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Abstract Background Extensive research has been conducted on embryonic developmental disorders linked to Polycystic Ovary Syndrome (PCOS), a pathological condition that affects 5−10% of women and is characterized by irregularities in the menstrual cycle and infertility. By employing RNA sequencing (RNA-seq), we performed an in-depth investigation of PCOS-related changes in gene expression patterns at the mouse blastocyst stage. Methods The zygotes of female B6D2 mice were obtained and then differentiated into blastocysts in K + Simplex Optimised Medium (KSOM) cultures containing exo-NC (negative control for exosomes) or exo-LIPE-AS1 (a novel exosomal marker of PCOS). Subsequently, blastocysts were collected for RNA-seq. The bioinformatics was performed to analyze and compare the differences of gene expression profile between blastocysts of control and PCOS group. Results There were 1150 differentially expressed genes (DEGs) between the two groups of mouse blastocysts; 243 genes were upregulated and 907 downregulated in the blastocysts of the exo-LIPE-AS1 group compared to those of the exo-NC group. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the genes involved in amino acid synthesis and glutathione metabolic pathways were down-regulated in exo-LIPE-AS1 group. Conclusion This study has revealed that blastocyst developmental retardation may be associated with the downregulation of amino acid synthesis and glutathione metabolism, which may affect energy metabolism, biosynthesis, cellular osmotic pressure, antioxidant synthesis, ROS clearance or mitochondrial function, and ultimately cause blastocyst cell development abnormalities. Our research offers encouraging data on the mechanisms underlying aberrant embryonic development in patients with PCOS as well as potential treatment strategies.

ObjectiveTo explore the status of knowledge graph-based research into breast cancer microenvironment and to predict future research hotspots. MethodsThe literature related to breast cancer microenvironment in recent 20 years was retrieved from CNKI and Web of Science Core Collection database and analyzed with CiteSpace and VOSviewer. ResultsA total of 825 Chinese articles and 16,221 English articles were retrieved. Visual analysis showed that research focus has gradually shifted from cellular research to molecular research and drug innovation. Cancer stem cells, PD-1, PD-L1, immune checkpoint inhibitors, and nanoparticles are the main subjects of interest in research on breast cancer microenvironment, and the United States has the largest number of studies on breast cancer microenvironment, followed by China and Italy. ConclusionCurrent research mainly focuses on tumor stemness, immunotherapy, and nanodelivery. Owing to deepening research in this field, the targeting of the breast cancer microenvironment for the prevention of tumor development and metastasis and improvement of tumor prognosis has emerged as a new research direction.

Objective: A biological system's internal morphological structure or function can be changed as a result of the mechanical effect of focused ultrasound. Pulsed low-intensity focused ultrasound (LIFU) has mechanical effects that might induce follicle development with less damage to ovarian tissue. The potential development of LIFU as a non-invasive method for the treatment of female infertility is being considered, and this study sought to explore and confirm that LIFU can activate ovarian follicles. Results: We found a 50% increase in ovarian weight and in the number of mature follicles on the ultrasound-stimulated side with pulsed LIFU and intraperitoneal injection of 10 IU PMSG in 10-day-old rats. After ultrasound stimulation, the PCOS-like rats had a decrease in androgen levels, restoration of regular estrous cycle and increase in the number of mature follicles and corpora lutea, and the ratio of M1 and M2 type macrophages was altered in antral follicles of PCOS-like rats, consequently promoting further development and maturation of antral follicles. Conclusion: LIFU treatment could trigger actin changes in ovarian cells, which might disrupt the Hippo signal pathway to promote follicle formation, and the mechanical impact on the ovaries of PCOS-like rats improved antral follicle development.

Abstract Background In recent years, breast cancer (BC) incidence and mortality have been the highest in females. Menopause-like syndrome (MLS), arising from hypoestrogenism caused by endocrine therapy, significantly affects the quality of life for females. Traditional Chinese Medicine (TCM) has advantages in ameliorating MLS, but the efficacy of TCM in patients with BC has not been systematically evaluated. Methods A comprehensive search was performed on PubMed, Web of Science, Embase, Ovid, Cochrane Library, China National Knowledge Infrastructure, Wanfang database, Chinese Scientific Journals Database, and Clinical Trial Registry from inception to September 4, 2023. The Cochrane Risk of Bias assessment tool was used for the quality evaluation of the randomized controlled trials (RCTs). Review Manager 5.4 software was used for statistical analysis, and the Grading of Recommendations Assessment, Development, and Evaluation was used for quality evaluation of the synthesized evidence. Results This review included 42 studies involving 3112 female patients with BC. The results showed that the TCM group was better at decreasing the Kupperman Menopausal Index (KMI) scores (standardized MD, SMD = − 1.84, 95% confidence interval, CI [− 2.21–-1.46], Z = 9.63, P

