👤 Yifei Guo

Tumor heterogeneity is jointly determined by the components of the tumor ecosystem (TES) including tumor cells, immune cells, stromal cells, and non-cellular components. We aimed to identify subtypes using TES-related genes and determine subtype specific drivers and treatments for hepatocellular carcinoma (HCC). We collected 68 genesets depicting tumor biology, immune infiltration, and liver function, totaling 2831 genes, and collected mRNA profiles and clinical data for over 6000 tumors from 65 datasets in the GEO, TCGA, ICGC, and several other databases. We designed a three-step clustering pipeline to identify subtypes. The microenvironment, genomic alteration, and drug response differences were systematically compared among subtypes. Seven subtypes (TES-1/2/3/4/5/6/7) were revealed in 159 tumors from the CHCC-HBV cohort. We constructed a single sample classifier using paired genes (sscpgsTES). TES subtypes were significantly associated with multiple clinical variables including etiology, and survival in 14 of 17 cohorts and the meta-cohort. TES-1 had the poorest prognosis and highest proliferation level. Both TES-2 and TES-7 were immune-enriched, however, TES-2 had a significantly worse prognosis, and hypoxic and immunosuppressive microenvironment. TES-4 had activated Wnt pathway, driven by CTNNB1 mutation. Good prognosis TES-6 exhibited the best differentiation. TES-5 and TES-3 were considered as novel subclasses by comparing with ten previous subtyping systems. TES-5 tumors had high AFP but good overall survival, and ∼45% of them harbored AXIN1 mutation. TES-3 was immune and stromal desert, may be driven by high copy number alteration burden, and had the poorest response to immune checkpoint inhibitor. TES-1 and TES-2 had significantly lower response to transarterial chemoembolization, but they showed significantly higher sensitivity to compound YM-155. Tumor ecosystem subtypes expand existing HCC subtyping systems, have distinct drivers, prognosis, and treatment vulnerabilities. Show less

Hematoma-induced neuroinflammation is the cause of poor prognosis in intracerebral hemorrhage (ICH); therefore, promoting blood clearance and blocking overactivated inflammation are rational approaches for ICH treatment. β-site amyloid precursor protein (APP) lyase-1 (BACE1) is a key molecule regulating the microglial phenotype transition in neurodegenerative diseases. Therefore, the aim of this study was to investigate the role of BACE1 in microglial phagocytosis and inflammatory features in ICH. Here, we demonstrated the unique advantages of targeting BACE1 in microglia using an autologous blood model and primary microglia hemoglobin stimulation. When BACE1 was inhibited early in ICH, fewer residual hematomas remained, consistent with an increase in genetic features that favor phagocytosis and anti-inflammation. In addition, inhibition of BACE1 enhanced the secretion of anti-inflammatory cytokines and substantially reduced the expression of proinflammatory genes, which was regulated by signal transduction and phosphorylation of activator of transcription 3 (STAT3). Further pharmacological inhibition of STAT3 phosphorylation effectively blocked the proinflammatory and weak phagocytic phenotype of microglia due to BACE1 induction. In summary, BACE1 is the critical molecule regulating the inflammatory and phagocytic phenotypes of microglia after ICH, and targeted inhibition of the BACE1/STAT3 pathway is an important strategy for the future treatment of ICH-induced neurological injury. Show less

Icariin (ICA) is the main active component of Epimedium, a traditional Chinese medicine (TCM), known to enhance cognitive function in Alzheimer's disease (AD). This study aims to investigate and summarize the mechanisms through which ICA treats AD. The PubMed and CNKI databases were utilized to review the advancements in ICA's role in AD prevention and treatment by analyzing literature published between January 2005 and April 2023. To further illustrate ICA's impact on AD development, tables, and images are included to summarize the relationships between various mechanisms. The study reveals that ICA ameliorates cognitive deficits in AD model mice by modulating Aβ via multiple pathways, including BACE-1, NO/cGMP, Wnt/Ca This study indicates that ICA possesses multiple beneficial effects in AD treatment. Through the integration of pharmacological and molecular biological research, ICA may emerge as a promising candidate to expedite the advancement of TCM in the clinical management of AD. Show less

