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41.
Madhuri Salker Gijs Teklenburg Mariam Molokhia Stuart Lavery Geoffrey Trew Tepchongchit Aojanepong Helen J. Mardon Amali U. Lokugamage Raj Rai Christian Landles Bernard A. J. Roelen Siobhan Quenby Ewart W. Kuijk Annemieke Kavelaars Cobi J. Heijnen Lesley Regan Nick S. Macklon Jan J. Brosens 《PloS one》2010,5(4)
Background
Recurrent pregnancy loss (RPL), defined as 3 or more consecutive miscarriages, is widely attributed either to repeated chromosomal instability in the conceptus or to uterine factors that are poorly defined. We tested the hypothesis that abnormal cyclic differentiation of endometrial stromal cells (ESCs) into specialized decidual cells predisposes to RPL, based on the observation that this process may not only be indispensable for placenta formation in pregnancy but also for embryo recognition and selection at time of implantation.Methodology/Principal Findings
Analysis of mid-secretory endometrial biopsies demonstrated that RPL is associated with decreased expression of the decidual marker prolactin (PRL) but increased levels of prokineticin-1 (PROK1), a cytokine that promotes implantation. These in vivo findings were entirely recapitulated when ESCs were purified from patients with and without a history of RPL and decidualized in culture. In addition to attenuated PRL production and prolonged and enhanced PROK1 expression, RPL was further associated with a complete dysregulation of both markers upon treatment of ESC cultures with human chorionic gonadotropin, a glycoprotein hormone abundantly expressed by the implanting embryo. We postulated that impaired embryo recognition and selection would clinically be associated with increased fecundity, defined by short time-to-pregnancy (TTP) intervals. Woman-based analysis of the mean and mode TTP in a cohort of 560 RPL patients showed that 40% can be considered “superfertile”, defined by a mean TTP of 3 months or less.Conclusions
Impaired cyclic decidualization of the endometrium facilitates implantation yet predisposes to subsequent pregnancy failure by disabling natural embryo selection and by disrupting the maternal responses to embryonic signals. These findings suggest a novel pathological pathway that unifies maternal and embryonic causes of RPL. 相似文献42.
43.
Patterning in multi-cellular organisms involves progressive restriction of cell fates by generation of boundaries to divide an organ primordium into smaller fields. We have employed the Drosophila eye model to understand the genetic circuitry responsible for defining the boundary between the eye and the head cuticle on the ventral margin. The default state of the early eye is ventral and depends on the function of Lobe (L) and the Notch ligand Serrate (Ser). We identified homothorax (hth) as a strong enhancer of the L mutant phenotype of loss of ventral eye. Hth is a MEIS class gene with a highly conserved Meis-Hth (MH) domain and a homeodomain (HD). Hth is known to bind Extradenticle (Exd) via its MH domain for its nuclear translocation. Loss-of-function of hth, a negative regulator of eye, results in ectopic ventral eye enlargements. This phenotype is complementary to the L mutant phenotype of loss-of-ventral eye. However, if L and hth interact during ventral eye development remains unknown. Here we show that (i) L acts antagonistically to hth, (ii) Hth is upregulated in the L mutant background, and (iii) MH domain of Hth is required for its genetic interaction with L, while its homeodomain is not, (iv) in L mutant background ventral eye suppression function of Hth involves novel MH domain-dependent factor(s), and (v) nuclear localization of Exd is not sufficient to mediate the Hth function in the L mutant background. Further, Exd is not a critical rate-limiting factor for the Hth function. Thus, optimum levels of L and Hth are required to define the boundary between the developing eye and head cuticle on the ventral margin. 相似文献
44.
