GB18-06, a nanobody targeting GDF15, effectively alleviates weight loss and restores physical function in cachexia models.

Cachexia is a complicated metabolic syndrome mainly associated with cancers, characterized by extreme weight loss and muscle wasting. It is a debilitating condition that negatively affects prognosis and survival. However, there is currently no effective pharmacological intervention that can reverse body weight loss and improve physical performance in patients with cachexia. Growth differentiation factor 15 (GDF15) can suppress appetite and regulate energy balance through binding to glial cell-derived neurotrophic factor receptor alpha-like (GFRAL). In order to develop a novel, effective treatment for cachexia, we generated a GDF15-targeting VHH nanobody, GB18-06, that was able to bind GDF15 with high affinity. In vitro, GB18-06 potently inhibited the GDF15-GFRAL signaling pathway, leading to a reduction of downstream ERK and AKT phosphorylation levels; in vivo, GB18-06 alleviated weight loss (>20%) in cancer and chemotherapy-induced cachexia models in mice. Compared with the control (phosphate-buffered saline) group, the ambulatory activity of mice in the GB18-06-treated group also increased 77%. Furthermore, GB18-06 exhibited desirable pharmacokinetic properties and an excellent developability profile. Our study has demonstrated a means of developing targeted treatment for cachexia with high efficacy, potentially leading to improved clinical outcomes and quality of life for patients with cachexia.

[Fonction de l'ARNnc exosomal HEIH dans le carcinome hépatocellulaire associé au virus de l'hépatite B]. / Function of exosomal lncRNA-HEIH in hepatocellular carcinoma associated with hepatitis B virus.

Long non-coding RNA-HEIH (lncRNA-HEIH) is a potential biomarker for patients with hepatocellular carcinoma (HCC), but exosomal lncRNA-HEIH in patients with hepatitis B virus-associated HCC (B-HCC) is unclear. This study aimed to investigate the expression of exosomal lncRNA-HEIH in B-HCC patients and explore its clinical significance. We collected blood samples from 60 B-HCC patients, 60 non-hepatitis virus-associated HCC (N-HCC) patients, and 50 healthy volunteers. Exosomal lncRNA-HEIH levels were measured by real-time PCR and analyzed for their correlation with patient prognosis using Kaplan-Meier analysis. Multivariate COX regression analysis was conducted to identify factors affecting patient outcomes. The effects of lncRNA-HEIH on carcinogenesis were also investigated by constructing a Huh7 cell line stably expressing the hepatitis B virus. In the B-HCC group, there was a positive correlation between hepatitis B virus and exosomal lncRNA-HEIH. The 5-year survival rate of the exosomal lncRNA-HEIH high-expression group was significantly lower than that of the low-expression group in the B-HCC group, but not in the N-HCC group. Exosomal lncRNA-HEIH level was related to the TNM stage, lymph node metastasis and AFP. Exosomal lncRNA-HEIH level was independent risk factors for poor prognosis in B-HCC patients. In Huh7-HBV cells, lncRNA-HEIH level was significantly higher than in control, and the migration capacity of Huh7-HBV cells decreased significantly after down-regulating lncRNA-HEIH. Our findings suggest that exosomal lncRNA-HEIH is abnormally expressed and closely related to poor prognosis in B-HCC patients, indicating its potential as a diagnostic and therapeutic target for HBV-associated HCC.

