Anti-proliferation and apoptosis induced via the mTOR/PGC-1α signaling pathway in trophoblast cells of miscarriage.

Miscarriage is a common complication during early pregnancy and affects approximately 10%-15% of all pregnant women. Several studies have reported that the abnormal expression of mitochondrial oxidative stress-related genes might be involved in the occurrence and progression of miscarriage. The present study attempted to uncover the role of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) in miscarriage chorionic villous tissue. The hypothesis that PGC-1α is crucial for glycolysis and oxidative phosphorylation during early pregnancy was tested. The results showed that the mRNA and protein levels of PGC-1α were significantly increased in the miscarriage chorionic villous tissues compared with the artificial selective abortion group, and that the expression was regulated by mTOR in knockdown and overexpression of mTOR in HTR8 cell lines. PGC-1α also promoted mitochondrion oxidative phosphorylation but inhibited glycolysis process. In addition, PGC-1α could drive ROS production, reduce mitochondrial membrane potential and block NADPH synthesis, resulting in cell cycle arrest and cell apoptosis, eventually leading to miscarriage. These results suggested that the aberrant expression of PGC-1α is involved in the etiology of early miscarriage, providing new perspectives regarding the mechanisms of miscarriage and a potential therapeutic target for miscarriage.

Expression patterns and prognostic value of key regulators associated with m7G RNA modification based on all gene expression in colon adenocarcinoma.

BACKGROUND: N7-methylguanosine (m7G) is present in a wide variety of organisms and has important roles. m7G has been reported to be involved in multiple biological processes, and recent studies have reported that changes in RNA modifications result in tumor cellular transformation and cancer, such as colon adenocarcinoma, lung cancer, and intrahepatic cholangiocarcinoma. However, little is known about the function of the m7G in colon adenocarcinoma. METHODS: We established two clusters based on the expression of all genes associated with m7G to explore the expression pattern of 31 key regulatory factors of m7G RNA and assess the prognostic value of regulatory factors. Wilcoxon test and differential box line plots were applied for bioinformatics analysis. Receiver Operating and Kaplan‒Meier curves were utilized to evaluate the prognostic value. Finally, four genes' expression in the colon cancer cell line was confirmed by qRT-PCR. RESULTS: From The Cancer Genome Atlas database, we found that the expression levels of 25 out of the 31 key N7-methylguanosine RNA modification regulators were significantly different in colon adenocarcinoma. According to 25 methylation regulators' expression, we identified two subgroups by consensus clustering, in which the prognosis was worse in Group 2 than in Group 1 and was significantly correlated with age. Cluster 2 was significantly enriched in tumor-associated pathways, and immune cells were highly infiltrated in Cluster 1 but weakly infiltrated in Cluster 2. Further results indicated that this risk profile may serve as a standalone predictive factor for colon adenocarcinoma, and the four genetic risk profiles' prognostic relatedness was successfully verified through Gene Expression Omnibus dataset. At last, A nomogram for prognosis was created according to age, sex, histological grading, clinicopathological staging, and hazard score to accurately predict patient prognosis in colon adenocarcinoma. We successfully validated the differential expression of four genes using qRT-PCR. CONCLUSIONS: In the present study, we revealed the important contribution of key regulators associated with m7G RNA modifications based on all gene expression in colon adenocarcinoma and developed a signature of risk that serves as a promising prognostic marker for patients with colon adenocarcinoma.

Bi-allelic mutations in MOS cause female infertility characterized by preimplantation embryonic arrest.

