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Genómica funcional y disección molecular de FOXD1 para la identificación de nuevos biomarcadores genéticos asociados a patologías de la reproducción de origen endometrial y placentario

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dc.contributor.advisorLaissue, Paul
dc.creatorQuintero Ronderos, Paula Juliana
dc.creator.degreeDoctor en Ciencias Biomédicasspa
dc.creator.degreetypeFull timespa
dc.date.accessioned2019-01-28T13:20:53Z
dc.date.available2019-01-28T13:20:53Z
dc.date.created2018-12-03
dc.date.issued2018
dc.descriptionEl aborto espontáneo recurrente (AER) se define como dos o más pérdidas consecutivas de la gestación antes de la semana 20 del desarrollo intrauterino. Esta patología afecta a aproximadamente entre el 1% y el 5% de las parejas. La etiología del AER se puede dividir en causas no-genéticas como genéticas. Sin embargo, ~50% de los casos se considera idiopático. De manera análoga, la etiología molecular de la falla de implantación recurrente (FIR), definida como la falla de la implantación en al menos 2 o más ciclos consecutivos de fertilización in vitro, es poco conocida. La etiología molecular del AER y de la FIR está asociada potencialmente a variantes de secuencia en cientos de genes candidato que participan en las cascadas moleculares fisiológicas de la implantación y durante toda la gestación. La aproximación gen candidato, usando la secuenciación de Sanger, ha sido de utilidad para la descripción de pocos genes implicados en el AER. La secuenciación de siguiente generación (NGS) ha sido una herramienta eficiente puesto que permite el estudio simultáneo de múltiples genes relacionados con enfermedades complejas. En la primera parte de este trabajo de tesis se utilizó la aproximación NGS-exoma para identificar nuevos genes y mutaciones potencialmente implicadas en el desarrollo del AER. Algunas de las mutaciones encontradas por este abordaje fueron estudiadas mediante ensayos funcionales in vitro para determinar su posible efecto deletéreo. La identificación de la variante THBD p.Trp153Gly en mujeres colombianas con AER y su validación mediante ensayos funcionales in vitro sugiere, por primera vez, una relación directa entre formas mutantes de esta proteína y la fisiopatología del AER, considerándose como un posible marcador molecular para el diagnóstico en pacientes colombianas con AER idiopático. En la segunda parte del presente trabajo de tesis identificamos y estudiamos funcionalmente nuevas mutaciones de FOXD1, un gen relevante en la fisiología endometrial y placentaria, identificadas en pacientes FIR, AER, preeclampsia (PE) y retardo del crecimiento intrauterino (RCIU). Los ensayos funcionales in vitro demostraron que las mutaciones FOXD1-p.His267Tyr y FOXD1-p.Arg57del. modifican la transactivación del promotor de C3, contribuyendo con el fenotipo. FOXD1 podría considerarse en consecuencia un marcador molecular diagnóstico para las pacientes con AER, FIR, RCIU y PE. Por último, ensayos por inmunoprecipitación de la cromatina secuenciación NGS (ChIP-seq) permitieron determinar potenciales nuevos genes blanco directos de FOXD1 (CTSC, CD86, CMA1 y TRPC6) en un contexto placentario. La información generada durante este trabajo de tesis aporta al conocimiento sobre el origen genético del AER, la FIR, y el RCIU/PE. Estos resultados podrían ser de utilidad para los especialistas clínicos en el contexto del desarrollo de la medicina traslacional.spa
dc.description.abstractRecurrent pregnancy loss (RPL) is defined as the loss of two or more consecutive and spontaneous miscarriages before the 20th week of gestation. This pathology affects ~1% to 5% of the couples. The RPL aetiology is classified as non-genetics and genetics. However, the 50% of the cases remains idiopathic. Similarly, the aetiology of the recurrent implantation failure (RIF), defined as the implantation failure in at least 2 or more consecutive cycles of in vitro fertilization (IVF), is poorly understood. To note, the molecular RPL and RIF aetiology is potentially associated with hundreds of genes which participate in the physiological molecular pathways related to the implantation and gestation. The candidate gene approach using Sanger sequencing has been useful to identify some genes associated with RPL. However, the next generation sequencing (NGS) has been an effective tool to overcome this limitation because it allows the simultaneous study of multiple genes related to complex diseases. In first part of this thesis, we used the NGS-exome approach to identify new genes and mutation potentially implicated in the development of RPL. Some of the mutations found by this approach were tested by functional in vitro assays to determine their possible deleterious effect within the pathology. The identification of the variant THBD p.Trp153Gly in Colombian women with RPL and its validation through functional in vitro assays suggested, for the first time, a direct association with the RPL pathophysiology. Therefore, it may be considered as a molecular biomarker for the RPL diagnosis in Colombian patients. In the second part of this thesis, we identified and studied the potential implication of new FOXD1 mutations, a relevant gene in the endometrium and placenta physiology, in patients with RIF, RPL, preeclampsia (PE) and intrauterine growth restriction (IUGR). The functional in vitro assays demonstrated that FOXD1 p.His267Tyr and FOXD1 p.Arg57del mutations modify the C3 promoter transactivation, thus contributing to the phenotype. Therefore, FOXD1 could be considered a molecular biomarker for the diagnosis of RPL, RIF, PE and IUGR patients. The chromatin immunoprecipitation assays (ChIP) allowed to determine new direct FOXD1 target genes (CTSC, CD86, CMA1 y TRPC6) within the placenta context. The information generated during this thesis contributes to the general knowledge about the origin and development of RPL, RIF, PE/IUGR. These results might be useful for the clinical specialist in a context of translational medicine.spa
dc.description.embargo2021-01-29 01:01:01: Script de automatizacion de embargos. info:eu-repo/date/embargoEnd/2021-01-28spa
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dc.identifier.doihttps://doi.org/10.48713/10336_18933
dc.identifier.urihttp://repository.urosario.edu.co/handle/10336/18933
dc.language.isospa
dc.publisherUniversidad del Rosariospa
dc.publisher.departmentFacultad de Ciencias Naturales y Matemáticasspa
dc.publisher.programDoctorado en Ciencias Biomédicasspa
dc.rightsAtribución-NoComercial-SinDerivadas 2.5 Colombiaspa
dc.rights.accesRightsinfo:eu-repo/semantics/openAccess
