Activation of cGAS/STING Drives Inflammation and Cellular Senescence of Macrophages in Ovarian Endometrioma Induced by Endometriotic Cyst Fluid.

Ovarian endometrioma (OE) is a common gynecological condition characterized by the formation of "chocolate cysts". Recent research indicates that the cyst fluid acts as a "toxic environment" for the ovary and plays a significant role in the development of OE, with macrophages being pivotal. However, the specific molecular and cellular mechanisms of it are not fully understood. In this study, clinical samples are integrated, single-cell sequencing, in vivo and in vitro experimental models to comprehensively investigate the effects of OE fluid on ovarian function and the mechanisms of it. Combined with bioinformatics analysis and experimental validation, the findings demonstrate that OE fluid can cause ovarian function decline, which associated with inflammatory response, and mitochondrial dysfunction and cellular senescence, while activating the cGAS/STING signaling pathway. As a STING inhibitor, H-151 effectively alleviates ovarian dysfunction, inflammatory state and cell apoptosis induced by OE fluid. Furthermore, it is also discovered that H-151 can inhibit OE fluid-induced mitochondrial dysfunction and cellular senescence. These findings provide important theoretical and experimental foundations for further research and development of STING inhibitors as potential drugs for treating ovarian dysfunction.

Klotho accelerates the progression of polycystic ovary syndrome through promoting granulosa cell apoptosis and inflammation.

The morbidity of polycystic ovary syndrome (PCOS) is in highly increasing rate nowadays. PCOS not only affects the fertility in women, but also threatens the health of whole life. Hence, to find the prognostic risk factors is of great value. However, the effective predictors in clinical practice of PCOS are still in blackness. In this study, we found Klotho was increased in FF (Follicular Fluid) and primary luteinized granulosa cells (GCs) from PCOS patients with hyperandrogenism. Furthermore, we found follicular Klotho was negatively correlated with numbers of mature oocytes, and positively correlated with serum testosterone, LH, and LH/FSH levels menstrual cycle and number of total antral follicles in PCOS patients. In primary luteinized GCs, the increased Klotho was accompanied with upregulation of cell apoptosis and inflammation-related genes. In ovaries of PCOS mice and cultured human KGN cell line, Klotho was up-regulated and accompanied by apoptosis, inflammation and mitochondrial dysfunction. Therefore, our findings suggest new mechanisms for granulosa cell injury and revealed to target inhibit Klotho maybe a new therapeutic strategy for treatment of PCOS.

FAM3A plays a key role in protecting against tubular cell pyroptosis and acute kidney injury.

Acute kidney injury (AKI) is in high prevalence worldwide but with no therapeutic strategies. Programmed cell death in tubular epithelial cells has been reported to accelerate a variety of AKI, but the major pathways and underlying mechanisms are not defined. Herein, we identified that pyroptosis was responsible for AKI progression and related to ATP depletion in renal tubular cells. We found that FAM3A, a mitochondrial protein that assists ATP synthesis, was decreased and negatively correlated with tubular cell injury and pyroptosis in both mice and patients with AKI. Knockout of FAM3A worsened kidney function decline, increased macrophage and neutrophil cell infiltration, and facilitated tubular cell pyroptosis in ischemia/reperfusion injury model. Conversely, FAM3A overexpression alleviated tubular cell pyroptosis, and inhibited kidney injury in ischemic AKI. Mechanistically, FAM3A promoted PI3K/AKT/NRF2 signaling, thus blocking mitochondrial reactive oxygen species (mt-ROS) accumulation. NLRP3 inflammasome sensed the overload of mt-ROS and then activated Caspase-1, which cleaved GSDMD, pro-IL-1ß, and pro-IL-18 into their mature forms to mediate pyroptosis. Of interest, NRF2 activator alleviated the pro-pyroptotic effects of FAM3A depletion, whereas the deletion of NRF2 blocked the anti-pyroptotic function of FAM3A. Thus, our study provides new mechanisms for AKI progression and demonstrates that FAM3A is a potential therapeutic target for treating AKI.