Inhibition of Drp1- Fis1 interaction alleviates aberrant mitochondrial fragmentation and acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is a common clinical disorder with complex etiology and poor prognosis, and currently lacks specific and effective treatment options. Mitochondrial dynamics dysfunction is a prominent feature in AKI, and modulation of mitochondrial morphology may serve as a potential therapeutic approach for AKI. METHODS: We induced ischemia-reperfusion injury (IRI) in mice (bilateral) and Bama pigs (unilateral) by occluding the renal arteries. ATP depletion and recovery (ATP-DR) was performed on proximal renal tubular cells to simulate in vitro IRI. Renal function was evaluated using creatinine and urea nitrogen levels, while renal structural damage was assessed through histopathological staining. The role of Drp1 was investigated using immunoblotting, immunohistochemistry, immunofluorescence, and immunoprecipitation techniques. Mitochondrial morphology was evaluated using confocal microscopy. RESULTS: Renal IRI induced significant mitochondrial fragmentation, accompanied by Dynamin-related protein 1 (Drp1) translocation to the mitochondria and Drp1 phosphorylation at Ser616 in the early stages (30 min after reperfusion), when there was no apparent structural damage to the kidney. The use of the Drp1 inhibitor P110 significantly improved kidney function and structural damage. P110 reduced Drp1 mitochondrial translocation, disrupted the interaction between Drp1 and Fis1, without affecting the binding of Drp1 to other mitochondrial receptors such as MFF and Mid51. High-dose administration had no apparent toxic side effects. Furthermore, ATP-DR induced mitochondrial fission in renal tubular cells, accompanied by a decrease in mitochondrial membrane potential and an increase in the translocation of the pro-apoptotic protein Bax. This process facilitated the release of dsDNA, triggering the activation of the cGAS-STING pathway and promoting inflammation. P110 attenuated mitochondrial fission, suppressed Bax mitochondrial translocation, prevented dsDNA release, and reduced the activation of the cGAS-STING pathway. Furthermore, these protective effects of P110 were also observed renal IRI model in the Bama pig and folic acid-induced nephropathy in mice. CONCLUSIONS: Dysfunction of mitochondrial dynamics mediated by Drp1 contributes to renal IRI. The specific inhibitor of Drp1, P110, demonstrated protective effects in both in vivo and in vitro models of AKI.

Prediction of Gleason score in prostate cancer patients based on radiomic features of transrectal ultrasound images.

OBJECTIVES: The aim of this study was to develop a model for predicting the Gleason score of patients with prostate cancer based on ultrasound images. METHODS: Transrectal ultrasound images of 838 prostate cancer patients from The Cancer Imaging Archive database were included in this cross-section study. Data were randomly divided into the training set and testing set (ratio 7:3). A total of 103 radiomic features were extracted from the ultrasound image. Lasso regression was used to select radiomic features. Random forest and broad learning system (BLS) methods were utilized to develop the model. The area under the curve (AUC) was calculated to evaluate the model performance. RESULTS: After the screening, 10 radiomic features were selected. The AUC and accuracy of the radiomic feature variables random forest model in the testing set were 0.727 (95% CI, 0.694-0.760) and 0.646 (95% CI, 0.620-0.673), respectively. When PSA and radiomic feature variables were included in the random forest model, the AUC and accuracy of the model were 0.770 (95% CI, 0.740-0.800) and 0.713 (95% CI, 0.688-0.738), respectively. While the BLS method was utilized to construct the model, the AUC and accuracy of the model were 0.726 (95% CI, 0.693-0.759) and 0.698 (95% CI, 0.673-0.723), respectively. In predictions for different Gleason grades, the highest AUC of 0.847 (95% CI, 0.749-0.945) was found to predict Gleason grade 5 (Gleason score ≥9). CONCLUSIONS: A model based on transrectal ultrasound image features showed a good ability to predict Gleason scores in prostate cancer patients. ADVANCES IN KNOWLEDGE: This study used ultrasound-based radiomics to predict the Gleason score of patients with prostate cancer.

Comprehensive Analysis of circRNA, lncRNA, miRNA and mRNA Expression Profiles and Their Competing Endogenous RNA Networks in Hepatitis B Virus-Related Hepatocellular Carcinoma.

