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  • 1.

    【2hr】Testicular abnormalities in mice with Y chromosome deficiencies

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    机译 Y染色体缺陷小鼠的睾丸异常
    摘要：We recently investigated mice with Y chromosome gene contribution limited to two, one, or no Y chromosome genes in respect to their ability to produce haploid round spermatids and live offspring following round spermatid injection. Here we explored the normalcy of germ cells and Sertoli cells within seminiferous tubules, and the interstitial tissue of the testis in these mice. We performed quantitative analysis of spermatogenesis and interstitial tissue on Periodic acid-Schiff and hematoxylin-stained mouse testis sections. The seminiferous epithelium of mice with limited Y gene contribution contained various cellular abnormalities, the total number of which was higher than in the males with an intact Y chromosome. The distribution of specific abnormality types varied among tested genotypes. The males with limited Y genes also had an increased population of testicular macrophages and internal vasculature structures. The data indicate that Y chromosome gene deficiencies in mice are associated with cellular abnormalities of the seminiferous epithelium and some changes within the testicular interstitium.
  • 2.

    【2hr】Obesity alters phosphoramide mustard-induced ovarian DNA repair inmice

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    机译 肥胖改变了磷酰胺芥菜诱导的卵巢DNA修复老鼠
    摘要：Phosphoramide mustard (PM) destroys rapidly dividing cells and activates the DNA double strand break marker, γH2AX, and DNA repair in rat granulosa cells and neonatal ovaries. The effects of PM exposure on DNA damage and activation of DNA damage repair in lean and obese female mice were investigated. Wild type (lean) non agouti (a/a) and KK.Cg-Ay/J heterozygote (obese) mice received sesame oil or PM (95%; 25 mg/kg; intraperitoneal injection). Obesity increased (P < 0.05) hepatic and spleen but decreased (P < 0.05) uterine weight. PM exposure reduced (P < 0.05) spleen weight regardless of body composition, however, decreased (P < 0.05) ovarian and hepatic weight were observed in the obese PM-exposed females. PM decreased (P < 0.05) primordial and primary follicle number in lean females. Obesity and PM increased (P < 0.05) γH2AX protein. DNA damage repair genes Prkdc, Parp1, and Rad51 mRNA were unaltered by obesity, however, Atm and Xrcc6 mRNA were increased (P < 0.05) while Brca1 was reduced (P < 0.05). Obesity reduced (P < 0.05) PRKDC, XRCC6 and but increased (P < 0.05) ATM protein. ATM, BRCA1 and RAD51protein levels were increased (P < 0.05) by PM exposure in both leanand obese mice, while PM-induced increased (P < 0.05) XRCC6 and PARP1were observed only in lean mice. Thus, PM induces ovarian DNA damage invivo; obesity alters DNA repair response gene mRNA and protein level; the ovaryactivates DNA repair proteins in response to PM; but obesity compromises the ovarian PMresponse.
  • 3.

    【2hr】Identification of KIAA1210 as a novel X-chromosome-linked protein that localizes to the acrosome and associates with the ectoplasmic specialization in testes

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    机译 将KIAA1210鉴定为定位于顶体并与睾丸的胞浆特化相关的新型X染色体连接蛋白
    摘要：Cell junctions are necessary for spermatogenesis, and there are numerous types of junctions in testis, such as blood–testis barrier, intercellular bridge, and ectoplasmic specialization (ES). The details of their functions and construction are still unknown. To identify a novel protein essential to the function of a cell junction, we enriched testis membrane protein and analyzed it using a proteomics approach. Here, we report a novel ES protein, which is encoded on the X chromosome and an ortholog of hypothetical human protein KIAA1210. KIAA1210 is expressed in testis predominantly, localized to the sex body in spermatocyte, acrosome, and near ES. Moreover, KIAA1210 possesses a topoisomerase 2 (TOP2)-associated protein PAT1 domain, a herpes simplex virus 1 (HSV-1) large tegument protein UL36 hypothetical domain, and a provisional DNA translocase FtsK domain. Using IP-proteomics with specific antibody to KIAA1210, we identified proteins including TOP2 isoforms as components of a complex with KIAA1210, in cell junctions in testis. The interaction between KIAA1210 and TOP2 was confirmed by two different proteomic analyses. Furthermore, immunofluorescence showed that KIAA1210 and TOP2B co-localize around the sex body in spermatocyte, apical ES, and residual bodies in elongated spermatids. Our findings suggest that KIAA1210 may be essential cell junction protein that interacts with TOP2B to regulate the dynamic change of chromatin structures during spermiogenesis.
  • 4.