The CXCR4-AT1 axis plays a vital role in glomerular injury via mediating the crosstalk between podocyte and mesangial cell.

Glomeruli stand at the center of nephrons to accomplish filtration and albumin interception. Podocytes and mesangial cells are the major constituents in the glomeruli. However, their interdependency in glomerular injury has rarely been reported. Herein, we investigated the role of C-X-C chemokine receptor type 4 (CXCR4) in mediating the crosstalk between podocytes and mesangial cells. We found CXCR4 and angiotensin II (AngII) increased primarily in injured podocytes. However, type-1 receptor of angiotensin II (AT1) and stromal cell-derived factor 1α (SDF-1α), a ligand of CXCR4, were evidently upregulated in mesangial cells following the progression of podocyte injury. Ectopic expression of CXCR4 in 5/6 nephrectomy mice increased the decline of renal function and glomerular injury, accelerated podocyte injury and mesangial cell activation, and initiated CXCR4-AT1 axis signals. Additionally, treatment with losartan, an AT1 blocker, interrupted the cycle of podocyte injury and mesangial matrix deposition triggered by CXCR4. Podocyte-specific ablation of CXCR4 gene blocked podocyte injury and mesangial cell activation. In vitro, CXCR4 overexpression induced oxidative stress and renin angiotensin system (RAS) activation in podocytes, and triggered the communication between podocytes and mesangial cells. In cultured mesangial cells, AngII treatment induced the expression of SDF-1α, which was secreted into the supernatant to further promote oxidative stress and cell injury in podocytes. Collectively, these results demonstrate that the CXCR4-AT1 axis plays a vital role in glomerular injury via mediating pathologic crosstalk between podocytes and mesangial cells. Our findings uncover a novel pathogenic mechanism by which the CXCR4-AT1 axis promotes glomerular injury.

Serum granulosa cell-derived TNF-α promotes inflammation and apoptosis of renal tubular cells and PCOS-related kidney injury through NF-κB signaling.

Polycystic ovary syndrome (PCOS) is a disorder with endocrinal and metabolic problems in reproductive aged women. Evidence shows that PCOS is in a high prone trend to develop kidney diseases. In this study, we investigated the mediators responsible for PCOS-related kidney injury. We found that tumor necrosis factor (TNF-α) levels were significantly increased in serum and primary cultured granulosa cells (GCs) from PCOS patients. Serum TNF-α levels were positively correlated with serum testosterone and luteinizing hormone (LH)/follicle-stimulating hormone (FSH) ratio, suggesting its positive role in the severity of PCOS. Serum TNF-α levels were also positively correlated with the levels of urinary KapU, LamU, α1-MU and ß2-MU, the markers for renal tubular cell-derived proteinuria. We established a PCOS mouse model by resection of the right kidney, followed by daily administration of dihydrotestosterone (DHT, 27.5 µg, i.p.) from D7 for 90 days. We found that TNF-α levels were significantly increased in the ovary and serum of the mice, accompanied by increased renal tubular cell apoptosis, inflammation and fibrosis in kidneys. Furthermore, the receptor of TNF-α, tumor necrosis factor receptor 1 (TNFR1), was significantly upregulated in renal tubular cells. We treated human ovarian granulosa-like tumor cells (KGN) with DHT (1 µg/ml) in vitro, the conditioned medium derived from the granulosa cell culture greatly accelerated apoptotic injury in human proximal tubular epithelial cells (HKC-8), which was blocked after knockdown of TNF-α in KGN cells. Furthermore, knockdown of TNFR1 in renal tubular epithelial cells greatly ameliorated cell injury induced by granulosa cell-derived conditioned medium. These results suggest that serum TNF-α plays a key role in mediating inflammation and apoptosis in renal tubular cells associated with PCOS-related kidney injury.

Effects of conflict in cognitive control: Evidence from mouse tracking.

