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Biomedical subjects

Kui Liu

Publications and source records attributed to Kui Liu.

At least 19 recordsLinked to original sources
PubMed2007

Infertility caused by retardation of follicular development in mice with oocyte-specific expression of Foxo3a.

In recent years, mammalian oocytes have been proposed to have important roles in the orchestration of ovarian follicular development and fertility. To determine whether intra-oocyte Foxo3a, a component of the phosphatidylinositol 3-kinase (PI3K) signaling pathway, influences follicular development and female fertility, a transgenic mouse model was generated with constitutively active Foxo3a expressed in oocytes. We found that the female transgenic mice were infertile, which was caused by retarded oocyte growth and follicular development, and anovulation. Further mechanistic studies revealed that the constitutively active Foxo3a in oocytes caused a dramatic reduction in the expression of bone morphogenic protein 15 (Bmp15), connexin 37 and connexin 43, which are important molecules for the establishment of paracrine and gap junction communications in follicles. Foxo3a was also found to facilitate the nuclear localization of p27(kip1) in oocytes, a cyclin-dependent kinase (Cdk) inhibitor that may serve to inhibit oocyte growth. The results from the current study indicate that Foxo3a is an important intra-oocyte signaling molecule that negatively regulates oocyte growth and follicular development. Our study may therefore give some insight into oocyte-borne genetic aberrations that cause defects in follicular development and anovulation in human diseases, such as premature ovarian failure.

Animals↗
PubMed2006

Functional corpora lutea are formed in matrix metalloproteinase inhibitor-treated plasminogen-deficient mice.

Corpus luteum (CL) formation involves dramatic tissue remodeling and angiogenesis. To determine the functional roles of the plasminogen activator and matrix metalloproteinase (MMP) systems in these processes, we have studied CL formation and function in plasminogen (plg)-deficient mice, with or without treatment with the broad-spectrum synthetic MMP inhibitor galardin. Both the adult pseudopregnant CL model and the gonadotropin-primed immature mouse model were used. We found that CL formed normally not only in plasminogen-deficient mice and in galardin-treated wild-type mice, but also in galardin-treated plg-deficient mice, suggesting that neither of the plasminogen activator and MMP systems is essential for CL formation. Nevertheless, in plg-deficient mice, serum progesterone levels were reduced by approximately 50%, and the progesterone levels were not reduced further by galardin treatment. When CL from plg-deficient mice were stained for several molecular markers for CL development and regression, they appeared healthy and vascularized, and were indistinguishable from CL from wild-type mice. This implies that the reduced progesterone levels were not caused by impaired CL formation. Taken together, our data suggest that neither plasmin nor MMPs, alone or in combination, are required for CL formation. Therefore, the tissue remodeling and angiogenesis processes during CL formation may be mediated by redundant protease systems. However, the reduced serum progesterone levels in plg-deficient mice suggest that plasmin, but not MMPs, plays a role in maintenance of luteal function. This role may be performed through proteolytic activation of growth factors and other paracrine factors.

Animals↗
PubMed2006

Control of mammalian oocyte growth and early follicular development by the oocyte PI3 kinase pathway: new roles for an old timer.

A large amount of information has accumulated over the past decade on how gonadotropins, steroid hormones and growth factors regulate development of the mammalian ovarian follicle. Moreover, the bi-directional communication between mammalian oocytes and their surrounding somatic (granulosa) cells has also been shown to be crucial for this process. The intra-ovarian factors, or more specifically, the intra-oocyte signaling pathways that control oocyte growth and early follicular development are largely unknown, however. Based on both in vitro studies and in vivo functional studies using gene-modified mouse models, this review focuses on the key features of the phosphatidylinositol 3 kinase (PI3K) pathway in growing mouse oocytes and on the novel functions of the oocyte PI3K pathway in controlling mammalian oocyte growth and follicular development that have come to light only recently. We propose that the PI3K pathway in the oocyte, which is activated by granulosa cell-produced Kit ligand (KL) via the oocyte-surface receptor Kit, may serve as an intra-oocyte network that regulates both oocyte growth and the early development of ovarian follicles.

Animals↗
PubMed2006

Successful ovulation in plasminogen-deficient mice treated with the broad-spectrum matrix metalloproteinase inhibitor galardin.

