Two ferrous iron transporter-like proteins independently participate in asexual development under iron limitation and virulence in Beauveria bassiana.

Reductive assimilation pathway involves ferric reductase and ferrous iron transporter, which is integral for fungal iron acquisition. A family of ferric reductase-like proteins has been functionally characterized in the filamentous entomopathogenic fungus Beauveria bassiana. In this investigation, two ferrous iron transporter-like proteins (Ftr) were functionally annotated in B. bassiana. BbFtr1 and BbFtr2 displayed high similarity in structure and were associated with the plasma and nuclear membrane. Their losses had no negatively influence on fungal growth on various nutrients and development under the iron-replete condition. Single mutants of BbFTR1 and BbFTR2 displayed the iron-availability dependent developmental defects, and double mutant exhibited the significantly impaired developmental potential under the iron-limited conditions. In insect bioassay, the double mutant also showed the weaker virulence than either of two single disruption mutants. These results suggested that two ferrous iron transporter-like proteins function independently in fungal physiologies under the iron-deficient condition. Intriguingly, a bZIP transcription factor BbHapX was required for expression of BbFTR1 and BbFTR2 under iron-depleted conditions. This study enhances our understanding of the iron uptake system in the filamentous entomopathogenic fungi.

CTRP6 alleviates endometrial fibrosis by regulating Smad3 pathway in intrauterine adhesion†.

Intrauterine adhesion (IUA) is manifestations of endometrial fibrosis and excessive extracellular matrix deposition. C1q/tumor necrosis factor-related protein-6 (CTRP6) is a newly identified adiponectin paralog which has been reported to modulate the fibrosis process of several diseases; however, the endometrial fibrosis function of CTRP6 remains unknown. Our study aimed to assess the role of CTRP6 in endometrial fibrosis and further explore the underlying mechanism. Here, we found that the expression of CTRP6 was downregulated in the endometrial tissues of IUA. In vitro experiments demonstrated the reduced level of CTRP6 in facilitated transforming growth factor-ß1 (TGF-ß1)-induced human endometrial stromal cells (HESCs). In addition, CTRP6 inhibited the expression of α-smooth muscle actin (α-SMA) and collagen I in TGF-ß1-treated HESCs. Mechanistically, CTRP6 activated the AMP-activated protein kinase (AMPK) and protein kinase B (AKT) pathway in HESCs, and AMPK inhibitor (AraA) or PI3K inhibitor (LY294002) pretreatment abolished the protective effect of CTRP6 on TGF-ß1-induced fibrosis. CTRP6 markedly decreased TGF-ß1-induced Smad3 phosphorylation and nuclear translocation, and AMPK or AKT inhibition reversed these effects. Notably, CTRP6-overexpressing treatment alleviated the fibrosis of endometrium in vivo. Therefore, CTRP6 ameliorates endometrial fibrosis, among which AMPK and AKT are essential for the anti-fibrotic effect of CTRP6 via the Smad3 pathway. Taken together, CTRP6 may be a potential therapeutic target for the treatment of intrauterine adhesion.

Trophoblast-derived miR-410-5p induces M2 macrophage polarization and mediates immunotolerance at the fetal-maternal interface by targeting the STAT1 signaling pathway.