It has long been debated whether the "congruency sequence effect (CSE)" in conflict tasks such as Flanker could reflect adaptive control. The current study used "mouse tracking" to tackle the issue in a combination of three conflict tasks (i.e., Flanker, Simon, and Spatial Stroop tasks). Congruency effects from previous and current trials emerged in latencies as well as curvature of movement trajectories in all three tasks. Critically, movement initiation times were affected only by congruency on previous but not on current trials. A further analysis showed that even when initiation time on the previous trials was taken into account, a subtle but highly significant effect of conflict arising from trial N-1 on initiation times remained. Although not necessarily implying "conflict adaptation," i.e., a dynamic up- and downregulation of cognitive control in response to a recent conflict, our finding indicates a specific sensitivity to the presence or absence of recent "conflict" in the cognitive environment.

Extraordinary Antiwear Properties of Graphene-Reinforced Ti Composites Induced by Interfacial Decoration.

The expected excellent lubricant effect of graphene in metals during friction and wear is rarely achieved because of the difficulty in synthesizing suitable interfaces. Particularly, the situation is more challenging in titanium (Ti) matrix composites (TMCs) because of the high chemical-interface-reaction tendency between graphene and Ti during composite fabrication. In this study, few-layered graphene (FLG) decorated with SiC nanoparticles (SiCp) was synthesized as reinforcement in Ti-6Al-4V alloy to improve the interface of the composites. It was found that interfacial SiCp not only strengthened the interface bonding by the Si solid solution but also inhibited the chemical reaction between FLG and the Ti matrix with reduced sp3 defects. The composite with 30 wt % SiC-decorated FLG showed an 86.8% decrement in wear rate compared to the unreinforced matrix, resulting in exceptionally high antiwear enhancing efficiency, which was around fourfold of the available values of other TMCs in the literature. The antiwear mechanism was investigated by thorough characterization of the interfaces and microstructures of the composites. The idea of interfacial decoration can be potentially applied to other nanocarbon/metal composites with the advantages of retaining the function performance of nanocarbon materials.

Exploring task switch costs in a color-shape decision task via a mouse tracking paradigm.

Several decades of cognitive research have explored the processes and mechanisms that underlie task switching. Here we report an experiment in which young adult participants were presented with colored shapes, and were randomly cued to categorize them according to color, or to shape. Responses were made via dynamic movements of the computer mouse ("mouse tracking"), which allows insight into how decision making unfolds. The results showed that a range of classic findings (mix cost, switch cost, task congruency effects, etc.) emerged strongly in movement trajectories. Initiation of movements was sensitive to task/cue driven but not to stimulus/response driven variables, as well as to task switching. This constellation suggests that task switch costs emerge as a combination of task set reconfiguration, and stimulus-driven sensory-motor mappings. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Design and Characterization of Self-Lubricating Refractory High Entropy Alloy-Based Multilayered Films.

Refractory high entropy alloys (RHEAs) have been proven to have excellent mechanical properties with a potential use as protective thin films. However, the combination of high hardness with low friction and wear is a major challenge in the design of RHEA films. In this study, we show that NbMoWTa/Ag self-lubricating multilayered films give a remarkable reduction in friction and at same time maintain high hardness. Interestingly, it is found that the bcc superlattice dominates in both NbMoWTa and Ag layers and the interfaces become coherent when the individual layer thickness h is reduced below 10 nm. The film properties are then strongly dependent on h ranging from 100 to 2.5 nm, and the most promising properties are obtained when the interface structure transforms from incoherent to coherent one. Especially, the multilayer with h = 2.5 nm exhibits superior tribological performance over monolithic NbMoWTa due to the significant coherent strengthening along with the self-lubricating ability in the multilayer. This tailored phase transition and coherent structure between the matrix and lubrication phases can also provide an optimal wear rate-coefficient of friction combination, which is higher than most of the Ag-containing self-lubricating films. The current work might open a new route toward the development of innovative self-lubricating RHEA films with excellent tribological properties.