Many studies have suggested the hypothesis that the plasminogen activator (PA) system and the matrix metalloproteinase (MMP) system, either separately or in combination, may provide the proteolytic activity that is required for rupture of the follicular wall at the time of ovulation. Our recent studies on ovulation in plasminogen (plg)-deficient mice have, however, shown that plasmin is not required for normal ovulation, leading us to the hypothesis that MMPs may be a more important source of proteolysis for this process. To investigate the role of MMPs and also the possibility of a functional overlap or synergy between the MMP and PA systems during ovulation, we have studied ovulation efficiency in wild-type and plg-deficient mice treated with the broad-spectrum MMP inhibitor galardin. We found that in both wild-type mice and heterozygous plg-deficient (plg+/-) mice that had been treated with galardin prior to ovulation, there was a mild (18-20%) reduction in ovulation efficiency. Surprisingly, galardin treatment of plg-deficient (plg-/-) mice only caused an additional 14% reduction in ovulation efficiency as compared to vehicle-treated plg-/- mice. Our data therefore suggest that although MMPs may play a role in degradation of the follicular wall, they may not be obligatory for ovulation. In contrast to previous studies on tissue remodeling during wound healing and placental development, we have demonstrated that there is no obvious functional overlap or synergy between the PA and MMP systems, which has previously been thought to be essential for the ovulatory process.

Animals↗
PubMed2006

Stem cell factor (SCF)-kit mediated phosphatidylinositol 3 (PI3) kinase signaling during mammalian oocyte growth and early follicular development.

The bi-directional communication between mammalian oocytes and their surrounding granulosa cells has been shown to be crucial for ovarian follicular development. Studies on molecules derived from the oocytes, such as growth differentiation factor-9 (GDF-9) and bone morphogenetic protein-15 (BMP-15), have attracted great interest during the past decade, and it is common knowledge nowadays that these molecules participate in the bi-directional dialogue between the oocytes and their surrounding granulosa cells as well as follicular development. However, signaling molecules and pathways inside mammalian oocytes that control oocyte growth and early development of ovarian follicles, which may be monitored by factors produced by granulosa cells, have not been studied extensively. Based on our own data as well as ovarian phenotypes observed in several gene modified mice strains that were generated for studies of signal transduction, immunology and cancer, the current review focuses on the key features of the activation of oocyte phosphatidylinositol 3 kinase (PI3 kinase) pathway and its possible roles during mammalian oocyte growth and follicular development. We propose that the cascade from the granulosa cell-produced stem cell factor (SCF) to the oocyte surface SCF receptor Kit, and to the oocyte PI3 kinase pathway, may play an important role in the regulation of growth rate of mammalian oocytes, as well as in the activation and development of ovarian follicles.

Animals↗
PubMed2006

Development of nocturnal urinary control in Chinese children younger than 8 years old.

OBJECTIVES: To estimate the development of nocturnal urinary control (NUC) with age in Chinese children younger than 8 years of age using cross-sectional and retrospective surveys. METHODS: We used a cross-sectional survey of 4754 children (1 to 8 years old), a retrospective investigation of 2745 children younger than 9 years old, and an anonymous questionnaire of 8222 children 9 to 18 years old . The children without NUC were subdivided into infant (1 to 3 years old), preschool age (4 to 6 years old), and primary school (7 to 8 years old) groups. RESULTS: The response rate to the cross-sectional and retrospective surveys was 90% and 89%, respectively. In the cross-sectional survey, the prevalence of children attaining NUC was 52% for those younger than 2 years of age, 76% for those aged 2 to 3 years, and 93% at age 8. Girls were more likely than boys to acquire NUC earlier. In the retrospective survey, the prevalence of children attaining NUC before age 2 was 17% and was 72% for those aged 2 to 3 years, and 98% by age 8. The proportion of nonmonosymptomatic bedwettings in children without NUC was 14%. Arousal difficulty and a positive family history were found in 67% and 11% of children with nocturnal wetting, respectively. The severity of bedwetting and arousal difficulty was significantly greater in infants than in preschool and school-age children. CONCLUSIONS: The results from the cross-sectional and retrospective surveys showed that the most important period of attaining NUC is 2 to 3 years of age. Nearly 90% of children attained NUC by the age of 5.

Adolescent↗
PubMed2005

An epidemiological study of primary nocturnal enuresis in Chinese children and adolescents.