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dc.source.bibliographicCitationLi, T. C. et al. Recurrent miscarriage: aetiology, management and prognosis. Hum. Reprod. Update 8, 463–81 (2002).spa
dc.source.bibliographicCitationRai, R. & Regan, L. Recurrent miscarriage. Lancet 368, 601–611 (2006).spa
dc.source.bibliographicCitationStirrat, G. M. Recurrent miscarriage. Lancet 336, 673–675 (1990).spa
dc.source.bibliographicCitationHogge, W. A., Byrnes, A. L., Lanasa, M. C. & Surti, U. The clinical use of karyotyping spontaneous abortions. Am. J. Obstet. Gynecol. 189, 397-400; discussion 400–2 (2003).spa
dc.source.bibliographicCitationBricker Leanne & Farquharson Roy G. Recurring miscarriage. Obstet. Gynaecol. 2, 17–23 (2000).spa
dc.source.bibliographicCitationRai, R. S., Clifford, K., Cohen, H. & Regan, L. High prospective fetal loss rate in untreated pregnancies of women with recurrent miscarriage and antiphospholipid antibodies. Hum. Reprod. 10, 3301–3304 (1995).spa
dc.source.bibliographicCitationSantos, T. da S. et al. Antiphospholipid syndrome and recurrent miscarriage: A systematic review and meta-analysis. J. Reprod. Immunol. 123, 78–87 (2017).spa
dc.source.bibliographicCitationMak, I. Y. H. et al. Regulated expression of signal transducer and activator of transcription, Stat5, and its enhancement of PRL expression in human endometrial stromal cells in vitro. J. Clin. Endocrinol. Metab. 87, 2581–2588 (2002).spa
dc.source.bibliographicCitationBose, P. et al. Heparin and aspirin attenuate placental apoptosis in vitro: Implications for early pregnancy failure. Am. J. Obstet. Gynecol. 192, 23–30 (2005).spa
dc.source.bibliographicCitationSalim, R., Regan, L., Woelfer, B., Backos, M. & Jurkovic, D. A comparative study of the morphology of congenital uterine anomalies in women with and without a history of recurrent first trimester miscarriage. Hum. Reprod. (2003). doi:10.1093/humrep/deg030spa
dc.source.bibliographicCitationGrimbizis, G. F., Camus, M., Tarlatzis, B. C., Bontis, J. N. & Devroey, P. Clinical implications of uterine malformations and hysteroscopic treatment results. Human Reproduction Update 7, 161–174 (2001).spa
dc.source.bibliographicCitationHart, R. et al. A prospective controlled study of the effect of intramural uterine fibroids on the outcome of assisted conception. Human reproduction (Oxford, England) 16, (2001).spa
dc.source.bibliographicCitationRackow, B. W. & Taylor, H. S. Submucosal uterine leiomyomas have a global effect on molecular determinants of endometrial receptivity. Fertil. Steril. 93, 2027–2034 (2010).spa
dc.source.bibliographicCitationHirahara, F. et al. Hyperprolactinemic recurrent miscarriage and results of randomized bromocriptine treatment trials. Fertil. Steril. 70, 246–252 (1998).spa
dc.source.bibliographicCitationGarzia, E. et al. Lack of expression of endometrial prolactin in early implantation failure: A pilot study. Hum. Reprod. 19, 1911–1916 (2004).spa
dc.source.bibliographicCitationCraig, L. B., Ke, R. W. & Kutteh, W. H. Increased prevalence of insulin resistance in women with a history of recurrent pregnancy loss. Fertil. Steril. 78, 487–490 (2002).spa
dc.source.bibliographicCitationRai, R., Backos, M., Rushworth, F. & Regan, L. Polycystic ovaries and recurrent miscarriage--a reappraisal. Hum. Reprod. 15, 612–615 (2000).spa
dc.source.bibliographicCitationKaur, R. & Gupta, K. Endocrine dysfunction and recurrent spontaneous abortion: An overview. Int. J. Appl. Basic Med. Res. 6, 79 (2016).spa
dc.source.bibliographicCitationClifford, K., Flanagan, A. M. & Regan, L. Endometrial CD56+ natural killer cells in women with recurrent miscarriage: a histomorphometric study. Hum. Reprod. 14, 2727–2730 (1999).spa
dc.source.bibliographicCitationReinhard, G., Noll, A., Schlebusch, H., Mallmann, P. & Ruecker, A. Shifts in the TH1/TH2 balance during human pregnancy correlate with apoptotic changes. Biochem. Biophys. Res. Commun. 245, 933–938 (1998).spa
dc.source.bibliographicCitationBeaman, K. D. et al. Immune Etiology of Recurrent Pregnancy Loss and Its Diagnosis. Am. J. Reprod. Immunol. 67, 319–325 (2012).spa
dc.source.bibliographicCitationRalph, S. G., Rutherford, A. J. & Wilson, J. D. Influence of bacterial vaginosis on conception and miscarriage in the first trimester: cohort study. BMJ 319, 220–223 (1999).spa
dc.source.bibliographicCitationHay, P. E. et al. Abnormal bacterial colonisation of the genital tract and subsequent preterm delivery and late miscarriage. BMJ 308, 295–298 (1994).spa
dc.source.bibliographicCitationIsik, G., Demirezen, Ş., Dönmez, H. & Beksaç, M. Bacterial vaginosis in association with spontaneous abortion and recurrent pregnancy losses. J. Cytol. 33, 135 (2016).spa
dc.source.bibliographicCitationGiakoumelou, S. et al. The role of infection in miscarriage. Hum. Reprod. Update 22, 116–133 (2016).spa
dc.source.bibliographicCitationJia, C.-W. et al. Aneuploidy in Early Miscarriage and its Related Factors. Chin. Med. J. (Engl). 128, 2772 (2015).spa
dc.source.bibliographicCitationHyde, K. J. & Schust, D. J. Genetic Considerations in Recurrent Pregnancy Loss. Cold Spring Harb. Perspect. Med. 5, a023119–a023119 (2015).spa
dc.source.bibliographicCitationSierra S & Stephenson M. Genetics of recurrent pregnancy loss. Semin Reprod Med. 24, 17–24. (2006).spa
dc.source.bibliographicCitationStephenson, M. D., Awartani, K. A. & Robinson, W. P. Cytogenetic analysis of miscarriages from couples with recurrent miscarriage: a case-control study. Hum. Reprod. (2002). doi:10.1016/S0015-0282(01)02285-3spa
dc.source.bibliographicCitationHassold, T. & Hunt, P. To err (meiotically) is human: the genesis of human aneuploidy. Nat. Rev. Genet. 2, 280–291 (2001).spa
dc.source.bibliographicCitationRubio, C. et al. Chromosomal abnormalities and embryo development in recurrent miscarriage couples. Hum. Reprod. (2003). doi:10.1093/humrep/deg015spa
dc.source.bibliographicCitationChoi, T. Y., Lee, H. M., Park, W. K., Jeong, S. Y. & Moon, H. S. Spontaneous abortion and recurrent miscarriage: A comparison of cytogenetic diagnosis in 250 cases. Obstet. Gynecol. Sci. 57, 518 (2014).spa
dc.source.bibliographicCitationCoelho, F. F. et al. Detection of aneuploidies in spontaneous abortions by quantitative fluorescent PCR with short tandem repeat markers: a retrospective study. Genet. Mol. Res. 15, (2016).spa
dc.source.bibliographicCitationESHRE Capri Workshop Group. Genetic aspects of female reproduction. Hum. Reprod. Update 14, 293–307. (2008).spa
dc.source.bibliographicCitationMenasha, J., Levy, B., Hirschhorn, K. & Kardon, N. B. Incidence and spectrum of chromosome abnormalities in spontaneous abortions: New insights from a 12-year study. Genet. Med. 7, 251–263 (2005).spa
dc.source.bibliographicCitationUehara, S. et al. Preferential X-chromosome inactivation in women with idiopathic recurrent pregnancy loss. in Fertility and Sterility 76, 908–914 (2001).spa