The role of androgen and its related signals in PCOS.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women at reproductive age. However, the underlying pathogenic mechanisms have not been completely understood. Hyperandrogenism is an important clinic feature in patients with PCOS, suggesting its pathologic role in the development and progression of PCOS. However, the actual role of androgen and the related signals in PCOS and PCOS-related complications have not yet been clarified. In this review, we surveyed the origin and effects of androgen on PCOS and the related complications, highlighted the cellular signals affecting androgen synthesis and summarized the pathological processes caused by hyperandrogenism. Our review well reveals the important mechanisms referring the pathogenesis of PCOS and provides important clues to the clinic strategies in patients with PCOS.

The Emerging Key Role of Klotho in the Hypothalamus-Pituitary-Ovarian Axis.

The hypothalamus-pituitary-ovary axis is the most important system for regulating female reproductive endocrine function. Its dysfunction would lead to the abnormal secretion of gonadotropin-releasing hormone, follicle-stimulating hormone, or luteinizing hormone, and eventually result in the occurrence of reproductive disease, such as congenital hypogonadotropic hypogonadism, polycystic ovary syndrome, and premature ovarian failure. Recently, an anti-aging gene, Klotho, has gained broad attention in female reproductive diseases. Reports have shown that Klotho is closely correlated to the hypothalamus-pituitary-ovary axis and plays a key role in the development and progression of reproductive diseases. With this issue, we generally review the physiological and pathological role of Klotho in the hypothalamus-pituitary-ovary axis. We also review the underlying mechanisms of Klotho in promoting and preventing female reproductive diseases, which involve the dysfunction of the fibroblast growth factor-Klotho endocrine system, the abnormal signaling regulation of Wnt-ß-catenin and insulin-like growth factor-1, the accumulation of oxidative stress, and the inhibition of autophagy, eventually affecting the genesis, development, ovulation, or atresia of follicles. The present review would provide new insights and potential therapeutic target strategies for clinical strategies.

Association of seminal angiotensinogen with sperm motility and morphology in male infertility.

Many researchers have shown that renin-angiotensin system (RAS) is involved in various important aspects of male reproduction. In this study, we assessed whether abnormal levels of seminal angiotensinogen (AGT) may be associated with semen parameters in infertile males. A total of 115 male patients were recruited, and semen parameters, seminal AGT and the electrolytes including K+ , Na+ , Cl- , P and Ca were evaluated. According to the World Health Organization (WHO) 2010 criteria, the patients were divided into two groups: G1 group with normal semen parameters (n = 42) and G2 group with subnormal semen parameters (n = 73). The level of seminal AGT was significantly higher in G2 group compared with G1 group. Moreover, the level of AGT was negatively correlated with the percentage of total motility (r = -.322, p = .000), progressive motility (PR) (r = -.339, p = .000) and morphologically normal forms (r = -.263, p = .004). This study suggests that elevated seminal AGT level is associated with increased risk of asthenospermia and teratozoospermia.

[Association of advanced oxidation protein products in seminal plasma with teratospermia and outcome parameters of in vitro fertilization].