Obesity is a metabolic disease with excess weight. LncRNA SNHG14 is abnormally expressed in numerous diseases. This research aimed to enucleate the lncRNA SNHG14 role in obesity. Adipocytes were treated with free fatty acid (FFA) to establish an in vitro model for obesity. Mice were fed a high-fat diet to construct an in vivo model. Gene levels were determined using quantitative real-time PCR (RT-PCR). The protein level was checked by western blot. The lncRNA SNHG14 role in obesity was assessed using western blot and enzyme-linked immunosorbent assay. The mechanism was estimated by Starbase, dual-luciferase reporter gene assay, and RNA pull-down. LncRNA SNHG14 function in obesity was estimated using mouse xenograft models, RT-PCR, western blot, and enzyme-linked immunosorbent assay. LncRNA SNHG14 and BACE1 levels were increased, but the miR-497a-5p level was decreased in FFA-induced adipocytes. Interference with lncRNA SNHG14 reduced endoplasmic reticulum (ER) stress-related molecules GRP78 and CHOP expressions in FFA-induced adipocytes, and decreased IL-1β, IL-6, and TNF-α expressions, indicating that lncRNA SNHG14 knockdown mitigated FFA-induced ER stress and inflammation in adipocytes. Mechanistically, lncRNA SNHG14 combined with miR-497a-5p, and miR-497a-5p targeted BACE1. Meanwhile, lncRNA SNHG14 knockdown reduced levels of GRP78, CHOP, IL-1β, IL-6, and TNF-α, while cotransfection with anti-miR-497a-5p or pcDNA-BACE1 abolished these trends. Rescue assays illustrated that lncRNA SNHG14 knockdown relieved FFA-induced adipocyte ER stress and inflammation through miR-497a-5p/BACE1. Meanwhile, lncRNA SNHG14 knockdown restrained adipose inflammation and ER stress caused by obesity in vivo. LncRNA SNHG14 mediated obesity-induced adipose inflammation and ER stress through miR-497a-5p/BACE1. Show less

Alzheimer's disease (AD) is characterized by amyloid β (Aβ) aggregation and neuroinflammation. This study aimed to investigate the therapeutic effect of isoniazid (INH) against AD. The APP/PS1 transgenic mouse model of AD was adopted. The APP/PS1 mice received oral INH (45 mg/kg/d) for 14 days. The cognitive capability was assessed by the Morris Water Maze test. Amyloid plaques and Aβ levels were determined by immunohistochemistry and ELISA assay. The dendritic spines were analyzed by DiOlistic labeling. Immunofluorescence staining was used to observe the microglia and astrocytes. The Morris Water Maze test suggested that INH administration can effectively attenuate the reference memory deficit and improve the working memory of the APP/PS1 mice compared to the untreated mice (all Isoniazid administration effectively improved cognitive performance, cleared Aβ plaques, protected dendritic synapses, and reduced innate immune cells around the Aβ plaques, suggesting that INH could be a potential drug for AD treatment. Show less

Energy efficiency (EE) plays an important role in achieving the dual-carbon goal, and improving EE is thus indispensable. This paper evaluates the impact of carbon emission trading policy (CETP) on EE based on a difference-in-difference (DID) method, using 16-year data of 30 provinces and cities from 2005 to 2020. Conclusions are as follows: (1) CETP significantly promotes EE, and this conclusion still appears valid after robustness tests. (2) The positive impact of CETP on EE is more effective in regions of high foreign direct investment (FDI) and high government intervention (GOVI). (3) The positive impact of CETP on EE is through impact mechanisms of energy structure adjustment (ESA), green innovation (GI), and industrial structure upgrading (ISU). The findings in this paper may enrich current research in CETP and offer more pragmatic suggestions for policy advancement as well. Show less