AIMS: Assessment of the prevalence of primary nocturnal enuresis (PNE) and its risk factors in Chinese children and adolescents in the central areas of mainland China. METHODS: A cross-sectional study of PNE was performed by distributing 11799 self-administered questionnaires to parents of 5-18-year-old students in 32 schools of Henan province China. The questionnaire asked about sociodemographic data, PNE data, physical or psychological disorders, and family stressors. The PNE children were divided into a pediatric group (age 5-12) and an adolescent group (age 13-18). RESULTS: The response rate was 88% (10383/11799) in which 10088 (85.5%) were qualified to enter the final statistical analysis. The overall prevalence of PNE was 4.07% (95%CI 3.68-4.46) and that of marked PNE was 1.46% (95%CI 1.23-1.69). PNE was significantly more in boys than in girls. The prevalence decreased with age without gender bias. Of all enuretic children, 21.17% had daytime urinary symptoms and 22.87% had a positive family history. Only 6.08% of PNE had sought professional help. The episodic severity of PNE, associated daytime symptoms, positive family history, and seeking for professional help in adolescent group were significantly higher than those of pediatric group. Age, inhabitation (living in rural or urban areas), arousal dysfunction, associated daytime symptoms and family history were found to be significant predictors of marked PNE. Among PNE cases with a positive family history, there was no significant difference in the familial distribution between boys and girls. CONCLUSIONS: The prevalence of age-related PNE from Chinese school children is lower than those reported from western countries and other Asian countries. Age, inhabitation (rural or urban), arousal dysfunction, associated daytime symptom and family history are significant as predictors of marked PNE. The misconceptions among Chinese parents require health education intervention.

Adolescent↗
PubMed2005

Epistatic suppression of systemic lupus erythematosus: fine mapping of Sles1 to less than 1 mb.

Sle is a susceptibility locus for systemic autoimmunity derived from the lupus-prone NZM2410 mouse. The New Zealand White-derived suppressive modifier Sles1 was identified as a specific modifier of Sle1 and prevents the development of IgG anti-chromatin autoantibodies mediated by Sle1 on the C57BL/6 (B6) background. Fine mapping of Sles1 with truncated congenic intervals localizes it to a approximately 956-kb segment of mouse chromosome 17. Sles1 completely abrogates the development of activated T and B cell populations in B6.Sle1. Despite this suppression of the Sle1-mediated cell surface activation phenotypes, B6.Sle1 Sles1 splenic B cells still exhibit intrinsic ERK phosphorylation. Classic genetic complementation tests using the nonautoimmmune 129/SvJ mouse suggests that this strain possesses a Sles1 allele complementary to that of New Zealand White, as evidenced by the lack of glomerulonephritis, splenomegaly, and antinuclear autoantibody production seen in (129 x B6.Sle1 Sles1)F(1)s. These findings localize and characterize the suppressive properties of Sles1 and implicate 129 as a useful strain for aiding in the identification of this elusive epistatic modifier gene.

Animals↗
PubMed2005

Formation of E-cadherin-mediated cell-cell adhesion activates AKT and mitogen activated protein kinase via phosphatidylinositol 3 kinase and ligand-independent activation of epidermal growth factor receptor in ovarian cancer cells.

E-cadherin is a well characterized adhesion molecule that plays a major role in epithelial cell adhesion. Based on findings that expression of E-cadherin is frequently lost in human epithelial cancers, it has been implicated as a tumor suppressor in carcinogenesis of most human epithelial cancers. However, in ovarian cancer development, our data from the current study showed that E-cadherin expression is uniquely elevated in 86.5% of benign, borderline, and malignant ovarian carcinomas irrespective of the degree of differentiation, whereas normal ovarian samples do not express E-cadherin. Thus, we hypothesize that E-cadherin may play a distinct role in the development of ovarian epithelial cancers. Using an E-cadherin-expressing ovarian cancer cell line OVCAR-3, we have demonstrated for the first time that the establishment of E-cadherin mediated cell-cell adhesions leads to the activation of Akt and MAPK. Akt activation is mediated through the activation of phosphatidylinositol 3 kinase, and both Akt and MAPK activation are mediated by an E-cadherin adhesion-induced ligand-independent activation of epidermal growth factor receptor. We have also demonstrated that suppression of E-cadherin function leads to retarded cell proliferation and reduced viability. We therefore suggest that the concurrent formation of E-cadherin adhesion and activation of downstream proliferation signals may enhance the proliferation and survival of ovarian cancer cells. Our data partly explain why E-cadherin is always expressed during ovarian tumor development and progression.