Pursuing knowledge about circular RNA (circRNA), long non-coding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA) expression profiles and their competing endogenous RNA (ceRNA) networks in hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC) was the focus of this research. Expression patterns of circRNAs, lncRNAs, miRNAs, and mRNAs were searched for in relation to HBV-related HCC using whole-transcriptome sequencing. The expression levels of chosen circRNA, lncRNA, miRNA, and mRNA were analyzed using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The potential connections and roles of ceRNA were deduced via bioinformatics research. The sum of 284 circRNAs, 2,927 lncRNAs, 693 miRNAs, and 5566 mRNAs were discovered to be expressed at considerably different levels in HBV-related HCC tissue and adjacent normal tissue. And the most significantly up- and down-regulated circRNAs, lncRNAs, miRNAs, and mRNAs were verified in HBV-related HCC by qRT-PCR. The circRNA/miRNA/mRNA and lncRNA/miRNA/mRNA networks of HBV-related HCC were established, and the ceRNA regulatory networks revealed the gene expression mechanisms controlled by ncRNAs. Collectively, we revealed the contribution of various circRNA, lncRNA, miRNA, and mRNA expression profiles and identified their ceRNA regulatory networks in HBV-related HCC, providing a theoretical basis for further exploration.

Innovative explorations: unveiling the potential of organoids for investigating environmental pollutant exposure.

As the economy rapidly develops, chemicals are widely produced and used. This has exacerbated the problems associated with environmental pollution, raising the need for efficient toxicological evaluation techniques to investigate the toxic effects and mechanisms of toxicity of environmental pollutants. The progress in the techniques of cell culture in three dimensions has resulted in the creation of models that are more relevant in terms of biology and physiology. This enables researchers to study organ development, toxicology, and drug screening. Adult stem cells (ASCs) and induced pluripotent stem cells (iPSCs) can be obtained from various mammalian tissues, including cancerous and healthy tissues. Such stem cells exhibit a significant level of tissue memory and ability to self-assemble. When cultivated in 3D in vitro environments, the resulting organoids demonstrate a remarkable capacity to recapitulate the cellular composition and function of organs in vivo. Recently, many tumors' tissue-derived organoids have been widely used in research on tumor pathogenesis, drug development, precision medicine, and other fields, including those derived from colon cancer, cholangiocarcinoma, liver cancer, and gastric cancer. However, the application of organoid models for evaluating the toxicity of environmental pollutants is still in its infancy. This review introduces the characteristics of the toxicity responses of organoid models upon exposure to pollutants from the perspectives of organoid characteristics, tissue types, and their applications in toxicology; discusses the feasibility of using organoid models in evaluating the toxicity of pollutants; and provides a reference for future toxicological studies on environmental pollutants based on organoid models.

Gas-particle partitioning of organophosphate esters in indoor and outdoor air and its implications for individual exposure.

The extensive utilization of organophosphate esters (OPEs) has resulted in their widespread presence in the environment, raising concerns about potential human health risks. In this study, 13 OPEs were analyzed in both gas and particle phases as well as in indoor and outdoor atmospheric environments. Moreover, human exposure to OPEs were investigated within a university environment, focusing on forehead contact and individual PM2.5 inhalation. The results showed similar distribution patterns of OPEs indoors and outdoors, although higher concentrations were found indoors. The average atmospheric concentration of ∑OPEs (combining particle and gaseous OPEs) was 1575 pg/m3 in the outdoor environment and 6574 pg/m3 ∑OPEs in the indoor microenvironments. The overwhelming majority of OPEs exhibit a pronounced propensity to adsorb onto PM2.5 particles. Notably, the concentration of OPEs on the forehead differed significantly from that in the atmospheric environment, whereas individual PM2.5 exposure was consistent with the concentration of indoor PM2.5. Intriguingly, some OPEs with high octanol-water partition coefficient (log Kow) were not detected in the environment but found on human foreheads. Gas-particle partitioning was predicted using the Harner-Bidleman and Li-Ma-Yang models and the results were in agreement with the monitoring data for approximately half of the OPE monomers. Correlations between OPEs exposure and gas-particle partitioning were found to be more significant for novel OPEs. No non-cancer risk to humans through individual exposure to OPEs was identified via forehead exposure or inhalation. The previously unreported relationship between individual exposure and the environmental occurrence of traditional and novel OPEs demonstrated in this study highlights the importance of evaluating the potential health risks associated with actual OPE exposure.

