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Abstract Background Diabetic cardiomyopathy (DCM) is a crucial complication of long-term chronic diabetes that can lead to myocardial hypertrophy, myocardial fibrosis, and heart failure. There is increasing evidence that DCM is associated with pyroptosis, a form of inflammation-related programmed cell death. Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor β superfamily, which regulates oxidative stress, inflammation, and cell survival to mitigate myocardial hypertrophy, myocardial infarction, and vascular injury. However, the role of GDF11 in regulating pyroptosis in DCM remains to be elucidated. This research aims to investigate the role of GDF11 in regulating pyroptosis in DCM and the related mechanism. Methods and results Mice were injected with streptozotocin (STZ) to induce a diabetes model. H9c2 cardiomyocytes were cultured in high glucose (50 mM) to establish an in vitro model of diabetes. C57BL/6J mice were preinjected with adeno-associated virus 9 (AAV9) intravenously via the tail vein to specifically overexpress myocardial GDF11. GDF11 attenuated pyroptosis in H9c2 cardiomyocytes after high-glucose treatment. In diabetic mice, GDF11 alleviated cardiomyocyte pyroptosis, reduced myocardial fibrosis, and improved cardiac function. Mechanistically, GDF11 inhibited pyroptosis by preventing inflammasome activation. GDF11 achieved this by specifically binding to apoptosis-associated speck-like protein containing a CARD (ASC) and preventing the assembly and activation of the inflammasome. Additionally, the expression of GDF11 during pyroptosis was regulated by peroxisome proliferator-activated receptor α (PPARα). Conclusion These findings demonstrate that GDF11 can treat diabetic cardiomyopathy by alleviating pyroptosis and reveal the role of the PPARα-GDF11-ASC pathway in DCM, providing ideas for new strategies for cardioprotection.

Abstract Background 17β-Estradiol (E2) is generally considered neuroprotective in humans. However, the current clinical use of estrogen replacement therapy (ERT) is based on the physiological dose of E2 to treat menopausal syndrome and has limited therapeutic efficacy. The efficacy and potential toxicity of superphysiological doses of ERT for menopausal neurodegeneration are unknown. Methods In this study, we investigated the effect of E2 with a supraphysiologic dose (0.5 mg/kg, sE2) on the treatment of menopausal mouse models established by ovariectomy. We performed the open field, Y-maze spontaneous alternation, forced swim tests, and sucrose preference test to investigate behavioral alterations. Subsequently, the status of microglia and neurons was detected by immunohistochemistry, HE staining, and Nissl staining, respectively. Real-time PCR was used to detect neuroinflammatory cytokines in the hippocampus and cerebral cortex. Using mass spectrometry proteomics platform and LC–MS/ MS-based metabolomics platform, proteins and metabolites in brain tissues were extracted and analyzed. BV2 and HT22 cell lines and primary neurons and microglia were used to explore the underlying molecular mechanisms in vitro. Results sE2 aggravated depression-like behavior in ovariectomized mice, caused microglia response, and increased proinflammatory cytokines in the cerebral cortex and hippocampus, as well as neuronal damage and glycerophospholipid metabolism imbalance. Subsequently, we demonstrated that sE2 induced the pro-inflammatory phenotype of microglia through ERα/NF-κB signaling pathway and downregulated the expression of cannabinoid receptor 1 in neuronal cells, which were important in the pathogenesis of depression. Conclusion These data suggest that sE2 may be nonhelpful or even detrimental to menopause-related depression, at least partly, by regulating microglial responses and glycerophospholipid metabolism.

The laser ablation of aluminum alloy 6061 was studied both experimentally and by computational modeling in this work. Six variations of the number of pulses of irradiation (1, 5, 10, 20, 50, and 100 pulses) combined with four different laser fluence (2.0 J/cm2, 1.5 J/cm2, 1.0 J/cm2, and 0.5 J/cm2) were chosen to study the effect of heat input and laser action time on microstructural changes and the generation of particulate pollutants. Laser fluence and the number of pulses of laser irradiation were found to have a direct influence on thermal diffusion and the ablation depth of aluminum alloy 6061. At a relatively high laser fluence (2 J/cm2) and with the application of 10 pulses of irradiation, ablation cracks were observed on the surface of aluminum alloy 6061 and the production of pollutant particles increased according to a particle counter. Maintaining the laser fluence at 0.5 J/cm2 while increasing the number of pulses of irradiation to 50 also enhanced the depth of thermal diffusion while laser ablation continued to occur. The occurrence of vaporization in the surface region was influenced largely by laser fluence and the number of pulses of irradiation, as evident from the simulation and from experimental results. The single laser pulse duration was 6 ns and the repetition rate was 1 s−1. This article provides a novelty numerical model which could reveal the metal alloys' evapotation at a high-fluence nanosecond laser ablation. A 3D computational model was used to predict the temperature variation upon laser irradiation in a solid material over time. The results of the model (thermal diffusion versus laser ablation) agreed well with the experimental results.

