[Genetic Causation Analysis of Hyperandrogenemia Testing Indicators and Preeclampsia]. / é«˜é›„æ¿€ç´ è¡€ç—‡æ£€æµ‹æŒ‡æ ‡ä¸Žå­ç—«å‰æœŸçš„é—ä¼ å› æžœæ€§ç ”ç©¶.

Objective: Some epidemiological studies have shown that pregnant women who develop preeclampsia (PE) have elevated levels of testosterone in their maternal plasma compared to women with normal blood pressure during pregnancy, revealing a potential association between hyperandrogenism in women and PE. To explore the causal relationship between hyperandrogenism and PE, this study selected total testosterone (TT), bioavailable testosterone (BIOT), and sex hormone binding globulin (SHBG) as exposure factors and PE and chronic hypertension with superimposed PE as disease outcomes. Two-sample Mendelian randomization (MR) analyses were used to genetically dissect the causal relationships between the three exposure factors (TT, BIOT, and SHBG) and the outcomes of PE and chronic hypertension with superimposed PE. Methods: Two independent genome-wide association study (GWAS) databases were used for the two-sample MR analysis. In the GWAS data of female participants from the UK Biobank cohort, single nucleotide polymorphisms (SNPs) associated with TT, BIOT, and SHBG were analyzed, involving 230454, 188507, and 188908 samples, respectively. GWAS data on PE and chronic hypertension with superimposed PE from the Finnish database were used to calculate SNP, involving 3556 PE cases and 114735 controls, as well as 38 cases of chronic hypertension with superimposed PE and 114735 controls. To meet the assumptions of instrumental relevance and independence in MR analysis, SNPs associated with exposure were identified at the genome-wide level (P<5.0×10-8), and those in linkage disequilibrium interference were excluded based on clustering thresholds of R 2<0.001 and an allele distance greater than 10000 kb. Known confounding factors, including previous PE, chronic kidney disease, chronic hypertension, diabetes, systemic lupus erythematosus, or antiphospholipid syndrome, were also identified and the relevant SNPs were removed. Finally, we extracted the outcome data based on the exposure-related SNPs in the outcome GWAS, integrating exposure and outcome data, and removing palindromic sequences. Five genetic causal analysis methods, including inverse variance-weighted method (IVW), MR-Egger regression, weighted median method, simple mode method, and weighted mode method, were used to infer causal relationships. In the IVW, it was assumed that the selected SNPs satisfied the three assumptions and provided the most ideal estimate of the effect. IVW was consequently used as the primary analysis method in this study. Considering the potential heterogeneity among the instrumental variables, random-effects IVW was used for MR analysis. The results were interpreted using odds ratios (OR) and the corresponding 95% confidence interval (CI) to explain the impact of exposure factors on PE and chronic hypertension with superimposed PE. If the CI did not include 1 and had a P value less than 0.05, the difference was considered statistically significant. Sensitivity analysis was conducted to assess heterogeneity and pleiotropy. Heterogeneity was examined using Cochran's Q test, and pleiotropy was assessed using MR-Egger intercept analysis. Additionally, leave-one-out analysis was conducted to examine whether individual SNPs were driving the causal associations. To further validate the findings, MR analyses were performed using the same methods and outcome variables, but with different exposure factors, including waist-to-hip ratio adjusted for BMI (WHRadjBMI) and 25-hydroxyvitamin D levels, with MR results for WHRadjBMI and PE serving as the positive controls and MR results for 25-hydroxyvitamin D levels and PE as the negative controls. Results: According to the criteria for selecting genetic instrumental variables, 186, 127, and 262 SNPs were identified as genetic instrumental variables significantly associated with testosterone indicators TT, BIOT, and SHBG. MR analysis did not find a causal relationship between the TT, BIOT, and SHBG levels and the risk of developing PE and chronic hypertension with superimposed PE. The IVW method predicted that genetically predicted TT (OR [95% CI]=1.018 [0.897-1.156], P=0.78), BIOT (OR [95% CI]=1.11 [0.874-1.408], P=0.392), and SHBG (OR [95% CI]=0.855 [0.659-1.109], P=0.239) were not associated with PE. Similarly, genetically predicted TT (OR [95% CI]=1.222 [0.548-2.722], P=0.624), BIOT (OR [95% CI]=1.066 [0.242-4.695], P=0.933), and SHBG (OR [95% CI]=0.529 [0.119-2.343], P=0.402) were not significantly associated with chronic hypertension with superimposed PE. Additionally, MR analysis using the MR-Egger method, weighted median method, simple mode method, and weighted mode method yielded consistent results, indicating no significant causal relationship between elevated testosterone levels and PE or chronic hypertension with superimposed PE. Heterogeneity was observed for SHBG in the analysis with PE (Cochran's Q test, P=0.01), and pleiotropy was detected for BIOT in the analysis with PE (MR-Egger intercept analysis, P=0.014), suggesting that the instrumental variables did not affect PE through BIOT. Other instrumental variables did not show significant heterogeneity or pleiotropy. Leave-one-out analysis confirmed that the results of the MR analysis were not driven by individual instrumental variables. Consistent with previous MR studies, the results of the control MR analyses using WHRadjBMI and 25-hydroxyvitamin D levels supported the accuracy of the MR analysis approach and the methods used in this study. Conclusion: The MR analysis results suggest that current genetic evidence does not support a causal relationship between TT, BIOT, and SHBG levels and the development of PE and chronic hypertension with superimposed PE. This study suggests that elevated testosterone may be a risk factor for PE but not a direct cause.