STUDY QUESTION: Are mutations in MOS (MOS proto-oncogene, serine/threonine kinase) involved in early embryonic arrest in infertile women? SUMMARY ANSWER: We identified mutations in MOS that may cause human female infertility characterized by preimplantation embryonic arrest (PREMBA), and the effects of the mutations in human embryonic kidney 293T (HEK293T cells) and mouse oocytes provided evidence for a causal relation between MOS and female infertility. WHAT IS KNOWN ALREADY: MOS, an activator of mitogen-activated protein kinase, mediates germinal vesicle breakdown and metaphase II arrest. Female MOS knockout mice are viable but sterile. Thus, MOS seems to be an important part of the mammalian cell cycle mechanism that regulates female meiosis. STUDY DESIGN, SIZE, DURATION: Whole-exome sequencing, bioinformatics filtering analysis and genetic analysis were performed to identify two different biallelic mutations in MOS in two independent families. The infertile patients presenting with early embryonic arrest were recruited from October 2018 to June 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: The female patients diagnosed with primary infertility were recruited from the reproduction centres of local hospitals. Genomic DNA from the affected individuals, their family members and healthy controls was extracted from peripheral blood. We performed whole-exome sequencing in patients diagnosed with PREMBA. Functional effects of the mutations were investigated in HEK293T cells by western blotting and in mouse oocytes by microinjection and immunofluorescence. MAIN RESULTS AND THE ROLE OF CHANCE: We identified the homozygous missense mutation c.285C>A (p.(Asn95Lys)) and the compound heterozygous mutations c.467delG (p.(Gly156Alafs*18)) and c.956G>A (p.(Arg319His)) in MOS in two independent patients. The mutations c.285C>A (p.(Asn95Lys)) and c.467delG (p.(Gly156Alafs*18)) reduced the protein level of MOS, and all mutations reduced the ability of MOS to phosphorylate its downstream target, extracellular signal-regulated kinase1/2. In addition, the identified mutations reduced the capacity of exogenous human MOS to rescue the metaphase II exit phenotype, and the F-actin cytoskeleton of mouse oocytes was affected by the patient-derived mutations. LIMITATIONS, REASONS FOR CAUTION: Owing to the lack of in vivo data from patient oocytes, the exact molecular mechanism affected by MOS mutations and leading to PREMBA is still unknown and should be further investigated using knock-out or knock-in mice. WIDER IMPLICATIONS OF THE FINDINGS: We identified recessive mutations in MOS in two independent patients with the PREMBA phenotype. Our findings reveal the important role of MOS during human oocyte meiosis and embryonic development and suggest that mutations in MOS may be precise diagnostic markers for clinical genetic counselling. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (81725006, 81822019, 81771581, 81971450, 81971382,82001538 and 82071642), the project supported by the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), the Project of the Shanghai Municipal Science and Technology Commission (19JC1411001), the Natural Science Foundation of Shanghai (19ZR1444500 and 21ZR1404800), the Shuguang Program of the Shanghai Education Development Foundation and the Shanghai Municipal Education Commission (18SG03), the Foundation of the Shanghai Health and Family Planning Commission (20154Y0162), the Capacity Building Planning Program for Shanghai Women and Children's Health Service and the collaborative innovation centre project construction for Shanghai Women and Children's Health. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Autophagy markers are dysregulated in the endometrial tissues of patients with unexplained repeated implantation failure.

Endometrium decidualization is a complex biological process, which includes the interplay of transcription factors, cytokines, cell cycle regulators, and other signaling pathways. However, the underlying molecular mechanisms of this process are not fully elucidated to date. In this study, we aimed to investigate the possible association between autophagy and recurrent implantation failure (RIF). A total of 81 genes were downregulated and 231 genes were upregulated in the RIF group compared with the control group, and the differences were statistically significant (p < 0.05). Further, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway were analyzed, and we found that some autophagy markers, for example, LC3-II, LAMP2, and HIF-1α were significantly increased, whereas P62 was drastically downregulated in the RIF group. Similar results were observed in proteins level; and the autophagy puncta were also markedly enhanced in the endometrial tissues of RIF patients. Autophagy is closely associated with the RIF occurs and may be involved in the pathogenesis of RIF.

NEAT1 regulates neuroglial cell mediating Aß clearance via the epigenetic regulation of endocytosis-related genes expression.

The accumulation of intracellular ß-amyloid peptide (Aß) is important pathological characteristic of Alzheimer's disease (AD). However, the exact underlying molecular mechanism remains to be elucidated. Here, we reported that Nuclear Paraspeckle Assembly Transcript 1 (NEAT1), a long n on-coding RNA, exhibits repressed expression in the early stage of AD and its down-regulation declines neuroglial cell mediating Aß clearance via inhibiting expression of endocytosis-related genes. We find that NEAT1 is associated with P300/CBP complex and its inhibition affects H3K27 acetylation (H3K27Ac) and H3K27 crotonylation (H3K27Cro) located nearby to the transcription start site of many genes, including endocytosis-related genes. Interestingly, NEAT1 inhibition down-regulates H3K27Ac but up-regulates H3K27Cro through repression of acetyl-CoA generation. NEAT1 also mediates the binding between STAT3 and H3K27Ac but not H3K27Cro. Therefore, the decrease of H3K27Ac and/or the increase of H3K27Cro declines expression of multiple related genes. Collectively, this study first reveals the different roles of H3K27Ac and H3K27Cro in regulation of gene expression and provides the insight of the epigenetic regulatory mechanism of NEAT1 in gene expression and AD pathology.