BACKGROUND: Macrophages phenotypic deviation and immune imbalance play vital roles in pregnancy-associated diseases such as spontaneous miscarriage. Trophoblasts regulate phenotypic changes in macrophages, however, their underlying mechanism during pregnancy remains unclear. Therefore, this study aimed to elucidate the potential function of trophoblast-derived miRNAs (miR-410-5p) in macrophage polarization during pregnancy. METHODS: Patient decidual macrophage tissue samples in spontaneous abortion group and normal pregnancy group (those who had induced abortion for non-medical reasons) were collected at the Reproductive Medicine Center of Renmin Hospital of Wuhan University from April to December 2021. Furthermore, placental villi and decidua tissue samples were collected from patients who had experienced a spontaneous miscarriage and normal pregnant women for validation and subsequent experiments at the Shenzhen Zhongshan Obstetrics & Gynecology Hospital (formerly Shenzhen Zhongshan Urology Hospital), from March 2021 to September 2022. As an animal model, 36 female mice were randomly divided into six groups as follows: naive-control, lipopolysaccharide-model, agomir-negative control prevention, agomir-410-5p prevention, agomir-negative control treatment, and agomir-410-5p treatment groups. We analyzed the miR-410-5p expression in abortion tissue and plasma samples; and supplemented miR-410-5p to evaluate embryonic absorption in vivo. The main source of miR-410-5p at the maternal-fetal interface was analyzed, and the possible target gene, signal transducer and activator of transcription (STAT) 1, of miR-410-5p was predicted. The effect of miR-410-5p and STAT1 regulation on macrophage phenotype, oxidative metabolism, and mitochondrial membrane potential was analyzed in vitro. RESULTS: MiR-410-5p levels were lower in the spontaneous abortion group compared with the normal pregnancy group, and plasma miR-410-5p levels could predict pregnancy and spontaneous abortion. Prophylactic supplementation of miR-410-5p in pregnant mice reduced lipopolysaccharide-mediated embryonic absorption and downregulated the decidual macrophage pro-inflammatory phenotype. MiR-410-5p were mainly distributed in villi, and trophoblasts secreted exosomes-miR-410-5p at the maternal-fetal interface. After macrophages captured exosomes, the cells shifted to the tolerance phenotype. STAT1 was a potential target gene of miR-410-5p. MiR-410-5p bound to STAT1 mRNA, and inhibited the expression of STAT1 protein. STAT1 can drive macrophages to mature to a pro-inflammatory phenotype. MiR-410-5p competitive silencing of STAT1 can avoid macrophage immune disorders. CONCLUSION: MiR-410-5p promotes M2 macrophage polarization by inhibiting STAT1, thus ensuring a healthy pregnancy. These findings are of great significance for diagnosing and preventing spontaneous miscarriage, providing a new perspective for further research in this field.

Comparative Transcriptomics of the Entomopathogenic Fungus Beauveria bassiana Grown on Aerial Surface and in Liquid Environment.

Beauveria bassiana, the causative agent of arthropod, proliferates in the host hemolymph (liquid environment) and shits to saprotrophic growth on the host cadaver (aerial surface). In this study, we used transcriptomic analysis to compare the gene expression modes between these two growth phases. Of 10,366 total predicted genes in B. bassiana, 10,026 and 9985 genes were expressed in aerial (AM) and submerged (SM) mycelia, respectively, with 9853 genes overlapped. Comparative analysis between two transcriptomes indicated that there were 1041 up-regulated genes in AM library when compared with SM library, and 1995 genes were down-regulated, in particular, there were 7085 genes without significant change in expression between two transcriptomes. Furthermore, of 25 amidase genes (AMD), BbAMD5 has high expression level in both transcriptomes, and its protein product was associated with cell wall in aerial and submerged mycelia. Disruption of BbAMD5 significantly reduced mycelial hydrophobicity, hydrophobin translocation, and conidiation on aerial plate. Functional analysis also indicated that BbAmd5 was involved in B. bassiana blastospore formation in broth, but dispensable for fungal virulence. This study revealed the high similarity in global expression mode between mycelia grown under two cultivation conditions.

Ubiquitin-specific protease 7 prevents recurrent spontaneous abortion by targeting enhancer of zeste homolog 2 to regulate trophoblast proliferation, apoptosis, migration, and invasion through the Wnt/ß-catenin pathway†.

