Jerome F Strauss

Virginia Commonwealth University, Ричмонд, Virginia, United States

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Publications (313)1570.43 Total impact

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    ABSTRACT: Cilia and flagella are specialized organelles. The axoneme genes, their encoded proteins, their functions and the structures they form are believed to be conserved across species. Much of our knowledge of the function and structure of axoneme proteins in cilia and flagella is derived from studies on model organisms like the green algae, Chlamydomonas reinhardtii. The core structure of cilia and flagella is the axoneme, which in most motile cilia and flagella contains a 9 + 2 configuration of microtubules. The two central microtubules are the scaffold of the central pair complex (CPC). Mutations that disrupt CPC genes in Chlamydomonas and other model organisms result in defects in assembly, stability and function of the axoneme, leading to flagellar motility defects. However, targeted mutations generated in mice in the orthologous CPC genes have revealed significant differences in phenotypes of mutants compared to Chlamydomonas. Here we review observations that support the concept of cell-type specific roles for the CPC genes in mice, and an expanded repertoire of functions for the products of these genes in cilia, including non-motile cilia, and other microtubule-associated cellular functions. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Cytoskeleton
  • William H Nugent · Nikita Mishra · Jerome F Strauss · Scott W Walsh
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    ABSTRACT: Matrix metalloproteinase 1 (MMP-1) is an activator of protease-activated receptor 1 (PAR-1), which is known to mediate the release of endothelin 1 (ET-1) in endothelial cells and activate the RhoA kinase (ROCK) pathway. Recently, we reported increased serum and vascular MMP-1 in women with preeclampsia and hypothesized that the action of MMP-1 on PAR-1 might have vasoconstrictive effects. Resistance-sized omental arteries obtained from normal pregnant women were mounted on a myograph system and perfused with MMP-1 in a dose range of 0.025 to 25 ng/mL or with angiotensin II (Ang II) in a dose range of 0.001 to 10 µmol/L in the presence of intraluminal MMP-1 (2.5 ng/mL) perfusion. Angiotensin II dose response was also performed with omental arteries from women with preeclampsia. Matrix metalloproteinase 1 caused dose-dependent vasoconstriction in endothelium-intact, but not in endothelium-denuded, vessels from normal pregnant women, which was blocked by inhibitors of PAR-1 and ET-1 type A receptor blocker. Intraluminal perfusion with a constant amount of MMP-1 enhanced vessel reactivity to Ang II, which was blocked by inhibitors of PAR-1, ROCK, and ET-1. Enhanced vascular reactivity to Ang II was observed in endothelium-intact, but not in endothelium-denuded, arteries of women with preeclampsia. Inhibitors of PAR-1, ROCK, and ET-1 blocked enhanced vascular reactivity to Ang II in endothelium-intact preeclamptic arteries. These data demonstrate that MMP-1 has potent vasoconstrictor effects and the ability to enhance vascular reactivity to vasoconstrictor hormones, which are mediated by an endothelial PAR-1, ROCK, and ET-1 pathway. Increased circulating levels of MMP-1 and its increased expression in systemic vessels of women with preeclampsia may contribute to the development of maternal hypertension.
    No preview · Article · Oct 2015 · Reproductive sciences (Thousand Oaks, Calif.)