Abstract Background Significant lower genital tract (LGT) dysbiosis and an associated lower rate of clinical pregnancy after in vitro fertilization–frozen embryo transfer (IVF-FET) among polycystic ovary syndrome (PCOS) patients have been previously reported by our group. We aimed to assess whether transvaginal Lactobacillus supplementation can reverse LGT dysbiosis and further improve perinatal outcomes in PCOS patients after IVF-FET. Methods/design This is a protocol for a multicenter, open-label, randomized controlled trial in China. Women diagnosed with PCOS who are undergoing IVF-FET treatment will be recruited. Allocation to the intervention/control arms at a ratio of 1:1 will be executed by an electronic randomization system. Participants in the intervention arm will receive the live Lactobacillus capsule vaginally for 10 consecutive days before embryo transfer, while those in the control arm will receive standard individualized care. The primary outcomes will be the clinical pregnancy rate, implantation rate, and live birth rate. 16S rRNA sequencing and liquid chromatography–mass spectrometry will be conducted to evaluate the LGT microbiome and systemic metabonomics before and after the intervention. A sample of 260 participants will provide 95% power to detect a 20% increase in the rate of clinical pregnancy (α = 0.025, one-tailed test, 15% dropout rate). A total of 300 participants will be recruited. Discussion This is the first large and multicenter randomized controlled trial aimed at assessing the efficacy of transvaginal Lactobacillus supplementation on restoring the LGT microbiome and improving perinatal outcomes in PCOS patients after IVF-FET. This pragmatic trial is promising for increasing the rates of clinical pregnancy and live birth in PCOS patients after IVF-FET. Ethics and dissemination Ethical review approval was obtained from the Medical Research Ethics Committees of the International Peace Maternity and Child Health Hospital of Shanghai Jiao Tong University (15 October 2020, GKLW 2020-29). To maximize dissemination, these findings will be reported in open access publications in journals with high impact, and oral and poster conference presentations will be performed. Trial registration ChiCTR ChiCTR2000036460. Registered on 13 September 2020, https://www.chictr.org.cn/showproj.html?proj=59549 .

Abstract Background Iguratimod (IGU) reduces hypergammaglobulinemia and disease activity in pSS (primary Sjögren’s syndrome) patients. However, the therapeutical mechanism of IGU for pSS remains largely unknown. This study aimed to investigate the regulation of Tfh cell differentiation by IGU in pSS patients. Methods We prospectively enrolled 13 pSS patients treated with IGU for 3 months and examined circulating T cell and B cell subsets by flow cytometry. We measured Tfh cell differentiation treated by IGU in pSS patients and healthy controls. Transcriptome analysis combined with molecular docking were employed to identify potential therapeutical targets of IGU, which were verified by Western blot and Tfh cell differentiation. Results Tfh, plasmablast, and plasma cells were suppressed by IGU treatment at 1 and 3 months. Tfh cell differentiation and function were significant inhibited by IGU in pSS patients and healthy controls in vitro. Pyruvate dehydrogenase kinase 1 (PDK1) was identified as a target of IGU during Tfh cell differentiation, and the downstream Akt phosphorylation was attenuated by IGU. Moreover, the activity of mTORC1 and phosphorylation of STAT3 were suppressed by IGU, with downregulation of BCL6 and upregulation of PRDM1. Finally, Akt activator restored IGU-suppressed Tfh cell differentiation. Conclusions IGU suppresses Tfh cell differentiation in pSS patients through interacting with PDK1 and suppressing Akt-mTOR-STAT3 signaling.

Abstract Purpose Exosomal circRNA, as an essential mediator of the follicular microenvironment, has been implicated in the etiological and pathobiological studies of polycystic ovarian syndrome (PCOS). This study aimed to determine abnormal circular RNA (circRNA) expression profiles in follicle fluid (FF) exosomes in patients with PCOS and identify the role of circ_0008285/microRNA (miR)-4644/low-density lipoprotein receptor (LDLR) axis in PCOS. Methods Sixty-seven women undergoing IVF/ICSI, 31 PCOS patients and 36 non-PCOS patients were included in the cohort study. The circRNA expression profiles of FF exosomes in PCOS (n = 3) and control group (n = 3) were compared by RNA sequencing. In an additional cohort (PCOS:28 vs Control:33), the mRNA expression levels of four circRNAs from FF exosomes were further verified by qRT-PCR. Bioinformatic analysis and dual luciferase reporter gene assay verified the relationship between circ_0008285 and miR-4644 and between miR-4644 and LDLR. KGN cells were infected with sh-circ0008285 and transfected with miR-4644 mimic to verify their roles in lipid metabolism. Results Four circRNAs showed significantly different expressions. Circ_0044234 was overexpressed in PCOS patients, while circ_0006877, circ_0013167 and circ0008285 were decreased in PCOS. Among four differentially expressed circRNAs, circ0008285 was enriched in lipoprotein particle receptor activity and cholesterol metabolism pathway by GO and KEGG pathway analyses. Luciferase assay confirmed the competing endogenous RNA (ceRNA) network circ_0008285/miR-4644 /LDLR. The intercellular experiments on circ_0008285 and its reduction in KGN cells showed that the consumption of circ_0008285 in exosomes could increase the expression of miR-4644 in recipient cells and inhibit the expression of LDLR, as well as increase free fatty acid secretion. Conclusion Circ_0008285 can combine with miR-4644 to promote the expression of LDLR and affect the cholesterol metabolism of ovarian granulosa cells in PCOS. Our findings revealed the ceRNA network of circ_0008285 and provided a new path to investigate lipid metabolism abnormalities in PCOS.

AbstractBackground This study was designed to investigate the association between nutrients and female infertility.Methods A cross-sectional study on 18–45 years of age reproductive-age women was conducted using the data from the National Health and Nutrition Examination Surveys (NHANES) for the periods 2013–2014 and 2015–2016. Multivariate logistic regression analysis was performed to evaluate the association between nutrients and female infertility. Subgroup analysis was applied to the body mass index (BMI). Results were summarised using an odds ratio (OR) with a 95% confidence interval (CI).Results Of the total 1713 women, 204 women (11.91%) were infertile. The result demonstrated that higher intake of carbohydrate (OR: 0.46, 95% CI: 0.24–0.86, p = 0.018), vitamin A (OR: 0.44, 95% CI: 0.24–0.80, p = 0.009), vitamin C (OR: 0.48, 95% CI: 0.26–0.88, p = 0.020), magnesium (OR: 0.36, 95% CI: 0.17–0.76, p = 0.009), iron (OR: 0.43, 95% CI: 0.23–0.82, p = 0.012), lycopene (OR: 0.55, 95% CI: 0.33–0.91, p = 0.022), and total folate (OR: 0.38, 95% CI: 0.20–0.70, p = 0.003) were associated with a lower risk of female infertility. The subgroup analysis also reported that intakes of vitamin A, vitamin C, and lycopene were related to a lower risk of female infertility among women with a BMI being 18.5–24.9 kg/m2. Among women with BMI > 24.9 kg/m2, high intakes of magnesium, iron and total folate were associated with a decreased risk of female infertility.Conclusions The intake of several nutrients is associated with a decreased risk of female infertility. These findings provide insight into potentially modifiable lifestyle factors associated with female infertility.