Trophoblasts are significant components of the placenta and play crucial roles in maternal-fetal crosstalk. Adequate trophoblast migration and invasion are essential for embryo implantation and healthy pregnancy. Ubiquitin-specific protease 7 (USP7), a member of the deubiquitinating enzyme family, regulates the processes of migration and invasion in multiple tumor cells. However, the effects of USP7 on trophoblasts and its possible mechanism in the development of recurrent spontaneous abortion (RSA) are still unclear. In this study, we analyzed the expression of USP7 in villous tissues obtained from RSA patients and healthy controls, and then GNE-6776 (a USP7-specific inhibitor) and USP7 siRNA were used in a trophoblast cell line, HTR-8/SVneo, to further assess the effect of USP7 on the biological function of trophoblasts. Our results provide convincing evidence that USP7 is downregulated in the placental villous tissues of RSA patients. USP7 was found to have a crucial role in the proliferation, apoptosis, migration, invasion, and epithelial-mesenchymal transition (EMT) process of trophoblast cells. Further experiments revealed that USP7 directly interacted with the enhancer of zeste homolog 2 (EZH2) and regulated the Wnt/ß-catenin signaling pathway in trophoblasts. Taken together, these findings indicate the vital role of USP7 in regulating trophoblast proliferation, migration and invasion, thus affecting the pathogenesis of RSA, providing new insights into the important role of USP7 in the maternal-fetal interface.

Prediction of H3K27M Alteration Status in Brainstem Glioma Using Multi-Shell Diffusion MRI Metrics.

BACKGROUND: Multi-shell diffusion characteristics may help characterize brainstem gliomas (BSGs) and predict H3K27M status. PURPOSE: To identify the diffusion characteristics of BSG patients and investigate the predictive values of various diffusion metrics for H3K27M status in BSG. STUDY TYPE: Prospective. POPULATION: Eighty-four BSG patients (median age 10.5 years [IQR 6.8-30.0 years]) were included, of whom 56 were pediatric and 28 were adult patients. FIELD STRENGTH/SEQUENCE: 3 T, multi-shell diffusion imaging. ASSESSMENT: Diffusion kurtosis imaging and neurite orientation dispersion and density imaging analyses were performed. Age, gender, and diffusion metrics, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity, radial diffusivity (RD), mean kurtosis (MK), axial kurtosis (AK), radial kurtosis, intracellular volume fraction (ICVF), orientation dispersion index, and isotropic volume fraction (ISOVF), were compared between H3K27M-altered and wildtype BSG patients. STATISTICAL TESTS: Chi-square test, Mann-Whitney U test, multivariate analysis of variance (MANOVA), step-wise multivariable logistic regression. P-values <0.05 were considered significant. RESULTS: 82.4% pediatric and 57.1% adult patients carried H3K27M alteration. In the whole group, the H3K27M-altered BSGs demonstrated higher FA, AK and lower RD, ISOVF. The combination of age and median ISOVF showed fair performance for H3K27M prediction (AUC = 0.78). In the pediatric group, H3K27M-altered BSGs showed higher FA, AK, MK, ICVF and lower RD, MD, ISOVF. The combinations of median ISOVF, 5th percentile of FA, median MK and median MD showed excellent predictive power (AUC = 0.91). In the adult group, H3K27M-altered BSGs showed higher ICVF and lower RD, MD. The 75th percentile of RD demonstrated fair performance for H3K27M status prediction (AUC = 0.75). DATA CONCLUSION: Different alteration patterns of diffusion measures were identified between H3K27M-altered and wildtype BSGs, which collectively had fair to excellent predictive value for H3K27M alteration status, especially in pediatric patients. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

Nanocomposites based on nanoceria regulate the immune microenvironment for the treatment of polycystic ovary syndrome.

The immune system is closely associated with the pathogenesis of polycystic ovary syndrome (PCOS). Macrophages are one of the important immune cell types in the ovarian proinflammatory microenvironment, and ameliorate the inflammatory status mainly through M2 phenotype polarization during PCOS. Current therapeutic approaches lack efficacy and immunomodulatory capacity, and a new therapeutic method is needed to prevent inflammation and alleviate PCOS. Here, octahedral nanoceria nanoparticles with powerful antioxidative ability were bonded to the anti-inflammatory drug resveratrol (CeO2@RSV), which demonstrates a crucial strategy that involves anti-inflammatory and antioxidative efficacy, thereby facilitating the proliferation of granulosa cells during PCOS. Notably, our nanoparticles were demonstrated to possess potent therapeutic efficacy via anti-inflammatory activities and effectively alleviated endocrine dysfunction, inflammation and ovarian injury in a dehydroepiandrosterone (DHEA)-induced PCOS mouse model. Collectively, this study revealed the tremendous potential of the newly developed nanoparticles in ameliorating the proinflammatory microenvironment and promoting the function of granulosa cells, representing the first attempt to treat PCOS by using CeO2@RSV nanoparticles and providing new insights in combating clinical PCOS.