    【2hr】Augmented H2S production via cystathionine-beta-synthaseupregulation plays a role in pregnancy-associated uterine vasodilation

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    机译 通过胱硫醚-β-合酶增加了H2S的产生上调在妊娠相关的子宫血管舒张中起作用
    摘要：Endogenous hydrogen sulfide (H2S) synthesized via metabolizing L-cysteine by cystathionine-beta-synthase (CBS) and cystathionine-gamma-lyase (CSE) is a potent vasodilator and angiogenic factor. The objectives of this study were to determine if human uterine artery (UA) H2S production increases with augmented expression and/or activity of CBS and/or CSE during the menstrual cycle and pregnancy and whether exogenous H2S dilates UA. Uterine arteries from nonpregnant (NP) premenopausal proliferative (pPRM) and secretory (sPRM) phases of the menstrual cycle and pregnant (P) women were studied. H2S production was measured by the methylene blue assay. CBS and CSE mRNAs were assessed by quantitative real-time PCR, and proteins were assessed by immunoblotting and semiquantitative immunofluorescence microscopy. Effects of H2S on rat UA relaxation were determined by wire myography ex vivo. H2S production was greater in NP pPRM and P than NP sPRM UAs and inhibited by the specific CBS but not CSE inhibitor. CBS but not CSE mRNA and protein were greater in NP pPRM and P than NP sPRM UAs. CBS protein was localized to endothelium and smooth muscle and its levels were in a quantitative order of P >NP UAs of pPRM>sPRM. CSE protein was localized in UA endothelium and smooth muscle with no difference among groups. A H2S donor relaxed P > NP UAs but not mesenteryartery. Thus, human UA H2S production is augmented with endothelium and smoothmuscle CBS upregulation, contributing to UA vasodilation in the estrogen-dominantphysiological states in the proliferative phase of the menstrual cycle and pregnancy.
  • 5.

    【2hr】Decreased epithelial progesterone receptor A at the window of receptivity isrequired for preparation of the endometrium for embryo attachment

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    机译 接受窗口中的上皮孕激素受体A减少制备子宫内膜用于胚胎附着所需
    摘要：The precise timing of progesterone signaling through its cognate receptor, the progesterone receptor (PGR), is critical for the establishment and maintenance of pregnancy. Loss of PGR expression in the murine uterine epithelium during the preimplantation period is a marker for uterine receptivity and embryo attachment. We hypothesized that the decrease in progesterone receptor A (PGRA) expression is necessary for successful embryo implantation. To test this hypothesis, a mouse model constitutively expressing PGRA (mPgrALsL/+) was generated. Expression of PGRA in all uterine compartments (Pgrcre) or uterine epithelium (Wnt7acre) resulted in infertility with defects in embryo attachment and stromal decidualization. Expression of critical PGRA target genes, indian hedgehog, and amphiregulin (Areg), was maintained through the window of receptivity while the estrogen receptor target gene, the leukemia inhibitory factor (Lif), a key regulator of embryo receptivity, was decreased. Transcriptomic and cistromic analyses of the mouse uterus at day 4.5 of pregnancy identified an altered group of genes regulating molecular transport in the control of fluid and ion levels within the uterine interstitial space. Additionally, LIF and its cognate receptor, the leukemia inhibitory factor receptor (LIFR), exhibitedPGR-binding events in regions upstream of the transcriptional start sites, suggesting PGRAis inhibiting transcription at these loci. Therefore, downregulation of the PGRA isoformat the window of receptivity is necessary for the attenuation of hedgehog signaling,transcriptional activation of LIF signaling, and modulation of solutes and fluid,producing a receptive environment for the attaching embryo.
  • 6.

    【2hr】Chronic hypoxia upregulates DNA methyltransferase and represses largeconductance Ca2+-activated K+ channel function in ovine uterinearteries