Abstract Background Polycystic ovary syndrome (PCOS) is a common endocrine disorder in premenopausal women, whose etiology remains uncertain, although it is known to be highly heterogeneous and genetically complex. PCOS often presents with hyperandrogenism symptoms. The present study aimed to determine whether polymorphisms in the FK-506 binding protein 5 (FKBP5) gene (androgen target gene) are associated with an association for PCOS and hyperandrogenism. Methods This is a case–control study, and association analyses were conducted. A total of 13 single-nucleotide polymorphisms (SNPs) in the FKBP5 gene were evaluated in 775 PCOS patients who were diagnosed based on the Rotterdam Standard and 783 healthy Chinese Han women. Associations between FKBP5 SNPs and hormone levels were investigated. These 13 SNPs were genotyped using the Sequenom MassARRAY system, and an association analysis between the phenotype and alleles and genotypes were conducted. Results The genotype frequencies for the rs1360780 and rs3800373 SNPs differed significantly between the PCOS cases and healthy controls (p = 0.025, OR is 1.63 (1.05–2.53) and p = 0.029, OR is 1.59 (1.03–2.45) respectively under co-dominant model). Moreover, the genotype frequencies and genetic model analysis for the SNPs rs1360780, rs9470080, rs9296158, rs1043805 and rs7757037 differed significantly between the hyperandrogenism and non-hyperandrogenism groups of PCOS patients. The TT genotype of rs1360780, the TT genotype of rs9470080, the TT genotype of rs1043805 or the GG genotype of rs7705037 (ORs are 2.13 (1.03–4.39), 1.81 (1.03–3.17), 2.94 (1.32–6.53) and 1.72 (1.04–2.84) respectively) were correlated with androgen level of PCOS patients. Conclusion Our study showed that FKBP5 gene polymorphisms are associated with PCOS generally (rs1360780 and rs3800373) and with the hyperandrogenism subtype specifically (rs1360780, rs9470080, rs9296158, rs1043805 and rs7757037).

Sperm motility and structural integrity are essential for successful fertilization in vivo, and any hindrance of the correct assembly of the axoneme and peri-axonemal structures in the sperm flagellum can lead to fertility problems. While there has been considerable advancement in studying diseases related to the flagellum, the underlying mechanisms that control sperm movement are not yet fully understood. In this study, we reveal that the tetratricopeptide repeat protein 6 (Ttc6) gene, expressed mainly in the testes, plays a crucial role in maintaining male fertility in mice. We further demonstrate that the knockout of Ttc6 in mice results in decreased sperm motility and induces an abnormal circular swimming pattern, consequently leading to male subfertility. Morphological analysis showed an atypical hairpin-like appearance of the spermatozoa, and ultrastructural studies showed unsheathed flagella at the juncture between the midpiece and principal piece. Collectively, these findings suggest that TTC6 plays an essential role in maintaining the stability of the annulus region of the sperm flagellum, thus ensuring the swift and directed motion of sperm.

Human female fecundity decreases irreversibly as chronological age rises, adversely affecting oocyte quality, consequently worsening pregnancy outcomes and increasing the extent of birth defects. The first-line type 2 diabetes treatment metformin has been associated with delayed aging and reduction of oxidative stress; yet it remains unclear if metformin confers any benefits for oocytes from aged mice, particularly in the context of the assisted human reproductive technology (ART) known as in vitro maturation (IVM). Here, we found that adding metformin into the M16 culture medium of oocytes from aged mice significantly improved both oocyte maturation and early embryonic development. This study showed that metformin reduced the extent of meiotic defects and maintained a normal distribution of cortical granules (CGs). RNA-seq analysis of metformin-treated oocytes revealed genes apparently involved in the reduction of mitochondrial ROS. Further, the results supported that the metformin improved mitochondrial function, reduced apoptosis, increased the extent of autophagy, and reduced mitochondrial ROS via SIRT3-mediated acetylation status of SOD2K68 in oocytes from aged mice. Thus, this finding demonstrated a protective effect for metformin against the decreased quality of oocytes from aged mice to potentially improve ART success rates and illustrated a potential strategy to prevent or delay reproductive aging.