  • Jan M. McAllister · Richard S. Legro · Bhavi P. Modi · Jerome F. Strauss
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    ABSTRACT: Polycystic ovary syndrome (PCOS) is a common disorder affecting 5% to 7% of women of reproductive age worldwide. The syndrome is characterized by increased ovarian androgen biosynthesis, anovulation, and infertility. Its etiology is poorly understood. Hyperandrogenemia (hyperandrogenism) is a hallmark of the disorder and has been included as an essential element in all “consensus” diagnosis schemes. There is strong evidence for a genetic component in PCOS from familial clustering and twin studies. Genome-wide association studies (GWASs) in Han Chinese women identified several PCOS candidate loci in or near the genes encoding receptors for LHCGR, FSHR, DENND1A, INSR, ZNF217, YAP1, RAB5B, THADA, and C9orf3. The association of several of these loci with PCOS was confirmed in studies conducted in European populations; these loci include FSHR, LHCGR, and DENND1A, as well as RAB5B and THADA. However, there is no convincing evidence at present that the variants identified in these genes are functionally significant and contribute to the PCOS phenotype. This review examined the functional roles of strong candidate PCOS loci identified in the GWASs and subsequently replicated in other populations, with primary focus on FHSR, LHCGR, INSR, and DENND1A. Previous studies have shown that ovarian theca cells are the primary source of high levels of androgens in women with PCOS and that a variant of DENND1A, called DENND1A.V2, may play a major role in PCOS. This variant of DENND1A is a new diagnostic and therapeutic target for PCOS. Forced overexpression of DENND1A.V2 in cultured theca cells from women without PCOS increases androgen production converting them to a PCOS phenotype, whereas blocking V2 expression in PCOS theca cells markedly reduces androgen secretion. The authors propose that these GWAS candidate genes comprise a hierarchical signaling network by which DENND1A, LHCGR, INSR, RAB5B, adapter proteins, and their associated downstream signaling cascades converge to regulate theca cell expression and androgen biosynthesis. These findings may lead to new diagnostic and therapeutic approaches for women with PCOS. DENND1A.V2 is present in the urine, and its increased urinary excretion could be a diagnostic biomarker for PCOS. Having such a molecular marker may identify a population of young girls who develop the disorder at adrenarche or pubarche and allow earlier intervention. Future studies should investigate the possibility that DENND1A.V2 is a biomarker for PCOS and examine its role in predicting response to common treatments for women with PCOS.
    No preview · Article · Sep 2015 · Obstetrical and Gynecological Survey
  • Timothy P York · Jerome F Strauss · Lindon J Eaves

    No preview · Article · Jun 2015 · Human Genetics
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    ABSTRACT: Height is the result of many growth and development processes. Most of the genes associated with height are known to play a role in skeletal development. Single-nucleotide poly-morphisms in the SPAG17 gene have been associated with human height. However, it is not clear how this gene influences linear growth. Here we show that a targeted mutation in Spag17 leads to skeletal malformations. Hind limb length in mutants was significantly
    Full-text · Article · May 2015 · PLoS ONE
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    ABSTRACT: RC/BTB2 is a binding partner of sperm associated antigen 16S (SPAG16S), which is regulator of spermiogenesis in mice, a process during which sperm flagella are formed. The expression of Rc/btb2 is also regulated by multicilin, a protein that controls ciliogenesis. Given that mouse Rc/btb2 mRNA is not only expressed in tissues bearing motile cilia, but also in tissues without motile cilia, we investigated whether RC/BTB2 plays a role in the general process of ciliogenesis by studying two somatic cells lines that have primary cilia, NIH3T3 and IMCD3. We discovered that the subcellular localization of RT/BTB2 in the NIH3T3 and IMCD3 cells encompasses the pathway for ciliogenesis. RC/BTB2 was found in the Golgi bodies and centrosomes, two key structures essential for normal ciliogenesis. Knockdown of Rc/btb2 gene expression in these cell lines disrupted ciliogenesis. The percentage of cells with primary cilia was significantly reduced in stable cell lines transduced with specific Rc/btb2 shRNA viruses compared to the control cells. When cilia were formed in the knockdown cells, they were significantly shorter than those in the control cells. Knockdown of Rc/btb2 expression did not affect cell proliferation and the cell cycle. Exogenous expression of RC/BTB2 in these stable knockdown cells restored ciliogenesis. These findings suggest that RC/BTB2 is a necessary component of the process of formation of primary cilia in somatic cells, perhaps through the transportation of cargos from Golgi bodies to centrosomes for cilia assembling. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Mar 2015 · Cytoskeleton
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    ABSTRACT: A key event in the process of spermiogenesis is the formation of the flagella, which enables sperm to reach eggs for fertilization. Yeast two-hybrid studies revealed that meiosis-expressed gene 1 (MEIG1) and Parkin co-regulated gene (PACRG) interact, and that sperm-associated antigen 16, which encodes an axoneme central apparatus protein, is also a binding partner of MEIG1. In spermatocytes of wild-type mice, MEIG1 is expressed in the whole germ cell bodies, but the protein migrates to the manchette, a unique structure at the base of elongating spermatid that directs formation of the flagella. In the elongating spermatids of wild-type mice, PACRG colocalizes with α-tubulin, a marker for the manchette, whereas this localization was not changed in the few remaining elongating spermatids of Meig1-deficient mice. In addition, MEIG1 no longer localizes to the manchette in the remaining elongating spermatids of Pacrg-deficient mice, indicating that PACRG recruits MEIG1 to the manchette. PACRG is not stable in mammalian cells, but can be stabilized by MEIG1 or by inhibition of proteasome function. SPAG16L is present in the spermatocyte cytoplasm of wild-type mice, and in the manchette of elongating spermatids, but in the Meig1 or Pacrg-deficient mice, SPAG16L no longer localizes to the manchette. By contrast, MEIG1 and PACRG are still present in the manchette of Spag16L-deficient mice, indicating that SPAG16L is a downstream partner of these two proteins. Together, our studies demonstrate that MEIG1/PACRG forms a complex in the manchette and that this complex is necessary to transport cargos, such as SPAG16L, to build the sperm flagella. © 2015. Published by The Company of Biologists Ltd.