dc.source.bibliographicCitationSangha, K. K., Stephenson, M. D., Brown, C. J. & Robinson, W. P. Extremely skewed X-chromosome inactivation is increased in women with recurrent spontaneous abortion. American journal of human genetics 65, 913–917 (1999).spa
dc.source.bibliographicCitationAldrich, C. L. et al. HLA-G genotypes and pregnancy outcome in couples with unexplained recurrent miscarriage. Molecular human reproduction 7, (2001).spa
dc.source.bibliographicCitationPfeiffer, K. A., Fimmers, R., Engels, G., van der Ven, H. & van der Ven, K. The HLA-G genotype is potentially associated with idiopathic recurrent spontaneous abortion. Mol. Hum. Reprod. 7, 373–8 (2001).spa
dc.source.bibliographicCitationKovalevsky, G., Gracia, C. R., Berlin, J. A., Sammel, M. D. & Barnhart, K. T. Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss: a meta-analysis. Arch. Intern. Med. 164, 558–563 (2004).spa
dc.source.bibliographicCitationRey, E., Kahn, S. R., David, M. & Shrier, I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet (London, England) 361, 901–8 (2003).spa
dc.source.bibliographicCitationRai, R., Backos, M., Elgaddal, S., Shlebak, A. & Regan, L. Factor V Leiden and recurrent miscarriage-prospective outcome of untreated pregnancies. Hum. Reprod. 17, 442–445 (2002).spa
dc.source.bibliographicCitationLaissue, P. et al. Association of FOXD1 variants with adverse pregnancy outcomes in mice and humans. Open Biol. 6, 160109 (2016).spa
dc.source.bibliographicCitationPolanski, L. T. et al. What exactly do we mean by ‘recurrent implantation failure’? A systematic review and opinion. Reprod. Biomed. Online 28, 409–423 (2014).spa
dc.source.bibliographicCitationCroucher, C. A., Lass, A., Margara, R. & Winston, R. M. Predictive value of the results of a first in-vitro fertilization cycle on the outcome of subsequent cycles. Hum. Reprod. 13, 403–8 (1998).spa
dc.source.bibliographicCitationYang, R. et al. Biochemical pregnancy and spontaneous abortion in first IVF cycles are negative predictors for subsequent cycles: an over 10,000 cases cohort study. Arch. Gynecol. Obstet. 292, 453–458 (2015).spa
dc.source.bibliographicCitationSimon, A. & Laufer, N. Assessment and treatment of repeated implantation failure (RIF). J. Assist. Reprod. Genet. 29, 1227–1239 (2012).spa
dc.source.bibliographicCitationRinehart, J. Recurrent implantation failure: Definition. J. Assist. Reprod. Genet. 24, 284–287 (2007).spa
dc.source.bibliographicCitationTimeva, T., Shterev, A. & Kyurkchiev, S. Recurrent implantation failure: The role of the endometrium. J. Reprod. Infertil. 15, 173–183 (2014).spa
dc.source.bibliographicCitationSimon, A. & Laufer, N. Repeated implantation failure: Clinical approach. Fertil. Steril. 97, 1039–1043 (2012).spa
dc.source.bibliographicCitationEl-Toukhy, T. & Taranissi, M. Towards better quality research in recurrent implantation failure: standardizing its definition is the first step. Reprod. Biomed. Online 12, 383–5 (2006).spa
dc.source.bibliographicCitationLevi Setti, P. E. et al. Implantation failure in assisted reproduction technology and a critical approach to treatment. Ann. N. Y. Acad. Sci. 1034, 184–199 (2004).spa
dc.source.bibliographicCitationOcal, P. et al. Recurrent implantation failure is more frequently seen in female patients with poor prognosis. Int. J. Fertil. Steril. 6, 71–8 (2012).spa
dc.source.bibliographicCitationRegan, L., Braude, P. R. & Trembath, P. L. Influence of past reproductive performance on risk of spontaneous abortion. BMJ 299, 541–545 (1989).spa
dc.source.bibliographicCitationKnudsen, U. B., Hansen, V., Juul, S. & Secher, N. J. Prognosis of a new pregnancy following previous spontaneous abortions. Eur. J. Obstet. Gynecol. Reprod. Biol. 39, 31–36 (1991).spa
dc.source.bibliographicCitationStrobino, B. et al. Characteristics of women with recurrent spontaneous abortions and women with favorable reproductive histories. Am. J. Public Health 76, 986–91 (1986).spa
dc.source.bibliographicCitationKolte, A. M. M. et al. A genome-wide scan in affected sibling pairs with idiopathic recurrent miscarriage suggests genetic linkage. MHR Basic Sci. Reprod. Med. 17, 379–385 (2011).spa
dc.source.bibliographicCitationShekouhi, S. et al. Identification of Xq22.1-23 as a region linked with hereditary recurrent spontaneous abortion in a family. Iran. J. Reprod. Med. 11, 659–64 (2013).spa
dc.source.bibliographicCitationLi Wang, Zeng Chan Wang, Cui Xie, Xiao Feng Liu & Mao Sheng Yang. Genome-Wide Screening for Risk Loci of Idiopathic Recurrent Miscarriage in a Han Chinese Population: A Pilot Study. Reprod. Sci. 17, 578–584 (2010).spa
dc.source.bibliographicCitationKaare, M. et al. Variations in the thrombomodulin and endothelial protein C receptor genes in couples with recurrent miscarriage. Hum. Reprod. 22, 864–8 (2007).spa
dc.source.bibliographicCitationMercier, E., Lissalde-Lavigne, G. & Gris, J.-C. JAK2 V617F Mutation in Unexplained Loss of First Pregnancy. N. Engl. J. Med. 357, 1984–1985 (2007).spa
dc.source.bibliographicCitationKaare, M., Painter, J. N., Ulander, V. M., Kaaja, R. & Aittomäki, K. Variations of the amnionless gene in recurrent spontaneous abortions. Mol. Hum. Reprod. 12, 25–29 (2006).spa
dc.source.bibliographicCitationNeveling, K. et al. A Post-Hoc Comparison of the Utility of Sanger Sequencing and Exome Sequencing for the Diagnosis of Heterogeneous Diseases. Hum. Mutat. 34, 1721–1726 (2013).spa
dc.source.bibliographicCitationBaudhuin, L. M. et al. Confirming Variants in Next-Generation Sequencing Panel Testing by Sanger Sequencing. J. Mol. Diagnostics 17, 456–461 (2015).spa
dc.source.bibliographicCitationLaissue, P. Aetiological coding sequence variants in non-syndromic premature ovarian failure: From genetic linkage analysis to next generation sequencing. Mol. Cell. Endocrinol. 411, 243–257 (2015).spa
dc.source.bibliographicCitationLee, K. Y. & DeMayo, F. J. Animal models of implantation. Reproduction 128, 679–695 (2004).spa
dc.source.bibliographicCitationWilcox, A. J., Baird, D. D. & Weinberg, C. R. Time of Implantation of the Conceptus and Loss of Pregnancy. N. Engl. J. Med. 340, 1796–1799 (1999).spa
dc.source.bibliographicCitationWimsatt, W. A. Some comparative aspects of implantation. Biol. Reprod. 12, 1–40 (1975).spa
dc.source.bibliographicCitationAghajanova, L. et al. Comparative Transcriptome Analysis of Human Trophectoderm and Embryonic Stem Cell-Derived Trophoblasts Reveal Key Participants in Early Implantation. Biol. Reprod. 86, 1–21 (2012).spa
dc.source.bibliographicCitationCha, J., Sun, X. & Dey, S. K. Mechanisms of implantation: strategies for successful pregnancy. Nat. Med. 18, 1754–1767 (2012).spa