Pregnancy-induced hypertension (PIH) is one of the most common pregnancy complications that seriously affects the mother and fetus. The incidence of PIH is higher in pregnancies conceived after assisted reproductive technology (ART) than in spontaneous pregnancies; thus, exploring potential serum biomarkers before PIH onset is of great significance for effective early prediction and prevention of PIH in the ART population. Cytokines are involved in the inflammatory response and immune regulation, which play an essential role in the pathogenesis of PIH. A description of the cytokine profile in the first trimester of pregnancy could help identify new diagnostic tools and develop targeted therapies for PIH in the ART population. The concentrations of classical predictive markers for PIH and another 48 cytokines were measured in the first-trimester pregnancy serum samples from 33 PIH patients and 33 matched normotensive controls (NC), both of whom conceived after ART treatment. The measured values were compared and analyzed between NC and PIH, followed by comprehensive bioinformatic analysis and logistic regression analysis. There was no significant difference in classical predictive markers, including Activin A, PlGF, sFLT1 (VEGFR), and sFLT1/PlGF, between the PIH and NC groups (P > 0.05), while 29 cytokines were significantly lower in the PIH group than in the NC group (P < 0.05). Logistic regression analysis revealed that 17 cytokines (IL-2Rα, M-CSF, IL-6, IL-2, β-NGF, IL-7, IL-12 (p70), SCF, IL-10, IL-9, MIG, GM-CSF, LIF, IL-1α, MCP-3, IL-4, and HGF) in the first-trimester pregnancy serum were significantly negatively correlated with the subsequent onset of PIH. With the top 3 cytokines (IL-7, MIG, and SCF) of receiver operating characteristic (ROC) analysis, we constructed an efficient multifactor combined detection and prediction model for PIH in ART pregnancy. Classical early predictors for hypertensive disorder complicating pregnancy cannot distinguish PIH from their normal peers in ART pregnancy. In comparison, the description of the cytokine profile in the first trimester of pregnancy enables us to distinguish high-risk ART pregnancy for PIH, permitting enough time for PIH prevention therapy. The cytokine profile we described also provides immunological insight into the further mechanistic exploration of PIH.

Abstract STAG3 is essential for male meiosis and testis of male Stag3 −/− mice shows the histopathological type of germ cell maturation arrest (MA). Whether variants of the STAG3 gene exist in Chinese idiopathic non-obstructive azoospermia (NOA) patients needs to be determined. We recruited 58 Chinese NOA men with MA who underwent testis biopsy and 192 fertile men as the control group. The 34 exons of the STAG3 gene were amplified using polymerase chain reaction (PCR) and sequenced. We identified eight novel single nucleotide polymorphisms (SNPs), including two missense SNPs (c.433T > C in exon2 and c.553A > G in exon3), three synonymous SNPs (c.539G > A, c.569C > T in exon3, and c.1176C > G in exon8), and three SNPs in introns. The allele and genotype frequencies of the novel and other SNPs have no significant differences between two groups. Our results indicated that variants in the coding sequence of the STAG3 gene were uncommon in NOA patients with MA in Chinese population. Future studies in large cohorts of different ethnic populations will be needed to determine the association between the STAG3 gene and NOA.