Effect of obstructive sleep apnea on semen quality.

BACKGROUND: Obstructive sleep apnea (OSA) has several notable complications such as hypertension and diabetes. Studies have also shown that OSA is associated with erectile dysfunction and reduced androgen levels. However, the effect of OSA on semen quality remains poorly studied. METHODS: Men attending a tertiary reproductive center for semen analysis were tested with a portable sleep breathing monitor. Patients were divided into four groups based on their apnea hypopnea index: none, mild, moderate, and severe obstructive sleep apnea. Differences between groups were assessed using χ2, and associations were tested with multiple regression analysis. RESULTS: We included a total of 175 male subjects with a mean age of 32.2 ± 3.6 years. There were significant differences between groups in progressive sperm motility (%) (43 ± 16, 42 ± 17, 36 ± 18, 29 ± 18, respectively; p = 0.002), total motility (%) (59 ± 19, 59 ± 20, 49 ± 21, 42 ± 20, respectively; p = 0.010), and vitality (%) (80 ± 10, 81 ± 11, 79 ± 8, 72 ± 19, respectively; p = 0.039). Asthenospermia (progressive motility < 35%) was significantly more common in subjects with OSA (χ2 = 5.195, p = 0.023). In multiple regression models, after adjusting for age and body mass index, apnea hypopnea index remained negatively and significantly associated with progressive motility, total motility, and vitality. CONCLUSIONS: OSA is an independent risk factor for sperm motility and vitality, and further investigation is now needed to determine if continuous positive pressure ventilation or other therapies can improve semen quality in these patients.

A computer model of the effect of venous-arterial-venous extracorporeal membrane oxygenation venous return of oxygenated blood on right atrial recirculation and tricuspid valve blood oxygen saturation.

OBJECTIVE: Venous-arterial venous extracorporeal membrane oxygenation (V-AV ECMO), as a new clinical application of ECMO, showed great clinical application potential in the treatment of patients with combined cardiopulmonary failure. Given the complicated cannulation strategy of V-AV ECMO, its influence on the hemodynamics of the human circulatory system remained unclear. METHODS: In this paper, a fluid-structure interaction was used to study the effect of V-AV ECMO oxygenated blood shunt ratio on right atrial recirculation and tricuspid valve (TV) blood oxygen saturation. In this study, the right atrium, superior vena cava supplying cannulae and inferior vena cava draining cannulae model of a specific patient was constructed. Seven cases with shunt ratio of 12.50%, 18.75%, 25.00%, 31.25%, 37.50%, 43.75% and 50.00% were designed. RESULTS: The streamline diagram and velocity contour of oxygenated blood, recirculation fraction (RF), correlation of three variables (shunt ratio, RF, and oxygen saturation), and the oxygen saturation of blood at the TV were extracted for the study. Study results showed that, first, as the shunt ratio increased, the RF of the seven cases was 14.64%, 29.87%, 33.85%, 40.12%, 40.40%, 40.02%, and 38.09%. Second, with the increase of the shunt ratio, oxygen saturation of blood at the TV in seven cases was 82.1%, 82.5%, 83.3%, 83.3%, 84.0%, 84.6%, and 85.3%. CONCLUSIONS: In this study, the shunt ratio had a strong correlation with the RF and oxygen saturation of blood at the TV. As the shunt ratio increased, the RF initially increased and then stabilized. However, oxygen saturation of blood at the TV would increase with the increase of the shunt ratio, but the degree of increase was small. This research provided useful information for surgeons and operators using V-AV ECMO.

Systematic contributions of CFEM domain-containing proteins to iron acquisition are essential for interspecies interaction of the filamentous pathogenic fungus Beauveria bassiana.