dc.source.bibliographicCitationKing, A. Uterine leukocytes and decidualization. Hum. Reprod. Update 6, 28–36 (2000).spa
dc.source.bibliographicCitationChristian, M. et al. Interferon-gamma modulates prolactin and tissue factor expression in differentiating human endometrial stromal cells. Endocrinology 142, 3142–51 (2001).spa
dc.source.bibliographicCitationIrwin, J. C. & Giudice, L. C. Insulin-like growth factor binding protein-1 binds to placental cytotrophoblast alpha5beta1 integrin and inhibits cytotrophoblast invasion into decidualized endometrial stromal cultures. Growth Horm. IGF Res. 8, 21–31 (1998).spa
dc.source.bibliographicCitationKusama, K., Yoshie, M., Tamura, K., Imakawa, K. & Tachikawa, E. EPAC2-mediated calreticulin regulates LIF and COX2 expression in human endometrial glandular cells. J. Mol. Endocrinol. 54, 17–24 (2014).spa
dc.source.bibliographicCitationLi, Q. et al. WNT4 Acts Downstream of BMP2 and Functions via β-Catenin Signaling Pathway to Regulate Human Endometrial Stromal Cell Differentiation. Endocrinology 154, 446–457 (2013).spa
dc.source.bibliographicCitationAghajanova, L. Leukemia inhibitory factor and human embryo implantation. Ann N Y Acad Sci 1034, 176–183 (2004).spa
dc.source.bibliographicCitationKojima, K. et al. Expression of leukaemia inhibitory factor (LIF) receptor in human placenta: a possible role for LIF in the growth and differentiation of trophoblasts. Hum. Reprod. 10, 1907–11 (1995).spa
dc.source.bibliographicCitationCarson, D. D. et al. Changes in gene expression during the early to mid-luteal (receptive phase) transition in human endometrium detected by high-density microarray screening. Mol. Hum. Reprod. 8, 871–879 (2002).spa
dc.source.bibliographicCitationKao, L. C. et al. Global gene profiling in human endometrium during the window of implantation. Endocrinology 143, 2119–2138 (2002).spa
dc.source.bibliographicCitationPopovici, R. M., Kao, L. C. & Giudice, L. C. Discovery of new inducible genes in in vitro decidualized human endometrial stromal cells using microarray technology. Endocrinology 141, 3510–3513 (2000).spa
dc.source.bibliographicCitationUegaki, K. et al. PTEN is involved in the signal transduction pathway of contact inhibition in endometrial cells. Cell Tissue Res. 323, 523–528 (2006).spa
dc.source.bibliographicCitationEjskjaer, K. et al. Expression of the epidermal growth factor system in human endometrium during the menstrual cycle. Mol. Hum. Reprod. 11, 543–551 (2005).spa
dc.source.bibliographicCitationKats, R., Al-Akoum, M., Guay, S., Metz, C. & Akoum, A. Cycle-dependent expression of macrophage migration inhibitory factor in the human endometrium. Hum. Reprod. 20, 3518–3525 (2005).spa
dc.source.bibliographicCitationPrint, C. et al. Soluble factors from human endometrium promote angiogenesis and regulate the endothelial cell transcriptome. Hum. Reprod. 19, 2356–2366 (2004).spa
dc.source.bibliographicCitationStavreus-Evers, A. et al. Co-existence of heparin-binding epidermal growth factor-like growth factor and pinopodes in human endometrium at the time of implantation. Mol. Hum. Reprod. 8, 765–769 (2002).spa
dc.source.bibliographicCitationNikas, G. & Aghajanova, L. Endometrial pinopodes: some more understanding on human implantation? Reprod. Biomed. Online 4 Suppl 3, 18–23 (2002).spa
dc.source.bibliographicCitationJones, R. L., Stoikos, C., Findlay, J. K. & Salamonsen, L. A. TGF-?? superfamily expression and actions in the endometrium and placenta. Reproduction (2006). doi:10.1530/rep.1.01076spa
dc.source.bibliographicCitationLi, Y.-H., Kuo, C.-H., Shi, G.-Y. & Wu, H.-L. The role of thrombomodulin lectin-like domain in inflammation. J. Biomed. Sci. 19, 34 (2012).spa
dc.source.bibliographicCitationConway, E. M. et al. The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kappaB and mitogen-activated protein kinase pathways. J. Exp. Med. 196, 565–77 (2002).spa
dc.source.bibliographicCitationVan Dreden, P., Woodhams, B., Rousseau, A., Favier, M. & Favier, R. Comparative evaluation of Tissue factor and Thrombomodulin activity changes during normal and idiopathic early and late foetal loss: The cause of hypercoagulability? Thromb. Res. 129, 787–792 (2012).spa
dc.source.bibliographicCitationIsermann, B. et al. The thrombomodulin–protein C system is essential for the maintenance of pregnancy. Nat. Med. 9, 331–337 (2003).spa
dc.source.bibliographicCitationGriesshammer, M., Struve, S. & Harrison, C. M. Essential thrombocythemia/polycythemia vera and pregnancy: The need for an observational study in Europe. Semin. Thromb. Hemost. 32, 422–429 (2006).spa
dc.source.bibliographicCitationKralovics, R. et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N. Engl. J. Med. 352, 1779–90 (2005).spa
dc.source.bibliographicCitationMelillo, L. et al. Outcome of 122 pregnancies in essential thrombocythemia patients: A report from the Italian registry. Am. J. Hematol. 84, 636–640 (2009).spa
dc.source.bibliographicCitationPassamonti, F. et al. Increased risk of pregnancy complications in patients with essential thrombocythemia carrying the JAK2 (617V>F) mutation. Blood 110, 485–9 (2007).spa
dc.source.bibliographicCitationBarber, L. J. et al. Comprehensive genomic analysis of a BRCA2 deficient human pancreatic cancer. PLoS One (2011). doi:10.1371/journal.pone.0021639spa
dc.source.bibliographicCitationLaissue, P. The molecular complexity of primary ovarian insufficiency aetiology and the use of massively parallel sequencing. Mol. Cell. Endocrinol. 460, 170–180 (2018).spa
dc.source.bibliographicCitationÇalişkan, M. et al. Exome sequencing reveals a novel mutation for autosomal recessive non-syndromic mental retardation in the TECR gene on chromosome 19p13. Hum. Mol. Genet. (2011). doi:10.1093/hmg/ddq569spa
dc.source.bibliographicCitationVeltman, J. A. & Brunner, H. G. De novo mutations in human genetic disease. Nature Reviews Genetics (2012). doi:10.1038/nrg3241spa
dc.source.bibliographicCitationHrdlickova, B., de Almeida, R. C., Borek, Z. & Withoff, S. Genetic variation in the non-coding genome: Involvement of micro-RNAs and long non-coding RNAs in disease. Biochim. Biophys. Acta - Mol. Basis Dis. 1842, 1910–1922 (2014).spa
dc.source.bibliographicCitationHuang, Q. Genetic Study of Complex Diseases in the Post-GWAS Era. J. Genet. Genomics 42, 87–98 (2015).spa
dc.source.bibliographicCitationGibson, G. Rare and common variants: twenty arguments. Nat. Rev. Genet. 13, 135–145 (2012).spa
dc.source.bibliographicCitationLettre, G. Rare and low-frequency variants in human common diseases and other complex traits. J. Med. Genet. 51, 705–14 (2014).spa
dc.source.bibliographicCitationZuk, O. et al. Searching for missing heritability: Designing rare variant association studies. Proc. Natl. Acad. Sci. 111, E455–E464 (2014).spa