OBJECTIVE: To study the association of the level of advanced oxidation protein products (AOPPs) in seminal plasma with teratospermia and the outcome parameters of in vitro fertilization (IVF). METHODS: We conducted a cross-sectional study among 272 male patients receiving assisted reproduction treatment in the Center for Reproductive Medicine of our hospital between October, 2018 and March, 2019. The levels of seminal AOPPs and reactive oxygen species (ROS), demographic data, sperm parameters and IVF outcome parameters were analyzed for all the patients. According to the percentage of sperms with normal morphology, the patients were divided before IVF into teratozoospermia group and normal sperm morphology group, and those in teratozoospermia group were further divided into 3 subgroups with mild, moderate and severe teratozoospermia. The patients were also divided on the day oocyte retrieval into 2 groups with fertilizing rates lower (group Ⅰ) and higher (group Ⅱ) than the median rate. RESULTS: We found a significant negative correlation of seminal AOPP level before treatment with the percentage of normal sperm morphology (P=0.003) and seminal ROS level (P=0.013). The seminal levels of AOPPs (P= 0.027) and ROS (P=0.036) were significantly elevated in patients with teratospermia, and seminal AOPP level was significantly higher in severe teratospermia group than in mild (P=0.019) and moderate (P=0.015) teratospermia groups. The seminal levels of AOPPs (P=0.003) and ROS (P=0.017) on the day of oocyte retrieval were negatively correlated with the fertilization rate in IVF cycles, and the levels of AOPPs (P=0.049) and ROS (P=0.036) were significantly higher in group Ⅰ than in group Ⅱ. CONCLUSIONS: An elevated level of seminal AOPPs may indicate an increased risk of severe teratospermia and a lower fertilization rate in IVF.

Serum testosterone acts as a prognostic indicator in polycystic ovary syndrome-associated kidney injury.

Polycystic ovary syndrome (PCOS) is closely related with the onset and development of metabolic abnormalities. However, the correlation between PCOS and kidney injury has not been clarified, and the underlying mechanism remains unknown. Herein, we performed a prospective survey in 55 PCOS and 69 healthy participants. Furthermore, the correlation analyses between serum testosterone and renal functional manifestations of patients and healthy subjects, including urinary albumin to creatinine ratio (UACR), urinary κ-light chains (KapU), urinary λ-light chains (LamU), urinary α1-microglobulin (α1-MU), and urinary ß2-microglobulin (ß2-MU), were analyzed. Compared with that in normal subjects, the levels of serum testosterone and UACR were significantly higher in PCOS patients. Serum testosterone is significantly correlated with the disease severity of PCOS. Although urinary excretions of KapU, LamU, α1-MU, and ß2-MU did not increase in PCOS patients, they had a significantly positive correlation with the extent of serum testosterone in PCOS patients. IN vitro, primary cultured human ovary granulosa cells (GCs) were isolated from the follicular fluid (FF) extracting from PCOS patients and controls. FF, especially which extracted from PCOS patients with a high expression of serum testosterone, significantly induced cell apoptosis and inflammation in human GCs. To examine the communication between PCOS and kidney injury, a human proximal tubular epithelial cell line (HKC-8) was cultured and administered FF. Interestingly, FF from PCOS patients with a higher level of serum testosterone induced fibrotic lesions in HKC-8 cells. These data suggest serum testosterone plays a critical role in PCOS and PCOS-associated kidney injury. Serum testosterone may serve as a promising indicator for kidney fibrotic injury outcomes in PCOS patients.

Automatic Human-like Mining and Constructing Reliable Genetic Association Database with Deep Reinforcement Learning.

The increasing amount of scientific literature in biological and biomedical science research has created a challenge in continuous and reliable curation of the latest knowledge discovered, and automatic biomedical text-mining has been one of the answers to this challenge. In this paper, we aim to further improve the reliability of biomedical text-mining by training the system to directly simulate the human behaviors such as querying the PubMed, selecting articles from queried results, and reading selected articles for knowledge. We take advantage of the efficiency of biomedical text-mining, the exibility of deep reinforcement learning, and the massive amount of knowledge collected in UMLS into an integrative artificial intelligent reader that can automatically identify the authentic articles and effectively acquire the knowledge conveyed in the articles. We construct a system, whose current primary task is to build the genetic association database between genes and complex traits of human. Our contributions in this paper are three-fold: 1) We propose to improve the reliability of text-mining by building a system that can directly simulate the behavior of a researcher, and we develop corresponding methods, such as Bi-directional LSTM for text mining and Deep Q-Network for organizing behaviors. 2) We demonstrate the effectiveness of our system with an example in constructing a genetic association database. 3) We release our implementation as a generic framework for researchers in the community to conveniently construct other databases.