Bacterial communities form biofilms on various surfaces by synthesizing a cohesive and protective extracellular matrix, and these biofilms protect microorganisms against harsh environmental conditions. Bacillus subtilis is a widely used experimental species, and its biofilms are used as representative models of beneficial biofilms. Specifically, B. subtilis biofilms are known to be rich in extracellular polymeric substances (EPS) and other biopolymers such as DNA and proteins like the amyloid protein TasA and the hydrophobic protein BslA. These materials, which form an interconnected, cohesive, three-dimensional polymer network, provide the mechanical stability of biofilms and mediate their adherence to surfaces among other functional contributions. Here, we explored how genetically-encoded components specifically contribute to regulate the growth status, mechanical properties, and antibiotic resistance of B. subtilis biofilms, thereby establishing a solid empirical basis for understanding how various genetic engineering efforts are likely to affect the structure and function of biofilms. We noted discrete contributions to biofilm morphology, mechanical properties, and survival from major biofilm components such as EPS, TasA and BslA. For example, EPS plays an important role in maintaining the stability of the mechanical properties and the antibiotic resistance of biofilms, whereas BslA has a significant impact on the resolution that can be obtained for printing applications. This work provides a deeper understanding of the internal interactions of biofilm components through systematic genetic manipulations. It thus not only broadens the application prospects of beneficial biofilms, but also serves as the basis of future strategies for targeting and effectively removing harmful biofilms.

Background: Depression is one of the common complications in patients with postoperative breast cancer (BC). Conventional therapies for postoperative depression of BC always have modest treatment outcomes and undesirable side effects. Clinical practice and many studies have shown that traditional Chinese medicine (TCM) has a good effect on postoperative depression of BC. This meta-analysis aimed to assess the clinical effect of TCM as an add-on treatment for postoperative depression of BC.Methods: A systematic and thorough search was conducted on eight online electronic databases up to 20 July 2022. The control group received conventional therapies, and intervention groups received what control groups received plus TCM treatment. Review Manager 5.4.1 was used for statistical analysis.Results: Nine RCTs involved 789 participants who met the inclusion standards. The results showed the intervention group was better at decreasing the score of the Hamilton rating scale for depression (HAMD) (mean difference, MD = −4.21, 95% CI −5.54 to −2.88) and the self-rating depression scale (SDS) (MD = −12.03, 95% CI −15.94 to −8.13), improving clinical efficacy (RR = 1.25, 95% CI 1.14–1.37), increasing the levels of 5-hydroxytryptamine (5-HT) (MD = 0.27, 95% CI 0.20–0.34), dopamine (DA) (MD = 26.28, 95% CI 24.18–28.77), and norepinephrine (NE) (MD = 11.05, 95% CI 8.07–14.04), and influencing the immune index, including the levels of CD3+ (MD = 15.18, 95% CI 13.61–16.75), CD4+ (MD = 8.37, 95% CI 6.00–10.74), and CD4+/CD8+ (MD = 0.33, 95% CI 0.27–0.39). The level of CD8+ (MD = −4.04, 95% CI −11.98 to 3.99) had no obvious difference between the two groups.Conclusion: The meta‐analysis stated that a therapeutic regimen involving TCM could better improve the depression status in postoperative BC.

Disruption of iron homeostasis plays a negative role in follicle development. The dynamic changes in follicle growth are dependent on Hippo/YAP signaling and mechanical forces. However, little is known about the liaison between iron overload and the Hippo/YAP signalling pathway in term of folliculogenesis. Here, based on the available evidence, we established a hypothesized model linking excessive iron, extracellular matrix (ECM), transforming growth factor-β (TGF-β) and Hippo/Yes-associated protein (YAP) signal regarding follicle development. Hypothetically, the TGF-β signal and iron overload may play a synergistic role in ECM production via YAP. We speculate that the dynamic homeostasis of follicular iron interacts with YAP, increasing the risk of ovarian reserve loss and may enhance the sensitivity of follicles to accumulated iron. Hence, therapeutic interventions targeting iron metabolism disorders, and Hippo/YAP signal may alter the consequences of the impaired developmental process based on our hypothesis, which provides potential targets and inspiration for further drug discovery and development applied to clinical treatment.

Abstract Background Mesenchymal stem cell (MSC) senescence is a phenotype of aging. Long noncoding RNAs (lncRNAs) are emerging as potential key regulators of senescence. However, the role of lncRNAs in MSC senescence remains largely unknown. Results We performed transcriptome analysis in senescent human adipose-derived MSCs (hADSCs) and identified that the lncRNA LYPLAL1 antisense RNA1 (LYPLAL1-AS1) was significantly downregulated in senescent hADSCs. LYPLAL1-AS1 expression in peripheral blood was lower in middle-aged healthy donors than in young adult donors, and correlated negatively with age. Knockdown of LYPLAL1-AS1 accelerated hADSC senescence, while LYPLAL1-AS1 overexpression attenuated it. Chromatin isolation by RNA purification (ChIRP) sequencing indicated that LYPLAL1-AS1 bound to the MIRLET7B promoter region and suppressed its transcription activity, as demonstrated by dual-luciferase assay. miR-let-7b, the transcript of MIRLET7B, was upregulated during hADSC senescence and was regulated by LYPLAL1-AS1. Furthermore, miR-let-7b mimics promoted hADSC senescence, while the inhibitors repressed it. Finally, LYPLAL1-AS1 overexpression reversed miR-let-7b-induced hADSC senescence. Conclusions Our data demonstrate that LYPLAL1-AS1 rejuvenates hADSCs through the transcriptional inhibition of MIRLET7B. Our work provides new insights into the mechanism of MSC senescence and indicates lncRNA LYPLAL1-AS1 and miR-let-7b as potential therapeutic targets in aging.