dc.source.bibliographicCitationMitropoulos, K. et al. Success stories in genomic medicine from resource-limited countries. Hum. Genomics 9, 11 (2015).spa
dc.source.bibliographicCitationFonseca, D. J. et al. Next generation sequencing in women affected by nonsyndromic premature ovarian failure displays new potential causative genes and mutations. Fertil. Steril. 104, 154–62.e2 (2015).spa
dc.source.bibliographicCitationPatiño, L. C. et al. Exome Sequencing Is an Efficient Tool for Variant Late-Infantile Neuronal Ceroid Lipofuscinosis Molecular Diagnosis. PLoS One 9, e109576 (2014).spa
dc.source.bibliographicCitationOrtega-Recalde, O. et al. Whole-Exome Sequencing Enables Rapid Determination of Xeroderma Pigmentosum Molecular Etiology. PLoS One 8, e64692 (2013).spa
dc.source.bibliographicCitationDiggle, C. P. et al. Prostaglandin transporter mutations cause pachydermoperiostosis with myelofibrosis. Hum. Mutat. 33, 1175–1181 (2012).spa
dc.source.bibliographicCitationPatiño, L. C. et al. New mutations in non-syndromic primary ovarian insufficiency patients identified via whole-exome sequencing. Hum. Reprod. 32, 1512–1520 (2017).spa
dc.source.bibliographicCitationCarlosama, C. et al. A homozygous donor splice-site mutation in the meiotic gene MSH4 causes primary ovarian insufficiency. Hum. Mol. Genet. 26, 3161–3166 (2017).spa
dc.source.bibliographicCitationQiao, Y. et al. Whole exome sequencing in recurrent early pregnancy loss. Mol. Hum. Reprod. 22, 364–72 (2016).spa
dc.source.bibliographicCitationSõber, S. et al. RNA sequencing of chorionic villi from recurrent pregnancy loss patients reveals impaired function of basic nuclear and cellular machinery. Sci. Rep. 6, 38439 (2016).spa
dc.source.bibliographicCitationWang, J. mei et al. Deep-sequencing identification of differentially expressed miRNAs in decidua and villus of recurrent miscarriage patients. Arch. Gynecol. Obstet. 293, 1125–1135 (2016).spa
dc.source.bibliographicCitationQuintero-Ronderos, P. et al. Novel genes and mutations in patients affected by recurrent pregnancy loss. PLoS One 12, e0186149 (2017).spa
dc.source.bibliographicCitationLissalde-Lavigne, G. et al. Factor V Leiden and prothrombin G20210A polymorphisms as risk factors for miscarriage during a first intended pregnancy: the matched case-control ‘NOHA first’ study. J. Thromb. Haemost. 3, 2178–84 (2005).spa
dc.source.bibliographicCitationWang, Q., Shashikant, C. S., Jensen, M., Altman, N. S. & Girirajan, S. Novel metrics to measure coverage in whole exome sequencing datasets reveal local and global non-uniformity. Sci. Rep. 7, 885 (2017).spa
dc.source.bibliographicCitationLee, S. M., Wu, B. & Kersey, J. H. Likelihood-Based Approach to Gene Set Enrichment Analysis with a Finite Mixture Model. Stat. Biosci. 6, 38–54 (2014).spa
dc.source.bibliographicCitationHeifetz, A. et al. The Fragment Molecular Orbital Method Reveals New Insight into the Chemical Nature of GPCR–Ligand Interactions. J. Chem. Inf. Model. 56, 159–172 (2016).spa
dc.source.bibliographicCitationFedorov, D. G., Nagata, T. & Kitaura, K. Exploring chemistry with the fragment molecular orbital method. Phys. Chem. Chem. Phys. 14, 7562 (2012).spa
dc.source.bibliographicCitationStewart, J. J. MOPAC: a semiempirical molecular orbital program. J. Comput. Aided. Mol. Des. 4, 1–105 (1990).spa
dc.source.bibliographicCitationHitaoka, S., Chuman, H. & Yoshizawa, K. A QSAR study on the inhibition mechanism of matrix metalloproteinase-12 by arylsulfone analogs based on molecular orbital calculations. Org. Biomol. Chem. 13, 793–806 (2015).spa
dc.source.bibliographicCitationRozen, S. & Skaletsky, H. Primer3 on the WWW for general users and for biologist programmers. Methods Mol. Biol. 132, 365–86 (2000).spa
dc.source.bibliographicCitationHu, Z. et al. Structural Insights into the pH-Dependent Conformational Change and Collagen Recognition of the Human Mannose Receptor. Structure 26, 60–71.e3 (2018)spa
dc.source.bibliographicCitationRoy, A., Kucukural, A. & Zhang, Y. I-TASSER: a unified platform for automated protein structure and function prediction. Nat. Protoc. 5, 725–738 (2010).spa
dc.source.bibliographicCitationZhang, Y. I-TASSER server for protein 3D structure prediction. BMC Bioinformatics 9, 40 (2008).spa
dc.source.bibliographicCitationYang, J. et al. The I-TASSER Suite: protein structure and function prediction. Nat. Methods 12, 7–8 (2015).spa
dc.source.bibliographicCitationPettersen, E. F. et al. UCSF Chimera?A visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).spa
dc.source.bibliographicCitationDunbrack, R. L. Rotamer libraries in the 21st century. Curr. Opin. Struct. Biol. 12, 431–40 (2002).spa
dc.source.bibliographicCitationPhillips, J. C. et al. Scalable molecular dynamics with NAMD. J. Comput. Chem. 26, 1781–1802 (2005).spa
dc.source.bibliographicCitationHuang, J. & MacKerell, A. D. CHARMM36 all-atom additive protein force field: Validation based on comparison to NMR data. J. Comput. Chem. 34, 2135–2145 (2013).spa
dc.source.bibliographicCitationJorgensen, W. L., Chandrasekhar, J., Madura, J. D., Impey, R. W. & Klein, M. L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 79, 926–935 (1983).spa
dc.source.bibliographicCitationBenkert, P., Biasini, M. & Schwede, T. Toward the estimation of the absolute quality of individual protein structure models. Bioinformatics 27, 343–350 (2011).spa
dc.source.bibliographicCitationChen, V. B. et al. MolProbity : all-atom structure validation for macromolecular crystallography. Acta Crystallogr. Sect. D Biol. Crystallogr. 66, 12–21 (2010).spa
dc.source.bibliographicCitationHumphrey, W., Dalke, A. & Schulten, K. VMD: Visual molecular dynamics. J. Mol. Graph. 14, 33–38 (1996).spa
dc.source.bibliographicCitationVoss, N. R. & Gerstein, M. 3V: cavity, channel and cleft volume calculator and extractor. Nucleic Acids Res. 38, W555–W562 (2010).spa
dc.source.bibliographicCitationSøndergaard, C. R., Olsson, M. H. M., Rostkowski, M. & Jensen, J. H. Improved Treatment of Ligands and Coupling Effects in Empirical Calculation and Rationalization of p K a Values. J. Chem. Theory Comput. 7, 2284–2295 (2011).spa
dc.source.bibliographicCitationBaker, N. A., Sept, D., Joseph, S., Holst, M. J. & McCammon, J. A. Electrostatics of nanosystems: Application to microtubules and the ribosome. Proc. Natl. Acad. Sci. 98, 10037–10041 (2001).spa
dc.source.bibliographicCitationDolinsky, T. J., Nielsen, J. E., McCammon, J. A. & Baker, N. A. PDB2PQR: an automated pipeline for the setup of Poisson-Boltzmann electrostatics calculations. Nucleic Acids Res. 32, W665–W667 (2004).spa
dc.source.bibliographicCitationSims, D., Sudbery, I., Ilott, N. E., Heger, A. & Ponting, C. P. Sequencing depth and coverage: key considerations in genomic analyses. Nat. Rev. Genet. 15, 121–132 (2014).spa