ObjectiveTo assess the effect of uterine septum resection on reproductive outcomes of in vitro fertilization (IVF) / intracytoplasmic sperm injection (ICSI) in patients with secondary infertility complicated with uterine septum.MethodsA retrospective cohort study included 269 patients. Surgical group included 169 patients with secondary infertility complicated with uterine septum, who underwent 252 embryo-transfer (ET) cycles following septum resection. Control group consisted of 100 patients with secondary infertility and uterine septum, who underwent 178 ET cycles. Cumulative pregnancy rate and cumulative live birth rate after one complete assisted reproductive technology (ART) cycle were the primary outcomes.ResultsThe results showed that the cumulative pregnancy rate was higher in the surgery group, and statistically significant difference was observed in the cumulative pregnancy rate between the two groups (71.0 vs. 59%, P = 0.044). In fresh ET cycle, no statistically significant difference between the two groups was evident (54.9 vs. 40.6%, P = 0.061). Statistical analysis of other results of the fresh ET cycle did not differ significantly between the two groups. In terms of frozen embryo transfer (FET) cycle outcomes, the clinical pregnancy rate and delivery rate in surgery group were 52.7 and 38.2%, respectively, which were significantly higher than those in the control group (38.2 and 22.5%, respectively) (P = 0.028 and P = 0.011).ConclusionThe reproductive outcomes of IVF/ICSI after septum resection in patients with secondary infertility were better than that in the untreated group, suggesting that uterine septum resection can be performed in patients with uterine septum combined with infertility to improve their reproductive outcomes.

Privacy protection is considered as an important problem in learning-based systems. Recently, various works based on differential privacy have been proposed to protect an individual's privacy in the machine learning and deep learning contexts. One of the state-of-the-art approaches is Private Aggregation of Teacher Ensembles (PATE), a generic framework which can be successfully applied to many different learning algorithms. In PATE, we need to split the private dataset into many disjoint subsets and train an ensemble of teachers on these subsets. Then, we transfer noisy predictions from the ensemble of teachers to a student model. In this paper, we show that for complex datasets and tasks, such as nature image classification, the training set allocated for one teacher may be too small with respect to the corresponding task to achieve an ideal performance. To alleviate this problem, we propose the TrPATE framework which extends PATE with transfer learning. Based on PATE, we transfer and share the knowledge extracted from a publicly available non-private dataset to the teachers. The extensive experiments are conducted on various datasets, and the empirical results demonstrate the effectiveness of our method.

Numerical calculations of ultraviolet to near-infrared absorption spectra by cadmium selenide quantum dots (CdSe QDs) doped in anodic aluminum oxide pores were performed using a finite-difference time-domain model. The height, diameter, and periodic spacing of the pores were optimized. Light absorption by the dots was enhanced by increasing the height and decreasing the diameter of the pores. When the height was less than 1 μm, visible light absorption was enhanced as the spacing was reduced from 400 nm to 100 nm. No enhancement was observed for heights greater than 6 μm. Finally, the optical mode coupling of the aluminum oxide and the quantum dots was enhanced by decreasing the pore diameter and periodic spacing and increasing the height. Laser ablation verified light absorption enhancement by the CdSe QDs. The experiments verified the improvement in the laser-induced damage ability with a nanosecond laser at a wavelength of 355 nm after aluminum alloy 6061 was coated with functional films and fabricated based on numerical calculations.

Polycystic ovary syndrome is characterized by reproductive and metabolic disturbances throughout the female lifespan. Therefore, this study aimed to determine whether genome-wide association studies (GWAS)-identified risk variants for PCOS could confer risk of metabolic syndrome (MS) or insulin resistance (IR). Fifteen independent SNPs mapping to 11 GWAS loci genotyped in a total of 2,082 Han Chinese women independent of previous GWAS and phenotype-genotype correlations were assessed. The CC group for rs12478601 in THADA was associated with decreased rate of MS after adjustment for age (23.2 vs. 27%, P = 0.042, OR = 0.81). Using a dominant model, the GG+AG group for rs2059807 in INSR was associated with increased risk of MS after adjustment for age (26.8 vs. 22.5%, P = 0.023, OR = 1.27). The GG + GT group for rs4784165 in TOX3 was found to be associated with an increased rate of IR after adjustment for age and BMI(53.3 vs. 48.5%, P = 0.027, OR = 1.27). The GG+AG group for rs2479106 in DENND1A was associated with a decreased rate of IR (48.3 vs. 53.6%, adjusted P = 0.039, OR = 0.80). After exclusion of PCOS cases with a family history of diabetes, hypertension, or dyslipidemia, the phenotype-genotype correlations between the genes INSR and TOX3 and MS or IR were still significant (P < 0.05). Three SNPs (rs13429458 in THADA, rs10818854 in DENND1A, and rs2059807 in INSR) were significantly associated with IR; however, their association was not significant after adjustment for age and BMI. This genotype-phenotype study thus provides clues that THADA, INSR, TOX3, and DENND1A play a role in PCOS possibly through a metabolic disorder-related pathway.