Transcranial Magneto-Acoustic Stimulation Protects Synaptic Rehabilitation from Amyloid-Beta Plaques via Regulation of Microglial Functions.

Transcranial magneto-acoustic stimulation (TMAS), which is characterized by high spatiotemporal resolution and high penetrability, is a non-invasive neuromodulation technology based on the magnetic-acoustic coupling effect. To reveal the effects of TMAS treatment on amyloid-beta (Aß) plaque and synaptic plasticity in Alzheimer's disease, we conducted a comparative analysis of TMAS and transcranial ultrasound stimulation (TUS) based on acoustic effects in 5xFAD mice and BV2 microglia cells. We found that the TMAS-TUS treatment effectively reduced amyloid plaque loads and plaque-associated neurotoxicity. Additionally, TMAS-TUS treatment ameliorated impairments in long-term memory formation and long-term potentiation. Moreover, TMAS-TUS treatment stimulated microglial proliferation and migration while enhancing the phagocytosis and clearance of Aß. In 5xFAD mice with induced microglial exhaustion, TMAS-TUS treatment-mediated Aß plaque reduction, synaptic rehabilitation improvement, and the increase in phospho-AKT levels were diminished. Overall, our study highlights that stimulation of hippocampal microglia by TMAS treatment can induce anti-cognitive impairment effects via PI3K-AKT signaling, providing hope for the development of new strategies for an adjuvant therapy for Alzheimer's disease.

Treg-Related Genes Representing a Potential Shared Biological Mechanism Between Clear Cell Renal Carcinoma and Obesity.

OBJECTIVE: To determine the potential shared biological mechanism between obesity and clear cell renal carcinoma (ccRCC). STUDY DESIGN: Observational study. Place and Duration of the Study: Department of Urology, Lishui People's Hospital, Lishui City, China, from December 2022 to March 2023. METHODOLOGY: The test and validation cohorts were selected from the GEO database. WGCNA and PPI networks were applied to identify shared hub genes. GO/KEGG, GSEA, and ROC curve analyses were applied to explore the potential underlying mechanisms and diagnostic power. Logistic regression was used to select genes to construct the signature. The risk score and various immune-related analyses were performed to assess the clinical and immune performance of the signature. The CellMiner platform was used to screen potential FDA-approved drugs. RESULTS: PTPRC, TYROBP, ITGB2, CD86, and ITGAM were defined as shared hub genes with good diagnostic power for obesity and ccRCC. Eight immune cells exhibited a positive correlation with the hub genes, while two immune cells showed negative associations. MDSCs and Tregs had the strongest positive associations with the hub genes. The Treg-related pathway exhibited predominant enrichment. The TYROBP, ITGB2, and CD86 genes were selected to construct an immune signature that has good clinical and immune performance. Six FDA-approved drugs were screened. CONCLUSION: Five Treg-related genes were identified as shared hub genes in obese patients and ccRCC patients. A signature was constructed to describe the immune features of ccRCC. KEY WORDS: Treg-related genes, Shared biological mechanism, Immune signature, Obesity, Clear cell renal carcinoma (ccRCC).

Sleeve gastrectomy with one anastomosis bipartition versus one anastomosis gastric bypass: A pilot study.

BACKGROUND: One anastomosis gastric bypass (OAGB) is a new recognized metabolic surgery, but the problem that we cannot screen the excluded stomach is a troubling issue in China. The emergence of sleeve gastrectomy plus one anastomosis bipartition (SG + OAB) makes us see a hope to solve this problem. OBJECTIVES: By comparing the efficacy of the two surgical methods, to evaluate whether SG + OAB surgery can solve the dilemma faced by OAGB that the excluded stomach cannot be screened. METHODS: A retrospective study to compare the patients who underwent OAGB and SG + OAB was conducted. The main outcome measures were (1) operation risk, (2) weight loss, and (3) diabetes remission at 6 months. RESULTS: This study was conducted in the bariatric/metabolic surgical center. From November 2021 to February 2022, a total of 30 patients with obesity who received SG + OAB surgery were recruited. Another matched 60 patients undergoing OAGB were recruited as control group. There was no difference in preoperative age (32.15 ± 9.02 vs. 34.47 ± 7.22; p = .224), female ratio (83% vs. 85%; p = .837), and BMI (36.18 ± 5.30 vs. 34.68 ± 5.58; p = .217) between the two groups. OAGB had a shorter mean operation time (121.67 ± 20.41 vs. 143.50 ± 25.07 min; p < .001) and a lower intraoperative blood loss (21.92 ± 12.35 vs. 32.43 ± 22.01 mL; p = .005), but a longer postoperative flatus passage (2.13 ± 0.43 vs. 1.87 ± 0.43 days; p = .007) compared with the SG + OAB group. Two patients (6.7%) developed major surgical complication in SG + OAB group but no major complication developed in OAGB group. At 6 months after surgery, SG + OAB had a higher %total weight loss than OAGB (31.05 ± 3.12 vs. 28.14 ± 5.43%; p = .015), but diabetes remission rate was similarly high in both groups. CONCLUSIONS: SG + OAB operation had a non-inferior or even better weight loss than OAGB, with a similar glycemic control efficacy. However, the high complication rate of SG + OAB is the major drawback that needs attention.