Increased Platelet Distribution Width Predicts 3-Year Recurrence in Patients with Hepatocellular Carcinoma After Surgical Resection.

Background: Platelet distribution width (PDW) is a marker of platelet anisocytosis that increases with platelet activation. The clinical implications of PDW in HCC are not well-defined. This study aimed to determine whether PDW could predict recurrence in patients with HCC after resection. Methods: Between January and December 2008, 471 patients with HCC were recruited retrospectively. The clinicopathological characteristics of patients with HCC were analyzed based on the relationship between the two PDW groups. Kaplan-Meier curves and multivariate Cox regression analyses were used to evaluate the relationship between PDW and disease-free survival (DFS). A novel nomogram was developed based on the identified independent risk factors. Its accuracy was evaluated using a calibration curve and concordance index. The predictive value was evaluated using a receiver operating characteristic (ROC) curve. Results: PDW was significantly associated with direct bilirubin, total bilirubin, urea, and prothrombin time. Patients with PDW ≥ 17.1 were a significantly shorter DFS than those with PDW < 17.1 (17.98% vs 49.83%, p< 0.001). Multivariate analysis determined that alpha-fetoprotein (AFP), carcinoembryonic antigen, microvascular invasion (MVI), tumor size, and tumor number were the independent variables associated with DFS. Patients with PDW ≥ 17.1 had a hazard ratio of 1.381 (95% confidence interval: 1.069-1.783, p = 0.014) for DFS. AFP, PDW, MVI, tumor size, and tumor number were identified as preoperative independent risk factors for DFS and used to establish the nomogram. Calibration curve analysis revealed that the standard curve fitted well with the predicted curve. ROC curve analysis demonstrated the high efficiency of the nomogram. Conclusion: Increased PDW may predict recurrence-free survival in patients with HCC. Our nomogram model also performed well in predicting patient prognoses.

CCNF is a potential pancancer biomarker and immunotherapy target.

Background: CCNF catalyzes the transfer of ubiquitin molecules from E2 ubiquitin-conjugating enzymes to target proteins, thereby regulating the G1/S or G2/M transition of tumor cells. Thus far, CCNF expression and its potential as a pancancer biomarker and immunotherapy target have not been reported. Methods: TCGA datasets and the R language were used to analyze the pancancer gene expression, protein expression, and methylation levels of CCNF; the relationship of CCNF expression with overall survival (OS), recurrence-free survival (RFS), immune matrix scores, sex and race; and the mechanisms for posttranscriptional regulation of CCNF. Results: CCNF expression analysis showed that CCNF mRNA expression was higher in cancer tissues than in normal tissues in the BRCA, CHOL, COAD, ESCA, HNSC, LUAD, LUSC, READ, STAD, and UCEC; CCNF protein expression was also high in many cancer tissues, indicating that it could be an important predictive factor for OS and RFS. CCNF overexpression may be caused by CCNF hypomethylation. CCNF expression was also found to be significantly different between patients grouped based on sex and race. Overexpression of CCNF reduces immune and stromal cell infiltration in many cancers. Posttranscriptional regulation analysis showed that miR-98-5p negatively regulates the expression of the CCNF gene. Conclusion: CCNF is overexpressed across cancers and is an adverse prognostic factor in terms of OS and RFS in many cancers; this phenomenon may be related to hypomethylation of the CCNF gene, which could lead to cancer progression and worsen prognosis. In addition, CCNF expression patterns were significantly different among patients grouped by sex and race. Its overexpression reduces immune and stromal cell infiltration. miR-98-5p negatively regulates CCNF gene expression. Hence, CCNF is a potential pancancer biomarker and immunotherapy target.

A multifunctional integrated carbon nanotubes/polyphenylene sulfide composite: preparation, properties and applications.