[Analysis of Risk Factors for Recurrent Pregnancy Loss in Patients Undergoing in vitro Fertilization-Embryo Transfer]. / 体外受精-èƒšèƒŽç§»æ¤æ‚£è€ ä¸­åå¤å¦Šå¨ ä¸¢å¤±çš„å±é™©å› ç´ åˆ†æž.

Objective: Recurrent pregnancy loss (RPL) presents a formidable challenge for individuals undergoing in vitro fertilization-embryo transfer (IVF-ET), forming both a clinical dilemma and a focal point for scientific inquiry. This study endeavors to investigate the intricate interplay between clinical features, such as age, body mass index (BMI), and waist-to-hip ratio (WHR), and routine laboratory parameters, including sex hormones, blood composition, liver and thyroid functions, thyroid antibodies, and coagulation indicators, in RPL patients undergoing IVF-ET. By meticulously analyzing these variables, we aim to uncover the latent risk factors predisposing individuals to RPL. Identifying potential factors such as advanced maternal age, obesity, and insulin resistance will provide clinicians with vital insights and empirical evidence to strengthen preventive strategies aimed at reducing miscarriage recurrence. Methods: This retrospective case-controlled study included RPL patients who underwent IVF-ET treatment at Sun Yat-sen Memorial Hospital, Sun Yat-sen University, between January 2012 and March 2021 as the case cohort, compared with women receiving assisted reproductive treatment due to male infertility as the control cohort. The fasting peripheral blood was collected 5 days before the first menstrual cycle at least 12 weeks after the last abortion. The clinical characteristics and relevant laboratory indexes of the two groups were compared. Employing both univariate and multivariate logistic regression analyses, we sought to unearth potential high-risk factors underlying RPL. Additionally, a linear trend analysis was conducted to assess the linear relationship between total testosterone (TT) levels and the number of miscarriages. Results: In contrast to the control cohort, the RPL cohort exhibited significant increases in age, BMI, and WHR (P<0.05). Notably, TT levels were markedly lower in the RPL cohort (P=0.022), while no significant differences were observed between the two groups concerning basal follicle-stimulating hormone, luteinizing hormone, estradiol, progesterone, prolactin levels, and anti-Müllerian hormone levels (P>0.05). Moreover, fasting insulin (FINS) levels and HOMA-IR index were notably elevated in the RPL cohort relative to the control cohort (P<0.001), although no significant differences were observed in fasting blood glucose levels (P>0.05). Furthermore, the neutrophil (NEU) count and NEU-to-lymphocyte ratio were notably higher in the RPL cohort (P<0.01). Univariate logistic regression analysis identified several factors, including age≥35 years old, BMI≥25 kg/m2, WHR>0.8, FINS>10 mU/L, HOMA-IR>2.14, NEU count>6.3×109 L－1, and an elevated NEU/lymphocyte ratio (NLR), as significantly increasing the risk of RPL (P<0.05). Although TT levels were within the normal range for both cohorts, higher TT levels were associated with a diminished RPL risk (odds ratio [OR]=0.67, 95% confidence interval [CI]: 0.510-0.890, P=0.005). After adjustments for confounding factors, age≥35 years old (OR=1.91, 95% CI: 1.06-3.43), WHR>0.8 (OR=2.30, 95% CI: 1.26-4.19), and FINS>10 mU/L (OR=4.50, 95% CI: 1.30-15.56) emerged as potent risk factors for RPL (P<0.05). Conversely, higher TT levels were associated with a reduced RPL risk (OR=0.59, 95% CI: 0.38-0.93, P=0.023). Furthermore, the linear trend analysis unveiled a discernible linear association between TT levels and the number of miscarriages (P trend=0.003), indicating a declining trend in TT levels with escalating miscarriage occurrences. Conclusion: In patients undergoing IVF-ET, advanced maternal age, lower TT levels, increased WHR, and elevated FINS levels emerged as potent risk factors for RPL. These findings provide clinicians with valuable insights and facilitate the identification of patients who are at high risks and the formulation of preventive strategies to reduce the recurrence of miscarriages.

