpe, Tracey J Woodruff, Tippi MacKenzie, Marina Sirota
Preterm birth (PTB) is the leading cause of newborn deaths around the world. Spontaneous preterm birth (sPTB) accounts for two-thirds of all PTBs; however, there remains an unmet need of detecting and preventing sPTB. Although the dysregulation of the immune system has been implicated in various studies, small sizes and irreproducibility of results have limited identification of its role. Here, we present a cross-study meta-analysis to evaluate genome-wide differential gene expression signals in sPTB. A comprehensive search of the NIH genomic database for studies related to sPTB with maternal whole blood samples resulted in data from three separate studies consisting of 339 samples...
2018: Frontiers in Immunology
Xian Adiconis, Adam L Haber, Sean K Simmons, Ami Levy Moonshine, Zhe Ji, Michele A Busby, Xi Shi, Justin Jacques, Madeline A Lancaster, Jen Q Pan, Aviv Regev, Joshua Z Levin
Specialized RNA-seq methods are required to identify the 5' ends of transcripts, which are critical for studies of gene regulation, but these methods have not been systematically benchmarked. We directly compared six such methods, including the performance of five methods on a single human cellular RNA sample and a new spike-in RNA assay that helps circumvent challenges resulting from uncertainties in annotation and RNA processing. We found that the 'cap analysis of gene expression' (CAGE) method performed best for mRNA and that most of its unannotated peaks were supported by evidence from other genomic methods...
June 4, 2018: Nature Methods
Umberto Simeoni, Jean-Baptiste Armengaud, Benazir Siddeek, Jean-François Tolsa
Epidemiological and experimental studies have shown that the peri-conception period, pregnancy, and infancy are windows of particular sensibility to environmental clues which influence lifelong trajectories across health and disease. Nutrition, stress, and toxins induce epigenetic marks that control long-term gene expression patterns and can be transmitted transgenerationally. Chronic diseases of adulthood such as hypertension, diabetes, and obesity thus have early, developmental origins in the perinatal period...
2018: Neonatology
Tamio Furuse, Shigeharu Wakana
OBJECTIVES: The developmental origins of health and disease paradigm (DOHaD) is a concept that fetal environmental factors affect adult phenotypes. We performed experiments to evaluate the DOHaD theory in developmental disorders using mouse models. METHODS: In vitro fertilization and embryo transfer techniques were used for mouse production. The AIN93G-control diet, which contains 20% protein (CD), 5% protein-restricted diet (PR), and PR with supplemental folic acid (FA) were provided as experimental diets to mothers...
2018: Nihon Eiseigaku Zasshi. Japanese Journal of Hygiene
Maria Kaukonen, Sean Woods, Saija Ahonen, Seppo Lemberg, Maarit Hellman, Marjo K Hytönen, Perttu Permi, Tom Glaser, Hannes Lohi
Maternally skewed transmission of traits has been associated with genomic imprinting and oocyte-derived mRNA. We report canine congenital eye malformations, caused by an amino acid deletion (K12del) near the N terminus of retinol-binding protein (RBP4). The disease is only expressed when both dam and offspring are deletion homozygotes. RBP carries vitamin A (retinol) from hepatic stores to peripheral tissues, including the placenta and developing eye, where it is required to synthesize retinoic acid. Gestational vitamin A deficiency is a known risk factor for ocular birth defects...
May 29, 2018: Cell Reports
Christina Halgren, Nete M Nielsen, Lusine Nazaryan-Petersen, Asli Silahtaroglu, Ryan L Collins, Chelsea Lowther, Susanne Kjaergaard, Morten Frisch, Maria Kirchhoff, Karen Brøndum-Nielsen, Allan Lind-Thomsen, Yuan Mang, Zahra El-Schich, Claire A Boring, Mana M Mehrjouy, Peter K A Jensen, Christina Fagerberg, Lotte N Krogh, Jan Hansen, Thue Bryndorf, Claus Hansen, Michael E Talkowski, Mads Bak, Niels Tommerup, Iben Bache
The 6%-9% risk of an untoward outcome previously established by Warburton for prenatally detected de novo balanced chromosomal rearrangements (BCRs) does not account for long-term morbidity. We performed long-term follow-up (mean 17 years) of a registry-based nationwide cohort of 41 individuals carrying a prenatally detected de novo BCR with normal first trimester screening/ultrasound scan. We observed a significantly higher frequency of neurodevelopmental and/or neuropsychiatric disorders than in a matched control group (19...
May 17, 2018: American Journal of Human Genetics
Hidetaka Miyauchi, Hiroshi Ohta, Mitinori Saitou
Meiosis is a key mechanism that ensures sexual reproduction and creates genetic diversity. Here we describe a method that induces fetal oocytes and the prophase of the first meiotic division from mouse pluripotent stem cells (PSCs) under defined conditions. PSCs are induced into epiblast-like cells (EpiLCs), which are in turn induced into primordial germ cell-like cells (PGCLCs). PGCLCs are expanded robustly in the presence of forskolin and rolipram, which elevate intracellular cyclic AMP levels. The expanded PGCLCs comprehensively erase their DNA methylome in a manner that recapitulates genome-wide DNA demethylation in germ cells in vivo, and are in turn induced efficiently into the oogenic pathway and the prophase of the first meiotic division up to the pachytene stage in response to bone morphogenetic protein and retinoic acid...
2018: Methods in Cell Biology
Tanja S Hartwig, Louise Ambye, Lene Werge, Martin Kenneth Weiergang, Pernille Nørgaard, Steen Sørensen, Finn Stener Jørgensen
OBJECTIVES: We have established an open source platform for non-invasive prenatal testing (NIPT) based on massively parallel whole-genome sequencing in a public setting. The objective of this study was to investigate factors of importance for correct interpretation of NIPT results to ensure a high sensitivity and specificity. STUDY DESIGN: This investigation is a retrospective case-control study performed in a public NIPT center. The study included 108 aneuploid cases and 165 euploid controls...
July 2018: European Journal of Obstetrics, Gynecology, and Reproductive Biology
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