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    机译 慢性缺氧会上调DNA甲基转移酶并抑制大分子子宫中电导Ca2 +激活的K +通道功能动脉
    摘要：Chronic hypoxia during gestation suppresses large-conductance Ca2+-activated K+ (BKCa) channel function and impedes uterine arterial adaptation to pregnancy. This study tested the hypothesis that chronic hypoxia has a direct effect in upregulating DNA methyltransferase (DNMT) and epigenetically repressing BKCa channel beta-1 subunit (KCNMB1) expression in uterine arteries. Resistance-sized uterine arteries were isolated from near-term pregnant sheep maintained at ∼300 m above sea level or animals acclimatized to high-altitude (3,801 m) hypoxia for 110 days during gestation. For ex vivo hypoxia treatment, uterine arteries from normoxic animals were treated with 21.0% O2 or 10.5% O2 for 48 h. High-altitude hypoxia significantly upregulated DNMT3b expression and enzyme activity in uterine arteries. Similarly, ex vivo hypoxia treatment upregulated DNMT3b expression and enzyme activity that was blocked by a DNMT inhibitor 5-aza-2'-deoxycytidine (5-Aza). Of importance, 5-Aza inhibited hypoxia-induced hypermethylation of specificity protein (SP) 1 binding site at the KCNMB1 promoter and restored transcription factor binding to the KCNMB1 promoter, resulting in the recovery of KCNMB1 gene expression in uterine arteries. Furthermore, 5-Aza blocked the effect of hypoxia and rescued BKCa channel activity and reversed hypoxia-induced decrease in BKCa channel-mediated relaxations and increase inmyogenic tone of uterine arteries. Collectively, these results suggest that chronichypoxia during gestation upregulates DNMT expression and activity, resulting inhypermethylation and repression of KCNMB1 gene and BKCa channel function,impeding uterine arterial adaptation to pregnancy.
  • 7.

    【2hr】Ovine uterine space restriction causes dysregulation of the renin–angiotensinsystem in fetal kidneys

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    机译 绵羊子宫空间受限导致肾素-血管紧张素失调胎儿肾脏中的系统
    摘要：In ovine pregnancy, uterine space restriction (USR) resulting from decreased space for placental attachment caused intrauterine growth restriction and impaired nephrogenesis. The fetal kidney renin–angiotensin system (RAS) is involved in nephrogenesis, fluid balance, and iron deposition. Angiotensin II exerts its effects via multiple receptors: angiotensin II1-8 receptor type 1 (AT1R) and type 2 (AT2R), and angiotensin II1-7 Mas receptor (MASR). Objective: To test the hypothesis that ovine USR is associated with dysregulation of the fetal renal RAS. Methods: Multiparous pregnant ewes (n = 32), 16 with surgical bifurcated disconnection of one uterine horn to further reduce placental attachment sites, were studied. USR (n = 31) ovine fetuses were compared to nonspace restricted (NSR) singleton controls (n = 22) on gestational day (GD) 120 or GD130, term GD147. Fetal plasma was collected to evaluate plasma renin activity and iron indices. Fetal kidney AT1R, AT2R, and MASR proteins were assessed by Western immunoblotting and immunohistochemistry. Results: AT1R, AT2R, and MASR protein expression was higher in USR at GD130 than aged-matched NSR and USR at GD120, (P <0.05 all). AT1R and AT2R localization was homogenous throughoutproximal and distal tubules in both USR and NSR at both gestational dates. MASRlocalization was punctate throughout renal cortical structures including tubules andglomeruli in both USR and NSR, shifted to intranuclear at GD130. Plasma renin activity wasinversely related to plasma osmolarity (P < 0.02) and wasdownregulated in USR at GD130 (P < 0.05).Conclusions: By late gestation, USR upregulated renal angiotensin receptorexpression, an effect with potential functional implications.
  • 8.

    【2hr】Natural killer-cell deficiency alters placental development in rats

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    机译 自然杀伤细胞缺乏改变大鼠胎盘发育
    摘要：Natural killer (NK) cells are the most prevalent leukocyte population in the uterus during early pregnancy. Natural killer cells contribute to uterine vascular (spiral artery) remodeling in preparation for the increased demand on these vessels later in pregnancy. A second wave of spiral artery modification is directed by invasive trophoblast cells. The significance of the initial wave of NK-cell-mediated vascular remodeling in species exhibiting deep trophoblast invasion such as humans and rats is not known. The purpose of this study was to generate a genetic model of NK-cell deficiency in rats, and determine the consequences of NK-cell deficiency on spiral artery remodeling and reproductive outcomes. To accomplish this task, we utilized zinc finger nuclease-mediated genome editing of the rat interleukin-15 (Il15) gene. Il15 encodes a cytokine required for NK-cell lineage development. Using this strategy, a founder rat was generated containing a frameshift deletion in Il15. Uteri of females harboring a homozygous mutation at the Il15 locus contained no detectable NK cells. NK-cell deficiency did not impact fetal growth or viability. However, NK-cell deficiency caused major structural changes to the placenta, including expansion of the junctional zone and robust, early-onset activation of invasive trophoblast-guided spiral artery remodeling. Insummary, we successfully generated an NK-cell-deficient rat and showed, using this model,that NK cells dampen the extent of trophoblast invasion and delay trophoblast-directedspiral artery remodeling. This study furthers our understanding of the role of NK cells onuterine vascular remodeling, trophoblast invasion, and placental development.
  • 9.