Carbamoyl phosphate synthetase I defect (CPS1D) is a rare disease with clinical case reports mainly in early neonates or adults, with few reports of first onset in late neonatal to childhood. We studied the clinical and genotypic characteristics of children with childhood onset CPS1D caused by two loci mutations (one of these is a rarely reported non-frame shift mutation) in the CPS1. We present a rare case of adolescent-onset CPS1D that had been misdiagnosed due to atypical clinical features, and further investigations revealed severe hyperammonemia (287µmol/L; reference range 11.2 ~ 48.2umol/L). MRI of the brain showed diffuse white matter lesions. Blood genetic metabolic screening showed elevated blood alanine (757.06umol/L; reference range 148.8 ~ 739.74umol/L) and decreased blood citrulline (4.26umol/L; reference range 5.45 ~ 36.77umol/L). Urine metabolic screening showed normal whey acids and uracil. Whole-exome sequencing revealed compound heterozygous mutations in the CPS1, a missense mutation (c.1145 C > T) and an unreported de novo non-frame shift mutation (c.4080_c.4091delAGGCATCCTGAT), respectively, which provided a clinical diagnosis. A comprehensive description of the clinical and genetic features of this patient, who has a rare age of onset and a relatively atypical clinical presentation, will facilitate the early diagnosis and management of this type of late onset CPS1D and reduce misdiagnosis, thus helping to reduce mortality and improve prognosis. It also provides a preliminary understanding of the relationship between genotype and phenotype, based on a summary of previous studies, which reminds us that it may help to explore the pathogenesis of the disease and contribute to genetic counselling and prenatal diagnosis. Show less

Breast cancer (BC) ranks first in incidence among women, with approximately 2 million new cases per year. Therefore, it is essential to investigate emerging targets for BC patients' diagnosis and prognosis. We analyzed gene expression data from 99 normal and 1,081 BC tissues in The Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) were identified using "limma" R package, and relevant modules were chosen through Weighted Gene Coexpression Network Analysis (WGCNA). Intersection genes were obtained by matching DEGs to WGCNA module genes. Functional enrichment studies were performed on these genes using Gene Ontology (GO), Disease Ontology (DO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Biomarkers were screened via Protein-Protein Interaction (PPI) networks and multiple machine-learning algorithms. The Gene Expression Profiling Interactive Analysis (GEPIA), The University of ALabama at Birmingham CANcer (UALCAN), and Human Protein Atlas (HPA) databases were employed to examine mRNA and protein expression of eight biomarkers. Kaplan-Meier mapper tool assessed their prognostic capabilities. Key biomarkers were analyzed via single-cell sequencing, and their relationship with immune infiltration was examined using Tumor Immune Estimation Resource (TIMER) database and "xCell" R package. Lastly, drug prediction was conducted based on the identified biomarkers. We identified 1,673 DEGs and 542 important genes through differential analysis and WGCNA, respectively. Intersection analysis revealed 76 genes, which play significant roles in immune-related viral infection and IL-17 signaling pathways. DIX domain containing 1 (DIXDC1), Dual specificity phosphatase 6 (DUSP6), Pyruvate dehydrogenase kinase 4 (PDK4), C-X-C motif chemokine ligand 12 (CXCL12), Interferon regulatory factor 7 (IRF7), Integrin subunit alpha 7 (ITGA7), NIMA related kinase 2 (NEK2), and Nuclear receptor subfamily 3 group C member 1 (NR3C1) were selected as BC biomarkers using machine-learning algorithms. NEK2 was the most critical gene for diagnosis. Prospective drugs targeting NEK2 include etoposide and lukasunone. Our study identified DIXDC1, DUSP6, PDK4, CXCL12, IRF7, ITGA7, NEK2, and NR3C1 as potential diagnostic biomarkers for BC, with NEK2 having the highest potential to aid in diagnosis and prognosis in clinical settings. Show less