Placental inflammatory injury induced by chlorinated polyfluorinated ether sulfonate (F-53B) through NLRP3 inflammasome activation.

Chlorinated polyfluorinated ether sulfonate, commercially known as F-53B, has been associated with adverse birth outcomes. However, the reproductive toxicology of F-53B on the placenta remains poorly understood. To address this gap, we examined the impact of F-53B on placental injury and its underlying molecular mechanisms in vivo. Pregnant C57BL/6 J female mice were randomly allocated to three groups: the control group, F-53B 0.8 µg/kg/day group, and F-53B 8 µg/kg/day group. After F-53B exposure through free drinking water from gestational day (GD) 0.5-14.5, the F-53B 8 µg/kg/day group exhibited significant increases in placental weights and distinctive histopathological alterations, including inflammatory cell infiltration, heightened syncytiotrophoblast knots, and a loosened trophoblastic basement membrane. Within the F-53B 8 µg/kg/day group, placental tissue exhibited increased apoptosis, as indicated by increased caspase3 activation. Furthermore, F-53B potentially induced the NF-κB signaling pathway activation through IκB-α phosphorylation. Subsequently, this activation upregulated the expression of inflammatory cytokines and components of the NLRP3 inflammasome, including activated caspase1, IL-1ß, IL-18, and cleaved gasdermin D (GSDMD), ultimately leading to pyroptosis in the mouse placenta. Our findings reveal a pronounced inflammatory injury in the placenta due to F-53B exposure, suggesting potential reproductive toxicity at concentrations relevant to the human population. Further toxicological and epidemiological investigations are warranted to conclusively assess the reproductive health risks posed by F-53B.

THBS1 regulates decidualization in URSA.

Inappropriate endometrial stromal decidualization has been implied as an important reason of many pregnancy-related complications, such as unexplained recurrent spontaneous abortion (URSA), preeclampsia and intrauterine growth restriction. Here, we observed that thrombospondin-1 (THBS1), an adhesive glycoprotein, was significantly downregulated in endometrial decidual cells from patients with URSA. The immortalized human endometrial stromal cell line T-HESC was used to investigate the possible THBS1-mediated regulation of decidualization. In vitro experiments found that the expression level of THBS1 increased with the normal decidualization process. Knockdown of THBS1 could decrease the expression levels of prolactin (PRL) and insulin-like growth factor binding protein-1 (IGFBP1), two acknowledged human decidualization markers. Whereas, THBS1 overexpression could reverse these effects. The RNA sequencing results demonstrated that the extracellular regulated protein kinases (ERK) signaling pathway was potentially affected by the knockdown of THBS1. And we further confirmed that the regulation of THBS1 on decidualization was achieved through the ERK signaling pathway by the treatment of inhibitors. Moreover, knockdown of THBS1 in pregnant mice could impair decidualization and result in an increased fetus resorption rate. Altogether, our study demonstrated a crucial role of THBS1 in the pathophysiological process of URSA and provided some new insights into the research of pregnancy-related complications.

Loss of histone reader Phf7 leads to immune pathways activation via endogenous retroviruses during spermiogenesis.

Genetic studies have elucidated the critical roles of Phf7 in germline development in animals; however, the exact etiology of Phf7 mutations leading to male infertility and the possibility of mechanism-based therapy are still unclear and warrant further investigation. Using the Phf7 knockout mouse model, we verified that genetic defects were responsible for male infertility by preventing histone-to-protamine exchange, as previously reported. The deficiency of spermatogenesis caused by Phf7 deletion through the endogenous retrovirus-mediated activation of the immune pathway is a common mechanism of infertility. Furthermore, we identified PPARα as a promising target of immunity and inflammation in the testis, where endogenous retroviruses are suppressed, and Phf7 as a crucial regulator of endogenous retrovirus-mediated immune regulation and revealed its role as an epigenetic reader. The loss of Phf7 activates immune pathways, which can be rescued by the PPARα agonist astaxanthin. These results showed that astaxanthin is a potential therapeutic agent for treating male infertility. The findings in our study provide insights into the molecular mechanisms underlying male infertility and suggest potential targets for future research and therapeutic development.