Common in fungal extracellular membrane (CFEM) domain is unique in fungal proteins and some of which contribute to iron acquisition in yeast. However, their roles in iron acquisition remain largely unknown in filamentous fungi. In this study, 12 CFEM-containing proteins were bioinformatically identified in the filamentous entomopathogenic fungus Beauveria bassiana, and the roles of 11 genes were genetically characterized. Transmembrane helices were critical for their association with intracellular membranes, and their number varied among proteins. Eleven CFEM genes significantly contribute to vegetative growth under iron starvation and virulence. Notably, the virulence of most disruptants could be significantly weakened by a decrease in iron availability, in which the virulence of ΔBbcfem7 and 8 strains was partially recovered by exogenous hemin. ΔBbcfem7 and 8 mutants displayed defective competitiveness against the sister entomopathogenic fungus Beauveria brongniartii. All 11 disruptants displayed impaired growth in the antagonistic assay with the saprotrophic fungus Aspergillus niger, which could be repressed by exogenous ferric ions. These findings not only reveal the systematic contributions of CFEM proteins to acquire two forms of iron (i.e. heme and ferric ion) in the entire lifecycle of entomopathogenic fungi but also help to better understand the mechanisms of fungus-host and inter-fungus interactions.

A homologue of yeast acyl-CoA synthetase Faa1 contributes to cytomembrane functionality involved in development and virulence in the insect pathogenic fungus Beauveria bassiana.

Acyl-CoA synthetase (ACS) functions as a hub linking lipid metabolism with in cellular physiologies by producing active intermediate of catalyzes acyl-CoA. However, the biological roles of ACS are largely unknown in filamentous fungi. In this study, an ortholog of yeast Faa1, named BbFaa1, was functionally characterized in the filamentous entomopathogenic fungus Beauveria bassiana. BbFaa1 was associated with vesicular membrane, and its loss resulted in the impaired cytomembrane integrity. Notably, in ΔBbfaa1 mutant strain, the translocation of hydrophobins across cell membrane was significantly hampered, which resulted in the reduced hydrophobicity of aerial mycelia and conidia. In addition, loss of BbFaa1 significantly weakened fungal virulence. Our findings indicate that the metabolism of acyl-CoA synthetase Faa1 contributes to the cytomembrane functionality which cascades hydrophobin translocation and differentiation, thus affecting virulence of B. bassiana.

Functional characterization of two homologs of yeast acetyl-coenzyme A synthetase in the entomopathogenic fungus Beauveria bassiana.

Acetyl-coenzyme A (CoA) synthetase (Acs) links cellular metabolism and physiology by catalyzing acetate and CoA into acetyl-CoA. However, the biological roles of Acs are not well studied in entomopathogenic fungi. In this study, two Acs proteins (BbAcs1 and BbAcs2) was functionally characterized in the filamentous insect pathogenic fungus Beauveria bassiana. BbAcs1 and BbAcs2 localize in cytoplasm and peroxisome, respectively. BbAcs1 contributes to vegetative growth on fatty acids as carbon source, and BbAcs2 did not. Both genes did not contribute to fungal response to stresses. The BbAcs1 loss conferred a slight influence on conidiation, and did not result in the defects in blastospore formation. On the contrary, BbAcs2 significantly contributes to lipid metabolism in germlings, blastospore formation, and virulence. The results indicated that Acs2 played a more predominant role than Acs1 in B. bassiana, which links the acetyl-CoA metabolism with the lifestyle of entomopathogenic fungi.

Chromosomal analysis of 262 miscarried conceptuses: a retrospective study.