    【2hr】Testicular adenosine to inosine RNA editing in the mouse is mediated by ADARB1

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    机译 ADARB1介导小鼠睾丸腺苷对肌苷RNA的编辑
    摘要：Adenosine to inosine (A-to-I) RNA editing occurs in a wide range of tissues and cell types and can be catalyzed by one of the two adenosine deaminase acting on double-stranded RNA enzymes, ADAR and ADARB1. Editing can impact both coding and noncoding regions of RNA, and in higher organisms has been proposed to function in adaptive evolution. Neither the prevalence of A-to-I editing nor the role of either ADAR or ADARB1 has been examined in the context of germ cell development in mammals. Computational analysis of whole testis and cell-type specific RNA-sequencing data followed by molecular confirmation demonstrated that A-to-I RNA editing occurs in both the germ line and in somatic Sertoli cells in two targets, Cog3 and Rpa1. Expression analysis demonstrated both Adar and Adarb1 were expressed in both Sertoli cells and in a cell-type dependent manner during germ cell development. Conditional ablation of Adar did not impact testicular RNA editing in either germ cells or Sertoli cells. Additionally, Adar ablation in either cell type did not have gross impacts on germ cell development or male fertility. In contrast, global Adarb1 knockout animals demonstrated a complete loss of A-to-I RNA editing in spite of normal germ cell development. Taken together, these observations demonstrate ADARB1 mediates A-to-I RNA editing in the testis and these editing events are dispensable for male fertility in an inbred mouse strain in the lab.
  • 10.

    【2hr】Role of Stro1+/CD44+ stem cells in myometrial physiology and uterine remodeling during pregnancy

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    机译 Stro1 + / CD44 +干细胞在妊娠期子宫肌层生理和子宫重构中的作用
    摘要：Regulation of myometrial functions during pregnancy has been considered the result of the integration of endocrine and mechanical signals. Nevertheless, uterine regeneration is poorly understood, and the cellular source within the gravid uterus is largely unexplored.In this study, we isolated and quantified the myometrial stem cells (MSC) population from pregnant female Eker rat uteri, by using Stro1/CD44 surface markers. We demonstrated that prior parity significantly increased the percentage of Stro1+/CD44+ MSC because of injured tissue response. Interestingly, we established that Stro1+/CD44+ MSC respond efficiently to physiological cues when they were treated in vitro under different dose-dependent pregnant rat serum.Previous studies reveal strong regulatory links between O2 availability and stem cell function. Based on these premises, cell proliferation assays showed that isolated Stro1+/CD44+ MSC possess a higher proliferative rate under hypoxic versus normoxic conditions. We also detected a total of 37 upregulated and 44 downregulated hypoxia-related genes, which were differentially expressed in Stro1+/CD44+ MSC, providing an alternative approach to infer into complex molecular mechanisms such as energy metabolism, inflammatory response, uterine expansion, and/or remodeling.Since these cells preferentially grow under low oxygen conditions, we propose that the increase of the rat uterus during pregnancy involves myometrial oxygen consumption, thereby enhancing MSC proliferation. Moreover, pregnancy-induced mechanical stretching results in hypoxic conditions, ultimately creating an environment that promotes stem cell proliferation and further uterine enlargement, which is essential for a successful pregnancy. In summary, all of these data support that rat Stro1+/CD44+ MSC contribute to uterine enlargement during pregnancy.
  • 11.

    【2hr】Vitamin D suppresses oxidative stress-induced microparticle release by human umbilical vein endothelial cells