dc.source.bibliographicCitationMeynert, A. M., Ansari, M., FitzPatrick, D. R. & Taylor, M. S. Variant detection sensitivity and biases in whole genome and exome sequencing. BMC Bioinformatics 15, 247 (2014).spa
dc.source.bibliographicCitationKim, K. et al. Effect of Next-Generation Exome Sequencing Depth for Discovery of Diagnostic Variants. Genomics Inform. 13, 31 (2015).spa
dc.source.bibliographicCitationKiezun, A. et al. Exome sequencing and the genetic basis of complex traits. Nat. Genet. 44, 623–630 (2012)spa
dc.source.bibliographicCitationGoldstein, D. B. et al. Sequencing studies in human genetics: Design and interpretation. Nat. Rev. Genet. 14, 460–470 (2013).spa
dc.source.bibliographicCitationTennessen, J. A. et al. Evolution and Functional Impact of Rare Coding Variation from Deep Sequencing of Human Exomes. Sci. (New York, NY) 337, 64–69 (2012).spa
dc.source.bibliographicCitationO’Roak, B. J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012).spa
dc.source.bibliographicCitationDelcour, C. et al. ATG7 and ATG9A loss-of-function variants trigger autophagy impairment and ovarian failure. Genet. Med. (2018). doi:10.1038/s41436-018-0287-yspa
dc.source.bibliographicCitationThusberg, J., Olatubosun, A. & Vihinen, M. Performance of mutation pathogenicity prediction methods on missense variants. Hum. Mutat. 32, 358–368 (2011).spa
dc.source.bibliographicCitationWalters-Sen, L. C. et al. Variability in pathogenicity prediction programs: impact on clinical diagnostics. Mol. Genet. Genomic Med. 3, 99–110 (2015).spa
dc.source.bibliographicCitationDawood, F., Mountford, R., Farquharson, R. & Quenby, S. Genetic polymorphisms on the factor V gene in women with recurrent miscarriage and acquired APCR. Hum. Reprod. 22, 2546–2553 (2007).spa
dc.source.bibliographicCitationAltintas, A. et al. Factor V Leiden and G20210A prothrombin mutations in patients with recurrent pregnancy loss: data from the southeast of Turkey. Ann. Hematol. 86, 727–731 (2007).spa
dc.source.bibliographicCitationAytekin, E., Ergun, S. G., Ergun, M. A. & Percin, F. E. Evaluation of GenoFlow Thrombophilia Array Test Kit in Its Detection of Mutations in Factor V Leiden (G1691A), Prothrombin G20210A, MTHFR C677T and A1298C in Blood Samples from 113 Turkish Female Patients. Genet. Test. Mol. Biomarkers 18, 717–721 (2014).spa
dc.source.bibliographicCitationAsselta, R., Tenchini, M. L. & Duga, S. Inherited defects of coagulation factor V: the hemorrhagic side. J. Thromb. Haemost. 4, 26–34 (2006).spa
dc.source.bibliographicCitationSteen, M. & Dahlbäck, B. Thrombin-mediated proteolysis of factor V resulting in gradual B-domain release and exposure of the factor Xa-binding site. J. Biol. Chem. 277, 38424–30 (2002).spa
dc.source.bibliographicCitationErdogan, E., Bukys, M. A. & Kalafatis, M. The contribution of amino acid residues 1508-1515 of factor V to light chain generation. J. Thromb. Haemost. 6, 118–24 (2008).spa
dc.source.bibliographicCitationPeng, W., Quinn-Allen, M. A. & Kane, W. H. Mutation of hydrophobic residues in the factor Va C1 and C2 domains blocks membrane-dependent prothrombin activation. J. Thromb. Haemost. 3, 351–4 (2005).spa
dc.source.bibliographicCitationOtto, P. & Ladik, J. Investigation of the interaction between molecules at medium distances. Chem. Phys. 8, 192–200 (1975).spa
dc.source.bibliographicCitationFiedler, Benjamin & Friedrich, Joachim. (2017). The incremental method - Theory and applications in chemistry and physics. 13. 132-190. 10.1039/9781782626862-00132.spa
dc.source.bibliographicCitationXie, W. & Gao, J. Design of a Next Generation Force Field: The X-POL Potential. J. Chem. Theory Comput. 3, 1890–1900 (2007).spa
dc.source.bibliographicCitationBatra, J. et al. Matrix Metalloproteinase-10 (MMP-10) Interaction with Tissue Inhibitors of Metalloproteinases TIMP-1 and TIMP-2: BINDING STUDIES AND CRYSTAL STRUCTURE. J. Biol. Chem. 287, 15935–15946 (2012).spa
dc.source.bibliographicCitationMaruyama, I., Bell, C. E. & Majerus, P. W. Thrombomodulin is found on endothelium of arteries, veins, capillaries, and lymphatics, and on syncytiotrophoblast of human placenta. J. Cell Biol. 101, 363–71 (1985).spa
dc.source.bibliographicCitationMartin, F. A., Murphy, R. P. & Cummins, P. M. Thrombomodulin and the vascular endothelium: insights into functional, regulatory, and therapeutic aspects. Am. J. Physiol. Heart Circ. Physiol. 304, H1585-97 (2013).spa
dc.source.bibliographicCitationMasini, S. et al. Thrombin-activatable fibrinolysis inhibitor polymorphisms and recurrent pregnancy loss. Fertil. Steril. 92, 694–702 (2009).spa
dc.source.bibliographicCitationIto, T., Kakihana, Y. & Maruyama, I. Thrombomodulin as an intravascular safeguard against inflammatory and thrombotic diseases. Expert Opin. Ther. Targets 20, 151–158 (2016).spa
dc.source.bibliographicCitationDelvaeye, M. et al. Thrombomodulin Mutations in Atypical Hemolytic–Uremic Syndrome. N. Engl. J. Med. 361, 345–357 (2009).spa
dc.source.bibliographicCitationHuang, H.-C. et al. Thrombomodulin-mediated cell adhesion: involvement of its lectin-like domain. J. Biol. Chem. 278, 46750–9 (2003).spa
dc.source.bibliographicCitationStortoni, P. et al. Placental thrombomodulin expression in recurrent miscarriage. Reprod. Biol. Endocrinol. 8, 1 (2010).spa
dc.source.bibliographicCitationSuzuki, K. et al. A domain composed of epidermal growth factor-like structures of human thrombomodulin is essential for thrombin binding and for protein C activation. J. Biol. Chem. 264, 4872–4876 (1989).spa
dc.source.bibliographicCitationSood, R. et al. Maternal Par4 and platelets contribute to defective placenta formation in mouse embryos lacking thrombomodulin. Blood 112, 585–91 (2008).spa
dc.source.bibliographicCitationde Saint Martin, L. et al. Increased thrombin generation measured in the presence of thrombomodulin in women with early pregnancy loss. Fertil. Steril. 95, 1813–5.e1 (2011).spa
dc.source.bibliographicCitationLi, Y.-H., Shi, G.-Y. & Wu, H.-L. The role of thrombomodulin in atherosclerosis: from bench to bedside. Cardiovasc. Hematol. Agents Med. Chem. 4, 183–7 (2006).spa
dc.source.bibliographicCitationParodi, A., Cummings, R. D. & Aebi, M. in Essentials of Glycobiology 3rd Editio, (2017).spa
dc.source.bibliographicCitationSuzuki, K. et al. Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation. EMBO J. 6, 1891–7 (1987).spa
dc.source.bibliographicCitationIto, T. et al. Proteolytic Cleavage of High Mobility Group Box 1 Protein by Thrombin-Thrombomodulin Complexes. Arterioscler. Thromb. Vasc. Biol. 28, 1825–1830 (2008).spa
dc.source.bibliographicCitationAbeyama, K. et al. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J. Clin. Invest. 115, 1267–1274 (2005).spa