The mitochondrial regulation in ferroptosis signaling pathway and its potential strategies for cancer.

Ferroptosis is an iron-dependent regulated cell death, mainly manifested by the production of reactive oxygen species and accumulation of lipid peroxides. It is distinct from other forms of cell death with regard to morphology and biochemistry, particularly in disrupting mitochondrial function. Mitochondria are essential compartments where the organism generates energy and are closely associated with the fate of ferroptosis. Currently, researchers focus on the potential value of ferroptosis and mitochondria for overcoming drug sensitivity and assisting in cancer therapy. In this review, we summarize the main mechanisms of ferroptosis (the GPX4-realated pathway, FSP1-related pathway, and iron metabolism pathway) and the functions and regulating pathways of mitochondria (the TCA cycle, oxidative phosphorylation, mitochondrial regulation of iron ions, and mtDNA) in ferroptosis. We believe that exploring the role of mitochondria in ferroptosis will help us understand the potential regulatory mechanisms of ferroptosis in cancer and help us find new therapeutic targets.

Comprehensive Transcriptomic Profiling of m6A Modification in Age-Related Hearing Loss.

Age-related hearing loss (ARHL), also known as presbycusis, is one of the most common neurodegenerative disorders in elderly individuals and has a prevalence of approximately 70-80% among individuals aged 65 and older. As ARHL is an intricate and multifactorial disease, the exact pathogenesis of ARHL is not fully understood. There is evidence that transcriptional dysregulation mediated by epigenetic modifications is widespread in ARHL. However, the potential role of N6-methyladenosine (m6A) modification, as a crucial component of epigenetics, in ARHL progression remains unclear. In this study, we confirmed that the downregulation of m6A modification in cochlear tissues is related to ARHL and found that the expression of the m6A methylation regulators Wilms tumour suppressor-1-associated protein (WTAP), methyltransferase-like 3 (METTL3), ALKB homologous protein 5 (ALKBH5) and fat mass and obesity-associated protein (FTO) is decreased significantly at the mRNA and protein levels in ARHL mice. Then, we used methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and RNA sequencing (RNA-Seq) to identify the differentially m6A-methylated genes in the cochlear tissues of ARHL mice. A total of 3438 genes with differential m6A methylation were identified, of which 1332 genes were m6A-hypermethylated and 2106 genes were m6A-hypomethylated in the ARHL group compared to the control group according to MeRIP-seq. Further joint analysis of RNA-Seq and MeRIP-Seq data showed that 262 genes had significant differences in both mRNA expression and m6A methylation. GO and KEGG analyses indicated that 262 unique genes were enriched mainly in the PI3K-AKT signalling pathway. In conclusion, the results of this study reveal differential m6A methylation patterns in the cochlear tissues of ARHL mice, providing a theoretical basis for further study of the pathogenesis of ARHL and potential therapeutic strategies.

Prospects and challenges of CRISPR/Cas9 gene-editing technology in cancer research.