The effect of letrozole overlapped with gonadotropin on IVF outcomes in women with DOR or aged over 40 years old with repeated cycles.

BACKGROUND: Evaluating the efficacy of letrozole overlapped with gonadotropin-modified letrozole protocol (mLP) for diminished ovarian reserve (DOR) or advanced-age women with repeated cycles. METHODS: This is a retrospectively registered, paired-match study including 243 women with DOR and 249 women aged over 40 years old who received in vitro fertilization (IVF) treatment. 123 women received stimulation with mLP (mLP group). GnRH agonist (GnRH-a) long, GnRH antagonist (GnRH-anta), and mild stimulation protocol were used as controls with 123 women in each group. We further analyzed 50 of 123 patients in the mLP group who have experienced more than one failed cycles with other ovarian stimulation protocols (non-mLP group). Clinical pregnancy rate (CPR), cumulative clinical pregnancy rate (CCPR), and live birth rate (LBR) were main outcomes. RESULTS: The CPR in the mLP group (38.46%) was significantly higher than mild stimulation (17.11%), but not significantly different from GnRH-a long (26.13%) and GnRH-anta (29.17%) group. The CCPR showed an increasing trend in the mLP group (33.33%) although without significance when compared with controls. The CCRP of GnRH-a long, GnRH-anta, mild stimulation group were 21.68%, 29.03%, and 13.04%, respectively. In women with repeated cycles, mLP achieved the higher available embryo rate (P < 0.05), the top-quality embryo rate, the CPR (P < 0.001), and the LBR (P < 0.001). Further study showed a positive correlation between testosterone and the number of oocytes retrieved in the mLP group (r = 0.395, P < 0.01). CONCLUSION: The mLP may be effective for aged or DOR women who have experienced previous cycle failure by improving the quality of embryos, the CPR, and the LBR. An increasing serum testosterone level may reflect follicular growth during ovarian stimulation.

Environmental pollutant pre- and polyfluoroalkyl substances are associated with electrocardiogram parameters disorder in adults.

Environmental pollutants exposure might disrupt cardiac function, but evidence about the associations of per- and polyfluoroalkyl substances (PFASs) exposure and cardiac conduction system remains sparse. To explore the associations between serum PFASs exposure and electrocardiogram (ECG) parameters changes in adults, we recruited 1229 participants (mean age: 55.1 years) from communities of Guangzhou, China. 13 serum PFASs with detection rate > 85% were analyzed finally. We selected 6 ECG parameters [heart rate (HR), PR interval, QRS duration, Bazett heart rate-corrected QT interval (QTc), QRS electric axis and RV5 + SV1 voltage] as outcomes. Generalized linear models (GLMs) and Bayesian kernel machine regression (BKMR) model were conducted to explore the associations of individual and joint PFASs exposure and ECG parameters changes, respectively. We detected significant associations of PFASs exposure with decreased HR, QRS duration, but with increased PR interval. For example, at the 95th percentile of 6:2 Cl-PFESA, HR and QRS duration were - 6.98 [95% confidence interval (CI): - 9.07, - 4.90] and - 6.54(95% CI: -9.05, -4.03) lower, but PR interval was 7.35 (95% CI: 3.52, 11.17) longer than those at the 25th percentile. Similarly, significant joint associations were observed in HR, PR interval and QRS duration when analyzed by BKMR model.

Gut Microbiota Dysbiosis Ameliorates in LNK-Deficient Mouse Models with Obesity-Induced Insulin Resistance Improvement.