Evaluation of two aneuploidy screening tests for chorionic villus samples: Multiplex ligation-dependent probe amplification and fluorescence in situ hybridization.

The vast majority of first-trimester pregnancy losses are the consequence of numerical aberrations in fetal chromosomes, which may involve nearly all chromosomes. Although commercial probes for all chromosomes are available for multiplex ligation-dependent probe amplification (MLPA) and fluorescence in situ hybridization (FISH) analyses, their use has rarely been reported for screening all 24 chromosomes for early fetal demise, especially by FISH. Here, we validated the ability of MLPA and FISH techniques as two low-cost aneuploidy screening methods for 24 chromosomes in 165 chorionic villus samples (CVSs). The results obtained by two methods were compared by the Chi-square test and the Kappa agreement test. Both methods gave conclusive results for all CVSs tested and showed highly consistent results (kappa = 0.890, p < 0.001). There was no statistically significant difference between the aneuploidy rate of the CVSs tested by the two methods (p = 0.180). Most of the samples showed fully concordant molecular karyotyping results (81.21%) between the two analytical methods, 10.91% had incompletely concordant results, and 7.88% had discordant results. The inconsistencies included segmental abnormalities, mosaicism, and polyploidy. Both assays used to screen 24 chromosomes were powerful techniques for detecting aneuploidy in CVSs. In terms of cost-effectiveness and diagnostic accuracy, the combination of subtelomeric (P036, P070) and centromeric (P181) MLPA assays is the better analytic strategy and follow-up analysis by FISH is recommended for MLPA-negative samples.

Prevalent genotypes of methylenetetrahydrofolate reductase (MTHFR) in recurrent miscarriage and recurrent implantation failure.

OBJECTIVE: To evaluate the association of two common methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms with recurrent miscarriage (RM) and repeated implantation failure (RIF) METHODS: The study comprised of 521 patients, with a history of RM (n = 370) or RIF (n = 151). One hundred forty-four women with fallopian tube blockages who had successfully conceived after the first in vitro fertilization embryo transfer treatment served as the control group. The MTHFR alleles, genotypes, and haplotypes were assessed in different groups. RESULTS: There was no difference in allele frequency and distribution of MTHFR polymorphisms between case and control patients. The 1298AA genotype was represented in a higher frequency, and 1298AC genotype was significantly lower in subfertile group when compared to the control group. A significant relationship was found between the 1298AC genotype and the RIF subgroup. The haplotype 677CC/1298AA was overrepresented in the RM subgroup (> 2 times) and haplotype 677CC/1298AC was underrepresented in the RIF subgroup (P < 0.05). Nevertheless, these two haplotypes were not connected to fertilization and embryo cleavage rates. CONCLUSION: Our findings indicate that the MTHFR gene polymorphism might play a role in the etiology of patients with RM or RIF. No adverse effects of different MTHFR haplotypes on embryo development were detected. Further studies on the biological role are needed to better understand the susceptibility to pregnancy complications.

Comparative study in infertile couples with and without Chlamydia trachomatis genital infection.

BACKGROUND: Chlamydia, caused by the bacterium Chlamydia trachomatis(C. trachomatis), is the most common sexually transmitted disease. The incidence is not clear due to the asymptomatic nature of early stage of infections. The incidence of Chlamydia has not been fully investigated in the Chinese Han population. Since chronic infection with can C. trachomatis can lead to infertility in males and females, it is important to determine the impact of infection on clinical outcomes. The aim of this study is to explore the epidemiology of C. trachomatis in subfertile couples and to determine whether infections will adversely affect clinical outcomes after assisted reproduction technique (ART) treatment. METHODS: Subfertile patients (n = 30760) were screened in the research for C. trachomatis in our center from January 2010 to December 2014. C. trachomatis-specific DNA was detected by Taq-man PCR from semen or swabs from the urethral, endocervix or vaginal. The control group consisted of 1140 subfertile patients without C. trachomatis infection. The prevalence and characteristics of C. trachomatis were identified for subfertile couples and clinical outcomes were collected and analyzed. A retrospective study was performed. RESULTS: Nine hundred and seventy patients were diagnosed with C. trachomatis infection, and the overall prevalence was 3.15% in the most recent five years, with a yearly increasing. The incidence was a higher in the second half of the year (3.40%) compared to the first half (2.69%). The age group with the highest-risk of infection with C. trachomatis was between 26 to 35 years old, and in about one third of the couples, both partners were infected. The basic parameters and clinical outcomes were not statistically significant between different the groups (P > 0.05), even though some minor data were different (P < 0.05). CONCLUSIONS: C. trachomatis is a common infection in subfertile people and it is essential to test for this organism in ART couples' screening. This study identified no adverse on clinical outcomes after successful treatment of C. trachomatis infection, regardless of gender, age and number of C. trachomatis copies.