BACKGROUND: Embryonic chromosomal abnormality is one of the significant causative factors of pregnancy loss. Our goal was to investigate the differences of chromosomal abnormality between different conception modes in miscarried products of conception (POCs). METHODS: A retrospective study included 262 miscarried POCs from 167 women undergoing assisted reproductive treatment (ART) and 95 spontaneous pregnant (SP) women during March 2019 to March 2022 in Renmin Hospital of Wuhan University. Subgroups were divided according to age, fertilization method, types and stages of embryo transfer. The profiles of cytogenetic abnormalities in the miscarried POCs were measured via next-generation sequencing. RESULTS: The rate of chromosomal abnormality in the fresh embryo transfer group and the cleavage embryo transfer group was significantly higher than that in the frozen embryo transfer group (79.2% vs. 36%, P = 0.0001) and the blastocyst transfer group (66.7% vs. 32.1%, P = 0.0001) respectively. There was no significant difference in the rate of chromosomal abnormalities when compared by maternal age (49.2% vs. 62%, P = 0.066), types of conception (49.7% vs. 57.9%, P = 0.202), fertilization method (49.6% vs. 48.7%, P = 0.927) and frequency of abortion (56% vs. 47.6%, P = 0.183). However, the women aged ≥ 35 years had more frequent numerical abnormality (P = 0.002); patients using assisted reproductive technology had more rate of chromosomal structural abnormalities (26.5% vs. 7.3%, P = 0.005); the ICSI fertilization group has more frequency of deletion/microdeletion than the IVF fertilization group (80% vs. 31.3%, P = 0.019). CONCLUSION: Blastocyst transfer might help to reduce the incidence of miscarriage. In addition, "freezing all" should be considered if encountered hyper ovarian stimulation, to avoid the negative effect of high estrogen environment on embryo development. The higher incidence of structural abnormalities in miscarried POCs from assisted reproductive patients reminds us to pay attention to the safety of the technology for offspring.

M2 macrophage-derived G-CSF promotes trophoblasts EMT, invasion and migration via activating PI3K/Akt/Erk1/2 pathway to mediate normal pregnancy.

Trophoblasts are important parts of the placenta and exert vital roles in the maternal-foetal crosstalk, and sufficient trophoblasts migration and invasion is critical for embryo implantation and normal pregnancy. Macrophages, as the major components of decidual microenvironment at maternal-foetal interface, can interact with trophoblasts to participate in the regulation of normal pregnancy. Previously, our group have demonstrated that trophoblasts could induce macrophages polarization to M2 subtype by secreting interleukin-6 (IL-6); however, the understanding of macrophages regulating the migration and invasion of trophoblasts is limited. In the present study, we used the co-cultured model to further investigate the effects of macrophages on trophoblasts migration and invasion. Our results showed that co-culture with macrophages promoted epithelial-to-mesenchymal transition (EMT) of trophoblasts, thereby enhancing their migrative and invasive abilities. Further experiments revealed that M2 macrophage-derived G-CSF was a key factor, which promoted the EMT, migration and invasion of trophoblasts via activating PI3K/Akt/Erk1/2 signalling pathway. Clinically, G-CSF was highly expressed in placental villous tissues of normal pregnancy patients compared to patients with recurrent spontaneous abortion, and its expression level was significantly correlation with EMT markers. Taken together, these findings indicate the important role of M2 macrophages in regulating trophoblasts EMT, migration and invasion, contributing to a new insight in concerning the crosstalk between macrophages and trophoblasts in the establishment and maintenance of normal pregnancy.

INO80 participates in the pathogenesis of recurrent miscarriage by epigenetically regulating trophoblast migration and invasion.

The INO80 complex, a SWI/SNF family chromatin remodeler, has regulatory effects on ESC self-renewal, somatic cell reprogramming and blastocyst development. However, the role of INO80 in regulating trophoblast cells and recurrent miscarriage (RM) remains elusive. To investigate the in vivo effects of Ino80 in embryo development, we disrupted Ino80 in C57 mice, which resulted in embryonic lethality. Silencing of Ino80 led to decreased survival capacity, migration and invasion of trophoblasts. Furthermore, RNA high-throughput sequencing (RNA-seq) revealed that Ino80 silencing closely resembled the gene expression changes in RM tissues. To investigate the mechanisms for these results, RNA-seq combined with high-throughput sequencing (ChIP-seq) was used in trophoblast cells, and it showed that Ino80 physically occupies promoter regions to affect the expression of invasion-associated genes. Last, Western blotting analyses and immunofluorescence staining revealed that the content of INO80 was reduced in RM patients compared to in healthy controls. This study indicates that INO80 has a specific regulatory effect on the viability, migration and invasion of trophoblast cells. Combined with its regulation of the expression of invasion-associated genes, it has been proposed that epigenetic regulation plays an important role in the occurrence of RM, potentially informing RM therapeutic strategies.

