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Yoel Sadovsky

Takuya Mishima, Elena Sadovsky, Margaret E Gegick, Yoel Sadovsky
Manipulation of microRNA (miRNA) levels, including overexpression of mature species, has become an important biological tool, even motivating miRNA-based therapeutics. To assess key determinants of miRNA overexpression in a mammalian system in vivo, we sought to bypass the laborious generation of a transgenic animal by exploiting placental trophoblast-specific gene manipulation using lentiviral vectors, which has been instrumental in elucidating trophoblast biology. We examined the impact of several key components of miRNA stem loops and their flanking sequences on the efficiency of mature miRNA expression in vivo...
2016: Scientific Reports
Avraham Bayer, Nicholas J Lennemann, Yingshi Ouyang, John C Bramley, Stefanie Morosky, Ernesto Torres De Azeved Marques, Sara Cherry, Yoel Sadovsky, Carolyn B Coyne
During mammalian pregnancy, the placenta acts as a barrier between the maternal and fetal compartments. The recently observed association between Zika virus (ZIKV) infection during human pregnancy and fetal microcephaly and other anomalies suggests that ZIKV may bypass the placenta to reach the fetus. This led us to investigate ZIKV infection of primary human trophoblasts (PHTs), which are the barrier cells of the placenta. We discovered that PHT cells from full-term placentas are refractory to ZIKV infection...
May 11, 2016: Cell Host & Microbe
Shinichiro Yabe, Andrei P Alexenko, Mitsuyoshi Amita, Ying Yang, Danny J Schust, Yoel Sadovsky, Toshihiko Ezashi, R Michael Roberts
Human embryonic stem cells (ESCs) readily commit to the trophoblast lineage after exposure to bone morphogenetic protein-4 (BMP-4) and two small compounds, an activin A signaling inhibitor and a FGF2 signaling inhibitor (BMP4/A83-01/PD173074; BAP treatment). During differentiation, areas emerge within the colonies with the biochemical and morphological features of syncytiotrophoblast (STB). Relatively pure fractions of mononucleated cytotrophoblast (CTB) and larger syncytial sheets displaying the expected markers of STB can be obtained by differential filtration of dispersed colonies through nylon strainers...
May 10, 2016: Proceedings of the National Academy of Sciences of the United States of America
Yoel Sadovsky, Vicki L Clifton, Martin Knöfler
No abstract text is available yet for this article.
April 2016: Placenta
Soo-Young Oh, Jae Ryoung Hwang, Yoonna Lee, Suk-Joo Choi, Jung-Sun Kim, Jong-Hwa Kim, Yoel Sadovsky, Cheong-Rae Roh
INTRODUCTION: The syncytiotrophoblast, a key barrier between the mother and fetus, is a polarized epithelium composed of a microvillus and basal membrane (BM). We sought to characterize BM proteins of BeWo cells in relation to hypoxia and to investigate their expression in placentas from pregnancies complicated by fetal growth restriction (FGR). METHODS: We isolated the BM fraction of BeWo cells by the cationic colloidal silica method and identified proteins enriched in this fraction by mass spectrometry...
March 2016: Placenta
Cameron A McConkey, Elizabeth Delorme-Axford, Cheryl A Nickerson, Kwang Sik Kim, Yoel Sadovsky, Jon P Boyle, Carolyn B Coyne
In eutherians, the placenta acts as a barrier and conduit at the maternal-fetal interface. Syncytiotrophoblasts, the multinucleated cells that cover the placental villous tree surfaces of the human placenta, are directly bathed in maternal blood and are formed by the fusion of progenitor cytotrophoblasts that underlie them. Despite their crucial role in fetal protection, many of the events that govern trophoblast fusion and protection from microbial infection are unknown. We describe a three-dimensional (3D)-based culture model using human JEG-3 trophoblast cells that develop syncytiotrophoblast phenotypes when cocultured with human microvascular endothelial cells...
March 2016: Science Advances
John V Ilekis, Ekaterini Tsilou, Susan Fisher, Vikki M Abrahams, Michael J Soares, James C Cross, Stacy Zamudio, Nicholas P Illsley, Leslie Myatt, Christine Colvis, Maged M Costantine, David M Haas, Yoel Sadovsky, Carl Weiner, Erik Rytting, Gene Bidwell
Although much progress is being made in understanding the molecular pathways in the placenta that are involved in the pathophysiology of pregnancy-related disorders, a significant gap exists in the utilization of this information for the development of new drug therapies to improve pregnancy outcome. On March 5-6, 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health sponsored a 2-day workshop titled Placental Origins of Adverse Pregnancy Outcomes: Potential Molecular Targets to begin to address this gap...