PURPOSE: To investigate the potential role of gut microbiota in obesity-induced insulin resistance (IR). METHODS: Four-week-old male C57BL/6 wild-type mice (n = 6) and whole-body SH2 domain-containing adaptor protein (LNK)-deficient in C57BL/6 genetic backgrounds mice (n = 7) were fed with a high-fat diet (HFD, 60% calories from fat) for 16 weeks. The gut microbiota of 13 mice feces samples was analyzed by using a 16 s rRNA sequencing analysis. RESULTS: The structure and composition of the gut microbiota community of WT mice were significantly different from those in the LNK-/- group. The abundance of the lipopolysaccharide (LPS)-producing genus Proteobacteria was increased in WT mice, while some short-chain fatty acid (SCFA)-producing genera in WT groups were significantly lower than in LNK-/- groups (p < 0.05). CONCLUSIONS: The structure and composition of the intestinal microbiota community of obese WT mice were significantly different from those in the LNK-/- group. The abnormality of the gut microbial structure and composition might interfere with glucolipid metabolism and exacerbate obesity-induced IR by increasing LPS-producing genera while reducing SCFA-producing probiotics.

Sex-specific meiosis responses to Gsdf in medaka (Oryzias latipes).

The meiotic entry of undifferentiated germ cells is sexually specific and strictly regulated by the testicular or ovarian environment. Germline stem cells with a set of abnormal sex chromosomes and associated autosomes undergo defective meiotic processes and are eventually eliminated by yet to be defined post-transcriptional modifications. Herein, we report the role of gsdf, a member of BMP/TGFß family uniquely found in teleost, in the regulation of meiotic entry in medaka (Oryzias latipes) via analyses of gametogenesis in gsdf-deficient XX and XY gonads in comparison with their wild-type siblings. Several differentially expressed genes, including the FKB506-binding protein 7 (fkbp7), were significantly upregulated in pubertal gsdf-deficient gonads. The increase in alternative pre-mRNA isoforms of meiotic synaptonemal complex gene sycp3 was visualized using Integrative Genomics Viewer and confirmed by real-time qPCR. Nevertheless, immunofluorescence analysis showed that Sycp3 protein products reduced significantly in gsdf-deficient XY oocytes. Transmission electron microscope observations showed that normal synchronous cysts were replaced by asynchronous cysts in gsdf-deficient testis. Breeding experiments showed that the sex ratio deviation of gsdf-/- XY gametes in a non-Mendelian manner might be due to the non-segregation of XY chromosomes. Taken together, our results suggest that gsdf plays a role in the proper execution of cytoplasmic and nuclear events through receptor Smad phosphorylation and Sycp3 dephosphorylation to coordinate medaka gametogenesis, including sex-specific mitotic divisions and meiotic recombination.

MiR-93-5p promotes granulosa cell apoptosis and ferroptosis by the NF-kB signaling pathway in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age. miR-93-5p has been reported to be elevated in granulosa cells of PCOS patients. However, the mechanism by which miR-93-5p drives granulosa cell (GC) progression remains unclear. Thus, this study focuses on the roles and mechanisms of miR-93-5p in the GCs of PCOS. Methods: KGN cells have similar ovarian physiological characteristics and are used to study the function and regulatory mechanism of GCs. In this study, KGN cells were transfected with si-NC, si-miR93-5p, oe-NC and oe-miR93-5p. A cell counting kit-8 assay, flow cytometry and western blotting were performed to observe the proliferation and apoptosis of KGN in different groups. Subsequently, the levels of reactive oxygen species, malondialdehyde, GPX4, SLC7A11 and Nrf2, which are indicators of ferroptosis, were measured by a dihydroethidium fluorescent dye probe, biochemical kit, western blotting and reverse transcription quantitative polymerase chain reaction. Ultimately, bioinformatic analysis and experimental methods were used to examine the interaction between miR-93-5p and the NF-κB signaling pathway. Results: miR-93-5p was upregulated in the GCs of PCOS patients. Overexpression of miR-93-5p promoted apoptosis and ferroptosis in KGN cells, while knockdown of miR-93-5p showed the reverse effect. Biological analysis and subsequent experiments demonstrated that miR-93-5p negatively regulates the NF- κB signaling pathway. Conclusion: miR-93-5p promotes the apoptosis and ferroptosis in GC by regulating the NF-κB signaling pathway. Silencing of miR-93-5p protects against GC dysfunction. Our study identified miR-93-5p as a new molecular target for improving the function of GCs in PCOS patients.

Associations of prenatal exposure to perfluoroalkyl substances with preterm birth: A family-based birth cohort study.