C1QTNF6 participates in the pathogenesis of PCOS by affecting the inflammatory response of granulosa cells‡.

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease. It has been reported that chronic low-grade inflammation might participate in its pathogenesis. C1q and TNF related 6 (C1QTNF6) is a newly identified adiponectin paralog associated with inflammation. The aim of the present study was to investigate the role of C1QTNF6 in the development of chronic inflammation in PCOS and the underlying molecular mechanism. After analyzing the expression of C1QTNF6 in the serum and granulosa cells (GCs) of PCOS patients and healthy controls, we verified the roles of C1QTNF6 in inflammation through dehydroepiandrosterone-induced PCOS mouse models and cell models of lipopolysaccharide (LPS)-induced inflammation. The results demonstrated that C1QTNF6 expression in the serum and GCs of patients with PCOS was significantly elevated compared with those of the controls, and similar results were observed in the serum and ovary of PCOS mouse models. In PCOS mice and C1QTNF6-overexpressing PCOS mice, serum levels of pro-inflammatory factors including C-reactive protein (CRP), interleukin 6 (IL6), and tumor necrosis factor-α (TNFα) were increased, while the opposite effects were observed when C1QTNF6 was down-regulated in PCOS mice. Furthermore, C1QTNF6 overexpression up-regulated the levels of TNFα, IL6, and CRP and activated the AKT/NF-κB pathway in LPS-treated KGN cells, whereas C1QTNF6 knockdown and BAY-117082 (an NF-κB inhibitor) treatment resulted in the opposite effects. Taken together, our results indicate that C1QTNF6 is involved in the pathogenesis of PCOS by affecting the inflammatory response via the AKT/NF-κB signaling pathway.

Prediction of H3K27M-mutant brainstem glioma by amide proton transfer-weighted imaging and its derived radiomics.

PURPOSE: H3K27M-mutant associated brainstem glioma (BSG) carries a very poor prognosis. We aimed to predict H3K27M mutation status by amide proton transfer-weighted (APTw) imaging and radiomic features. METHODS: Eighty-one BSG patients with APTw imaging at 3T MR and known H3K27M status were retrospectively studied. APTw values (mean, median, and max) and radiomic features within manually delineated 3D tumor masks were extracted. Comparison of APTw measures between H3K27M-mutant and wildtype groups was conducted by two-sample Student's T/Mann-Whitney U test and receiver operating characteristic curve (ROC) analysis. H3K27M-mutant prediction using APTw-derived radiomics was conducted using a machine learning algorithm (support vector machine) in randomly selected train (n = 64) and test (n = 17) sets. Sensitivity analysis with additional random splits of train and test sets, 2D tumor masks, and other classifiers were conducted. Finally, a prospective cohort including 29 BSG patients was acquired for validation of the radiomics algorithm. RESULTS: BSG patients with H3K27M-mutant were younger and had higher max APTw values than those with wildtype. APTw-derived radiomic measures reflecting tumor heterogeneity could predict H3K27M mutation status with an accuracy of 0.88, sensitivity of 0.92, and specificity of 0.80 in the test set. Sensitivity analysis confirmed the predictive ability (accuracy range: 0.71-0.94). In the independent prospective validation cohort, the algorithm reached an accuracy of 0.86, sensitivity of 0.88, and specificity of 0.85 for predicting H3K27M-mutation status. CONCLUSION: BSG patients with H3K27M-mutant had higher max APTw values than those with wildtype. APTw-derived radiomics could accurately predict a H3K27M-mutant status in BSG patients.

Brain structural and functional alterations in MOG antibody disease.