    Full-text · Article · Mar 2015 · Development
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    ABSTRACT: Proper regulation of human leukocyte antigen-C (HLA-C) expression on trophoblast cells is essential for the immunological privilege of these cells. Endoplasmic reticulum aminopeptidase 2 (ERAP2) is known to trim antigenic peptide precursors for loading onto HLA. Altered expression of the ERAP2 could play a critical role in shaping HLA-C expression and antigen presentation, but their relationships have not been defined. We examined the genotype and expression levels of ERAP2 and HLA-C in several choriocarcinoma cell lines (BeWo, JAr, and JEG-3) by allelic discrimination qPCR, Western blotting and immunocytochemistry. Additionally, expression profiling of untreated versus gamma-interferon (IFN-γ, 20ng/ml)-treated cells was performed. Lastly, to determine if there is a relationship between ERAP2 and HLA-C expression levels, transfection of major and minor allele ERAP2 variants was performed. JAr cells were homozygous for the rs2248374 minor A allele, and express ERAP2 protein. BeWo and JEG-3 cells are homozygous for ERAP2 genetic variant (major G allele of SNP rs2248374) that causes non-sense mediated RNA decay, and thus lack ERAP2 protein expression. Interestingly, BeWo and JEG-3 cells express HLA-C, whereas, JAr cells do not. IFN-γ treatment of BeWo and JEG-3 cells increased HLA-C expression by 2-fold (p=0.0037) and 3-fold (p=0.0446) above control levels, respectively, but ERAP2 remained undetectable. In contrast, JAr cells treated with IFN-γ had increased ERAP2 protein expression by 2-fold (p=0.003), but had no effect on HLA-C expression. Transfection of JEG-3 cells (ERAP2 null) with ERAP2 plasmids with the SNP rs2549782, encoding an amino acid substitution (N392K) that alters substrate specificities and antigen presentation, revealed that the different ERAP2 isoforms do not affect the expression level of HLA-C. Our observations suggest that the expression patterns of ERAP2 and HLA-C allow choriocarcinoma cells to escape immune surveillance. E.D. Lee: None. S. Brockett: None. D. Hilliard: None. M.E. Teves: None. R. Ramus: None. J.F. Strauss: None. Copyright © 2014.