In this paper, by using the Mawhin's continuation theorem, some easily verifiable sufficient conditions are obtained to guarantee the existence of almost periodic solutions of impulsive non-autonomous Lotka-Volterra predator-prey system with harvesting terms. Our result corrects the result obtained in [13]. An example and some remarks are given to illustrate the advantage of this paper.

During folliculogenesis, the oocyte and surrounding cumulus cells form an ensemble called the cumulus-oocyte complex (COC). Due to their interdependence, research on the COC has been a hot issue in the past few decades. A growing body of literature has revealed that intercellular communication is critical in determining oocyte quality and ovulation. This review provides an update on the current knowledge of COC intercellular communication, morphology, and functions. Transzonal projections (TZPs) and gap junctions are the most described structures of the COC. They provide basic metabolic and nutrient support, and abundant molecules for signaling pathways and regulations. Oocyte-secreted factors (OSFs) such as growth differentiation factor 9 and bone morphogenetic protein 15 have been linked with follicular homeostasis, suggesting that the communications are bidirectional. Using advanced techniques, new evidence has highlighted the existence of other structures that participate in intercellular communication. Extracellular vesicles can carry transcripts and signaling molecules. Microvilli on the oocyte can induce the formation of TZPs and secrete OSFs. Cell membrane fusion between the oocyte and cumulus cells can lead to sharing of cytoplasm, in a way making the COC a true whole. These findings give us new insights into related reproductive diseases like polycystic ovary syndrome and primary ovarian insufficiency and how to improve the outcomes of assisted reproduction.

PurposeHuman follicular fluid (FF) is a complex biological fluid that contributes to the micro-environment of oocyte development. The aim of this study was to evaluate the role of steroid and gonadotropic hormones levels and mitochondrial function in embryo development during in vitro fertilization cycles.MethodsThis was a cohort study of 138 women receiving IVF/ICSI, including 136 FF samples from 109 infertile women. FF steroid and gonadotropic hormones levels were tested by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and immunoassays. The mRNA expression levels of mitochondrial electron transport chain (ETC) complex genes from FF exosomes were detected by qPCR.ResultsAnalysis of these individual FF concentrations revealed that LH and FSH concentrations were higher in follicles in which the oocyte developed into a top quality (TQ) blastocyst (LH: 9.44 ± 2.32mIU/ml, FSH: 9.32 ± 1.01mIU/ml) than those in which there was a failure of fertilization (LH: 5.30 ± 0.84mIU/ml, FSH: 6.91 ± 0.62mIU/ml). In contrast, follicular cortisone concentrations were lower for oocytes that resulted in a TQ blastocyst (12.20 ± 0.82mIU/ml). The receiver operating characteristic analysis showed that FF LH and FSH levels predicted TQ blastocyst with excellent AUC value of 0.711 and 0.747. Mitochondrial ETC complex I and III mRNA levels were increased in the FF exosomes of TQ blastocyst. Correlation analysis showed that mRNA levels of ETC complex I was positively correlated with LH and FSH levels in FF.ConclusionThe levels of FF steroid and gonadotropic hormones from single follicle can predetermine subsequent embryo development to some extent. Furthermore, impaired exosome mitochondrial dysfunction is a potiential event that causes hormone change in embryo development.

Introduction: About one-third of primary biliary cholangitis (PBC) patients do not exhibit complete response to ursodeoxycholic acid (UDCA). Some of these patients were reported to benefit from the combination therapy of fibrates and UDCA, but more clinical evidence is required. In this study, we conducted a randomized, controlled trial on the safety and efficacy of fenofibrate in the treatment of patients with PBC. Methods: Forty-eight PBC patients with incomplete response to UDCA were enrolled and randomly assigned to two groups (24 in the experiment group and 24 in the control group). For the experimental group, the patients were administered 13–15 mg/kg/day UDCA in combination with 200 mg/day fenofibrate. For the control group, the patients continued to receive UDCA at 13–15 mg/kg/day. The patients were followed up for at least 12 months. The serum levels of alkaline phosphatase (ALP), gamma-glutamyl transferase (γ-GT), aspartate aminotransferase (AST), and other biochemical parameters were measured at 3, 6, and 12 months during the trial to assess patient conditions. Results: At 12 months, 20.8% of the patients in the experimental group had all three indexes of serum ALP, γ-GT, and total bilirubin normalized, while 0% of patients in the control group reached the primary outcome (difference, 20.8 percentage points; 95% CI, 4.6–37.0). 54.2% of the patients had normal ALP levels in the experimental group and 4.2% in the control group (difference, 50 percentage points; 95% CI, 28.5–71.5). The experimental group had greater improvement of ALP ( p