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    机译 维生素D抑制人脐静脉内皮细胞氧化应激诱导的微粒释放
    摘要：Endothelial microparticle (MP) release was increased in numerous cardiovascular diseases including preeclampsia. Oxidative stress is a potent inducer of endothelial dysfunction. In this study, we aimed to investigate if vitamin D could protect endothelial cells (ECs) from MP release induced by oxidative stress. Endothelial cell (from human umbilical vein) oxidative stress was induced by cultivation of cells under lowered oxygen condition (2%O2) for 48 h and cells cultured under standard condition (21%O2) served as control. 1,25(OH)2D3 was used as bioactive vitamin D. Using annexin-V as a marker of released MP assessed by flow cytometry and cytochrome c reduction assay to measure EC superoxide generation, we found that MP release and superoxide generation were significantly increased when cells were cultured under 2%O2, which could be significantly inhibited by 1,25(OH)2D3. To study the potential mechanisms of 1,25(OH)2D3 protective effects on ECs, EC expression of endothelial nitric oxide synthase (eNOS), p-eNOSSer1177, p-eNOSThr495, caveolin-1, extracellular signal-regulated kinase (ERK), p-ERK, Akt, p-AktSer473, Rho-associated coiled-coil protein kinase 1 (ROCK1), and vitamin D receptor were determined. Microparticle expression of eNOS and caveolin-1 were also determined. We found that under lowered oxygen condition, 1,25(OH)2D3 could upregulate EC eNOS, p-eNOSSer1177, and p-AktSer473 expression, but inhibit cleaved ROCK1 expression. The upregulatory and inhibitory effects induced by 1,25(OH)2D3 were dose dependent. Strikingly, we also found that oxidative stress-induced decrease in ratio of eNOS and caveolin-1 expression in MP could be attenuated when 1,25(OH)2D3 was present in culture. These results suggest that upregulation of eNOSSer1177 and AktSer473 phosphorylation and inhibition of ROCK1 cleavage in EC and modulation of eNOS and caveolin-1 expression in MP could be plausible mechanisms of vitamin D protective effects on ECs.
  • 12.

    【2hr】Contributions to the dynamics of cervix remodeling prior to term and preterm birth

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    机译 对足月和早产前子宫颈重塑动力学的贡献
    摘要：Major clinical challenges for obstetricians and neonatologists result from early cervix remodeling and preterm birth. Complications related to cervix remodeling or delivery account for significant morbidity in newborns and peripartum mothers. Understanding morphology and structure of the cervix in pregnant women is limited mostly to the period soon before and after birth. However, evidence in rodent models supports a working hypothesis that a convergence of factors promotes a physiological inflammatory process that degrades the extracellular collagen matrix and enhances biomechanical distensibility of the cervix well before the uterus develops the contractile capabilities for labor. Contributing factors to this remodeling process include innervation, mechanical stretch, hypoxia, and proinflammatory mediators. Importantly, the softening and shift to ripening occurs while progesterone is near peak concentrations in circulation across species. Since progesterone is required to maintain pregnancy, the premise of this review is that loss of responsiveness to progesterone constitutes a common final mechanism for remodeling the mammalian cervix in preparation for birth at term. Various inputs are suggested to promote signaling between stromal cells and resident macrophages to drive proinflammatory processes that advance the soft cervix into ripening. With infection, pathophysiological processes may prematurely drive components of this remodeling mechanism and lead to preterm birth. Identification of critical molecules and pathways from studies in various rodent models hold promise for novel endpoints to assess risk and provide innovative approaches to treat preterm birth or promote the progress of ripening at term.
  • 13.

    【2hr】Vascular endothelial growth factors C and D may promote angiogenesis in theprimate ovulatory follicle

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    机译 血管内皮生长因子C和D可能促进血管生成灵长类卵泡卵泡
    摘要：Angiogenesis in the ovary occurs rapidly as the ovarian follicle transforms into a mature corpus luteum. Granulosa cells produce vascular endothelial growth factor A (VEGFA) in response to the ovulatory gonadotropin surge. VEGFA is established as a key mediator of angiogenesis in the primate ovulatory follicle. To determine if additional VEGF family members may be involved in angiogenesis within the ovulatory follicle, cynomolgus monkeys (Macaca fascicularis) received gonadotropins to stimulate multiple follicular development, and human chorionic gonadotropin (hCG) substituted for the luteinizing hormone surge to initiate ovulatory events. Granulosa cells of monkey ovulatory follicles contained mRNA and protein for VEGFC and VEGFD before and after hCG administration. VEGFC and VEGFD were detected in monkey follicular fluid and granulosa cell-conditioned culture media, suggesting that granulosa cells of ovulatory follicles secrete both VEGFC and VEGFD. To determine if these VEGF family members can stimulate angiogenic events, monkey ovarian microvascular endothelial cells (mOMECs) were obtained from monkey ovulatory follicles and treated in vitro with VEGFC and VEGFD. Angiogenic events are mediated via three VEGF receptors; mOMECs express all three VEGF receptors in vivo and in vitro. Exposure of mOMECs to VEGFC increased phosphorylation of AKT, while VEGFD treatment increased phosphorylation of both AKT and CREB. VEGFC and VEGFD increasedmOMEC migration and the formation of endothelial cell sprouts in vitro. However, onlyVEGFD increased mOMEC proliferation. These findings suggest that VEGFC and VEGFD may workin conjunction with VEGFA to stimulate early events in angiogenesis of the primateovulatory follicle.
  • 14.