dc.source.bibliographicCitationRossini, A. et al. HMGB1-stimulated human primary cardiac fibroblasts exert a paracrine action on human and murine cardiac stem cells. J. Mol. Cell. Cardiol. 44, 683–693 (2008).spa
dc.source.bibliographicCitationYoshihara-Hirata, C. et al. Anti-HMGB1 Neutralizing Antibody Attenuates Periodontal Inflammation and Bone Resorption in a Murine Periodontitis Model. Infect. Immun. 86, (2018).spa
dc.source.bibliographicCitationAlsousi, A. A. & Igwe, O. J. Redox-active trace metal-induced release of high mobility group box 1(HMGB1) and inflammatory cytokines in fibroblast-like synovial cells is Toll-like receptor 4 (TLR4) dependent. Biochim. Biophys. Acta - Mol. Basis Dis. 1864, 3847–3858 (2018)spa
dc.source.bibliographicCitationShirasuna, K. et al. AGEs and HMGB1 Increase Inflammatory Cytokine Production from Human Placental Cells, Resulting in an Enhancement of Monocyte Migration. Am. J. Reprod. Immunol. 75, 557–568 (2016).spa
dc.source.bibliographicCitationAmin, A. R. & Islam, A. B. M. M. K. Genomic Analysis and Differential Expression of HMG and S100A Family in Human Arthritis: Upregulated Expression of Chemokines, IL-8 and Nitric Oxide by HMGB1. DNA Cell Biol. 33, 550–565 (2014)spa
dc.source.bibliographicCitationHuang, Q. T. et al. Advanced glycation end products as an upstream molecule triggers ROS-induced sFlt-1 production in extravillous trophoblasts: A novel bridge between oxidative stress and preeclampsia. Placenta 34, 1177–1182 (2013).spa
dc.source.bibliographicCitationMin, H. J. et al. ROS-dependent HMGB1 secretion upregulates IL-8 in upper airway epithelial cells under hypoxic condition. Mucosal Immunol. 10, 685–694 (2017).spa
dc.source.bibliographicCitationSagheddu, R. et al. Targeting RAGE as a potential therapeutic approach to Duchenne muscular dystrophy. Hum. Mol. Genet. 27, 3734–3746 (2018).spa
dc.source.bibliographicCitationPatel, V. et al. The stretch responsive microRNA miR-148a-3p is a novel repressor of IKBKB, NF- κ B signaling, and inflammatory gene expression in human aortic valve cells. FASEB J. 29, 1859–1868 (2015).spa
dc.source.bibliographicCitationAnjana, R. et al. Aromatic-aromatic interactions in structures of proteins and protein-DNA complexes: a study based on orientation and distance. Bioinformation 8, 1220–1224 (2012).spa
dc.source.bibliographicCitationBignucolo, O., Leung, H. T. A., Grzesiek, S. & Bernèche, S. Backbone Hydration Determines the Folding Signature of Amino Acid Residues. J. Am. Chem. Soc. 137, 4300–4303 (2015)spa
dc.source.bibliographicCitationZhang, Z., Witham, S. & Alexov, E. On the role of electrostatics in protein–protein interactions. Phys. Biol. 8, 035001 (2011).spa
dc.source.bibliographicCitationAndersson, U. et al. High Mobility Group 1 Protein (Hmg-1) Stimulates Proinflammatory Cytokine Synthesis in Human Monocytes. J. Exp. Med. 192, 565–570 (2000).spa
dc.source.bibliographicCitationBhutada, S. et al. High mobility group box 1 (HMGB1) protein in human uterine fluid and its relevance in implantation. Hum. Reprod. 29, 763–780 (2014).spa
dc.source.bibliographicCitationRiesewijk, A. et al. Gene expression profiling of human endometrial receptivity on days LH+2 versus LH+7 by microarray technology. Mol. Hum. Reprod. 9, 253–64 (2003).spa
dc.source.bibliographicCitationKwak-Kim, J. Y. H., Gilman-Sachs, A. & Kim, C. E. in Immunology of Gametes and Embryo Implantation 64–79 (KARGER, 2005). doi:10.1159/000087821spa
dc.source.bibliographicCitationBates, M. D., Quenby, S., Takakuwa, K., Johnson, P. M. & Vince, G. S. Aberrant cytokine production by peripheral blood mononuclear cells in recurrent pregnancy loss? Hum. Reprod. 17, 2439–44 (2002).spa
dc.source.bibliographicCitationTian, H., McKnight, S. L. & Russell, D. W. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev. 11, 72–82 (1997).spa
dc.source.bibliographicCitationTakeda, N. et al. Endothelial PAS domain protein 1 gene promotes angiogenesis through the transactivation of both vascular endothelial growth factor and its receptor, Flt-1. Circ. Res. 95, 146–53 (2004).spa
dc.source.bibliographicCitationMaemura, K. et al. Generation of a dominant-negative mutant of endothelial PAS domain protein 1 by deletion of a potent C-terminal transactivation domain. J. Biol. Chem. 274, 31565–70 (1999).spa
dc.source.bibliographicCitationDepoix, C. L. L., de Selliers, I., Hubinont, C. & Debieve, F. HIF1A and EPAS1 potentiate hypoxia-induced upregulation of inhibin alpha chain expression in human term cytotrophoblasts in vitro. Mol. Hum. Reprod. 23, gax002 (2017).spa
dc.source.bibliographicCitationL’Hôte, D. et al. Centimorgan-range one-step mapping of fertility traits using interspecific recombinant congenic mice. Genetics 176, 1907–21 (2007).spa
dc.source.bibliographicCitationLaissue, P., L’Hôte, D., Serres, C. & Vaiman, D. Mouse models for identifying genes modulating fertility parameters. animal 3, 55 (2009).spa
dc.source.bibliographicCitationLaissue, P. et al. Identification of Quantitative Trait Loci responsible for embryonic lethality in mice assessed by ultrasonography. Int. J. Dev. Biol. 53, 623–629 (2009).spa
dc.source.bibliographicCitationQuintero-Ronderos, P. et al. THBD sequence variants potentially related to recurrent pregnancy loss. Reprod. Biol. Endocrinol. 15, 92 (2017).spa
dc.source.bibliographicCitationVatin, M. et al. Refined Mapping of a Quantitative Trait Locus on Chromosome 1 Responsible for Mouse Embryonic Death. PLoS One 7, e43356 (2012).spa
dc.source.bibliographicCitationVatin, M. et al. Polymorphisms of human placental alkaline phosphatase are associated with in vitro fertilization success and recurrent pregnancy loss. Am. J. Pathol. 184, 362–368 (2014).spa
dc.source.bibliographicCitationL’Hôte, D. et al. Interspecific resources: a major tool for quantitative trait locus cloning and speciation research. BioEssays 32, 132–42 (2010).spa
dc.source.bibliographicCitationGuénet, J. L. & Bonhomme, F. Wild mice: an ever-increasing contribution to a popular mammalian model. Trends Genet. 19, 24–31 (2003).spa
dc.source.bibliographicCitationBurgio, G. et al. Interspecific Recombinant Congenic Strains Between C57BL/6 and Mice of the Mus spretus Species: A Powerful Tool to Dissect Genetic Control of Complex Traits. Genetics 177, 2321–33 (2007).spa
dc.source.bibliographicCitationQuintero-Ronderos, P. & Laissue, P. The multisystemic functions of FOXD1 in development and disease. J. Mol. Med. 96, 725–739 (2018).spa
dc.source.bibliographicCitationFeng, J., Liu, T., Qin, B., Zhang, Y. & Liu, X. S. Identifying ChIP-seq enrichment using MACS. Nat. Protoc. 7, 1728–1740 (2012).spa
dc.source.bibliographicCitationZhang, Y. et al. Model-based Analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008).spa