July 2016: American Journal of Obstetrics and Gynecology
Elizabeth Delorme-Axford, Yoel Sadovsky, Carolyn B Coyne
Throughout pregnancy, the placenta acts as a physical and immunological barrier against the hematogenous transmission of viruses from mother to fetus. Despite this, very little is known regarding the specific mechanisms by which the placenta shields the developing fetus from viral infections or about the strategies utilized by select viruses to bypass and/or weaken the placental barrier. In this review, we summarize studies regarding virus-host interactions at the placental interface and explore key areas for future investigation...
November 2014: Annual Review of Virology
Tracy A Manuck, M Sean Esplin, Joseph Biggio, Radek Bukowski, Samuel Parry, Heping Zhang, Hao Huang, Michael W Varner, William Andrews, George Saade, Yoel Sadovsky, Uma M Reddy, John Ilekis
BACKGROUND: Prematurity is the leading cause of neonatal morbidity and death among nonanomalous neonates in the United States. Intramuscular 17-alpha hydroxyprogesterone caproate injections reduce the risk of recurrent prematurity by approximately one third. Unfortunately, prophylactic 17-alpha hydroxyprogesterone caproate is not always effective, and one-third of high-risk women will have a recurrent preterm birth, despite 17-alpha hydroxyprogesterone caproate therapy. The reasons for this variability in response are unknown...
March 2016: American Journal of Obstetrics and Gynecology
Jean-François Mouillet, Yingshi Ouyang, Carolyn B Coyne, Yoel Sadovsky
MicroRNAs (miRNAs) constitute a large family of small noncoding RNAs that are encoded by the genomes of most organisms. They regulate gene expression through posttranscriptional mechanisms to attenuate protein output in various genetic networks. The discovery of miRNAs has transformed our understanding of gene regulation and sparked intense efforts intended to harness their potential as diagnostic markers and therapeutic tools. Over the last decade, a flurry of studies has shed light on placental miRNAs but has also raised many questions regarding the scope of their biologic action...
October 2015: American Journal of Obstetrics and Gynecology
Jean-Francois Mouillet, Takuya Mishima, Andrea Mollica do Amarante Paffaro, Tony W Parks, Judy A Ziegler, Tianjiao Chu, Yoel Sadovsky
INTRODUCTION: Follistatin-like-1 (FSTL1) is a widely expressed secreted protein with diverse but poorly understood functions. Originally described as a pro-inflammatory molecule, it has recently been reported to play a role in signaling pathways that regulate development and homeostasis. Distinctively, FSTL1 harbors within its 3'-UTR the sequence encoding microRNA-198 (miR-198), shown to be inversely regulated relative to FSTL1 expression and to exhibit opposite actions on cellular processes such as cell migration...
November 2015: Placenta
Qian Shu, Nicholas J Lennemann, Saumendra N Sarkar, Yoel Sadovsky, Carolyn B Coyne
Interferon stimulated genes (ISGs) target viruses at various stages of their infectious life cycles, including at the earliest stage of viral entry. Here we identify ArfGAP with dual pleckstrin homology (PH) domains 2 (ADAP2) as a gene upregulated by type I IFN treatment in a STAT1-dependent manner. ADAP2 functions as a GTPase-activating protein (GAP) for Arf6 and binds to phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) and PI(3,4)P2. We show that overexpression of ADAP2 suppresses dengue virus (DENV) and vesicular stomatitis virus (VSV) infection in an Arf6 GAP activity-dependent manner, while exerting no effect on coxsackievirus B (CVB) or Sendai virus (SeV) replication...
September 2015: PLoS Pathogens
M Sean Esplin, Tracy A Manuck, Michael W Varner, Bryce Christensen, Joseph Biggio, Radek Bukowski, Samuel Parry, Heping Zhang, Hao Huang, William Andrews, George Saade, Yoel Sadovsky, Uma M Reddy, John Ilekis
OBJECTIVE: We sought to use an innovative tool that is based on common biologic pathways to identify specific phenotypes among women with spontaneous preterm birth (SPTB) to enhance investigators' ability to identify and to highlight common mechanisms and underlying genetic factors that are responsible for SPTB. STUDY DESIGN: We performed a secondary analysis of a prospective case-control multicenter study of SPTB. All cases delivered a preterm singleton at SPTB ≤34...