    【2hr】Placental Hypoxia During Early Pregnancy Causes Maternal Hypertension and Placental Insufficiency in the Hypoxic Guinea Pig Model

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    机译 妊娠早期胎盘缺氧会导致母体高血压和缺氧豚鼠模型的胎盘供血不足。
    摘要：Chronic placental hypoxia is one of the root causes of placental insufficiencies that result in pre-eclampsia and maternal hypertension. Chronic hypoxia causes disruption of trophoblast (TB) development, invasion into maternal decidua, and remodeling of maternal spiral arteries. The pregnant guinea pig shares several characteristics with humans such as hemomonochorial placenta, villous subplacenta, deep TB invasion, and remodeling of maternal arteries, and is an ideal animal model to study placental development. We hypothesized that chronic placental hypoxia of the pregnant guinea pig inhibits TB invasion and alters spiral artery remodeling. Time-mated pregnant guinea pigs were exposed to either normoxia (NMX) or three levels of hypoxia (HPX: 16%, 12%, or 10.5% O2) from 20 day gestation until midterm (39–40 days) or term (60–65 days). At term, HPX (10.5% O2) increased maternal arterial blood pressure (HPX 57.9 ± 2.3 vs. NMX 40.4 ± 2.3, P < 0.001), decreased fetal weight by 16.1% (P < 0.05), and increased both absolute and relative placenta weights by 10.1% and 31.8%, respectively (P < 0.05). At midterm, there was a significant increase in TB proliferation in HPX placentas as confirmed by increased PCNA and KRT7 staining and elevated ESX1 (TB marker) gene expression (P < 0.05). Additionally, quantitative image analysis revealed decreased invasion of maternal blood vessels by TB cells. In summary, this animal model of placental HPX identifies several aspects of abnormal placental development, including increased TB proliferation and decreased migration and invasion of TBs into the spiral arteries, the consequences of which are associated with maternal hypertension and fetal growth restriction.
  • 15.

    【2hr】Calcitonin Gene-Related Peptide Rescues Proximity Associations of Its Receptor Components, Calcitonin Receptor-Like Receptor and Receptor Activity-Modifying Protein 1, in Rat Uterine Artery Smooth Muscle Cells Exposed to Tumor Necrosis Factor Alpha

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    机译 降钙素基因相关肽拯救了暴露于肿瘤坏死因子α的大鼠子宫动脉平滑肌细胞中其受体成分，降钙素受体样受体和受体活性修饰蛋白1的邻近关系
    摘要：Calcitonin gene-related peptide (CALCB), adrenomedullin (ADM), and ADM2/intermedin play critical roles in vascular adaptation during pregnancy through calcitonin receptor-like receptor (CALCRL) and receptor activity-modifying proteins (RAMPs). This study was designed to assess the predominant RAMP that associates with CALCRL to form a functional receptor in the rat uterine artery smooth muscle (RUASM). We also determined if these receptor component associations are decreased by tumor necrosis factor (TNF) alpha and if CALCB, ADM, or ADM2 can rescue CALCRL/RAMP associations. Using proximity ligation assay in RUASM cells, this study shows that CALCRL predominantly associates with RAMP1 forming a CALCB receptor, and minimally with RAMP2 and RAMP3 that confer specificity for ADM and ADM2. However, knockdown of RAMP1 mRNA increases the interaction between CALCRL and RAMP3 without affecting the association of CALCRL and RAMP2. Furthermore, CALCB, ADM, and ADM2 have no effects on the associations of CALCRL with any of the RAMPs in RUASM cells. Interestingly, CALCB reverses the TNFalpha-induced decreases in CALCRL/RAMP1 associations. Furthermore, CALCB increases ERK1/2 phosphorylation in a time-dependent manner in RUASM, and the protective effect of CALCB on TNFalpha-induced inhibition of CALCRL/RAMP1 associations was significantly blocked in presence of ERK inhibitor (PD98059). In conclusion, this study demonstrates that CALCRL predominantly associates with RAMP1 forming a CALCB-specific receptor complex in RUASM cells, which is dissociated by TNFalpha. Rescue of TNFalpha-induced dissociation of CALCRL/RAMP1 complex by CALCB in RUASM cells suggests a potential use of CALCB in developing therapeutic strategies for pregnancy-related complications that are vulnerable to abnormal levels of TNFalpha, such as fetal growth restriction and preeclampsia.
  • 16.