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P Show less

Prostate cancer is the most common malignant tumor of male urogenital system that occurs in prostate epithelium. However, relationship between CAV1 and KRT5 and prostate cancer remains unclear. The prostate cancer datasets GSE114740 and GSE200879 were downloaded from Gene Expression Omnibus generated by GPL11154 and GPL32170. De-batch processing was performed, differentially expressed genes (DEGs) were screened, and weighted gene co-expression network analysis. The construction and analysis of protein-protein interaction network, functional enrichment analysis, gene set enrichment analysis. Gene expression heat map was drawn and immune infiltration analysis was performed. Comparative toxicogenomics database analysis were performed to find the disease most related to core gene. In addition, the cell experiment was performed to verify the role of CAV1 and KRT5 by western blot. Divided into 4 groups: control, prostate cancer, prostate cancer-over expression, and prostate cancer- knock out. TargetScan screened miRNAs that regulated central DEGs; 770 DEGs were identified. According to Gene Ontology analysis, they were mainly concentrated in actin binding and G protein coupled receptor binding. In Kyoto Encyclopedia of Gene and Genome analysis, they were mainly concentrated in PI3K-Akt signal pathway, MAPK signal pathway, and ErbB signal pathway. The intersection of enrichment terms of differentially expressed genes and GOKEGG enrichment terms was mainly concentrated in ErbB signaling pathway and MAPK signaling pathway. Three important modules were generated. The protein-protein interaction network obtained 8 core genes (CAV1, BDNF, TGFB3, FGFR1, PRKCA, DLG4, SNAI2, KRT5). Heat map of gene expression showed that core genes (CAV1, TGFB3, FGFR1, SNAI2, KRT5) are highly expressed in prostate cancer tissues and low in normal tissues. Comparative toxicogenomics database analysis showed that core genes (CAV1, TGFB3, FGFR1, SNAI2, KRT5) were associated with prostate tumor, cancer, tumor metastasis, necrosis, and inflammation. CAV1 and KRT5 are up-regulated in prostate cancer. CAV1 and KRT5 are highly expressed in prostate cancer. The higher expression of CAV1 and KRT5, the worse prognosis. Show less

Melanoma is considered as the most common metastatic skin cancer with increasing incidence and high mortality globally. The vital roles of long non-coding RNAs (lncRNAs) in the tumorigenesis of melanoma are elucidated by emerging evidence. The lncRNA cervical carcinoma high-expressed 1 (CCHE1) was overexpressed and acted as an oncogene in a variety of cancers, while the function of CCHE1 in melanoma remains unclear. Here, we found that CCHE1 was highly expressed in melanoma and correlated with the poorer survival of melanoma patients. Depletion of CCHE1 inhibited the proliferation, induced cell apoptosis and suppressed in vivo tumor growth. To further understand the functional mechanism of CCHE1, the interacting partners of CCHE1 were identified via RNA pull-down assay followed by mass spectrometry. CCHE1 was found to bind lactate dehydrogenase A (LDHA) and acted as a scaffold to enhance the interaction of LDHA with the fibroblast growth factor receptor type 1 (FGFR1), which consequently enhanced LDHA phosphorylation and activity of LDHA. Inhibiting CCHE1 strikingly suppressed the glycolytic flux of melanoma cells and lactate generation in vivo. Further study demonstrated that CCHE1 desensitized melanoma cells to dacarbazine and inhibition of glycolysis reversed CCHE1-induced chemoresistance. These results uncovered the novel function of CCHE1 in melanoma by reprogramming the glucose metabolism via orchestrating the activity of LDHA. Show less