Decrease in fertilization and cleavage rates, but not in clinical outcomes for infertile men with AZF microdeletion of the Y chromosome.

This study aimed to explore whether the presence of a Y chromosome azoospermia factor (AZF) microdeletion confers any adverse effect on embryonic development and clinical outcomes after intracytoplasmic sperm injection (ICSI) treatment. Fifty-seven patients with AZF microdeletion were included in the present study and 114 oligozoospermia and azoospermia patients without AZF microdeletion were recruited as controls. Both AZF and control groups were further divided into subgroups based upon the methods of semen collection: the AZF-testicular sperm extraction subgroup (AZF-TESE, n = 14), the AZF-ejaculation subgroup (AZF-EJA, n = 43), the control-TESE subgroup (n = 28) and the control-EJA subgroup (n = 86). Clinical data were analyzed in the two groups and four subgroups respectively. A retrospective case-control study was performed. A significantly lower fertilization rate (69.27 versus 75.70%, P = 0.000) and cleavage rate (89.55 versus 94.39%, P = 0.000) was found in AZF group compared with the control group. Furthermore, in AZF-TESE subgroup, the fertilization rate (67.54 versus 74.25%, P = 0.037) and cleavage rate (88.96 versus 94.79%, P = 0.022) were significantly lower than in the control-TESE subgroup; similarly, the fertilization rate (69.85 versus 75.85%, P = 0.004) and cleavage rate (89.36 versus 94.26%, P = 0.002) in AZF-EJA subgroup were significantly lower than in the control-EJA subgroup; however, the fertilization rate and cleavage rate in AZF-TESE (control-TESE) subgroup was similar to that in the AZF-EJA (control-EJA) subgroup. The other clinical outcomes were comparable between four subgroups (P > 0.05). Therefore, sperm from patients with AZF microdeletion, obtained either by ejaculation or TESE, may have lower fertilization and cleavage rates, but seem to have comparable clinical outcomes to those from patients without AZF microdeletion.

[Molecular epidemiology analysis of glucose-6-phosphate dehydrogenase gene mutations among infertile patients in Shenzhen].

OBJECTIVE: To explore the incidence and genotypes of glucose-6-phosphate dehydrogenase (G6PD) gene mutations among infertile patients in Shenzhen. METHODS: DNA samples from 851 infertile patients were tested for 25 G6PD gene mutation sites using a multiplex SNaPshot assay. RESULTS: The incidence of G6PD gene mutations among infertile patients in Shenzhen was 17.63%. Male and female abnormal rates were 15.13% and 20.09% respectively. Most of the female abnormal cases were heterozygotes. Mutations involved 11 haplotypes in 10 sites. 1311C> T/IVS-11 93T> C was the most common mutation, accounting for 72.00% (108/150) abnormal cases. Forty three cases of missense mutations were detected, including 19 cases of 1376G> T, 9 cases of 1388G> A, 5 cases of 95A> G and 871G> A/1311C> T/IVS-11 93T> C, 1 case of 202G> A, 835A> T, 1360C> T, 1376G> T and 392G> T/1311C> T/IVS-11 93T> C. CONCLUSION: The incidence of G6PD gene mutations among infertile patients in Shenzhen was high and the mutation types were various. Therefore, the G6PD deficiency genetic screening should be performed prior to assisted reproduction. This investigated results provided valuable basic data for genetic counseling, preimplantation genetic diagnosis and prenatal diagnosis.