Virulent and moderately virulent strains of Newcastle disease virus (NDV), representing avian paramyxovirus serotype 1 (APMV-1), cause respiratory and neurological disease in chickens and other species of birds. In contrast, APMV-2 is avirulent in chickens. We investigated the role of the fusion (F) and hemagglutinin-neuraminidase (HN) envelope glycoproteins in these contrasting phenotypes by designing chimeric viruses in which the F and HN glycoproteins or their ectodomains were exchanged individually or together between the moderately virulent, neurotropic NDV strain Beaudette C (BC) and the avirulent APMV-2 strain Yucaipa. When we attempted to exchange the complete F and HN glycoproteins individually and together between the two viruses, the only construct that could be recovered was recombinant APMV-2 strain Yucaipa (rAPMV-2), containing the NDV F glycoprotein in place of its own. This substitution of NDV F into APMV-2 was sufficient to confer the neurotropic, neuroinvasive, and neurovirulent phenotypes, in spite of all being at reduced levels compared to what was seen for NDV-BC. When the ectodomains of F and HN were exchanged individually and together, two constructs could be recovered: NDV, containing both the F and HN ectodomains of APMV-2; and APMV-2, containing both ectodomains of NDV. This supported the idea that homologous cytoplasmic tails and matched F and HN ectodomains are important for virus replication. Analysis of these viruses for replication in vitro, syncytium formation, mean embryo death time, intracerebral pathogenicity index, and replication and tropism in 1-day-old chicks and 2-week-old chickens showed that the two contrasting phenotypes of NDV and APMV-2 could largely be transferred between the two backbones by transfer of homotypic F and HN ectodomains. Further analysis provided evidence that the homologous stalk domain of NDV HN is essential for virus replication, while the globular head domain of NDV HN could be replaced with that of APMV-2 with only a minimal attenuating effect. These results demonstrate that the F and HN ectodomains together determine the cell fusion, tropism, and virulence phenotypes of NDV and APMV-2 and that the regions of HN that are critical to replication and the species-specific phenotypes include the cytoplasmic tail and stalk domain but not the globular head domain. 相似文献
45.
Yu Qin Maoyong Fu Masamichi Takahashi Akio Iwanami Daisuke Kuga Rajiv G. Rao Deepthi Sudhakar Tiffany Huang Meagan Kiyohara Kathleen Torres Christen Dillard Akihito Inagaki Noriyuki Kasahara Lee Goodglick Jonathan Braun Paul S. Mischel Lynn K. Gordon Madhuri Wadehra 《The Journal of biological chemistry》2014,289(20):13974-13985
Despite recent advances in molecular classification, surgery, radiotherapy, and targeted therapies, the clinical outcome of patients with malignant brain tumors remains extremely poor. In this study, we have identified the tetraspan protein epithelial membrane protein-2 (EMP2) as a potential target for glioblastoma (GBM) killing. EMP2 had low or undetectable expression in normal brain but was highly expressed in GBM as 95% of patients showed some expression of the protein. In GBM cells, EMP2 enhanced tumor growth in vivo in part by up-regulating αvβ3 integrin surface expression, activating focal adhesion kinase and Src kinases, and promoting cell migration and invasion. Consistent with these findings, EMP2 expression significantly correlated with activated Src kinase in patient samples and promoted tumor cell invasion using intracranial mouse models. As a proof of principle to determine whether EMP2 could serve as a target for therapy, cells were treated using specific anti-EMP2 antibody reagents. These reagents were effective in killing GBM cells in vitro and in reducing tumor load in subcutaneous mouse models. These results support the role of EMP2 in the pathogenesis of GBM and suggest that anti-EMP2 treatment may be a novel therapeutic treatment. 相似文献
46.
Madhuri Bhandaru Magdalena Martinka Gang Li Anand Rotte 《Pigment cell & melanoma research》2014,27(3):366-375
Ultraviolet (UV) radiation‐induced DNA damage and genomic instability is one of the leading causes for melanoma. X‐ray repair cross‐complementary protein 1, XRCC1, plays a critically important role in base excision repair pathway. This study was therefore performed to analyze the correlation between XRCC1 expression, melanoma progression, and patient survival. Using a tissue microarray with a total of 119 patients with melanoma, we demonstrate that loss of XRCC1 expression is associated with the progression of disease from dysplastic nevi to primary melanoma and to metastatic melanoma. We found that the loss of XRCC1 was correlated with the progression of melanoma from AJCC stage II to stage III and with worse overall and disease‐specific 5‐yr and 10‐yr survival of patients with melanoma. Furthermore, we also illustrate the inhibitory effect of XRCC1 on melanoma cell invasion and migration, which are the regulatory events in melanoma metastasis. 相似文献
47.