Although great progress has been achieved in polyphenylene sulfide (PPS) composites by the use of carbon nanotubes (CNTs), the development of cost-efficient, well dispersive and multifunctional integrated PPS composites has yet to be achieved because of the strong solvent resistance of PPS. In this work, a CNTs-PPS/PVA composite material has been prepared by mucus dispersion-annealing, which employed polyvinyl alcohol (PVA) to disperse PPS particles and CNTs at room temperature. Dispersion and scanning electron microscopy observations revealed that PVA mucus can uniformly suspend and disperse micron-sized PPS particles, promoting the interpenetration of the micro-nano scale between PPS and CNTs. During the annealing process, PPS particles deformed and then crosslinked with CNTs and PVA to form a CNTs-PPS/PVA composite. The as-prepared CNTs-PPS/PVA composite possesses outstanding versatility, including excellent heat stability with resistant temperatures up to 350 °C, corrosion resistance against strong acids and alkalis for up to 30 days, and distinguished electrical conductivity with 2941 S m-1. Besides, a well-dispersed CNTs-PPS/PVA suspension could be used to 3D print microcircuits. Hence, such multifunctional integrated composites will be highly promising in the future of new materials. This research also develops a simple and meaningful method to construct composites for solvent resistant polymers.

Enhancement of glycolysis-dependent DNA repair regulated by FOXO1 knockdown via PFKFB3 attenuates hyperglycemia-induced endothelial oxidative stress injury.

The accumulation of DNA damage induced by oxidative stress is a crucial pathogenic factor of endothelial loss in diabetic vascular complications, but it is still unknown whether aberrant glucose metabolism leads to defective DNA repair and accounts for hyperglycemia-induced endothelial oxidative stress injury. Here, we showed that Foxo1 knockdown alleviated diabetes-associated retinal DNA damage and vascular dysfunction. Mechanistically, FOXO1 knockdown avoided persistent DNA damage and cellular senescence under high glucose in endothelial cells by promoting DNA repair mediated by the MRN (MRE11-RAD50-NBS1 complex)-ATM pathway in response to oxidative stress injury. Moreover, FOXO1 knockdown mediated robust DNA repair by restoring glycolysis capacity under high glucose. During this process, the key glycolytic enzyme PFKFB3 was stimulated and, in addition to its promoting effect on glycolysis, directly participated in DNA repair. Under genotoxic stress, PFKFB3 relocated into oxidative stress-induced DNA damage sites and promoted DNA repair by interaction with the MRN-ATM pathway. Our study proposed that defective glycolysis-dependent DNA repair is present in diabetic endothelial cells and contributes to hyperglycemia-induced vascular dysfunction, which could provide novel therapeutic targets for diabetic vascular complications.

Wodyetia bifurcate structured carbon fabrics with durable superhydrophobicity for high-efficiency oil-water separation.

The superhydrophobic fiber-based membranes with features of high separation efficiency and low energy consumption for oil-water separation remains a formidable challenge. In this paper, a robust and durable superhydrophobic cotton-derived carbon fabric (CDCF) with wodyetia bifurcate-like structure is fabricated via in situ cobalt-nickel basic carbonate (CNC) deposition and 1 H, 1 H, 2 H, 2 H-perfluorooctyltriethoxysilane (POTS) coating. The combined action of rough surface structure and low surface energy makes CDCF/CNC/POTS with superhydrophobicity/superoleophilicity, anti-wetting, and self-cleaning performance. Intriguingly, the CDCF/CNC/POTS can keep its superhydrophobicity under of the water droplet impact pressure of 781 Pa. In addition to its robust dynamic superhydrophobicity, CDCF/CNC/POTS can also maintain its non-wetting property under harsh environmental conditions such as mechanical abrasion treatment, acidic, alkaline and salt solutions, and ultraviolet radiation. Importantly, the CDCF/CNC/POTS can separate various oil-water mixtures and emulsions under gravity with ultrahigh oil-water mixtures permeate flux (∼19,126 L/m2h), high surfactant-stabilized emulsion permeate flux (∼821 L/m2h), and high separation efficiency (> 98.60 %). Moreover, remarkable recyclability endow the CDCF/CNC/POTS with promising application in treating oily wastewater. This work may benefit the low-cost mass production of cotton-based carbon fabrics for developing eco-friendly high-efficiency separators.