Studies have investigated associations between maternal exposure to PFAS and preterm birth, but the impact of paternal and overall family exposure to PFAS mixtures on preterm birth remains unknown. To address this knowledge gap, a total of 355 preterm births and 481 controls were selected for a family-based birth cohort study in a coastal area of China, between 2016 and 2018. Seven PFAS, including perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorohexanesulfonic acid (PFHxS), perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA), were quantified in maternal, paternal and neonatal sera. Preterm birth was defined as live delivery at <37 completed gestational weeks. Bayesian kernel machine regression (BKMR) model was used to inspect the combined effect of family PFAS mixtures. Latent class analysis was used to identify family-level PFAS exposure profiles. Multiple linear regression analysis showed higher odds of preterm birth in association with higher maternal PFBA (OR = 1.16, 95%CI:1.09, 1.25), PFOA (OR = 1.51, 95%CI:1.27, 1.80), PFOS (OR = 2.07, 95%CI:1.70, 2.52) and PFNA (OR = 1.36, 95%CI: 1.01, 1.83), and neonatal PFBA (OR = 1.16, 95%CI:1.05,1.29), PFHxA (OR = 1.46, 95%CI:1.32, 1.62), PFHxS (OR = 1.15, 95%CI:1.05, 1.26) and PFNA (OR = 1.30, 95%CI:1.09,1.56). The associations were reversed between individual paternal PFAS exposures and preterm birth. At the family level, higher PFAS mixture concentration was associated with higher odds of preterm birth. In particular, higher PFNA and PFDA exposure was associated with greater preterm birth risk (OR = 2.55, 95%CI:1.45, 4.50). The PFAS-preterm association was modified by family-level seafood consumption. Our results suggest that higher family-level PFNA and PFDA exposure was associated with greater preterm birth risk, although the results for individual paternal, maternal and neonatal PFAS exposures were contradictory. If replicated in other coastal areas, these findings highlight a need to focus on the family triad and to consider seafood consumption when assessing the reproductive toxicity of PFAS exposure.

The Degree of Menstrual Disturbance Is Associated With the Severity of Insulin Resistance in PCOS.

Objective: Insulin resistance (IR) is an important determinant of the phenotype and morbidity of the polycystic ovary syndrome (PCOS). In this study, we aimed to figure out the association between the degree of menstrual disturbance and the severity of IR in women with PCOS. Design: It is a cross-sectional study conducted in an academic tertiary setting. Patients: The patients comprised five hundred twenty-seven women diagnosed with PCOS by the 2003 Rotterdam criteria and 565 controls with regular vaginal bleeding. Interventions: The interventions done for this study are medical history collection, physical examination, and blood sampling. Main outcome measures: The main outcome measures are body mass index (BMI), fasting glucose, fasting insulin, homeostatic model assessment for IR (HOMA-IR), and hormonal parameters. Results: Women with PCOS had a higher level of BMI, HOMA-IR, and HOMA-ß than controls, with a decreased level of sex hormone-binding globulin and QUICK I index. The luteinizing hormone (LH)/follicle-stimulating hormone (FSH), testosterone (T), antral follicle count (AFC), dehydroepiandrosterone sulfate, free androgen index, modified Ferriman-Gallwey score, and the incidence of delayed insulin peak increased with the degree of menstrual disturbance, although there was no significance for the latter four parameters. Women with vaginal bleeding intervals of 45-90 days had a relatively higher level of HOMA-IR and HOMA-ß, although it was adjusted with age and BMI than the other two groups. Similar results were observed in AUCI (area under the curve of insulin) and I/G [the ratio of AUCI and AUCG (area under the curve of glucose)]. Anovulatory women with vaginal bleeding episodes of less than 45 days tended to have higher glucose and insulin levels, area under the curve of glucose (AUCG), area under the curve of insulin (AUCI), HOMA-IR, and HOMA-ß but decreased QUICK I and Matsuda index than those who were ovulatory. Women with vaginal bleeding intervals of longer than 45 days who had hyperandrogenism (HA) showed a higher level of glucose, insulin, HOMA-IR, and HOMA-ß but lower QUICK I and Matsuda Index. Conclusions: In women with PCOS, the severity of IR, the LH/FSH ratio, and androgen level increased with a higher degree of disturbance in menstrual cyclicity (i.e., the vaginal bleeding intervals). Subgroup analysis indicated that the situation of HA may aggravate the disorder of glucose metabolism in women with PCOS. Overall, the interval between episodes of vaginal bleeding may be useful as a ready measure for predicting the severity of IR in PCOS.

Interpenetrating Polymer Network Hydrogels Formed Using Antibiotics as a Dynamic Crosslinker for Treatment of Infected Wounds.