Cancer, one of the leading causes of death, usually commences and progresses as a result of a series of gene mutations and dysregulation of expression. With the development of clustered regularly interspaced palindromic repeat (CRISPR)/Cas9 gene-editing technology, it is possible to edit and then decode the functions of cancer-related gene mutations, markedly advance the research of biological mechanisms and treatment of cancer. This review summarizes the mechanism and development of CRISPR/Cas9 gene-editing technology in recent years and describes its potential application in cancer-related research, such as the establishment of human tumor disease models, gene therapy and immunotherapy. The challenges and future development directions are highlighted to provide a reference for exploring pathological mechanisms and potential treatment protocols of cancer.

VCFshiny: an R/Shiny application for interactively analyzing and visualizing genetic variants.

Summary: Next-generation sequencing generates variants that are typically documented in variant call format (VCF) files. However, comprehensively examining variant information from VCF files can pose a significant challenge for researchers lacking bioinformatics and programming expertise. To address this issue, we introduce VCFshiny, an R package that features a user-friendly web interface enabling interactive annotation, interpretation, and visualization of variant information stored in VCF files. VCFshiny offers two annotation methods, Annovar and VariantAnnotation, to add annotations such as genes or functional impact. Annotated VCF files are deemed acceptable inputs for the purpose of summarizing and visualizing variant information. This includes the total number of variants, overlaps across sample replicates, base alterations of single nucleotides, length distributions of insertions and deletions (indels), high-frequency mutated genes, variant distribution in the genome and of genome features, variants in cancer driver genes, and cancer mutational signatures. VCFshiny serves to enhance the intelligibility of VCF files by offering an interactive web interface for analysis and visualization. Availability and implementation: The source code is available under an MIT open source license at https://github.com/123xiaochen/VCFshiny with documentation at https://123xiaochen.github.io/VCFshiny.

Mini-PE, a prime editor with compact Cas9 and truncated reverse transcriptase.

Prime editor (PE) is a versatile genome editing tool that does not need extra DNA donors or inducing double-strand breaks. However, in vivo implementation of PE remains a challenge because of its oversized composition. In this study, we screened out the smallest truncated Moloney murine leukemia virus (MMLV) reverse transcriptase (RT) with the F155Y mutation to keep gene editing efficiency. We discovered the most efficient gene editing variants of MMLV RT with the smallest size. After optimization of the pegRNAs and incorporation with nick sgRNAs, the mini-PE delivered up to 10% precise editing at target sites in human and mouse cells. It also edited the mouse Hsf1 gene in the mouse retina precisely after delivery with adeno-associated viruses (AAVs), although the editing efficiency was lower than 1%. We will focus on improving the editing efficiency of mini-PE and exploiting its therapeutic potential against human genetic diseases.

Generation of hiPSCs with ABO c.767T>C substitution: resulting in splicing variants.

Introduction: The ABO blood group system has important clinical significance in the safety of blood transfusion and organ transplantation. Numerous ABO variations, especially variations in the splice sites, have been identified to be associated with some ABO subtypes. Methods: Here, we performed the c.767T>C substitution of the ABO gene in human induced pluripotent stem cells (hiPSCs) by the adenosine base editor (ABE) system and described its characteristics at the genome level in detail. Results: The hiPS cell line with c.767T>C substitution maintained a normal karyotype (46, XX), expressed pluripotency markers, and showed the capability to spontaneously differentiate into all three germ layers in vivo. The genome-wide analysis demonstrated that the c.767T>C substitution in the ABO gene did not cause any detected negative effect in hiPSCs at the genome level. The splicing transcript analysis revealed that splicing variants were observed in the hiPSCs with ABO c.767T>C substitutions. Conclusion: All these results indicated that some splicing variants occurred in hiPSCs with c.767 T>C substitution of ABO gene, which probably had a significant effect on the formation of the rare ABO*Ael05/B101 subtype.

Beneficial Effects of Pleurotus citrinopileatus Polysaccharide on the Quality of Cherry Tomatoes During Storage.

Cherry tomatoes are highly well-liked and have a lot of nutritional value. However, the edible value of cherry tomatoes rapidly declines as their storage duration is extended. Pleurotus citrinopileatus polysaccharide (PCP) is a kind of polysaccharide obtained from P. citrinopileatus by water extraction. The effects of PCP were investigated to identify a way to maximally postpone cherry tomato degradation. The results showed that PCP had inhibitory effects on all 10 tested strains, and the inhibitory effect on Pseudomonas aeruginosa was the strongest. PCP could effectively reduce the weight loss rate and malondialdehyde accumulation of cherry tomatoes during storage, weaken the activity of polyphenol oxidase, and delay the decline of hardness, titratable acid content, and VC content compared with untreated cherry tomatoes. PCP solution at a concentration of 2 g/L exerted the best preservation effects. Therefore, PCP can potentially contribute to the preservation of vegetables and fruits.