ObjectivesThe aim of this study is to investigate the clinical significance of myeloperoxidase (MPO)–antineutrophil cytoplasmic antibody (ANCA) on eosinophilic granulomatosis with polyangiitis (EGPA) from a longitudinal Chinese cohort.MethodsA total of 120 patients with EGPA were consecutively enrolled and followed up. Two patients with PR3 ANCA was excluded and our analysis focused on the 118 patients with EGPA. On the basis of MPO-ANCA status, baseline clinical manifestations, treatment, and outcomes were analyzed. Logistic regression analysis was performed to analyze the independently associated factors for renal involvement.ResultsANCA positivity was observed in 24.2% of patients with EGPA. Patients with MPO-ANCA accounted for 20.8%. Patients with positive MPO-ANCA had higher levels of erythrocyte sedimentation rate (ESR), C-reactive protein, Birmingham Vasculitis Activity Score (BVAS), higher ratios of fever, myalgia, renal involvement, and biopsy-proven vasculitis. Heart manifestations and asthma were more common in patients with negative ANCA. Baseline MPO-ANCA titers positively correlated with ESR, eosinophil count, and BVAS and were higher in patients with methylprednisolone pulse. Among patients with renal involvement, patients with positive MPO-ANCA had higher proportions of female, fever, biopsy-proven vasculitis, and faster ESR; patients with negative ANCA developed more skin and cardiac involvement. MPO-ANCA positivity, male, and ear involvement were the independent factors associated with renal involvement. Intravenous cyclophosphamide and immunoglobulins were prescribed more frequently in patients with positive MPO-ANCA.ConclusionIn this cohort, patients with positive MPO-ANCA and negative ANCA displayed distinct clinical features, suggesting that MPO-ANCA might be a valuable biomarker for EGPA stratification. Baseline MPO-ANCA level correlated positively with disease activity of EGPA. MPO-ANCA was a significant independent factor associated with renal involvement.

ObjectivesEnhancer of zeste homolog 2 (EZH2) is an epigenetic regulator that plays an essential role in immune system development and autoimmune diseases. This study aimed to characterize the role of EZH2 in the pathogenesis of primary Sjögren’s syndrome (pSS).MethodsWe analyzed EZH2 expression in two transcriptomic datasets of peripheral blood mononuclear cells (PBMCs) from pSS patients and healthy controls. We measured EZH2 expression in CD4+ T cells, CD8+ T cells, and CD19+ B cells from pSS patients and healthy controls and correlated EZH2 expression with clinical parameters. We also examined the activation, proliferation, and T-cell differentiation of CD4+ T cells using the EZH2 inhibitor GSK126, EZH2 siRNA, and EZH2-expressing vector. We further examined the STAT3 signaling pathway after EZH2 inhibition and detected Tfh differentiation in EZH2-overexpressed CD4+ T cells with STAT3 knocked down.ResultsEZH2 was upregulated in GSE164885 and GSE48378. EZH2 expression was higher in pSS CD4+ and CD8+ T cells, and EZH2 expression in circulating pSS CD4+ T cells was positively correlated with IgG, IgA, ESR, RF, and the circulating Tfh population. EZH2 inhibition and silencing EZH2 suppressed activation, proliferation, and Tfh differentiation. Furthermore, overexpressing EZH2 promoted activation, proliferation, and Tfh differentiation in CD4+ T cells. EZH2 inhibition attenuated STAT3 phosphorylation in CD4+ T cells. STAT3 knockdown abrogated EZH2-promoted Tfh differentiation.ConclusionsEZH2 expression was abnormally elevated in pSS CD4+ T cells, which facilitated Tfh differentiation of CD4+ T cells by enhancing STAT3 phosphorylation. EZH2 promotes Tfh differentiation and might be implicated in pSS pathogenesis.

Abstract Background Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder with various manifestations and complex etiology. Follicular fluid (FF) serves as the complex microenvironment for follicular development. However, the correlation between the concentration of steroid in FF and the pathogenesis of PCOS is still unclear. Methods Twenty steroid levels in FF from ten patients with PCOS and ten women with male-factor infertility undergoing in vitro fertilization were tested by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in order to explore their possibly correlation with PCOS. Meanwhile, the mRNA levels of core enzymes in steroid synthesis pathway from exosomes of FF were also detected by qPCR. Results The estriol (p

Abstract Background Central nervous system (CNS) involvement is extremely rare in eosinophilic granulomatosis with polyangiitis (EGPA), but is associated with a poor prognosis in the five-factor score. This study aims to elucidate the clinical features and independently associated factors of EGPA with CNS involvement. Results CNS involvement was observed in 17.3% (19/110) of EGPA patients from Peking Union Medical College Hospital between 2007 and 2019. We retrospectively reviewed their clinical data and analyzed the independently associated factors. Their mean age was 51.7 ± 11.56 years with no male/female predominance. Ischemic lesions were the most common manifestations, accounting for 63.2% of the 19 cases, followed by posterior reversible encephalopathy syndrome (36.8%), spinal cord involvement (15.8%), medulla oblongata involvement (15.8%), and intracranial hemorrhages (15.8%). Compared to the control group, patients with CNS involvement were of older age (51.7 ± 11.56 vs. 43.7 ± 13.78 years, p = 0.019) and had a higher ratio in the digestive tract involvement (52.6% vs. 28.6%, p = 0.042). Further multivariate analysis revealed that age, disease duration, and fever were the potential independent risk factors for CNS involvement of EGPA. Glucocorticoids combined with cyclophosphamide were the strategic therapy (94.7%). Intrathecal injections of dexamethasone and methotrexate were administered to 21.1% of the patients. Although seven patients relapsed during glucocorticoid reduction, seventeen patients finally achieved clinical remission. One patient died of acute intracerebral hemorrhage within one month, and another died of gastrointestinal perforation. Outcomes and cumulative survival show no significant differences between the two groups. Conclusions CNS involvement is uncommon in EGPA with various manifestations, and ischemic lesions are the most frequent. Age, disease duration, and fever are independent factors associated with CNS involvement in EGPA. The therapy of glucocorticoids combined with cyclophosphamide and intrathecal injections yields favorable responses. Acute intracranial hemorrhage and gastrointestinal perforation may be the principal causes of death.