Antibacterial hydrogels, particularly antibiotic-loaded hydrogels, are promising wound dressing materials for treatment of bacteria-infected wound. However, it is challenging to achieve sustained release of antibiotics from hydrogels through physical encapsulation of the antibiotics. Herein, an interpenetrating polymer network P(AA-co-HEMA)Gen hydrogel is reported with double crosslinking formed by free radical polymerization of 2-hydroxyethyl methacrylate (HEMA) and acrylic acid (AA), while using the antibiotic gentamicin (Gen) as the dynamic physical crosslinker. Gentamicin is incorporated into the hydrogel networks via electrostatic interaction between the carboxyl groups of poly(acrylic acid) and the amino groups of gentamicin, which leads to pH-responsive drug release and a significant increase in mechanical strength (i.e., elastic modulus, viscous modulus, and compressive modulus). More importantly, the hydrogels with optimal compositions demonstrate long-lasting antibacterial activity against both Gram-positive bacteria (Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli) over 28 d. The in vivo studies that are conducted in an S. aureus-infected full-thickness skin wound model demonstrate that the double crosslinking hydrogels loaded with gentamicin eliminate bacteria in the wounds more effectively and significantly accelerate wound healing as compared to 3M dressing and the control without any treatment. Taken together, this antibiotic-loaded interpenetrating polymer network hydrogel is potentially a promising wound dressing material for the treatment of bacteria-infected wound.

Temperature effect on vibrational properties of crystalline Dibenz[a,h]anthracene.

Vibrational properties associated with the intra- and intermolecular bonding of the crystalline Dibenz[a,h]anthracene at low temperatures are investigated by Raman scattering. A complete characterization of phonon spectra is given for this material. In the 120-150 K temperature region, several lattice modes show abrupt changes of splitting and the discontinuities in the temperature shift, but no emergence of new modes. Moreover, the intensity ratio of I68/38 is greater than 1 below 130 K. Meanwhile, the aromatic C-C stretching modes exhibit anomalous behaviors in frequencies, widths, and intensities at about 130 K. These spectroscopic results demonstrate a disorder-order transition occurred at about 130 K. However, the modes, corresponding to C-H out-of-plane bending, C-H in-plane bending, and/or C-H rocking, have no significant change in the whole temperature range. It indicates that the transition mainly results from the change of the tilt angle between the molecules. Our work is of great significance to understand the internal vibrational properties of Dibenz[a,h]anthracene, and it also provides considerable supports for the further study of this material.

Per- and perfluoroalkyl substances alternatives, mixtures and liver function in adults: A community-based population study in China.

Experimental evidence has shown that per- and polyfluoroalkyl substances (PFAS) alternatives and mixtures may exert hepatotoxic effects in animals. However, epidemiological evidence is limited. This research aimed to explore associations of PFAS and the alternatives with liver function in a general adult population. The study participants consisted of 1,303 adults from a community-based cross-sectional investigation in Guangzhou, China, from November 2018 to August 2019. We selected 13 PFAS with detection rates > 85% in serum samples and focused on perfluorooctane-sulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and their alternatives [6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA), 8:2 Cl-PFESA, and perfluorohexanoic acid (PFHxA)] as predictors of outcome. Six liver function biomarkers (ALB, ALT, AST, GGT, ALP, and DBIL) were chosen as outcomes. We applied regression models with restricted cubic spline function to explore correlations between single PFAS and liver function and inspected the combined effect of PFAS mixtures on liver by applying Bayesian kernel machine regression (BKMR). We discovered positive associations among PFAS and liver function biomarkers except for ALP. For example, compared with the 25th percentile of PFAS concentration, the level of ALT increased by 12.36% (95% CI: 7.91%, 16.98%) for ln-6:2 Cl-PFESA, 5.59% (95% CI: 2.35%, 8.92%) for ln-8:2 Cl-PFESA, 3.56% (95% CI: -0.39%, 7.68%) for ln-PFHxA, 13.91% (95% CI: 8.93%, 19.13%) for ln-PFOA, and 14.25% (95% CI: 9.91%, 18.77%) for ln-PFOS at their 75th percentile. In addition, higher exposed serum PFAS was found to be correlated with greater odds of abnormal liver function. Analysis from BKMR models also showed an adverse association between PFAS mixtures and liver function. The combined effect of the PFAS mixture appeared to be non-interactive, in which PFOS was the main contributor to the overall effect. Our findings provide evidence of associations between PFAS alternatives, PFAS mixtures, and liver function in the general adult population.