NEDD4L inhibits migration, invasion, cisplatin resistance and promotes apoptosis of bladder cancer cells by inactivating the p62/Keap1/Nrf2 pathway.

PURPOSE: This study identified the function of neural precursor cell expressed developmentally down-regulated 4-like (NEDD4L) on bladder cancer (BLCA). METHODS: NEDD4L expression in BLCA patients was scrutinized. The function of NEDD4L on the viability, apoptosis, migration and invasion of BLCA cells was evaluated by cell counting kit-8, flow cytometry and Transwell assays. The effect of NEDD4L on the cisplatin (DDP) resistance of the DDP-resistant BLCA cells was explored. The influence of NEDD4L on the p62/Keap1/Nrf2 pathway activity in BLCA cells was tested by Western blot. Rescue experiments were implemented to verify whether NEDD4L regulated BLCA cell malignant behavior by mediating the Keap1/Nrf2 pathway activity via p62. The effect of NEDD4L on the growth and the p62/Keap1/Nrf2 pathway activity in vivo was researched in xenograft tumor nude mice models. RESULTS: The down-regulated NEDD4L in BLCA patients was associated with unfavorable survival. NEDD4L suppressed the viability (inhibition rate 57.1%/49.0%), migration (inhibition rate 49.7%/77.1%), invasion (inhibition rate 50.6%/75.7%), promoted the apoptosis of T24/5637 cells (promotion rate 243.8%/201.9%), reduced IC 50 of DDP-resistant T24/5637 cells from 132.2/101.8 to 57.81/59.71 µM, respectively, and inactivated the p62/Keap1/Nrf2 pathway in T24/5637 cells. p62 up-regulation partially abrogated the inhibition of NEDD4L on the Keap1/Nrf2 pathway activity, the malignant behavior of BLCA cells, and the DDP resistance of DDP-resistant BLCA cells. NEDD4L overexpression inhibited the tumor growth and the p62/Keap1/Nrf2 pathway activity in vivo in BLCA. CONCLUSION: NEDD4L inhibits the progression of BLCA by inactivating the p62/Keap1/Nrf2 pathway. It may be an effective target for BLCA treatment.

Developing a non-invasive diagnostic model for pediatric Crohn's disease using RNA-seq analysis.

Introduction: Pediatric Crohn's disease is a chronic inflammatory condition that affects the digestive system in children and adolescents. It is characterized by symptoms such as abdominal pain, diarrhea, weight loss, and malnutrition, and can also cause complications like growth delays and delayed puberty. However, diagnosing pediatric Crohn's disease can be difficult, especially when it comes to non-invasive methods. Methods: In this study, we developed a diagnostic model using RNA-seq to analyze gene expression in ileal biopsy samples from children with Crohn's disease and non-pediatric Crohn's controls. Results: Our results showed that pediatric Crohn's disease is associated with altered expression of genes involved in immune response, inflammation, and tissue repair. We validated our findings using two independent datasets from the Gene Expression Omnibus (GEO) database, as well as through one prospective independent dataset, and found that our model had a high accuracy rate. Discussion: These findings suggest the possibility of non-invasive diagnosis for pediatric Crohn's disease and may inform the development of targeted therapies for this condition.

Bcl-xL Promotes the Survival of Motor Neurons Derived from Neural Stem Cells.

Neural stem cell (NSC) transplantation creates new hope for the treatment of neurodegenerative disorders by direct differentiation into neurons. However, this technique is limited by poor survival and functional neuron deficiency. In this research study, we generated pro-survival murine NSCs (mNSCs) via the ectopic expression of Bcl-xL. A doxycycline (Dox)-inducible Ngn2-Isl1-Lhx3 system was also integrated into the mNSC genome. The four gene-modified mNSCs can rapidly and effectively differentiate into motor neurons after Dox treatments. Ectopic Bcl-xL could resist replating-induced stress, glutamate toxicity, neuronal apoptosis and remarkably promote the survival of motor neurons. Taken together, we established genetically modified mNSCs with improved survival, which may be useful for motor neuron degenerative diseases.