    No preview · Article · Jan 2015
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    ABSTRACT: Microbial invasion of the amniotic cavity is associated with spontaneous preterm labor and adverse pregnancy outcome and Mycoplasma hominis is often present. However, the pathogenic process by which M. hominis invades the amniotic cavity and gestational tissues, often resulting in chorioamnionitis and preterm birth, remains unknown. We hypothesized that strains of M. hominis vary genetically with regards to their potential to invade and colonize the amniotic cavity and placenta. We sequenced the entire genomes of two amniotic fluid isolates and a placental isolate of M. hominis from pregnancies that resulted in preterm births, and compared them to the previously sequenced genome of the Type strain PG21. We identified genes specific to the amniotic fluid/placental isolates. We then determined the microbial burden and the presence of these genes in another set of subjects, from whom samples of amniotic fluid had been collected and were positive for M. hominis. We identified two genes encoding surface-located membrane proteins (Lmp1 and Lmp-like) in the sequenced amniotic fluid/placental isolates that were severely truncated in PG21. We also identified, for the first time, a microbial gene of unknown function referred to in this study as gene of interest C (goiC), that was significantly associated with bacterial burden in amniotic fluid and the risk of preterm delivery in patients with preterm labor. A gene in M. hominis was identified that is significantly associated with colonization and/or infection of the upper reproductive tract during pregnancy and with preterm birth. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Jan 2015 · American Journal of Obstetrics and Gynecology
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    Xiaofei Li · Lei Xu · Jianfeng Li · Boqin Li · Xiaohui Bai · Jerome F Strauss · Zhibing Zhang · Haibo Wang
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    ABSTRACT: Mammalian SPAG6 protein is localized to the axoneme central apparatus, and it is required for normal flagella and cilia motility. Recent studies demonstrated that the protein also regulates ciliogenesis and cilia polarity in the epithelial cells of brain ventricles and trachea. Motile cilia are also present in the epithelial cells of the middle ear and Eustachian tubes, where the ciliary system participates in the movement of serous fluid and mucus in the middle ear. Cilia defects are associated with otitis media (OM), presumably due to an inability to efficiently transport fluid, mucus and particles including microorganisms. We investigated the potential role of SPAG6 in the middle ear and Eustachian tubes by studying mice with a targeted mutation in the Spag6 gene. SPAG6 is expressed in the ciliated cells of middle ear epithelial cells. The orientation of the ciliary basal feet was random in the middle ear epithelial cells of Spag6-deficient mice, and there was an associated disrupted localization of the planar cell polarity (PCP) protein, FZD6. These features are associated with disordered cilia orientation, confirmed by scanning electron microscopy, which leads to uncoordinated cilia beating. The Spag6 mutant mice were also prone to develop OM. However, there were no significant differences in bacterial populations, epithelial goblet cell density, mucin expression and Eustachian tube angle between the mutant and wild-type mice, suggesting that OM was due to accumulation of fluid and mucus secondary to the ciliary dysfunction. Our studies demonstrate a role for Spag6 in the pathogenesis of OM in mice, possibly through its role in the regulation of cilia/basal body polarity through the PCP-dependent mechanisms in the middle ear and Eustachian tubes.
    Preview · Article · Nov 2014 · PLoS ONE
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    ABSTRACT: Objective To investigate the association between cigarette use during pregnancy and pregnancy-induced hypertension/preeclampsia/eclampsia (PIH) by maternal race/ethnicity and age. Methods This retrospective cohort study was based on the U.S. 2010 natality data. Our study sample included U.S. women who delivered singleton pregnancies between 20 and 44 weeks of gestation without major fetal anomalies in 2010 (n = 3,113,164). Multivariate logistic regression models were fit to estimate crude and adjusted odds ratios and the corresponding 95% confidence intervals. Results We observed that the association between maternal smoking and PIH varied by maternal race/ethnicity and age. Compared with non-smokers, reduced odds of PIH among pregnant smokers was only evident for non-Hispanic white and non-Hispanic American Indian women aged less than 35 years. Non-Hispanic Asian/Pacific Islander women who smoked during pregnancy had increased odds of PIH regardless of maternal age. Non-Hispanic white and non-Hispanic black women 35 years or older who smoked during pregnancy also had increased odds of PIH. Conclusion Our study findings suggest important differences by maternal race/ethnicity and age in the association between cigarette use during pregnancy and PIH. More research is needed to establish the biologic and social mechanisms that might explain the variations with maternal age and race/ethnicity that were observed in our study.
    Full-text · Article · Oct 2014 · PLoS ONE
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    ABSTRACT: Humans are colonized by thousands of bacterial species, but it is difficult to assess the metabolic and pathogenic potential of the majority of these because they have yet to be cultured. Here, we characterize an uncultivated vaginal mycoplasma tightly associated with trichomoniasis that was previously known by its 16S rRNA sequence as "Mnola." In this study, the mycoplasma was found almost exclusively in women infected with the sexually transmitted pathogen Trichomonas vaginalis, but rarely observed in women with no diagnosed disease. The genomes of four strains of this species were reconstructed using metagenome sequencing and assembly of DNA from four discrete mid-vaginal samples, one of which was obtained from a pregnant woman with trichomoniasis who delivered prematurely. These bacteria harbor several putative virulence factors and display unique metabolic strategies. Genes encoding proteins with high similarity to potential virulence factors include two collagenases, a hemolysin, an O-sialoglycoprotein endopeptidase and a feoB-type ferrous iron transport system. We propose the name "Candidatus Mycoplasma girerdii" for this potential new pathogen.