    【2hr】Random Allocation of Blastomere Descendants to the Trophectoderm and ICM of the Bovine Blastocyst

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    机译 卵裂球后代到牛胚囊的滋养层和ICM的随机分配
    摘要：The first lineage specification during mammalian embryo development can be visually distinguished at the blastocyst stage. Two cell lineages are observed on the embryonic-abembryonic axis of the blastocyst: the inner cell mass and the trophectoderm. The timing and mechanisms driving this process are still not fully understood. In mouse embryos, cells seem prepatterned to become certain cell lineage because the first cleavage plane has been related with further embryonic-abembryonic axis at the blastocyst stage. Nevertheless, this possibility has been very debatable. Our objective was to determine whether this would be the case in another mammalian species, the bovine. To achieve this, cells of in vitro produced bovine embryos were traced from the 2-cell stage to the blastocyst stage. Blastocysts were then classified according to the allocation of the labeled cells in the embryonic and/or abembryonic part of the blastocyst. Surprisingly, we found that there is a significant percentage of the embryos (∼60%) with labeled and nonlabeled cells randomly distributed and intermingled. Using time-lapse microscopy, we have identified the emergence of this random pattern at the third to fourth cell cycle, when cells started to intermingle. Even though no differences were found on morphokinetics among different embryos, these random blastocysts and those with labeled cells separated by the embryonic-abembryonic axis (deviant pattern) are significantly bigger; moreover deviant embryos have a significantly higher number of cells. Interestingly, we observed that daughter cells allocation at the blastocyst stage is not affected by biopsies performed at an earlier stage.
  • 17.

    【2hr】The Unfolded Protein Response Regulates Uterine Myocyte Antioxidant Responsiveness During Pregnancy

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    机译 妊娠过程中未表达的蛋白质反应调节子宫肌细胞抗氧化反应。
    摘要：There is considerable evidence that implicates oxidative stress in the pathophysiology of human pregnancy complications. However, the role and the mechanism of maintaining an antioxidant prosurvival uterine environment during normal pregnancy is largely unresolved. Herein we report that the highly active uterine unfolded protein response plays a key role in promoting antioxidant activity in the uterine myocyte across gestation. The unfolded protein response (UPR) senses the accumulation of misfolded proteins in the endoplasmic reticulum (ER) and activates a signaling network that consists of the transmembrane protein kinase eukaryotic translation initiation factor 2 alpha kinase 3/PKR-like-ER kinase (EIF2AK3), which acts to decrease protein translation levels, allowing for a lowered need for protein folding during periods of ER stress. However, independent of its translational regulatory capacity, EIF2AK3-dependent signals elicit the activation of the transcription factor, nuclear factor erythroid 2-like 2 (NFE2L2) in response to oxidative stress. NFE2L2 binds to antioxidant response elements in the promoters of a variety of antioxidant genes that minimize the opportunities for generation of reactive oxygen intermediates. Our analysis demonstrates that in the absence of EIF2AK3, the uterine myocyte experiences increased levels of reactive oxygen species due to decreased NFE2L2 activation. Elevated levels of intracellular reactive oxygen species were observed in the EIF2AK3 null cells, and this was associated with the onset of apoptotic cell death. These findings confirm the prosurvival and antioxidant role of UPR-mediated EIF2AK3 activation in the context of the human uterine myocyte.
  • 18.

    【2hr】Function and Hormonal Regulation of GATA3 in Human First Trimester Placentation

    包量

    机译 GATA3在人的早孕胎盘中的功能和激素调控
    摘要：Pregnancies resulting from fresh in vitro fertilization (IVF) cycles exposed to supraphysiologic estrogen levels have been associated with higher rates of low birth weight and small for gestational age babies. We identified GATA3, a transcription factor selectively expressed in the trophectoderm during the blastocyst stage of embryo development, in an upstream analysis of genes that were differentially methylated in chorionic villus samples between IVF and non-IVF infertility treatment pregnancies. In this study, we investigate the hypothesis that GATA3 is hormonally regulated and plays an important functional role in trophoblast migration, invasion, and placentation. We found that GATA3 expression was hormonally regulated by estradiol in HTR8/SVneo first trimester trophoblast cells; however, no change in expression was seen with progesterone treatment. Furthermore, GATA3 knockdown resulted in decreased HTR8/SVneo cell migration and invasion compared with controls. RNA sequencing of GATA3 knockdown cells demonstrated 96 differentially regulated genes compared with controls. Genes known to play an important role in cell-cell and cell-extracellular matrix interactions, cell invasion, and placentation were identified, including CTGF, CYR61, ADAMTS12, and TIMP3. Our results demonstrate estradiol down-regulates GATA3, and decreased GATA3 expression leads to impaired trophoblast cell migration and invasion, likely through regulation of downstream genes important in placentation. These results are consistent with clinical data suggesting that supraphysiologic estrogen levels seen in IVF pregnancies may play an important role in attenuated trophoblast migration, invasion, and impaired placentation. GATA3 appears to be an important regulator of placentation and may play a role in impaired outcomes associated with fresh IVF cycles.
  • 19.