Given the self-renewal, multi-differentiation, immunoregulatory, and tissue maintenance properties, mesenchymal stem cells (MSCs) are promising candidates for stem cell-based therapies. Breakthroughs have been made in uncovering MSCs as key contributors to homeostasis and the regenerative repair of tissues and organs derived from three germ layers. MSC differentiation into specialized cell types is sophisticatedly regulated, and accumulating evidence suggests long non-coding RNAs (lncRNAs) as the master regulators of various biological processes including the maintenance of homeostasis and multi-differentiation functions through epigenetic, transcriptional, and post-translational mechanisms. LncRNAs are ubiquitous and generally referred to as non-coding transcripts longer than 200 bp. Most lncRNAs are evolutionary conserved and species-specific; however, the weak conservation of their sequences across species does not affect their diverse biological functions. Although numerous lncRNAs have been annotated and studied, they are nevertheless only the tip of the iceberg; the rest remain to be discovered. In this review, we characterize MSC functions in homeostasis and highlight recent advances on the functions and mechanisms of lncRNAs in regulating MSC homeostasis and differentiation. We also discuss the current challenges and perspectives for understanding the roles of lncRNAs in MSC functions in homeostasis, which could help develop promising targets for MSC-based therapies.

Aims: To investigate the long-term survival of patients with primary Sjögren’s syndrome (pSS) in China. Methods: Patients with pSS who fulfilled the 2002 American–European Consensus Group classification criteria were prospectively enrolled from 2004 to 2011. Their baseline clinical, laboratory, and therapeutic data were collected. The primary endpoint was all-cause death by January 2018. The standard mortality ratio (SMR) was calculated by comparing with age-matched and sex-matched mortality data of the general population. Kaplan–Meier curves were obtained by time-to-event analysis. Univariate and multivariate Cox hazards regression analyses were performed to identify risk factors for mortality. Results: A total of 1054 patients were enrolled and 834 patients were followed up for a median of 94.8 months, with 48 confirmed deaths. The total SMR was 3.63 [95% confidence interval (CI) 2.60–4.66]. The 3-, 5-, and 10-year survival rates were 98.4%, 97.5%, and 92.9%, respectively. Infection, malignancy, and respiratory failure were the top three causes of mortality. We identified male sex [hazard ratio (HR) = 3.00, 95% CI 1.23–7.31], age at diagnosis ⩾50 years of age (HR = 7.69, 95% CI 3.01–19.62), thrombocytopenia (HR = 1.93, 95% CI 1.01–3.72), and interstitial lung disease (HR = 5.96, 95% CI 2.24–15.82) as the independent prognostic factors of death. Conclusions: The mortality rates of Chinese patients with pSS are higher than those of the general population. Male patients of elder age at diagnosis complicated with thrombocytopenia and interstitial lung disease might be suggestive for poorer survival and require closer follow up.

Abstract Background Previous studies have demonstrated that progestin-primed ovarian stimulation (PPOS) protocol was a feasible and efficient method in in vitro fertilization (IVF) cycle. However, its application in women with advanced age has not been determined yet. The purpose of this study was to investigate its efficacy in women aged ≥40 years old. Methods This retrospective cohort study included patients with ages of ≥40 years old at the time of ovarian stimulation. The embryonic and clinical outcome of mild stimulation and PPOS were compared. Primary outcome was top-quality embryo rate on day 3, and secondary outcome was clinical pregnancy rate. Results Baseline characteristics of patients was similar in mild stimulation (122 cycles) and PPOS (47 cycles). No significant difference was found in the number of retrieved and mature oocytes and the fertilization and cleavage rates. Of interest, the rate of top-quality embryos was significantly higher in PPOS group (50.08% vs 33.29%, p = 0.015), with an increasing trend of viable embryo rate (73.55% vs 61.16%). A greater amount of gonadotropin was observed in PPOS group (2061.17 ± 1254.63 IU vs 1518.14 ± 547.25 IU, p

Accumulating evidence revealed that the leading risk factor of endometrial cancer is exposure to endogenous and exogenous estrogens, while the exact mechanism underlying estrogen contribution to endometrial cancer progression has not been elucidated clearly. Interleukin (IL)-6 has been verified to be critical for tumor progression in several human cancers. In this study, we provided evidence that 17β-estradiol (E2) could significantly promote endometrial cancer cells viability, migration and invasion through activation of IL-6 pathway, which involved in its downstream pathway and target genes (p-Stat3, Bcl-2, Mcl-1, cyclin D1 and MMP2). Meanwhile, utilization of IL-6-neutralizing antibody could partially attenuate the increased cancer growth and invasion abilities in Ishikawa and RL95-2 endometrial cancer cell lines and an orthotopic endometrial cancer model. We established a causative link between estrogen and IL-6 signaling activation in the development of endometrial cancer. The molecular mechanism defined in this study provided the evidence that E2 promotes endometrial carcinoma progression via activating the IL-6 pathway, indicating that interruption of IL-6 might be an essential therapeutic strategy in estrogen-dependent endometrial cancer.