    Full-text · Article · Oct 2014 · PLoS ONE
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    ABSTRACT: SPAG6, an axoneme central apparatus protein, is essential for function of ependymal cell cilia and sperm flagella. A significant number of Spag6-deficient mice die with hydrocephalus, and surviving males are sterile because of sperm motility defects. In further exploring the ciliary dysfunction in Spag6-null mice, we discovered that cilia beat frequency was significantly reduced in tracheal epithelial cells, and that the beat was not synchronized. There was also a significant reduction in cilia density in both brain ependymal and trachea epithelial cells, and cilia arrays were disorganized. The orientation of basal feet, which determines the direction of axoneme orientation, was apparently random in Spag6-deficient mice, and there were reduced numbers of basal feet, consistent with reduced cilia density. The polarized epithelial cell morphology and distribution of intracellular mucin, α-tubulin, and the planar cell polarity protein, Vangl2, were lost in Spag6-deficient tracheal epithelial cells. Polarized epithelial cell morphology and polarized distribution of α-tubulin in tracheal epithelial cells was observed in one-week old wild-type mice, but not in the Spag6-deficient mice of the same age. Thus, the cilia and polarity defects appear prior to 7 days post-partum. These findings suggest that SPAG6 not only regulates cilia/flagellar motility, but that in its absence, ciliogenesis, axoneme orientation, and tracheal epithelial cell polarity are altered.
    Full-text · Article · Oct 2014 · PLoS ONE

  • No preview · Article · Sep 2014 · Placenta
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    ABSTRACT: Women of European ancestry are more likely to harbour a Lactobacillus-dominated microbiome, whereas African American women are more likely to exhibit a diverse microbial profile. African American women are also twice as likely to be diagnosed with bacterial vaginosis and are twice as likely to experience preterm birth. The objective of this study was to further characterize and contrast the vaginal microbial profiles in African American versus European ancestry women. Through the Vaginal Human Microbiome Project at Virginia Commonwealth University, 16S rRNA gene sequence analysis was used to compare the microbiomes of vaginal samples from 1268 African American women and 416 women of European ancestry. The results confirmed significant differences in the vaginal microbiomes of the two groups and identified several taxa relevant to these differences. Major community types were dominated by Gardnerella vaginalis and the uncultivated bacterial vaginosis-associated bacterium-1 (BVAB1) that were common among African Americans. Moreover, the prevalence of multiple bacterial taxa that are associated with microbial invasion of the amniotic cavity and preterm birth, including Mycoplasma, Gardnerella, Prevotella and Sneathia, differed between the two ethnic groups. We investigated the contributions of intrinsic and extrinsic factors, including pregnancy, body mass index, diet, smoking and alcohol use, number of sexual partners, and household income, to vaginal community composition. Ethnicity, pregnancy and alcohol use correlated significantly with the relative abundance of bacterial vaginosis-associated species. Trends between microbial profiles and smoking and number of sexual partners were observed; however, these associations were not statistically significant. These results support and extend previous findings that there are significant differences in the vaginal microbiome related to ethnicity and demonstrate that these differences are pronounced even in healthy women.
    No preview · Article · Jul 2014 · Microbiology
  • Jerome F. Strauss · Bhavi Modi · Jan M. McAllister
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    ABSTRACT: The ovary secretes steroid hormones that initiate female sexual development, program the secretion of gonadotropins from the hypothalamic-pituitary axis, and regulate the function of the female reproductive tract. The synthesis of bioactive steroid hormones involves a compartmentalized process within steroidogenic cells in which cholesterol is moved through organelles that modify the sterol backbone and side-chain. Collaborative interactions among steroidogenic cell types, particularly theca and granulosa cells and their luteinized forms, govern the secretion of ovarian androgens, progestins and estrogens. Rare mutations in the genes encoding gonadotropin receptors and steroidogenic enzymes impair steroid hormone production and result in disordered gonadotropin secretion and, consequently, defects in follicular growth and development and ovulation. Polycystic ovary syndrome, a common endocrine disease of women in reproductive age, is associated with abnormal expression of steroidogenic enzymes, also leading to abnormal follicular maturation. This chapter reviews the mutations and genetic variants that alter human ovarian steroidogenesis and the resulting phenotypes.