Effects of Holliday Junction-Recognition Protein-Mediated C-Jun N-Terminal Kinase/ Signal Transducer and Activator of Transcription 3 Signaling Pathway on Cell Proliferation, Cell Cycle and Cell Apoptosis in Bladder Urothelial Carcinoma.

The Holliday Junction-Recognition Protein (HJURP) was upregulated in several tumors, which was associated with poor outcome. This study investigated the effects of the HJURP-mediated c-Jun N-terminal kinase (JNK)/ signal transducer and activator of transcription 3 (STAT3) pathway on bladder urothelial carcinoma (BLUC). Online databases were used to analyze HJURP expression in BLUC and the correlation of HJURP to JNK1 [mitogen-activated protein kinase 8 (MAPK8)], JNK2 (MAPK9), STAT3, marker of proliferation Ki-67 (MKI67), proliferating cell nuclear antigen (PCNA), cyclin dependent kinase 2 (CDK2), CDK4 and CDK6. HJURP expression was detected in BLUC cells and human normal primary bladder epithelial cells (BdECs). BLUC cells were treated with HJURP lentivirus activation /shRNA lentivirus particles or JNK inhibitor SP600125. HJURP was upregulated in BLUC tissues and correlated with poor prognosis of patients (all P < 0.05). HJURP in tumor positively correlated with MAPK8 (R = 0.30), MAPK9 (R = 0.30), STAT3 (R = 0.15), MKI67 (R = 0.60), PCNA (R = 0.46), CDK2 (R = 0.39), CDK4 (R = 0.24) and CDK6 (R = 0.21). The JNK inhibitor SP600125 decreased p-JNK/JNK and p-STAT3/STAT3 in BLUC cells, which was reversed by HJURP overexpression (P < 0.05). The HJURP-mediated JNK/STAT3 pathway promoted BLUC cell proliferation and inhibited cell apoptosis (P < 0.05). HJURP reversed the arrested G0/G1 phase of BLUC cells by SP600125. HJURP acted as an oncogene to regulate BLUC cell proliferation, apoptosis and the cell cycle by mediating the JNK/STAT3 pathway. Therefore, HJURP targeting might be an attractive novel therapeutic target for early diagnosis and treatment in BLUC.

SMAR1 inhibits proliferation, EMT and Warburg effect of bladder cancer cells by suppressing the activity of the Wnt/ß-catenin signaling pathway.

This study aimed to investigate the effects of scaffold matrix attachment region binding protein 1 (SMAR1) on the development of bladder cancer (BCa). SMAR1 expression in paired tumor and corresponding adjacent normal tissues from 55 BCa patients was detected by quantitative reverse transcription-polymerase chain reaction. BCa cells were transfected to regulate SMAR1 expression. BCa cells were treated with XAV-939, LiCl and 2-deoxyglucose. The effect of SMAR1 on the viability, proliferation, migration, invasion and Warburg effect of BCa cells was researched by counting kit-8, colony formation assay, Transwell and aerobic glycolysis assays. Western blot was performed to detect protein expression. BCa cell growth in vivo was recorded in nude mice. Immunohistochemical staining was performed for clinical and xenografted tumor tissue specimens. SMAR1 expression was down-regulated in BCa patients, associating with worse prognoses. SMAR1 knockdown enhanced the viability, proliferation, migration, invasion, EMT and Warburg effect of BCa cells. The opposite effect was found in the SMAR1 overexpression BCa cells. XAV-939 treatment reversed the elevation of ß-catenin, c-Myc and Cyclin D1 proteins expression and Warburg effect in Bca cells post-SMAR1 knockdown. LiCl treatment abrogated the inhibition of ß-catenin, c-Myc and Cyclin D1 proteins expression and Warburg effect proteins due to SMAR1 overexpression in BCa cells. SMAR1 overexpression inhibited the growth of BCa cells in vivo. SMAR1 might suppress the Wnt/ß-catenin signaling pathway activity to inhibit the progression of BCa. It might be an effective treatment target for BCa.

Indirubin regulates T cell differentiation by promoting αVß8 expression in bone marrow-derived dendritic cells to alleviate inflammatory bowel disease.