    【2hr】Sperm-Coating Beta-Defensin 126 Is a Dissociation-Resistant Dimer Produced by Epididymal Epithelium in the Bovine Reproductive Tract

    包量

    机译 精子涂层的β-防御素126是一种抗解离的二聚体，由牛生殖道的附睾上皮产生。
    摘要：Beta-defensins are innate immune molecules, often described as antimicrobial peptides because of their bactericidal activity and are now known to have diverse additional functions, including cell signaling, chemoattraction, immunoregulation, and reproduction. In humans and primates, beta-defensin 126 has been shown to regulate the ability of sperm to swim through cervical mucus and to protect sperm from attack by the female immune system during transit toward the oviduct. Bovine beta-defensin 126 (BBD126) is the ortholog of human defensin 126, and computational analysis here revealed significant conservation between BBD126 and other mammalian orthologs at the N-terminus, although extensive sequence differences were detected at the C-terminus, implying possible species-specific roles for this beta-defensin in reproduction. We had previously demonstrated preferential expression of this and related beta-defensin genes in the bovine male reproductive tract, but no studies of bovine beta-defensin proteins have been performed to date. Here, we analyzed BBD126 protein using a monoclonal antibody (a-BBD126) generated against a 14 amino acid peptide sequence from the secreted fragment of BBD126. The specificity of a-BBD126 was validated by testing against the native form of the peptide recovered from bovine caudal epididymal fluid and recombinant BBD126 generated using a prokaryotic expression system. Western blot analysis of the native and recombinant forms showed that BBD126 exists as a dimer that was highly resistant to standard methods of dissociation. Immunohistochemical staining using a-BBD126 demonstrated BBD126 protein expression by epithelial cells of the caudal epididymis and vas deferens from both mature and immature bulls. BBD126 could also be seen (by confocal microscopy) to coat caudal sperm, with staining concentrated on the tail of the sperm cells. This study is the first to demonstrate beta-defensin 126 protein expression in the bovine reproductive tract and on bull sperm. Its dissociation-resistant dimeric structure is likely to have important functional implications for the role of BBD126 in bovine reproduction.
  • 20.

    【2hr】Hypoxic Stress Forces Irreversible Differentiation of a Majority of Mouse Trophoblast Stem Cells Despite FGF4

    包量

    机译 低氧胁迫迫使大多数小鼠滋养层干细胞尽管FGF4不可逆分化。
    摘要：Hypoxic, hyperosmotic, and genotoxic stress slow mouse trophoblast stem cell (mTSC) proliferation, decrease potency/stemness, and increase differentiation. Previous reports suggest a period of reversibility in stress-induced mTSC differentiation. Here we show that hypoxic stress at 0.5% O2 decreased potency factor protein by ∼60%–90% and reduced growth to nil. Hypoxia caused a 35-fold increase in apoptosis at Day 3 and a 2-fold increase at Day 6 above baseline. The baseline apoptosis rate was only 0.3%. Total protein was never less than baseline during hypoxic treatment, suggesting 0.5% O2 is a robust, nonmorbid stressor. Hypoxic stress induced ∼50% of trophoblast giant cell (TGC) differentiation with a simultaneous 5- to 6-fold increase in the TGC product antiluteolytic prolactin family 3, subfamily d, member 1 (PRL3D1), despite the presence of fibroblast growth factor 4 (FGF4). Hypoxia-induced TGC differentiation was also supported by potency and differentiation mRNA marker analysis. FGF4 removal at 20% O2 committed cell fate towards irreversible differentiation at 2 days, with similar TGC percentages after an additional 3 days of culture under potency conditions when FGF4 was readded or under differentiation conditions without FGF4. However, hypoxic stress required 4 days to irreversibly differentiate cells. Runted stem cell growth, forced differentiation of fewer cells, and irreversible differentiation limit total available stem cell population. Were mTSCs to respond to stress in a similar mode in vivo, miscarriage might occur as a result, which should be tested in the future.
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