    No preview · Article · May 2014
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    ABSTRACT: Polycystic ovary syndrome (PCOS), characterized by increased ovarian androgen biosynthesis, anovulation, and infertility, affects 5-7% of reproductive-age women. Genome-wide association studies identified PCOS candidate loci that were replicated in subsequent reports, including DENND1A, which encodes a protein associated with clathrin-coated pits where cell-surface receptors reside. However, these studies provided no information about functional roles for DENND1A in the pathogenesis of PCOS. DENND1A protein was located in the cytoplasm as well as nuclei of theca cells, suggesting a possible role in gene regulation. DENND1A immunostaining was more intense in the theca of PCOS ovaries. Using theca cells isolated and propagated from normal cycling and PCOS women, we found that DENND1A variant 2 (DENND1A.V2) protein and mRNA levels are increased in PCOS theca cells. Exosomal DENND1A.V2 RNA was significantly elevated in urine from PCOS women compared with normal cycling women. Forced overexpression of DENND1A.V2 in normal theca cells resulted in a PCOS phenotype of augmented CYP17A1 and CYP11A1 gene transcription, mRNA abundance, and androgen biosynthesis. Knock-down of DENND1A.V2 in PCOS theca cells reduced androgen biosynthesis and CYP17A1 and CYP11A1 gene transcription. An IgG specific to DENND1A.V2 also reduced androgen biosynthesis and CYP17 and CYP11A1 mRNA when added to the medium of cultured PCOS theca cells. We conclude that the PCOS candidate gene, DENND1A, plays a key role in the hyperandrogenemia associated with PCOS. These observations have both diagnostic and therapeutic implications for this common disorder.
    Full-text · Article · Mar 2014 · Proceedings of the National Academy of Sciences
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    ABSTRACT: In this Journal in 1972, 100 leaders in obstetrics and gynecology published a compelling statement that recognized the legalization of abortion in several states and anticipated the 1973 Supreme Court decision in Roe v Wade. They projected the numbers of legal abortions that likely would be required by women in the United States and described the role of the teaching hospital in meeting that responsibility. They wrote to express their concern for women's health in a new legal and medical era of reproductive control and to define the responsibilities of academic obstetrician-gynecologists. Forty years later, 100 professors examine the statement of their predecessors in light of medical advances and legal changes and suggest a further course of action for obstetrician gynecologists.
    Full-text · Article · Oct 2013 · Contraception
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    ABSTRACT: To quantitate 2-methoxyestradiol (2-ME) in human corpus luteum (CL) of different ages and to determine the expression of cytochrome-P450-1A1 (CYP1A1) and catechol-O-methyl transferase (COMT) in CL and the action of 2-ME on P, vascular endothelial growth factor (VEGF) secretion, and luteal angiogenesis. Experimental study. University division of reproductive endocrinology. Twenty-four women of reproductive age. CL was collected from 15 women during the minilaparotomy for tubal sterilization. Granulosa lutein cells were harvested 36 hours after hCG administration in patients undergoing IVF. Levels of 2-ME were determined by high-performance liquid chromatography in CL. CYP1A1 and COMT were assessed by immunohistochemistry and Western blot. P and VEGF were measured by radioimmunoassay and ELISA. The angiogenic potential was analyzed using EA.hy926 cells. Plasma levels of E2 decreased in the late luteal phase in association with an increase in luteal tissue of 2-ME concentrations. Concomitantly, there was a significant reduction of angiogenic activity in late CL. There was no significant variation in CYP1A1 and COMT expression in all CL. In physiological doses, 2-ME inhibited basal VEGF by granulosa lutein cells and diminished the angiogenic activity in conditioned media but did not prevent P and VEGF production stimulated by hCG. These data suggest the participation of 2-ME in physiological luteolysis by reducing angiogenesis. However, 2-ME did not prevent in vitro hCG stimulation of P biosynthesis, providing a mechanism for CL rescue in the cycle of conception.