Cadherins↗
PubMed2005

Activation of Akt (PKB) and suppression of FKHRL1 in mouse and rat oocytes by stem cell factor during follicular activation and development.

Although communications between mammalian oocytes and their surrounding granulosa cells mediated by the Kit-Kit ligand (KL, or stem cell factor, SCF) system have been proven to be crucial for follicular development, Kit downstream signaling pathways in mammalian oocytes are largely unknown. In this study, by using ovaries and isolated oocytes from postnatal mice and rats, we demonstrated for the first time that components of the PI3 kinase pathway, the serine/threonine kinase Akt (PKB) which enhances cellular proliferation and survival, and an Akt substrate FKHRL1 which is a transcription factor that leads to apoptosis and cell cycle arrest, are expressed in mammalian oocytes. By using an in vitro oocytes culture system, we found that oocytes-derived Akt and FKHRL1 are regulated by SCF. Treatment of cultured oocytes with SCF cannot only rapidly phosphorylate and activate Akt, but also simultaneously phosphorylate and may therefore functionally suppress FKHRL1, through the action of PI3 kinase. Together with our in situ hybridization and immunohistochemistry data that Akt and FKHRL1 are mostly expressed in oocytes in primordial and primary ovaries and reports that FKHRL1 gene-deficient mice exhibited excessive activation from primordial to primary follicles as well as enlarged oocyte sizes, we suppose that in mammalian oocytes, actions of granulosa cell derived SCF on primordial to primary follicle transition and subsequent follicle development may involve activation of Akt and inhibition of FKHRL1 activities in oocytes. The role of oocyte's Akt may be to enhance follicle development and the role of oocyte's FKHRL1 may be to inhibit follicle development. We propose that the cascade from granulosa cell SCF to oocyte Kit-PI3 kinase-Akt-FKHRL1 may play an important role to regulate the growth rate of mammalian oocytes and hypothetically also the oocyte secretion of factors that may regulate the activation and early development of ovarian follicles.

Animals↗
PubMed2005

Elevated soluble ICAM-1 levels induce immune deficiency and increase adiposity in mice.

Elevated soluble intercellular adhesion molecule-1 (sICAM-1) levels have been found in many pathological conditions, including obesity. To determine the effects of elevated sICAM-1 on immune responses and metabolism, we generated a transgenic mouse model overexpressing the extracellular domain of mouse ICAM-1 in the liver. The mice, showing 10-fold higher sICAM-1 levels than wild-type mice, presented elevated neutrophil count. Despite this, after intraperitoneal injection of thioglycollate, neutrophil recruitment into the peritoneal cavity was reduced, and the delayed macrophage recruitment was also affected in the transgenic mice compared with wild-type mice. Inhibition of contact hypersensitivity response in the sICAM-1 transgenic mice was comparable to ICAM-1-deficient mice and characterized by significantly less ear swelling and inflammatory cell infiltration than in wild-type mice. sICAM-1transgenic mice were more susceptible to weight gain on a Western-type diet than wild-type mice, and older animals showed excessive fat accumulation, again reminiscent of ICAM-1-deficient mice. Together, these data indicate that sICAM-1 interferes with ICAM-1-mediated cell-cell interactions, which could produce immune-suppressant effects and alteration of metabolism in persons with high levels of this soluble adhesion receptor.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Sle1ab mediates the aberrant activation of STAT3 and Ras-ERK signaling pathways in B lymphocytes.

The Sle1ab genomic interval on murine chromosome 1 mediates the loss of immune tolerance to chromatin resulting in antinuclear Abs (ANA) production in the lupus-prone NZM2410 mouse. Global gene expression analysis was used to identify the molecular pathways that are dysregulated at the initiation of B lymphocyte autoimmunity in B6.Sle1ab mice. This analysis identified that STAT3 and ras-ERK signaling pathways are aberrantly activated in Sle1ab B lymphocytes, consistent with increased production of IL-6 by splenic B lymphocytes and monocytes in B6.Sle1ab mice. In vitro treatment of splenic mononuclear cells isolated from ANA-positive Sle1ab mice with anti-IL-6 Ab or AG490, an inhibitor of STAT3 signaling pathway, suppressed ANA production in short-term culture, indicating that this pathway was essential to the production of autoantibodies. In vivo treatment of ANA-positive B6.Sle1ab mice with the ras pathway inhibitor, perillyl alcohol, suppressed the increase of ANA. These findings identify IL-6 as a early key cytokine in Sle1ab-mediated disease development and indicate that the STAT3 and ras-ERK signaling pathways are potential therapeutic targets for treating systemic lupus erythematosus.