Correlation of TBK1, AR, and other serum cancer-related biomarkers in breast cancer patients: An observational study.

Breast cancer (BC) ranks first for incidence and mortality in gynecological malignant tumors. This study aims to investigate the diagnostic value of Tank-binding kinase 1 (TBK1) and its correlation with androgen receptor (AR) and other serum cancer-related biomarkers in BC patient. The present observational study included 451 female BC patients and 451 healthy controls. Serum levels of TBK1, AR and other cancer-related biomarkers were detected in all the patients and healthy controls. Patients' demographic data and clinical data including age, body mass index (BMI), tumor node Metastasis (TNM), pathological type, tumor size and lymph node metastasis were collected. The follow-up lasted for 5 years. The deceased group had higher rate of patients with TNM III~IV, lymph node metastasis or tumor diameter >2. Deceased group had much higher rate of patients with negative ER and positive Ki67. Besides, increased TBK1 was found in BC patients with positive correlation with AR, CA15-3, CA125, CEA, and CA19-9. Serum TBK1 was associated with the clinic outcomes of BC patients and those with high TBK1 had lower 5-year survival rate. Moreover, cutoff value of 13.95 ng/mL TBK1 showed AUC of 0.981 (93.6% for sensitivity and 86.3% for specificity) for diagnosing BC, and cutoff value of 22.65 ng/mL TBK1 had AUC of 0.996 (97.7% for sensitivity and 96.3% for specificity) for diagnosing the death of BC patients. Serum TBK1 was positively correlated with AR and other serum cancer-related biomarkers. In addition, high TBK1 predicted the poor prognosis and might be used for the diagnosis of BC.

Combined identification of three lncRNAs in serum as effective diagnostic and prognostic biomarkers for hepatitis B virus-related hepatocellular carcinoma.

Hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC) is a common, highly invasive malignant tumor associated with a high mortality rate. This study aimed to identify the effective diagnostic and prognostic biomarkers for HBV-related HCC. With HBV-related HCC RNA-sequencing data of The Cancer Genome Atlas (TCGA) database, 159 differentially expressed long noncoding RNAs (lncRNAs) between HBV-related HCC and para-carcinoma normal samples were identified, and 12 lncRNAs were eventually assessed for deeper research. Classification analysis developed a three-lncRNA signature of AC005332.5, ELF3-AS1 and LINC00665, which was demonstrated to be the most discriminatory with an AUC (Area under the curve) value of 0.913 (95% CI: 0.8610-0.9665) and verified in validation patients. The expression levels of AC005332.5, ELF3-AS1 and LINC00665 were significantly changed with different tumor stages or grades. Survival analysis revealed that AC005332.5, ELF3-AS1 and LINC00665 were highly associated with the prognosis of overall survival. Additionally, the lncRNA signature yielded statistical significance to predict clinical outcomes independently from other clinical variables in validation patients, as suggested in the multivariate Cox hazards analysis. Conclusively, a three-lncRNA signature of AC005332.5, ELF3-AS1 and LINC00665 may serve as an excellent diagnostic biomarker for HBV-related HCC and potential prognostic significance for HBV-related HCC sufferers.

Centromeric protein K (CENPK) promotes gastric cancer proliferation and migration via interacting with XRCC5.