Dysbiosis of gut microbiota and metabolites is associated with radiation-induced colorectal fibrosis and is restored by adipose-derived mesenchymal stem cell therapy.

AIMS: This study aimed to investigate the effects of adipose-derived mesenchymal stem cells (ADSCs) on radiation-induced colorectal fibrosis (RICF) along with the associated dysbiosis of gut microbiota and metabolites. MAIN METHODS: Fecal microbiota were assessed through 16S rRNA gene sequencing, and the fecal metabolome was characterized using liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry. The correlation between microbiota and metabolome data was explored. KEY FINDINGS: ADSC injection demonstrated a significant restoration of radiation-induced intestinal damage in vivo. At the phylum level, irradiated rats exhibited an increase in Bacteroidota and Campilobacterota, and a decrease in Firmicutes and Desulfobacterota, contrasting with the ADSC treatment group. Metabolomic analysis revealed 72 differently expressed metabolites (DEMs) from gas chromatography-mass spectrometry and 284 DEMs from liquid chromatography-mass spectrometry in the radiation group compared to the blank group. In the ADSC treatment group versus the radiation group, 36 DEMs from gas chromatography-mass spectrometry and 341 DEMs from liquid chromatography-mass spectrometry were identified. KEGG enrichment analysis implicated pathways such as steroid hormone biosynthesis, gap junction, primary bile acid biosynthesis, citrate cycle, cAMP signaling pathway, and alanine, aspartate, and glutamate metabolism during RICF progression and after treated with ADSCs. Correlation analysis highlighted the role of ADSCs in modulating the metabolic process of Camelledionol in fecal Bacteroides. SIGNIFICANCE: These findings underscore the potential of ADSCs in reversing dysbiosis and restoring normal colonic flora in the context of RICF, offering valuable insights for therapeutic interventions targeting radiation-induced complications.

Mesenchymal stem cells derived from adipose tissue and umbilical cord reveal comparable efficacy upon radiation-induced colorectal fibrosis in rats.

Chemoradiotherapy (CRT) and radiotherapy (RT) have served as anticancer treatments and neoadjuvant therapies for conquering multimodal rectal cancers including colorectal carcinoma (CRC), yet the concomitant radiation-induced colorectal fibrosis (RICF) has caused chronic toxicity and stenosis in the colorectal mucosa of patients. Mesenchymal stem/stromal cells (MSCs) with unique bidirectional immunoregulation and anti-fibrotic effect have been recognized as splendid sources for regenerative purposes including intestinal diseases. Herein, we are aiming to verify the feasibility and variations of MSC-based cytotherapy for the remission of RICF from the pathological features and the potential impact upon the transcriptomic signatures of RICF rats. For the purpose, we utilized our well-established RICF Sprague-Dawley (SD) rats by radiation for five weeks, and conducted consecutive intraperitoneal injection of two distinct MSCs for treatment, including MSCs derived from adult adipose tissue (AD-MSCs) and perinatal umbilical cord (UC-MSCs). On the one hand, the efficacy of AD-MSCs and UC-MSCs was assessed by diverse indicators, including weight change, pathological detections (e.g., H&E staining, Masson staining, EVG staining, IF staining, and IHC staining), and proinflammatory and fibrotic factor expression. On the other hand, we turned to RNA-sequencing (RNA-SEQ) and multifaceted bioinformatics analyses (e.g., GOBP, Venn Map, KEGG, and GSEA) to compare the impact of AD-MSC and UC-MSC treatment upon the gene expression profiling and genetic variations. RICF rats after consecutive AD-MSC and UC-MSC administration revealed comparable remission in histopathogenic features and significant suppression of diverse proinflammatory and fibrotic factors expression. Meanwhile, RICF rats after both MSC treatment revealed decrease and variations in the alterations in diverse gene expression and somatic mutations compared to RICF rats. Collectively, our data indicated the comparable therapeutic effect of AD-MSCs and UC-MSCs upon RICF in SD rats, together with the conservations in gene expression profiling and the diverse variations in genetic mutations. Our findings indicated the multifaceted impact of MSC infusion for the supervision of RICF both at the therapeutic and transcriptomic levels, which would provide novel references for the further evaluation and development of MSC-based regimens in future.

Identification of a novel prognostic cuproptosis-associated LncRNA signature for predicting prognosis and immunotherapy response in patients with esophageal cancer.