BACKGROUND: The impact of myelin oligodendrocyte glycoprotein antibody disease (MOGAD) on brain structure and function is unknown. OBJECTIVES: The aim of this study was to study the multimodal brain MRI alterations in MOGAD and to investigate their clinical significance. METHODS: A total of 17 MOGAD, 20 aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorders (AQP4 + NMOSD), and 28 healthy controls (HC) were prospectively recruited. Voxel-wise gray matter (GM) volume, fractional anisotropy (FA), mean diffusivity (MD), and degree centrality (DC) were compared between groups. Clinical associations and differential diagnosis were determined using partial correlation and stepwise logistic regression. RESULTS: In comparison with HC, MOGAD had GM atrophy in frontal and temporal lobe, insula, thalamus, and hippocampus, and WM fiber disruption in optic radiation and anterior/posterior corona radiata; DC decreased in cerebellum and increased in temporal lobe. Compared to AQP4 + NMOSD, MOGAD presented lower GM volume in postcentral gyrus and decreased DC in cerebellum. Hippocampus/parahippocampus atrophy associated with Expanded Disability Status Scale (R = -0.55, p = 0.04) and California Verbal Learning Test (R = 0.62, p = 0.031). The differentiation of MOGAD from AQP4 + NMOSD achieved an accuracy of 95% using FA in splenium of corpus callosum and DC in occipital gyrus. CONCLUSION: Distinct structural and functional alterations were identified in MOGAD. Hippocampus/parahippocampus atrophy associated with clinical disability and cognitive impairment.

CircPSMC3 alleviates the symptoms of PCOS by sponging miR-296-3p and regulating PTEN expression.

Polycystic ovary syndrome (PCOS), the most common female endocrine disease that causes anovulatory infertility, still lacks promising strategy for the accurate diagnosis and effective therapeutics of PCOS attributed to its unclear aetiology. In this study, we determined the abnormal reduction in circPSMC3 expression by comparing the ovarian tissue samples of PCOS patients and normal individuals. The symptom relief caused by up-regulation of circPSMC3 in PCOS model mice suggested the potential for further study. In vitro functional experiments confirmed that circPSMC3 can inhibit cell proliferation and promote apoptosis by blocking the cell cycle in human-like granular tumour cell lines. Mechanism study revealed that circPSMC3 may play its role through sponging miR-296-3p to regulate PTEN expression. Collectively, we preliminarily characterized the role and possible insights of circPSMC3/miR-296-3p/PTEN axis in the proliferation and apoptosis of KGN cells. We hope that this work provides some original and valuable information for the research of circRNAs in PCOS, not only to better understand the pathogenesis but also to help provide new clues for seeking for the future therapeutic target of PCOS.

YY1-PVT1 affects trophoblast invasion and adhesion by regulating mTOR pathway-mediated autophagy.

Insufficient trophoblast invasion is the key factor for the occurrence of recurrent spontaneous abortions (RSA). Our previous studies identified Yin Yang 1 (YY1) as a transcription factor involved in the regulation of trophoblast invasiveness at the maternal-fetal interface. Long noncoding RNAs (lncRNAs) can regulate gene expression and autophagy in many ways. The purpose of this study was to explore the relationship between YY1 and lncRNAs and the mechanism by which lncRNAs affect the biological behavior of trophoblasts. Bioinformatic analysis predicted that YY1 had three binding sites in the plasmacytoma variant translocation 1 (PVT1) promoter region. Chromatin immunoprecipitation experiments and electrophoretic mobility shift assays verified that YY1 can directly bind to the PVT1 promoter. Compared with its expression levels in human placental villi tissue samples from the normal pregnancy group, the PVT1 expression levels were significantly lower in tissues from the RSA group. PVT1 knockdown significantly reduced adhesion, invasion, autophagy, and mTOR expression in HTR-8/SVneo cells and greatly increased apoptosis in vitro. This study revealed a novel regulatory pathway in which YY1 can act directly on PVT1 promoter to regulate its transcription, which further affects trophoblast invasion and adhesion by regulating autophagy via the mTOR pathway, and these effects might be involved in RSA pathogenesis.