Summary: Vaccination approaches have generally focused on the antigen rather than the resultant antibodies generated, which differ greatly in quality and function between individuals. The ability to replace the variable regions of the native B cell receptor (BCR) heavy and light chain loci with defined recombined sequences of a preferred monoclonal antibody could enable curative adoptive cell transfer. We report CRISPR-mediated homologous recombination (HR) into the BCR of primary human B cells. Ribonucleoprotein delivery enabled editing at the model CXCR4 locus, as demonstrated by T7E1 assay, flow cytometry, and TIDE analysis. Insertion via HR was confirmed by sequencing, cross-boundary PCR, and restriction digest. Optimized conditions were used to achieve HR at the BCR variable heavy and light chains. Insertion was confirmed at the DNA level, and transgene expression from the native BCR promoters was observed. Reprogramming the specificity of antibodies in the genomes of B cells could have clinical importance. : Molecular Biology; Immunology; Biotechnology; Cell Biology; Biological Sciences Research Methodologies Subject Areas: Molecular Biology, Immunology, Biotechnology, Cell Biology, Biological Sciences Research Methodologies

Objectives: To explore the potential role of CD3+CD8+CD161high TCRVα7.2+ mucosal-associated invariant T (MAIT) cells in the pathogenesis of primary biliary cholangitis (PBC).Methods: We enrolled 55 patients with PBC, 69 healthy controls (HCs), and 8 patients with hepatic hemangioma. Circulating MAIT cells and their chemokine receptor profiles and cytokine production were quantified using flow cytometry. Liver-resident MAIT cells were examined by immunofluorescence staining. CXCL12-mediated chemotaxis of MAIT cells was measured using a transwell migration assay. Plasma interleukin (IL)-18 was measured using ELISA, and cytokine production in IL-18-stimulated MAIT cells was detected using flow cytometry.Result: Peripheral MAIT cells were found to be significantly lower in patients with PBC (3.0 ± 3.2% vs. 9.4 ± 8.0%, p < 0.01) and negatively correlated with alkaline phosphatase (ALP) levels (r = −0.3209, p < 0.05). Liver immunofluorescence staining suggested that MAIT cells might accumulate in PBC liver. MAIT cells from patients with PBC expressed higher levels of CXCR4 (84.8 ± 18.0% vs. 58.7 ± 11.4%, p < 0.01), and the expression of CXCL12 was higher in PBC liver. CXCL12 promoted MAIT cell chemotaxis (70.4 ± 6.8% vs. 52.2 ± 3.5%, p < 0.01), which was attenuated by CXCR4 antagonist. MAIT cells from PBC produced significantly more interferon-γ (IFN-γ) (88.3 ± 4.2% vs. 64.2 ± 10.1%, p < 0.01), tumor necrosis factor-α (TNF-α) (93.0 ± 1.1% vs. 80.1 ± 5.3%, p < 0.01), Granzyme B (89.3 ± 3.3% vs. 72.1 ± 7.0%, p < 0.01), and perforin (46.8 ± 6.6% vs. 34.8 ± 7.7%, p < 0.05). MAIT cells from PBC expressed higher levels of IL18-Rα (83.8 ± 10.2% vs. 58.3 ± 8.7%, p < 0.01). Plasma IL-18 was more abundant in patients with PBC (286.8 ± 75.7 pg/ml vs. 132.9 ± 78.1 pg/ml, p < 0.01). IL-18 promoted IFN-γ production in MAIT cells (74.9 ± 6.6% vs. 54.7 ± 6.7%, p < 0.01), which was partially attenuated by blocking IL-18R (68.6 ± 8.3% vs. 43.5 ± 4.2%, p < 0.01).Conclusion: Mucosal-associated invariant T cells from patients with PBC accumulated in the liver via CXCL12-CXCR4-mediated chemotaxis, produced pro-inflammatory cytokines, and contributed to portal inflammation, which was potentially mediated by elevated IL-18. Targeting MAIT cells might be a therapeutic approach for PBC.

Autoimmune liver disease (AILD) is a series of chronic liver diseases with abnormal immune responses, including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). The treatment options for AILD remain limited, and the adverse side effects of the drugs that are typically used for treatment frequently lead to a low quality of life for AILD patients. Moreover, AILD patients may have a poor prognosis, especially those with an incomplete response to first-line treatment. Mesenchymal stem cells (MSCs) are pluripotent stem cells with low immunogenicity and can be conveniently harvested. MSC-based therapy is emerging as a promising approach for treating liver diseases based on their advantageous characteristics of immunomodulation, anti-fibrosis effects, and differentiation to hepatocytes, and accumulating evidence has revealed the positive effects of MSC therapy in AILD. In this review, we first summarize the mechanisms, safety, and efficacy of MSC treatment for AILD based on work in animal and clinical studies. We also discuss the challenges of MSC therapy in clinical applications. In summary, although promising data from preclinical studies are now available, MSC therapy is currently far for being applied in clinical practice, thus developing MSC therapy in AILD is still challenging and warrants further research.

Background: Cardiac manifestations are common and life-threatening in eosinophilic granulomatosis with polyangiitis (EGPA), which remains poorly studied in China. We aim to investigate its clinical features, associated factors, treatment, and outcomes. Methods: We reviewed the clinical records of 110 EGPA patients and examined the independent factors associated with cardiac manifestations using multivariate logistic regression. Receiver operating characteristic curves determined the cut-off values, and survival was calculated via Kaplan–Meier curves. Results: Cardiac involvement was present in 36.4% (40/110) of EGPA patients, which mainly manifested as pericardial effusion (16.4%, 18/110), myocardial involvement (13.6%, 15/110), and heart failure (8.2%, 9/110). The mean age was 42.1 ± 14.23 years with no female/male predominance. Compared with the cardiac-unaffected group, the cardiac-affected group showed a lower rate of biopsy-proved vasculitis (0% versus 20%, p = 0.002). The eosinophil count [odds ratio (OR) = 1.142, 95% confidence interval (CI) 1.029–1.267] was independently associated with cardiac manifestations in EGPA, with a cut-off value of 3.66 × 10 9 /L [area under the curve (AUC) = 0.692, p = 0.001]. Regarding treatment, the cardiac-affected group displayed a higher ratio of glucocorticoid pulse combined with intravenous cyclophosphamide (CYC-IV) (40% versus 21.4%, p = 0.037), and intravenous immunoglobulin combined with glucocorticoid plus CYC-IV (17.5% versus 4.3%, p = 0.035) than the control group. Outcomes ( p = 0.131) and survival ( p = 0.1972) were not significantly different between the groups. Conclusion: In this single-center Chinese EGPA cohort, cardiac manifestations are observed in 36.4% of patients, which primarily presents as myocardial involvement, pericardial effusion, and heart failure, independently associated with eosinophil count. Glucocorticoid combined with cyclophosphamide is the treatment cornerstone for EGPA patients with cardiac manifestations.