BACKGROUND: CENPK is a novel oncogene which is aberrantly expression in some malignant tumors. However, the role and mechanisms of CENPK in gastric cancer have not been explored. METHODS: In this study, we use RT-PCR and IHC to study CENPK expression in gastric cancer cells and tissues. In addition, we constructed the two kinds of CENPK siRNA lentivirus to knock down CENPK. Then, we use High content living cell imaging System, Cell Counting Kit-8, colony formation, wound healing and Transwell assays to demonstrate the function of CENPK on gastric cancer cells AGS and MKN45. Meanwhile, we use flow cytometry assay to study CENPK function on gastric cancer cell apoptosis and cell cycle arrest. Subcutaneous tumorigenesis in nude mice was also performed to confirm CENPK function on gastric cancer. Finally, we use Co-IP, LC-MS and function rescue assay to study the downstream interaction molecular of CENPK. RESULTS: We demonstrated that CENPK expression were up-regulated in GC cell lines. Poor differentiation and III-IV stage had more percentages of high CENPK expression. Knocking down CENPK could significantly suppress GC cells proliferation, migration and invasion, and induce GC cells apoptosis and G1/S phase transition arrest. Subcutaneous tumorigenesis confirmed the tumor-promoting effects of CENPK in vivo. Remarkably, we found for the first time that XRCC5 might be interacted with CENPK through Co-IP, LC-MS and rescue study. CONCLUSION: CENPK promotes GC cell proliferation and migration via interacting with XRCC5 and may be a novel prognostic factor or therapeutic target for CENPK.

A novel 4 immune-related genes as diagnostic markers and correlated with immune infiltrates in major depressive disorder.

BACKGROUND: Immune response is prevalently related with major depressive disorder (MDD) pathophysiology. However, the study on the relationship between immune-related genes (IRGs) and immune infiltrates of MDD remains scarce. METHODS: We extracted expression data of 148 MDD patients from 2 cohorts, and systematically characterized differentially expressed IRGs by using limma package in R software. Then, the LASSO and multivariate logistic regression analysis was used to identify the most powerful IRGs. Next, we analyzed the relationship between IRGs and immune infiltrates of MDD. Finally, GSE76826 was used to to verificate of IRGs as a diagnostic markers in MDD. RESULTS: 203 different IRGs s in MDD has been identified (P < 0.05). GSEA revealed that the different IRGs was more likely to be enriched in immune-specific pathways. Then, a 9 IRGs was successfully established to predict MDD based on LASSO. Next, 4 IRGs was obtained by multivariate logistic regression analysis, and AUC for CD1C, SPP1, CD3D, CAMKK2, and IRGs model was 0.733, 0.767, 0.816, 0.800, and 0.861, suggesting that they have a good diagnostic performance. Furthermore, the proportion of T cells CD8, T cells γδ, macrophages M0, and NK cells resting in MDD group was lower than that in the healthy controls, suggesting that the immune system in MDD group is impaired. Simultaneously, CD3D was validated a reliable marker in MDD, and was positively correlated with T cells CD8. GSEA revealed high expression CD3D was more likely to be enriched in immune-specific pathways, and low expression CD3D was more likely to be enriched in glucose metabolism metabolism-specific pathways. CONCLUSIONS: We applied bioinformatics approaches to suggest that a 4 IRGs could serve as diagnostic markers to provide a novel direction to explore the pathogenesis of MDD.

Estrogen Receptor-A in Medial Preoptic Area Contributes to Sex Difference of Mice in Response to Sevoflurane Anesthesia.

A growing number of studies have identified sex differences in response to general anesthesia; however, the underlying neural mechanisms are unclear. The medial preoptic area (MPA), an important sexually dimorphic structure and a critical hub for regulating consciousness transition, is enriched with estrogen receptor alpha (ERα), particularly in neuronal clusters that participate in regulating sleep. We found that male mice were more sensitive to sevoflurane. Pharmacological inhibition of ERα in the MPA abolished the sex differences in sevoflurane anesthesia, in particular by extending the induction time and facilitating emergence in males but not in females. Suppression of ERα in vitro inhibited GABAergic and glutamatergic neurons of the MPA in males but not in females. Furthermore, ERα knockdown in GABAergic neurons of the male MPA was sufficient to eliminate sex differences during sevoflurane anesthesia. Collectively, MPA ERα positively regulates the activity of MPA GABAergic neurons in males but not in females, which contributes to the sex difference of mice in sevoflurane anesthesia.

Clinical significance and mechanism of long noncoding RNA HAGLROS in triple negative breast cancer.