September 2015: American Journal of Obstetrics and Gynecology
Shaina L Stacy, LuAnn L Brink, Jacob C Larkin, Yoel Sadovsky, Bernard D Goldstein, Bruce R Pitt, Evelyn O Talbott
Unconventional gas drilling (UGD) has enabled extraordinarily rapid growth in the extraction of natural gas. Despite frequently expressed public concern, human health studies have not kept pace. We investigated the association of proximity to UGD in the Marcellus Shale formation and perinatal outcomes in a retrospective cohort study of 15,451 live births in Southwest Pennsylvania from 2007-2010. Mothers were categorized into exposure quartiles based on inverse distance weighted (IDW) well count; least exposed mothers (first quartile) had an IDW well count less than 0...
2015: PloS One
Yoel Sadovsky, Jean-Francois Mouillet, Yingshi Ouyang, Avraham Bayer, Carolyn B Coyne
In eutherian organisms, the placenta interfaces the fetal and maternal environments. Located at the placental villous surface, in direct contact with maternal blood, is the trophoblast layer, which mediates the crucial maternal-fetal exchange of gases, nutrients, and waste products, produces hormones that support the pregnancy, and provides immunologic defense. Discovery of microRNAs (miRNAs) and their role in development, differentiation, and homeostatic resilience has increased our understanding of genomic and epigenomic networks that regulate placental function...
August 2015: Cold Spring Harbor Perspectives in Medicine
Tracy A Manuck, M Sean Esplin, Joseph Biggio, Radek Bukowski, Samuel Parry, Heping Zhang, Hao Huang, Michael W Varner, William Andrews, George Saade, Yoel Sadovsky, Uma M Reddy, John Ilekis
OBJECTIVE: Spontaneous preterm birth (SPTB) is a complex condition that is likely a final common pathway with multiple possible causes. We hypothesized that a comprehensive classification system appropriately could group women with similar STPB causes and could provide an explanation, at least in part, for the disparities in SPTB that are associated with race and gestational age at delivery. STUDY DESIGN: This was a planned analysis of a multicenter, prospective study of singleton SPTBs...
April 2015: American Journal of Obstetrics and Gynecology
Tianjiao Chu, Jean-Francois Mouillet, Brian L Hood, Thomas P Conrads, Yoel Sadovsky
MOTIVATION: Inference of gene regulatory networks from high throughput measurement of gene and protein expression is particularly attractive because it allows the simultaneous discovery of interactive molecular signals for numerous genes and proteins at a relatively low cost. RESULTS: We developed two score-based local causal learning algorithms that utilized the Markov blanket search to identify direct regulators of target mRNAs and proteins. These two algorithms were specifically designed for integrated high throughput RNA and protein data...
June 1, 2015: Bioinformatics
Heping Zhang, Don A Baldwin, Radek K Bukowski, Samuel Parry, Yaji Xu, Chi Song, William W Andrews, George R Saade, M Sean Esplin, Yoel Sadovsky, Uma M Reddy, John Ilekis, Michael Varner, Joseph R Biggio
Preterm birth is the leading cause of infant morbidity and mortality. Despite extensive research, the genetic contributions to spontaneous preterm birth (SPTB) are not well understood. Term controls were matched with cases by race/ethnicity, maternal age, and parity prior to recruitment. Genotyping was performed using Affymetrix SNP Array 6.0 assays. Statistical analyses utilized PLINK to compare allele occurrence rates between case and control groups, and incorporated quality control and multiple-testing adjustments...
March 2015: Genetic Epidemiology
Craig E Rubens, Yoel Sadovsky, Louis Muglia, Michael G Gravett, Eve Lackritz, Courtney Gravett
Preterm birth is a leading cause of infant morbidity and mortality worldwide, but current interventions to prevent prematurity are largely ineffective. Preterm birth is increasingly recognized as an outcome that can result from a variety of pathological processes. Despite current research efforts, the mechanisms underlying these processes remain poorly understood and are influenced by a range of biological and environmental factors. Research with modern techniques is needed to understand the mechanisms responsible for preterm labor and birth and identify targets for diagnostic and therapeutic solutions...
November 12, 2014: Science Translational Medicine
Lan Xie, Jean-Francois Mouillet, Tianjiao Chu, W Tony Parks, Elena Sadovsky, Martin Knöfler, Yoel Sadovsky
Early in pregnancy, trophoblast invasion into the decidua and inner myometrium is essential for establishment of proper implantation, maternal-fetal exchange, and immunological tolerance of the feto-placental allograft. Unlike villous trophoblasts (VTs), extravillous trophoblasts (EVTs) are unique in their capacity to invade the maternal decidua and myometrium. The largest human microRNA (miRNA) gene cluster, the chromosome 19 miRNA cluster (C19MC), is expressed almost exclusively in the placenta and, rarely, in certain tumors and undifferentiated cells...
December 2014: Endocrinology
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