Animals↗
PubMed2005

Involvement of molecules related to angiogenesis, proteolysis and apoptosis in implantation in rhesus monkey and mouse.

We have established the well-defined cycling, pseudo-pregnant and pregnant rhesus monkey models, and used these to analyze expression of the common molecules specifically related to angiogenesis, apoptosis or proteolysis, such as vascular endothelial growth factor (VEGF) and its receptors KDR, flt-1, flt-4 and flk-1, basic fibroblast growth factor (bFGF) and its receptors Flg, transforming growth factor-alpha and beta1 (TGF-a/beta1), and TGF-beta1 receptor type I (TbetaR-I) and type II (TbetaR-II), as well as steroidogenic acute regulatory protein (StAR), tissue type plasminogen activator/urokinase plasminogen activator/plasminogen activator inhibitor type 1 (tPA/uPA/PAI-1) and matrix matalloproteinase type 1, -3/tissue inhibitor matalloproteinase type 1, -2, -3 (MMP-1, -3/TIMP-1, -2, -3), Fas/FasL, BcL-2/Bax, in the corpus luteum (CL), in the functional layer of the endometrium and in the materno-fetal boundary of the implantation site. We have demonstrated that: expression of these molecules in the monkey CL, endometrium and materno-fetal boundary of the implantation site is correlated well with CL functional and vascular development and with the processes involved in the establishment of the implantation window as well as with the early stages of placentation. A coordinated increase in tPA and its inhibitor PAI-1 expression in the monkey and rat CL may be instrumental in initiating luteal regression in both species, and correlated well with the timing of the closure of the implantation window, whereas high uPA activity in the CL is important for the early formation of the CL and for maintaining its function which is closely correlated to the period of establishment of the implantation window. Apoptosis, proteolysis and angiogenesis occur in the CL and in the endometrium during the time of establishment of the implantation window, as well as in the materno-fetal boundary of the implantation site at the early stages of placentation. It seems that these processes occur in these tissues in a coordinated and time- and cell-dependent manner, and are reliant on each other. Based on these observations, we have designed experiments to test the actions of some related available compounds on mouse implantation, used alone or in combination. The preliminary data showed that the compounds which could effectively affect apoptosis, angiogenesis or proteolysis in the implantation site were capable of effectively inhibiting implantation by acting on the endometrium and/or on the CL. Furthermore, the combined use of these compounds produced an obvious additive effect on inhibiting implantation. This finding suggested this may be a good approach for developing an anti-implantation agent.

Animals↗
PubMed2005

Pharmacokinetics and acute safety of inhaled testosterone in postmenopausal women.

This was a preliminary feasibility study to assess the pharmacokinetics and acute safety of a single dose of orally inhaled testosterone via the AERx system, a novel handheld aerosol delivery system in postmenopausal women. Twelve postmenopausal women stabilized on oral estrogen therapy were treated with a single dose of testosterone (0.1, 0.2, or 0.3 mg) by inhalation. Plasma concentrations of sex steroids were measured between 1 and 360 minutes. Pulmonary and cardiovascular adverse events were monitored. Inhaled testosterone produced a dose-dependent increase in plasma total and free testosterone. At the highest dose (0.3 mg), total and free testosterone increased from baseline (mean +/- SD, 0.6 +/- 0.3 nmol/L, 2.5 +/- 1.0 pmol/L) to maximum levels of 62.6 +/- 20.4 nmol/L (total) and 168.2 +/- 50.2 pmol/L(free), occurring 1 to 2 minutes after dosing. A 2-compartment model best described the free and total testosterone pharmacokinetic profile. Dihydrotestosterone levels were higher than baseline at 60 minutes (P < .0002). Estradiol did not vary, but sex hormone binding globulin and albumin fell. There were no adverse events related to the treatment. Administration of inhaled testosterone is safe and achieves a supraphysiologic "pulse" kinetic profile of total and free testosterone with a rapid return to pretreatment levels.