dc.source.bibliographicCitationLangmead, B. & Salzberg, S. L. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359 (2012).spa
dc.source.bibliographicCitationLi, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).spa
dc.source.bibliographicCitationENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).spa
dc.source.bibliographicCitationQuinlan, A. R. & Hall, I. M. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010).spa
dc.source.bibliographicCitationHe, Q., Johnston, J. & Zeitlinger, J. ChIP-nexus enables improved detection of in vivo transcription factor binding footprints. Nat. Biotechnol. 33, 395–401 (2015).spa
dc.source.bibliographicCitationWelch, R. P. et al. Chipenrich: Gene Set Enrichment For ChIP-seq Peak Data. (2017). at <https://bioconductor.org/packages/devel/bioc/vignettes/chipenrich/inst/doc/chipenrich-vignette.html>spa
dc.source.bibliographicCitationLiu, T. MACS2 pileup value in xls file. (2014). at <https://groups.google.com/d/msg/macs-announcement/c__KCotHsok/Wp1VdX3XgAUJ>spa
dc.source.bibliographicCitationElemento, O. & Giannopoulou, E. G. ChIP sequencing analysis in R/Bioconductor. (2014). at <http://physiology.med.cornell.edu/faculty/elemento/lab/data/courses/2014/CSHLseq/ChIP-seq.pdf>spa
dc.source.bibliographicCitationSahu, P. Biostars: Bioinformatics explained. (2015). at <https://www.biostars.org/p/198970/#210571>spa
dc.source.bibliographicCitationChow, W.-N. et al. Complement 3 deficiency impairs early pregnancy in mice. Mol. Reprod. Dev. 76, 647–655 (2009).spa
dc.source.bibliographicCitationPham, C. T. & Ley, T. J. Dipeptidyl peptidase I is required for the processing and activation of granzymes A and B in vivo. Proc. Natl. Acad. Sci. U. S. A. 96, 8627–32 (1999).spa
dc.source.bibliographicCitationAdkison, A. M., Raptis, S. Z., Kelley, D. G. & Pham, C. T. N. Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis. J. Clin. Invest. 109, 363–371 (2002).spa
dc.source.bibliographicCitationMéthot, N. et al. Inhibition of the Activation of Multiple Serine Proteases with a Cathepsin C Inhibitor Requires Sustained Exposure to Prevent Pro-enzyme Processing. J. Biol. Chem. 282, 20836–20846 (2007).spa
dc.source.bibliographicCitationMeade, J. L. et al. Proteolytic Activation of the Cytotoxic Phenotype during Human NK Cell Development. J. Immunol. 183, 803–813 (2009).spa
dc.source.bibliographicCitationMenkhorst, E. M. et al. Decidual-Secreted Factors Alter Invasive Trophoblast Membrane and Secreted Proteins Implying a Role for Decidual Cell Regulation of Placentation. PLoS One 7, e31418 (2012).spa
dc.source.bibliographicCitationZhu, X.-Y. et al. Blockade of CD86 Signaling Facilitates a Th2 Bias at the Maternal-Fetal Interface and Expands Peripheral CD4+CD25+ Regulatory T Cells to Rescue Abortion-Prone Fetuses1. Biol. Reprod. 72, 338–345 (2005).spa
dc.source.bibliographicCitationWang, J. et al. Vascular endothelial growth factor affects dendritic cell activity in hypertensive disorders of pregnancy. Mol. Med. Rep. 12, 3781–3786 (2015).spa
dc.source.bibliographicCitationWhitley, G. S. J. & Cartwright, J. E. Trophoblast-mediated spiral artery remodelling: a role for apoptosis. J. Anat. 215, 21–26 (2009).spa
dc.source.bibliographicCitationKhong, T. Y., De Wolf, F., Robertson, W. B. & Brosens, I. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br. J. Obstet. Gynaecol. 93, 1049–59 (1986).spa
dc.source.bibliographicCitationUrata, H., Kinoshita, A., Misono, K. S., Bumpus, F. M. & Husain, A. Identification of a highly specific chymase as the major angiotensin II-forming enzyme in the human heart. J. Biol. Chem. 265, 22348–57 (1990).spa
dc.source.bibliographicCitationTchougounova, E. et al. A Key Role for Mast Cell Chymase in the Activation of Pro-matrix Metalloprotease-9 and Pro-matrix Metalloprotease-2. J. Biol. Chem. 280, 9291–9296 (2005).spa
dc.source.bibliographicCitationMarx, L. et al. Decidual mast cells might be involved in the onset of human first-trimester abortion. Am. J. Reprod. Immunol. 41, 34–40 (1999).spa
dc.source.bibliographicCitationGarfield, R. E., Irani, A.-M., Schwartz, L. B., Bytautiene, E. & Romero, R. Structural and functional comparison of mast cells in the pregnant versus nonpregnant human uterus. Am. J. Obstet. Gynecol. 194, 261–267 (2006).spa
dc.source.bibliographicCitationMeyer, N. et al. Chymase-producing cells of the innate immune system are required for decidual vascular remodeling and fetal growth. Sci. Rep. 7, 45106 (2017).spa
dc.source.bibliographicCitationClarson, L. H., Roberts, V. H. J., Hamark, B., Elliott, A. C. & Powell, T. Store-operated Ca 2+ entry in first trimester and term human placenta. J. Physiol. 550, 515–528 (2003).spa
dc.source.bibliographicCitationJacobs, B. E., Liu, Y., Pulina, M. V., Golovina, V. A. & Hamlyn, J. M. Normal pregnancy: mechanisms underlying the paradox of a ouabain-resistant state with elevated endogenous ouabain, suppressed arterial sodium calcium exchange, and low blood pressure. Am. J. Physiol. Circ. Physiol. 302, H1317–H1329 (2012).spa
dc.source.bibliographicCitationDykes, I. M. & Emanueli, C. Transcriptional and Post-transcriptional Gene Regulation by Long Non-coding RNA. Genomics. Proteomics Bioinformatics 15, 177–186 (2017).spa
dc.source.bibliographicCitationHerriges, M. J. et al. Long noncoding RNAs are spatially correlated with transcription factors and regulate lung development. Genes Dev. 28, 1363–1379 (2014).spa
dc.source.instnameinstname:Universidad del Rosariospa
dc.source.reponamereponame:Repositorio Institucional EdocURspa
dc.subjectPérdida recurrente de la gestaciónspa
dc.subjectFalla de la implantaciónspa
dc.subjectGenéticaspa
dc.subjectGenómicaspa
dc.subjectMutacionesspa
dc.subjectFOXD1spa
dc.subjectBiomarcadores molecularesspa
dc.subject.ddcGinecología & otras especialidades médicasspa
dc.subject.keywordRecurrent pregnancy lossspa
dc.subject.keywordRecurrent implantation failurespa
dc.subject.keywordMolecular biomarkersspa
dc.subject.keywordFOXD1spa
dc.subject.keywordGeneticsspa
dc.subject.keywordGenomicsspa
dc.subject.keywordMutationsspa
dc.subject.lembAborto espontáneospa
dc.subject.lembAborto habitualspa
dc.subject.lembGenesspa
dc.subject.lembGenética molecularspa
dc.titleGenómica funcional y disección molecular de FOXD1 para la identificación de nuevos biomarcadores genéticos asociados a patologías de la reproducción de origen endometrial y placentariospa
dc.typedoctoralThesiseng
dc.type.documentTesisspa
dc.type.hasVersioninfo:eu-repo/semantics/acceptedVersion
dc.type.spaTesis de doctoradospa
local.department.reportEscuela de Medicina y Ciencias de la Saludspa
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Tesis Doctorado en Ciencias Biomédicas
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Doctorado en Ciencias Biomédicas