Nowadays, effective prognostic models for esophageal cancer (ESCA) are still lacking. Long noncoding RNAs (lncRNAs) are commonly utilized as indicators for diagnosing cancer and forecasting patient outcomes. Cuproptosis is regulated by multiple genes and is crucial to the progression of ESCA. However, it is not yet clear what role the cuproptosis-associated lncRNAs (CuALs) play in ESCA. To tackle this problem, a prognostic signature incorporating three CuALs was created. This signature was constructed by the use of the least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression. Subsequently, the signature effectively stratified ESCA samples into a high-risk group and a low-risk group. Those in the low-risk group demonstrated extended overall survival (OS), as well as increased infiltration of T cells, macrophages, and NK cells, suggesting a potentially enhanced response to immunotherapy. The ROC curve analysis demonstrated that this prognostic signature outperformed conventional clinical factors in predicting patient prognosis (AUC = 0.708). K-M survival analysis and correlation analysis identified UGDH-AS1 (a CuAL) as a protective factor positively associated with patient prognosis. The results of RT-qPCR and wound healing assays indicated that UGDH-AS1 is overexpressed in ESCA and could inhibit cancer cell migration. In general, the prognostic signature of CuALs demonstrated a robust capability in forecasting the immune environment and patient prognosis, highlighting its potential as a tool for enhancing personalized treatment strategies in ESCA.

Comparison of survival outcomes and survival prediction in patients with primary colorectal MANEC and primary colorectal SRCC: a population-based propensity-score matching study.

PURPOSE: Primary mixed adeno-neuroendocrine carcinoma (MANEC) and primary signet-ring cell cancer (SRCC) are two rare but highly malignant tumors in colorectal cancer. Therefore, we attempted to compare the tumors' survival outcomes, identify risk factors, and ultimately evaluate the prognosis by developing a nomogram. METHODS: We identified 755 MANEC and 5836 SRCC patients of colorectal cancer. PSM was used to balance the influence of baseline clinical and pathological differences. Kaplan-Meier method was used to compare the prognosis of different pathological grades and AJCC stages. Cox proportional hazards model was used to identify potential prognostic factors for the two groups. Finally, we developed a nomogram and evaluated the feasibility of the model. RESULTS: After PSM, the median OS and CSS of MANEC patients were significantly better than those of SRCC patients in stage III-IV (P < 0.001) but similar in stage I-II. The median OS and CSS of MANEC patients in each pathological grade were also greater than those of SRCC patients. Patients with MANEC and SRCC who underwent lymph node dissection in more than four areas had longer survival time. MANEC patients benefited from postoperative chemotherapy and radiotherapy; among SRCC patients, those who received preoperative and postoperative comprehensive chemotherapy and radiotherapy had benefits in OS and CSS. CONCLUSION: Both MANEC and SRCC are often diagnosed in advanced stages, highlighting the importance of early screening. Despite the better prognosis of MANEC compared to SRCC, both types of patients require the formulation of personalized treatment strategies based on different risk factors combined with column charts.

Construction and validation of stemness-related lncRNA pair signature for predicting prognosis in colorectal cancer.

PURPOSE: The purpose of this study was to identify a prognostic signature based on stemness-related differentially expressed lncRNAs in colorectal cancer (CRC) and to investigate their potential as biomarkers for diagnosis, prognosis, and therapeutic targets. METHODS: Stemness-related genes were collected from the TCGA cohort, and 13 differently expressed stemness-related lncRNAs were identified as prognostic factors for CRC using Kaplan-Meier analysis. A risk model was constructed based on the calculated risk score as a novel independent prognostic factor for CRC patients. The study also investigated the association between the risk model and immune checkpoints and m6A differentiation gene expression. qRT-PCR analysis was performed to validate the expression of differentially expressed stemness-related lncRNAs in CRC cell lines compared to normal colon mucosal cell line. RESULTS: The low-risk lncRNAs were associated with higher survival in CRC patients (Kaplan-Meier analysis, P < 0.001). The risk model was a significant independent prognostic factor for CRC patients. Type I INF response was statistically significant between low- and high-risk groups. CD44, CD70, PVR, TNFSF4, BTNL2, CD40, these immune checkpoints were expressed differently between two risk groups. There was a significant difference between m6A differentiation gene expression such as METTL3, METTL14, WTAP, RBM15, ZC3H13, YTHDC2, YTHDF2, ALKBH5. qRT-PCR analysis validated that there were five up-regulated and eight down-regulated differently expressed stemness-related lncRNAs in CRC cell lines compared to the normal colon mucosal cell line. CONCLUSION: This study suggests that the 13 CRC stemness-related lncRNA signature could become a promising and reliable prognostic factor for colorectal cancer. The risk model based on the calculated risk score may have implications for personalized medicine and targeted therapies for CRC patients. The study also suggests that immune checkpoints and m6A differentiation genes may play important roles in the development and progression of CRC.