Inflammatory bowel disease is a disease that can invade the whole digestive tract and is accompanied by immune abnormalities. Immune dysfunction involving dendritic cells (DCs) and T cells is recognized as a key factor in diseases. Indirubin (IDRB) exerts antiinflammatory effects and can help in treating immune diseases. This study aimed to isolate bone marrow-derived dendritic cells (BMDCs) using lipopolysaccharide (LPS) to obtain mature DCs (mDCs). The expression of CD80, CD86, CD40, and MHC-II was detected using flow cytometry after treatment with IDRB. αVß8 siRNA was used to knock down αVß8 in mDCs, and the expression of CD80, CD86, CD40, and MHC-II was detected. Meanwhile, DCs were co-cultured with T cells. Then, T cell differentiation was detected using flow cytometry, and the cytokine levels were detected using enzyme-linked immunosorbent assay. The animal model of dextran sulfate sodium (DSS)-induced inflammatory bowel disease was established in mice. After intervention with IDRB and αVß8 shRNA, the intestinal tissues were evaluated using H&E staining, disease activity index (DAI) score, and histological damage index, and the corresponding factors and cytokines to regulatory T cells (Treg) and Th17 were measured. The results showed that αVß8 was expressed in immature DCs and mDCs. CD80, CD86, CD40, and MHC-II expression decreased after IDRB treatment in mDCs. Meanwhile, the expression of TNF-α and TGF-ß also decreased after IDRB treatment. The effect of IDRB on the expression of CD80, CD86, CD40, MHC-II, TNF-α, and TGF-ß in mDCs was reversed by αVß8 siRNA. The Treg differentiation increased after IDRB treatment, while the differentiation of Th17 cells was inhibited. This effect of IDRB was reversed by mDCs after treatment with αVß8 siRNA. In vivo experiments showed that IDRB alleviated the symptoms of inflammatory bowel disease in animals. Enteritis significantly reduced, and the effect of IDRB was reversed by αVß8 shRNA. The results suggested that IDRB regulated the differentiation of T cells by mediating the maturation of BMDCs through αVß8. This study confirmed the therapeutic effect of IDRB in inflammatory bowel disease and suggested that IDRB might serve as a potential drug.

Application of an Interpretable Machine Learning Model to Predict Lymph Node Metastasis in Patients with Laryngeal Carcinoma.

Objectives: A more accurate preoperative prediction of lymph node metastasis (LNM) plays a decisive role in the selection of treatment in patients with laryngeal carcinoma (LC). This study aimed to develop a machine learning (ML) prediction model for predicting LNM in patients with LC. Methods: We collected and retrospectively analysed 4887 LC patients with detailed demographical characteristics including age at diagnosis, race, sex, primary site, histology, number of tumours, T-stage, grade, and tumour size in the National Institutes of Health (NIH) Surveillance, Epidemiology, and End Results (SEER) database from 2005 to 2015. A correlation analysis of all variables was evaluated by the Pearson correlation. Independent risk factors for LC patients with LNM were identified by univariate and multivariate logistic regression analyses. Afterward, patients were randomly divided into training and test sets in a ratio of 8 to 2. On this basis, we established logistic regression (LR), k-nearest neighbor (KNN), support vector machine (SVM), extreme gradient boosting (XGBoost), random forest (RF), and light gradient boosting machine (LightGBM) algorithm models based on ML. The area under the receiver operating characteristic curve (AUC) value, accuracy, precision, recall rate, F1-score, specificity, and Brier score was adopted to evaluate and compare the prediction performance of the models. Finally, the Shapley additive explanation (SHAP) method was used to interpret the association between each feature variable and target variables based on the best model. Results: Of the 4887 total LC patients, 3409 were without LNM (69.76%), and 1478 had LNM (30.24%). The result of the Pearson correlation showed that variables were weakly correlated with each other. The independent risk factors for LC patients with LNM were age at diagnosis, race, primary site, number of tumours, tumour size, grade, and T-stage. Among six models, XGBoost displayed a better performance for predicting LNM, with five performance metrics outperforming other models in the training set (AUC: 0.791 (95% CI: 0.776-0.806), accuracy: 0.739, recall rate: 0.638, F1-score: 0.663, and Brier score: 0.165), and similar results were observed in the test set. Moreover, the SHAP value of XGBoost was calculated, and the result showed that the three features, T-stage, primary site, and grade, had the greatest impact on predicting the outcomes. Conclusions: The XGBoost model performed better and can be applied to forecast the LNM of LC, offering a valuable and significant reference for clinicians in advanced decision-making.