Abstract Waterborne viruses frequently cause disease outbreaks and existing strategies to remove such viral pathogens often involve harsh or energy‐consuming water treatment processes. Here, a simple, efficient, and environmentally friendly approach is reported to achieve highly selective disinfection of specific viruses with living engineered biofilm materials. As a proof‐of‐concept, Escherichia coli biofilm matrix protein CsgA was initially genetically fused with the influenza‐virus‐binding peptide (C5). The resultant engineered living biofilms could correspondingly capture virus particles directly from aqueous solutions, disinfecting samples to a level below the limit‐of‐detection for a qPCR‐based detection assay. By exploiting the surface‐adherence properties of biofilms, it is further shown that polypropylene filler materials colonized by the CsgA‐C5 biofilms can be utilized to disinfect river water samples with influenza titers as high as 1 × 107 PFU L−1. Additionally, a suicide gene circuit is designed and applied in the engineered strain that strictly limits the growth of bacterial, therefore providing a viable route to reduce potential risks confronted with the use of genetically modified organisms. The study thus illustrates that engineered biofilms can be harvested for the disinfection of pathogens from environmental water samples in a controlled manner and highlights the unique biology‐only properties of living substances for material applications.

Objective. To investigate clinical features, independent associated factors, treatment, and outcome of patients with peripheral neuropathy (PN) in eosinophilic granulomatosis with polyangiitis (EGPA). Methods. We retrospectively analyzed clinical data of 110 EGPA patients from 2007 to 2019 in Peking Union Medical College Hospital. The independent factors associated with PN in EGPA were analyzed with univariate and multivariate logistic regressions. Results. In EGPA with PN, paresthesia and muscle weakness were observed in 82% and 33% of patients, respectively. Both the upper and lower limbs were involved in 51% of patients. 30% of EGPA patients had symmetrical multiple peripheral neuropathy, whereas only 16.4% presented with mononeuritis multiplex. Compared to patients without PN, patients with PN had a higher erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, Birmingham vasculitis activity score (BVAS), and positivity of myeloperoxidase-antineutrophil cytoplasmic antibodies (MPO-ANCA). Regarding manifestations, patients with PN tended to develop weight loss and arthritis or joint pain. Notably, ANCA positivity, arthritis or joint pain, and higher BVAS were found to be independent associated factors for PN in EGPA. Patients with PN more frequently need glucocorticoid pulses and intravenous infusion of cyclophosphamide. With the longest follow-up of 11.0 years, we found that age and cardiac involvement were risk factors for survival, and female was the protective factor. Conclusion. PN in EGPA frequently displays with symmetrical multiple peripheral neuropathy in China. Positive ANCA, arthritis or joint pain, and higher BVAS are the independent associated factors of PN in EGPA. Glucocorticoids with immunosuppressants are vital therapeutic strategy.

Let G be an infinite connected graph. We introduce two kinds of multilinear fractional maximal operators on G. By assuming that the graph G satisfies certain geometric conditions, we establish the bounds for the above operators on the endpoint Sobolev spaces and Hajłasz–Sobolev spaces on G.

Objectives: To investigate the risk factors for death in anti-melanoma differentiation–associated protein-5-positive dermatomyositis-associated interstitial lung disease (ILD). Methods: Studies were identified by searching PubMed, Embase, Web of Science, and Cochrane Library. We calculated pooled risk ratios (RRs) or standardized mean differences (SMDs) and 95% confidence intervals (CIs) using random-effects models. Results: Twenty studies were selected. Factors that may increase death risk included older age (SMD: 0.62, 95% CI: 0.42–0.81), elevated Krebs von den Lungen-6 (SMD: 0.66, 95% CI: 0.47–0.86), lactate dehydrogenase (SMD: 0.87, 95% CI: 0.72–1.02), C-reactive protein (SMD: 0.62, 95% CI: 0.44–0.80), ferritin (SMD: 0.93, 95% CI: 0.71–1.15), creatine kinase (SMD: 0.28, 95% CI: 0.13–0.44), neutrophil (SMD: 0.34, 95% CI: 0.04–0.64), neutrophil-to-lymphocyte ratio (SMD: 0.52, 95% CI: 0.24–0.79), aspartate aminotransferase (SMD: 0.70, 95% CI: 0.45–0.94), shorter disease duration (SMD: −0.44, 95% CI: −0.67 to −0.21), rapidly progressive ILD (RR: 4.08, 95% CI: 3.01–5.54), fever (RR: 1.98, 95% CI: 1.46–2.69), dyspnoea (RR: 1.63, 95% CI: 1.32–2.02), and anti-Ro52 antibody positive (RR: 1.28, 95% CI: 1.11–1.49). Female (RR: 0.86, 95% CI: 0.78–0.94), increased albumin (SMD: −1.20, 95% CI: −1.76 to −0.64), lymphocyte (SMD: −0.49, 95% CI: −0.67 to −0.30), and arthralgia (RR: 0.53, 95% CI: 0.37–0.78) were protective factors. Conclusion: Older age, shorter disease duration, rapidly progressive ILD, fever, dyspnoea, anti-Ro52 antibody positive, and some inflammatory markers were risk factors for death in patients with anti-melanoma differentiation–associated protein-5-positive dermatomyositis-associated ILD. [ABSTRACT FROM AUTHOR]