    No preview · Article · Aug 2013 · Fertility and sterility
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    ABSTRACT: Single nucleotide polymorphisms (SNPs) in the endoplasmic reticulum aminopeptidase 2 (ERAP2) gene are associated with preeclampsia (PE) in different populations. rs2549782, a coding variant (N392K) that significantly affects substrate specificity, is in linkage disequilibrium (LD) with rs2248374, a marker SNP associated with ERAP2 protein expression in previously studied populations. As a result of non-sense mediated RNA decay, ERAP2 protein is not expressed from the rs2248374 G allele. We previously reported that the fetal rs2549782 minor G allele is associated with PE in African-Americans, but not Chileans. In this study, we found that rs2549782 was in LD with rs2248374 in African-Americans, but not in Chileans. The unexpected lack of strong LD in Chileans raised the possibility that rs2248374 could be associated with PE in the absence of an association with rs2549782. However, we found no significant association for this allele with PE in Chileans. Chileans homozygous for the rs2248374 G allele did not express 110 kDa ERAP2 protein, consistent with non-sense mediated RNA decay, and carriers of the rs2248374 A allele did. We conclude that the Chilean ERAP2 haplotype structure allows for the expression of the major T allele of rs2549782 encoding 392N, which could impact peptide trimming and antigen presentation. Our discovery of racial differences in genetic structure and association with PE reveal here-to-fore unrecognized complexity of the ERAP2 locus.
    Full-text · Article · Jul 2013

Publication Stats

15k Citations
1,570.43 Total Impact Points


  • 2006-2015
    • Virginia Commonwealth University
      • • Department of Obstetrics and Gynecology
      • • Department of Biochemistry and Molecular Biology
      • • School of Medicine
      Ричмонд, Virginia, United States
  • 2007
    • University of Arkansas at Little Rock
      Little Rock, Arkansas, United States
    • University of Santiago, Chile
      CiudadSantiago, Santiago Metropolitan, Chile
    • University of Nebraska at Lincoln
      • Department of Animal Science
      Lincoln, Nebraska, United States
  • 1982-2007
    • University of Pennsylvania
      • • Department of Medicine
      • • Center for Research on Reproduction and Women's Health
      • • Department of Obstetrics and Gynecology
      • • Division of Cardiothoracic Surgery
      Philadelphia, Pennsylvania, United States
  • 1983-2006
    • Hospital of the University of Pennsylvania
      • • Department of Obstetrics and Gynecology
      • • Department of Pathology and Laboratory Medicine
      Philadelphia, Pennsylvania, United States
    • Temple University
      Filadelfia, Pennsylvania, United States
    • Kimron Veterinary Institute
      Beit Dajan, Central District, Israel
  • 2005
    • University of Texas at Dallas
      Richardson, Texas, United States
  • 1999-2005
    • Penn State Hershey Medical Center and Penn State College of Medicine
      • Cellular and Molecular Physiology
      Hershey, Pennsylvania, United States
    • Harvard University
      Cambridge, Massachusetts, United States
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 1994-2005
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 2004
    • Albert Einstein College of Medicine
      New York, New York, United States
  • 2002
    • National Institutes of Health
      • Chemical Biology Laboratory
      Bethesda, MD, United States
  • 2001
    • University of Chile
      • Departamento de Obstetricia y Ginecología
      CiudadSantiago, Santiago, Chile
    • University of Nebraska at Omaha
      Omaha, Nebraska, United States
  • 1987-1999
    • University of California, San Francisco
      • Department of Pediatrics
      San Francisco, California, United States
  • 1997
    • Universidad Nacional Autónoma de México
      • Department of Biochemistry
      Ciudad de México, Mexico City, Mexico
  • 1996
    • Instituto Nacional de Perinatología
      Ciudad de México, The Federal District, Mexico
  • 1991
    • Weizmann Institute of Science
      Rhovot, Central District, Israel
    • University of Texas at San Antonio
      San Antonio, Texas, United States