The progress of protein synthesis factors eIFs, eEFs and eRFs in inflammatory bowel disease and colorectal cancer pathogenesis.

Colorectal diseases are threatening human health, especially inflammatory bowel disease (IBD) and colorectal cancer (CRC). IBD is a group of chronic, recurrent and incurable disease, which may affect the entire gastrointestinal tract, increasing the risk of CRC. Eukaryotic gene expression is a complicated process, which is mainly regulated at the level of gene transcription and mRNA translation. Protein translation in tissue is associated with a sequence of steps, including initiation, elongation, termination and recycling. Abnormal regulation of gene expression is the key to the pathogenesis of CRC. In the early stages of cancer, it is vital to identify new diagnostic and therapeutic targets and biomarkers. This review presented current knowledge on aberrant expression of eIFs, eEFs and eRFs in colorectal diseases. The current findings of protein synthesis on colorectal pathogenesis showed that eIFs, eEFs and eRFs may be potential targets for CRC treatment.

Schisandrol A protects AGEs-induced neuronal cells death by allosterically targeting ATP6V0d1 subunit of V-ATPase.

Diabetes have been shown to cause progressive neuronal injury with pain and numbness via advanced glycation end-products (AGEs)-induced neuronal cell apoptosis; however, the valuable drug targets for diabetic neuropathy have been poorly reported so far. In this study, we discovered a natural small-molecule schisandrol A (SolA) with significant protective effect against AGEs-induced neuronal cell apoptosis. ATP6V0D1, a major subunit of vacuolar-type ATPase (V-ATPase) in lysosome was identified as a crucial cellular target of SolA. Moreover, SolA allosterically mediated ATP6V0D1 conformation via targeting a unique cysteine 335 residue to activate V-ATPase-dependent lysosomal acidification. Interestingly, SolA-induced lysosome pH downregulation resulted in a mitochondrial-lysosomal crosstalk by selectively promoting mitochondrial BH3-only protein BIM degradation, thereby preserving mitochondrial homeostasis and neuronal cells survival. Collectively, our findings reveal ATP6V0D1 is a valuable pharmacological target for diabetes-associated neuronal injury via controlling lysosomal acidification, and also provide the first small-molecule template allosterically activating V-ATPase for preventing diabetic neuropathy.

Inducible motor neuron differentiation of human induced pluripotent stem cells in vivo.

OBJECTIVES: Transplantation of neural progenitor cells (NPCs) derived from human-induced pluripotent stem cells (hiPSCs) is one of the promising treatment strategies for motor neuron diseases (MNDs). However, the inefficiency in committed differentiation of NPCs in vivo limits its application. Here, we tried to establish a potential therapeutic strategy for MNDs by in vivo directional differentiation of hiPSCs engineered with motor neuron (MN) specific transcription factors and Tet-On system. MATERIALS AND METHODS: We engineered hiPSCs with three MN-specific transcription factors and Tet-On system. The engineered cells were directly transplanted into immunodeficient mice through subcutaneous, intra-spinal cord and intracerebroventricular injections. Following doxycycline (Dox) induction, teratoma formation, and motor MN differentiation were evaluated. RESULTS: We generated genetically engineered hiPSCs, in which the expression of Ngn2, Isl1, and Lhx3 was controlled by a drug-inducible transgenic system. These cells showed normal pluripotency and proliferative capacity, and were able to directionally differentiate into mature motor neurons (MNs) and NPCs with high efficiency in spinal cords and cerebral lateral ventricles under the induction of Dox. The grafts showed long-term survival in the recipient mice without formation of teratoma. CONCLUSIONS: The induced mature MNs and NPCs were expected to replace the damaged endogenous MNs directly, and play a role of de novo stem cell stock for long-term neuron damage repair, respectively. Therefore, in vivo directional differentiation of the hiPSCs engineered with MN-specific transcription factors and Tet-On system via Dox induction could be a potential therapeutic strategy for MNDs with high efficacy and safety.