Optical sensor using space-domain active fiber cavity ringdown technique.

A novel active fiber cavity ringdown (FCRD) technique using frequency-shifted interferometry (FSI) is proposed for the first time. Using this scheme, external parameters can be monitored in the space domain by measuring the ringdown distance instead of ringdown time. A bidirectional erbium-doped fiber amplifier (Bi-EDFA) is employed to compensate the inherent cavity loss for achieving higher sensitivity. And two band-pass filters are used to reduce the amplified spontaneous emission (ASE) noise of the Bi-EDFA. Compared with the well-known time-domain active FCRD scheme, our proposed method enables us to avoid using pulsed laser needed in time-domain active FCRD, it uses continuous-wave laser to inject into the fiber cavity and stabilize the optical power in the fiber cavity, which can suppress the baseline drift of ringdown signal caused by the gain fluctuations of the EDFA and thus improve the detecting precision. Moreover, this novel method enables us to use differential detection method for further reducing the ASE noise, and thus eliminating the baseline drift of ringdown signal. A magnetic field sensor was developed as a proof-of-concept demonstration. The experimental results demonstrate that the proposed sensor with a sensitivity of 0.01537 (1/km·Gs) was achieved. This is the highest magnetic field sensitivity compared to the time-domain active FLRD method. Due to the reduced ASE noise, the stability of the proposed sensing system was also greatly improved.

LINC00472 inhibits cell migration by enhancing intercellular adhesion and regulates H3K27ac level via interacting with P300 in renal clear cell carcinoma.

Renal clear cell carcinoma (RCCC) is the most common type of renal cell carcinoma, which is also difficult to diagnose and easy to metastasize. Currently, there is still a lack of effective clinical diagnostic indicators and treatment targets. This study aims to find effective diagnostic markers and therapeutic targets from the perspective of noncoding RNA. In this study, we found that the expression of Long noncoding RNA LINC00472 was significantly decreased in RCCC and showed a downward trend with the progression of cancer stage. Patients with low LINC00472 expression have poor prognosis. Inhibition of LINC00472 significantly increased cell proliferation and migration, while overexpression of LINC00472 obviously inhibited cell proliferation and enhanced intercellular adhesion. Transcriptome sequencing analysis demonstrated that LINC00472 was highly correlated with extracellular matrix and cell metastasis-related pathways, and the consistent results were obtained by The Cancer Genome Atlas (TCGA) data analysis. Additionally, we discovered that the integrin family protein ITGB8 is a potential target gene of LINC00472. Mechanistically, we found that the change of LINC00472 affected the acetylation level of H3K27 site in cells, and we speculate that this effect is likely to be generated through the interaction with acetyltransferase P300. In conclusion, LINC00472 has an important impact on the proliferation and metastasis of renal clear cells, and probably participate in the regulation of histone modification, and it may be used as a potential diagnostic marker of RCCC.

NEAT1 regulates microtubule stabilization via FZD3/GSK3ß/P-tau pathway in SH-SY5Y cells and APP/PS1 mice.

Nuclear paraspeckles assembly transcript 1 (NEAT1) is a well-known long noncoding RNA (lncRNA) with various functions in different physiological and pathological processes. Notably, aberrant NEAT1 expression is implicated in the pathogenesis of various neurodegenerative diseases, including Alzheimer's disease (AD). However, the molecular mechanism of NEAT1 in AD remains poorly understood. In this study, we investigated that NEAT1 regulated microtubules (MTs) polymerization via FZD3/GSK3ß/p-tau pathway. Downregulation of NEAT1 inhibited Frizzled Class Receptor 3 (FZD3) transcription activity by suppressing H3K27 acetylation (H3K27Ac) at the FZD3 promoter. Our data also demonstrated that P300, an important histone acetyltransferases (HAT), recruited by NEAT1 to bind to FZD3 promoter and mediated its transcription via regulating histone acetylation. In addition, according to immunofluorescence staining of MTs, metformin, a medicine for the treatment of diabetes mellitus, rescued the reduced length of neurites detected in NEAT1 silencing cells. We suspected that metformin may play a neuroprotective role in early AD by increasing NEAT1 expression and through FZD3/GSK3ß/p-tau pathway. Collectively, NEAT1 regulates microtubule stabilization via FZD3/GSK3ß/P-tau pathway and influences FZD3 transcription activity in the epigenetic way.