Madhuri S. Salker Jaya Nautiyal Jennifer H. Steel Zoe Webster Sandra ?u?urovi? Marilena Nicou Yogesh Singh Emma S. Lucas Keisuke Murakami Yi-Wah Chan Sean James Yazan Abdallah Mark Christian B. Anne Croy Biserka Mulac-Jericevic Siobhan Quenby Jan J. Brosens 《PloS one》2012,7(12)
Decidualization renders the endometrium transiently receptive to an implanting blastocyst although the underlying mechanisms remain incompletely understood. Here we show that human endometrial stromal cells (HESCs) rapidly release IL-33, a key regulator of innate immune responses, upon decidualization. In parallel, differentiating HESCs upregulate the IL-33 transmembrane receptor ST2L and other pro-inflammatory mediators before mounting a profound anti-inflammatory response that includes downregulation of ST2L and increased expression of the soluble decoy receptor sST2. We demonstrate that HESCs secrete factors permissive of embryo implantation in mice only during the pro-inflammatory phase of the decidual process. IL-33 knockdown in undifferentiated HESCs was sufficient to abrogate this pro-inflammatory decidual response. Further, sequential activation of the IL-33/ST2L/sST2 axis was disordered in decidualizing HESCs from women with recurrent pregnancy loss. Signals from these cultures prolonged the implantation window but also caused subsequent pregnancy failure in mice. Thus, Il-33/ST2 activation in HESCS drives an autoinflammatory response that controls the temporal expression of receptivity genes. Failure to constrain this response predisposes to miscarriage by allowing out-of-phase implantation in an unsupportive uterine environment. 相似文献
48.
Rosi Bissinger Elisabeth Lang Irene Gonzalez-Menendez Leticia Quintanilla-Martinez Mehrdad Ghashghaeinia Lisann Pelzl Basma Sukkar Abdulla Al Mamun Bhuyan Madhuri S. Salker Yogesh Singh Birgit Fehrenbacher Hajar Fakhri Anja T. Umbach Martin Schaller Syed M. Qadri Florian Lang 《Apoptosis : an international journal on programmed cell death》2018,23(11-12):641-650
49.
Higher expression of human telomerase reverse transcriptase in productively‐infected CD4 cells possibly indicates a mechanism for persistence of the virus in HIV infection
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50.
Kuldeep K. Bhatia Francis L. Black Thomas A. Smith Madhuri L. Prasad George N. Koki 《American journal of physical anthropology》1995,97(3):291-305
Class I HLA antigens have been compared in 5,835 Melanesians of Papua New Guinea and 2,028 Amerindians of South America. The sample includes 50 PNGMel ethnolinguistic groups and 22 SAmlnd groups. Both carry 15 serologically defined antigens and an undefined C allele. Except for A2 in Papua New Guinea and Cwl in South America, these antigens are widely distributed in their respective populations. Nine (A2 and A24, B39, B60 and B62, and Cwl, Cw3, Cw4, and Cw7) are common to both. This commonality suggests that these two populations derive from an ancestral population with less polymorphism than modern East Asians. In both populations several theoretically possible haplotypes were absent, and other haplo-types were in positive disequilibrium in both. The parallels in disequilibria suggest that haplotypes are subject to selective forces acting on the level of allelic interaction. Based on three locus haplotype frequencies, the PNGMel groups form five clusters with internally typical linguistic and geographic characteristics and a miscellaneous category, but Samlnd groups show no cluster. © 1995 Wiley-Liss, Inc. 相似文献