Administration, Inhalation↗
PubMed2005

[Effects of temperature on Brontispa longissima population growth].

The study on the development, survival and reproduction of Brontispa longissima at 5 different temperature (16, 20, 24, 28, 32 degrees C) showed that the threshold temperature and effective accumulative temperature for the whole generations of Brontispa longissima were 11.08 degrees C and 966.22 degrees C, respectively, and 4-5 generations could occur in a year in Danzhou, Hainan Province. One generation had the highest survival rate (92.5%) at 28 degrees C, but failed to survive at 32 degrees C. Brontispa longissimna reared at 28 degrees C had the greatest intrinsic increasing rate (r(m) = 0.0260), finite increasing capacity (lamda = 1.0263), and population trend index (I = 50.8). The shortest mean generation time (123.1 d) and population doubling time (26.7 d) were obtained at 20 degrees C and 28 degrees C, respectively. The temperature from 24 degrees C to 28 degrees C was suitable for the development and reproduction of Brontispa longissima.

Animals↗
PubMed2004

Effect of gender and device mouthpiece shape on bolus insulin aerosol delivery using the AERx pulmonary delivery system.

PURPOSE: A study was designed to compare differences in insulin aerosol deposition profiles in healthy male and female subjects, as well as examine the effect of mouthpiece cross-sectional shape, volume, and taper on deposition profiles using a developmental AERx pulmonary delivery system. METHODS: Six mouthpieces were screened in the laboratory, and three were selected for clinical investigation: a cylindrical mouthpiece with constant-cross-sectional area, an elliptical mouthpiece with constant-cross-sectional area, and a tapered elliptical mouthpiece with an exit cross-sectional area equal to one half the entrance cross-sectional area. RESULTS: There was no significant difference in the lung dose or in the deposition pattern between males and females (p > 0.05, by ANOVA). The cross-sectional shape of the mouthpiece had no significant effect on the clinical lung dose or the deposition pattern (p > 0.05, by ANOVA), although in vitro testing showed lower emitted dose values with the tapered elliptical mouthpiece (by ANOVA and Duncan's multiple range test, alpha = 0.05). Using the tapered mouthpiece in the clinic resulted in significantly more deposition on the mouthpiece itself when compared to the nontapered mouthpieces. CONCLUSION: Inhalation of insulin using the AERx system was insensitive to differences in male and female respiratory tract geometry across all mouthpiece designs examined.

Adult↗
PubMed2003

Tissue-type plasminogen activator and its inhibitor plasminogen activator inhibitor type 1 are coordinately expressed during ovulation in the rhesus monkey.

Ovulation is a gonadotropin-controlled process that is essential for the propagation of all mammalian species. In the present study, we used a pregnant mare serum gonodotropin/human chorionic gonadotropin (hCG)-induced, synchronized ovulation model in rhesus monkeys and systematically investigated the roles of the plasminogen activator (PA) system in the ovulatory process of the primate. At different follicular developmental stages throughout the periovulatory period, samples of ovaries, granulosa cells, and theca-interstitial cells as well as follicular fluid were collected, and levels of PA and PA inhibitor type-1 (PAI-1) were evaluated by fibrin overlay, reverse fibrin overlay, Northern blot analysis, and in situ hybridization, respectively. We showed that in response to an injection of ovulation-triggering hCG, which mimics the preovulatory surge of LH in the circulation, granulosa cell-derived tissue-type PA (tPA) was substantially elevated in preovulatory follicles and reached its maximum level just before ovulation. Although theca-interstitial cell-derived PAI-1 was also stimulated by pregnant mare serum gonodotropin and hCG treatments, however, the maximum level of PAI-1 appeared 12 h earlier than that of tPA. When ovulation approached, accompanying the highest tPA level in the preovulatory follicles, the follicular PAI-1 level declined dramatically to its minimum value. Moreover, our data on the expression of follicular PA and PAI-1 over the periovulatory period were reinforced by results obtained at the mRNA level. Our data suggest that the coordinated expression of tPA and PAI-1 may be of importance for the follicular rupture process during ovulation in the primate.

Aging↗