Hybrid Degradation Equipment Remaining Useful Life Prediction Oriented Parallel Simulation considering Model Soft Switch.

Equipment parallel simulation is an emerging simulation technology in recent years, and equipment remaining useful life (RUL) prediction oriented parallel simulation is an important branch of parallel simulation. An important concept in equipment parallel simulation is the model evolution driven by real-time data, including model selection and model parameter evolution. The current research on equipment RUL prediction oriented parallel simulation mainly focuses on a single continuous degradation mode, such as linear degradation and nonlinear degradation. Under this degradation condition, the model parameter evolution methods in parallel simulation can effectively predict equipment RUL. However, in practice, most of the equipment degradation processes exhibit a mixture of continuous degradation and discrete shock. So this requires adaptive selection of simulation models based on real-time degradation data. In this paper, the hybrid degradation equipment RUL prediction oriented parallel simulation considering model soft switch is studied. Firstly, under the modeling framework of the state space model (SSM), two kinds of degradation simulation models are established using the Wiener process and Poisson effect. Driven by the real-time degradation data, the model probability is calculated by using the forward interactive multiple model filtering algorithm to realize the model soft switch and data assimilation. On the basis of model soft switch, the expectation maximization algorithm is utilized to achieve model parameter evolution. Through the iteration between model soft switch and model parameter evolution, the simulation fidelity can be effectively improved and the actual equipment degradation state is continuously approached. According to the full probability theorem and the concept of first hitting time, the simulated degradation state distribution is integrated into the inverse Gaussian distribution. Then the analytical expression of the RUL probability density function is obtained to achieve RUL real-time prediction. Finally, a case study was conducted by using a bearing degradation data. The results show that the parallel simulation can effectively model the hybrid degradation process of the bearing. Compared with the single-model method that only considers the model parameter evolution, the RUL obtained by the method proposed in this paper has higher prediction accuracy and smaller uncertainty.

LncRNA EPB41L4A-AS1 regulates glycolysis and glutaminolysis by mediating nucleolar translocation of HDAC2.

BACKGROUND: LncRNAs have been found to be involved in various aspects of biological processes. In this study, we aimed to uncover the molecular mechanisms of lncRNA EPB41L4A-AS1 in regulating glycolysis and glutaminolysis in cancer cells. METHODS: The expression of EPB41L4A-AS1 in cancer patients was analyzed in TCGA and GEO datasets. The level of cellular metabolism was determined by extracellular flux analyzer. The relationship between p53 and EPB41L4A-AS1 was explored by qRT-PCR, luciferase assay and ChIP assay. The interactions between EPB41L4A-AS1 and HDAC2 or NPM1 were determined by RNA immunoprecipitation, RNA pull-down assay and RNA-FISH- immunofluorescence. FINDINGS: EPB41L4A-AS1 was a p53-regulated gene. Low expression and deletion of lncRNA EPB41L4A-AS1 were found in a variety of human cancers and associated with poor prognosis of cancer patients. Knock down EPB41L4A-AS1 expression triggered Warburg effect, demonstrated as increased aerobic glycolysis and glutaminolysis. EPB41L4A-AS1 interacted and colocalized with HDAC2 and NPM1 in nucleolus. Silencing EPB41L4A-AS1 reduced the interaction between HDAC2 and NPM1, released HDAC2 from nucleolus and increased its distribution in nucleoplasm, enhanced HDAC2 occupation on VHL and VDAC1 promoter regions, and finally accelerated glycolysis and glutaminolysis. Depletion of EPB41L4A-AS1 increased the sensitivity of tumor to glutaminase inhibitor in tumor therapy. INTERPRETATION: EPB41L4A-AS1 functions as a repressor of the Warburg effect and plays important roles in metabolic reprogramming of cancer.