Single Cell Proteomics Profiling Reveals That Embryo-Secreted TNF-α Plays a Critical Role During Embryo Implantation to the Endometrium.

It has been long-known that endometrium-secreted cytokines play a critical role during embryo implantation. However, whether cytokines secreted from the embryo are relevant to the process of embryo implantation remains unclear. The concentration of cytokines in embryo culture medium was tested using a newly developed, high-sensitivity single-cell proteomic platform and evaluated in comparison to embryo quality and clinical outcome. The effect of TNF-α on embryo and endometrium Ishikawa cells was investigated using immunofluorescence staining, CCK-8 assay, TUNEL staining, and RT-qPCR. Of the 10 cytokines measured, only TNF-α concentration was significantly higher in the group with embryo implantation failure. Immunofluorescence staining showed that the expression of TNF-α was unevenly distributed in blastocysts, and the expression level was significantly correlated with the blastocyst inner cell mass (ICM) quality score. Gene profiling showed that addition of TNF-α led to increased expression of tumor necrosis factor receptor 1 (TNFR1) and apoptosis-related genes and that this could be inhibited by the TNF-α receptor inhibitor etanercept (ETA). In addition, an increased expression of water and ion channels, including AQP3, CFTR, ENaCA, and CRISP2 was also observed which could also be inhibited by ETA. Our results show that higher embryo-secreted TNF-α levels are associated with implantation failure through activation of TNF-α receptor, and TNF-α may be an independent predictor for pre-transfer assessment of the embryo development potential in IVF patients.

PCOS Phenotype in Unselected Populations Study (P-PUP): Protocol for a Systematic Review and Defining PCOS Diagnostic Features with Pooled Individual Participant Data.

The diagnosis of polycystic ovary syndrome (PCOS) remains challenging due to limited data regarding normative cut-offs for the diagnostic features in different subpopulations. We aim to conduct a systematic review, build a comprehensive repository of de-identified individual participant data (IPD), and define normative ranges and diagnostic cut-offs for all PCOS diagnostic features. We will conduct a systematic search of MEDLINE and EMBASE databases for studies that assessed PCOS diagnostic features in unselected women. Two reviewers will assess eligibility and perform quality appraisal. Authors of included studies will be invited to contribute IPD. Primary variables include directly assessed modified Ferriman Gallwey (mFG) scores; menstrual cycle lengths; follicle number per ovary (FNPO), ovarian volume (OV), anti-Müllerian hormone (AMH); circulating androgens, including total testosterone (TT), free testosterone, bioavailable testosterone, free androgen index (FAI), androstenedione (A4), and dehydroepiandrosterone sulphate (DHEAS). Normative ranges and cut-offs will be defined using cluster analysis. Monash University Human Research Ethics Committee granted ethical approval (26938/0 1/12/2020), all IPD will be de-identified and primary studies have ethical approval from their institutional ethics committees. Findings will clarify distinction between PCOS and non-PCOS populations, and inform the update of the international evidence-based guidelines for the assessment and management of PCOS.

Role of Transforming Growth Factor-ß1 in Regulating Fetal-Maternal Immune Tolerance in Normal and Pathological Pregnancy.

Transforming growth factor-ß (TGF-ß) is composed of three isoforms, TGF-ß1, TGF-ß2, and TGF-ß3. TGF-ß1 is a cytokine with multiple biological functions that has been studied extensively. It plays an important role in regulating the differentiation of immune cells and maintaining immune cell functions and immune homeostasis. Pregnancy is a carefully regulated process. Controlled invasion of trophoblasts, precise coordination of immune cells and cytokines, and crosstalk between trophoblasts and immune cells play vital roles in the establishment and maintenance of normal pregnancy. In this systematic review, we summarize the role of TGF-ß1 in regulating fetal-maternal immune tolerance in healthy and pathological pregnancies. During healthy pregnancy, TGF-ß1 induces the production of regulatory T cells (Tregs), maintains the immunosuppressive function of Tregs, mediates the balance of M1/M2 macrophages, and regulates the function of NK cells, thus participating in maintaining fetal-maternal immune tolerance. In addition, some studies have shown that TGF-ß1 is dysregulated in patients with recurrent spontaneous abortion or preeclampsia. TGF-ß1 may play a role in the occurrence and development of these diseases and may be a potential target for the treatment of these diseases.