PURPOSE: Triple Negative Breast Cancer (TNBC) is the malignant tumor with the fastest progression rate in breast cancer. LncRNAs are widely involved in various biological characteristics of tumor. The purpose of this study was to mine LncRNAs that can be used to diagnose and evaluate the prognosis of TNBC. METHODS: Base on TCGA dataset, we used three R language packages to analyze the differentially expressed (DE) lncRNAs in TNBC. Survival analysis and ROC curve analysis were conducted to estimate the potential diagnostic and prognostic value of LncRNAs for TNBC. Furthermore, CCK-8 and Transwell assays were used to assess the effects of LncRNA on MDA-MB-231 cells proliferation and migration. Additionally, targets mRNAs of candidate LncRNA were predicted by co-expression analysis and multiple target gene prediction databases, then KEGG pathway and GO analysis were conducted using DAVID online tool. RESULTS: 6165 DERNAs and 1258 DElncRNAs were obtained. 40 LncRNAs were significantly correlated with the survival time of TNBC patients. Among them, HAGLROS has the highest HR value. ROC curve analysis also showed that HAGLROS had high sensitivity and specificity. Further in vitro experiments showed that downregulation of HAGLROS inhibited the proliferation and migration of MDA-MB-231 cells. Moreover, by conducting bioinformatics analysis, we found that these target genes of HAGLROS were involved in regulating five signaling pathways. Mechanistic investigations demonstrated that HAGLROS might regulate the expression of PAX5 through miR-330-5p, the effects of miR-330-5p in MDA-MB-231 cells were also analyzed. CONCLUSION: Our results showed that HAGLROS was significantly overexpressed in TNBC, and high HAGLROS expression predicted poor overall survival. Downregulation of HAGLROS could inhibite the proliferation and migration of MDA-MB-231 cell by regulating PAX5 expression through miR-330-5p.

Alterations in chromatin accessibility during osteoblast and adipocyte differentiation in human mesenchymal stem cells.

Although differential expression of genes is apparent during the adipogenic/osteogenic differentiation of marrow mesenchymal stem cells (MSCs), it is not known whether this is associated with changes in chromosomal structure. In this study, we used ATAC-sequencing technology to observe variations in chromatin assembly during the early stages of MSC differentiation. This showed significant changes in the number and distribution of chromosome accessibility at different time points of adipogenic/osteogenic differentiation. Sequencing of differential peaks indicated alterations in transcription factor motifs involved in MSC differentiation. Gene Ontology (GO) and pathway analysis indicated that changes in biological function resulted from the alterations in chromatin accessibility. We then integrated ATAC-seq and RNA-seq and found that only a small proportion of the overlapping genes were screened out from ATAC-seq and RNA-seq overlapping. Through GO and pathway analysis of these overlapped genes, we not only observed some known biological functions related to adipogenic/osteogenic differentiation but also noticed some unusual biological clustering during MSC differentiation. In summary, our work not only presents the landscape of chromatin accessibility of MSC during differentiation but also helps to further our understanding of the underlying mechanisms of gene expression in these processes.

The role of ventral tegmental area orexinergic afferents in depressive-like behavior in a chronic unpredictable mild stress (CUMS) mouse model.

Orexin has been implicated in comorbid diseases of depression, making it a promising target for anti-depression treatment. Although orexin neurons exhibit abnormal activity in depression, the neurocircuit mechanism of orexin remains unclear. As one of the important downstream factors of orexin neurons, the ventral tegmental area (VTA) is considered crucial to the mechanism of depression. However, the role of VTA orexinergic afferents in depression remains unclear. In this study, we applied a combination of opto/chemogenetic and neuropharmacology methods to investigate whether the VTA orexinergic afferents participate in the pathogenesis of depression in a chronic unpredictable mild stress (CUMS) mouse model. We found that c-Fos expression in these VTA-projecting orexin neurons specifically decreased in CUMS-treated mice. Optogenetic and chemogenetic activation of orexin terminals in the VTA significantly reversed depressive behavior. Microinjection of orexin-A, but not orexin-B, into the VTA significantly improved depressive-like behavior. Our study provided direct evidence that the VTA orexinergic afferents participate in the mechanism of depression, and the orexin-1 receptor plays a major role.