As a member of the fibronectin leucine-rich transmembrane (flrt) gene family, fibronectin leucine-rich transmembrane 2 (flrt2) is strongly expressed in a subset of sclerotome cells, and the resultant protein interacts with FGFR1 in the FGF signaling pathway during development. Studies on flrt2 have focused mainly on its roles in the brain, heart and chondrogenesis. However, reports on its expression and function in the zebrafish retina are lacking. Here, we detected the high expression of flrt2 in zebrafish retina using in situ hybridization technique and developed an flrt2-knockout (KO) zebrafish line using CRISPR/Cas9 genome editing. Quantitative real-time PCR was used to measure the expression levels of flrt2, which results in an approximately 60% mRNA reduction. The flrt2-KO zebrafish eyes' altered morphological, cellular, and molecular events were identified using BrdU labeling, TUNEL assay, immunofluorescent staining, fluorescent dye injection and RNA sequencing. Abnormal eye development, known as microphthalmia, was found in flrt2-KO larvae, and the retinal progenitor cells exhibited increased apoptosis, perhaps owing to the combined effects of crx, neurod4, atoh7, and pcdh8 downregulation and Casp3a and Caspbl upregulation. In contrast, the retinal neural development, as well as retinal progenitor cell differentiation and proliferation, were not affected by the flrt2 deletion. Thus, flrt2 appears to play important roles in retinal development and function, which may provide the basis for further investigations into the molecular mechanisms of retinal development and evolution. Show less

A disintegrin and metalloproteinase 10 (ADAM10) plays an essential role in the regulation of survival, proliferation, migration, and differentiation of various neural cells. Nevertheless, the role of ADAM10 in oligodendrocyte precursors (OPCs) and myelination in the central nervous system (CNS) of developing and adult mouse brains is still unknown. We generated ADAM10 conditional knockout (ADAM10 cKO) mice lacking the ADAM10 gene primarily in OPCs by crossing NG2-Cre mice with ADAM10 Show less

Excessive NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation has an important function in the pathogenesis of Sjögren's syndrome (SS). Increased and dysfunctional myeloid-derived suppressor cells (MDSCs) promoted SS. However, NLRP3 inflammasome activation of MDSCs in SS and its regulated components are unclear. Splenic MDSCs were purified by immunomagnetic beads and cultured. Western blot was used to assess NLRP3 inflammasomes. Interleukin-1β (IL-1β) and IL-18 were measured using enzyme-linked immunosorbent assay. Here we showed that the NLRP3 inflammasome was activated in non-obese diabetic (NOD) mice with SS-like manifestations. We found that NLRP3 inflammasome activation was augmented in MDSCs of SS mice and NLRP3 inflammasome activation was suppressed in IL-27-deficient NOD mice. Consistent with findings of SS mice in vivo, we observed that NLRP3 inflammasome activation by adenosine triphosphate and lipopolysaccharide was remarkably intensified in MDSCs with IL-27 treatment in vitro. Collectively, our data highlighted that IL-27 regulates NLRP3 inflammasome activation of MDSCs in experimental SS. Show less

Sepsis engenders an imbalance in the body's inflammatory response, with cytokines assuming a pivotal role in its progression. A relatively recent addition to the interleukin-17 family, denominated interleukin-17D (IL-17D), is notably abundant within pulmonary confines. Nevertheless, its implication in sepsis remains somewhat enigmatic. The present study endeavors to scrutinize the participation of IL-17D in sepsis-induced acute lung injury (ALI). The levels of IL-17D in the serum and bronchoalveolar lavage fluid (BALF) of both healthy cohorts and septic patients were ascertained through an ELISA protocol. For the creation of a sepsis-induced ALI model, intraperitoneal lipopolysaccharide (LPS) injections were administered to male C57/BL6 mice. Subsequently, we examined the fluctuations and repercussions associated with IL-17D in sepsis-induced ALI, probing its interrelation with nuclear factor erythroid 2-related factor 2 (Nrf2), alveolar epithelial permeability, and heme oxygenase-1. IL-17D levels exhibited significant reduction both in the serum and BALF of septic patients (P<0.001). Similar observations manifested in mice subjected to LPS-induced acute lung injury (ALI) (P=0.002). Intraperitoneal administration of recombinant interleukin 17D protein (rIL-17D) prompted increased expression of claudin 18 and concomitant enhancement of alveolar epithelial permeability, thus, culminating in improved lung injury (P<0.001). Alveolar epithelial type II (ATII) cells were identified as the source of IL-17D, regulated by Nrf2. Furthermore, a deficiency in HO-1 yielded elevated IL-17D levels (P=0.004), albeit administration of rIL-17D ameliorated the exacerbated pulmonary damage resulting from HO-1 deficiency. Nrf2 fosters IL-17D production within AT II cells, thereby conferring a protective role in sepsis-induced ALI. Show less

Patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) are characterized by severe liver function impairment, coagulation disorder, and multiple organ function impairment. The aim of this study was to explore the predictive value of antithrombin Ⅲ activity to the prognosis of HBV-ACLF patients. A total of 186 HBV-ACLF patients were included in the analysis, and the baseline clinical data of patients were recorded to analyze the risk factors affecting the 30-day survival outcome of patients. Bacterial infection, sepsis, and hepatic encephalopathy were observed in ACLF patients. Antithrombin Ⅲ activity and serum cytokine levels were determined. The antithrombin Ⅲ activity of ACLF patients in the death group was significantly lower than that in the survival group, and antithrombin Ⅲ activity was independent factors affecting the 30-day outcome. The areas under the receiver operation characteristic (ROC) curve of antithrombin Ⅲ activity to predict the 30-day mortality of ACLF was 0.799. Survival analysis showed that the mortality of patients with antithrombin Ⅲ activity less than 13% was significantly increased. Patients with bacterial infection and sepsis had lower antithrombin Ⅲ activity than those without infection. Antithrombin Ⅲ activity was positively correlated with platelet count, fibrinogen, interferon (IFN)-γ, interleukin (IL)-13, IL-1β, IL-4, IL-6, tumor necrosis factor-α, IL-23, IL-27, and IFN-α, but negatively correlated with C-reactive protein, D dimer, total bilirubin, and creatinine levels. As a natural anticoagulant, antithrombin Ⅲ can be regarded as a marker of inflammation and infection in patients with HBV-ACLF, and as a predictor of survival outcome in patients with ACLF. Show less

Interleukin (IL) 27 is a member of the IL-12 family and is a heterodimeric cytokine composed of IL-27A and Epstein-Barr virus-induced 3 (EBI3). It plays an important role in regulating inflammation and cancer progression. IL-27A not only functions by dimerizing with EBI3 but also acts alone. Here, we report that IL-27A and EBI3 suppress spring viremia of carp virus (SVCV) replication in zebrafish. Expression analysis reveals that il-27a and ebi3 were significantly upregulated in the ZF4 cells by SVCV and poly(I:C), and in the zebrafish caudal fin (ZFIN) cells overexpressed with SVCV genes. Interestingly, il-27a and ebi3 were not modulated by IFNφ1, indicating that they are not IFN stimulated genes (ISGs). Furthermore, overexpression of IL-27A and EBI3 alone inhibited SVCV replication in the EPC cells, but less potent than co-expression of IL-27A and EBI3. Intriguingly, IL-27A could not induce the expression of irf3, ifn, isg15 and mx1. Taken together, our results demonstrate that IL-27A and EBI3 activate innate antiviral response in an IFN independent manner in zebrafish. Show less

Pulmonary arterial hypertension (PAH) is a chronic disorder characterized by hyperproliferation of pulmonary arterial smooth muscle cells (PASMCs). JMJD1C, a member of the Jumonji domain containing C (JMJC) histone demethylase family, contributes to cardiovascular dysfunction. However, the role of JMJD1C in PAH remains unknown. Mice were exposed to hypoxia to mimic several features associated with PAH clinically. We found that JMJD1C was highly expressed in the lungs of mice after hypoxia exposure. JMJD1C knockdown ameliorated hypoxia-induced right ventricular remodeling and thickening of the pulmonary arterial wall. PASMC hyperproliferation and resistance to apoptosis in mice exposed to hypoxia were suppressed by JMJD1C inhibition. We demonstrated that JMJD1C silencing reduced glycolytic enzymes (HK2, PGK1 and LDHA) and lactate overaccumulation in the lungs of mice exposed to hypoxia. In vitro, hypoxia-induced hyperproliferation and activated glycolytic processes in mouse PASMCs were impaired by JMJD1C knockdown. In addition, the activation of STAT3 signaling by hypoxia was suppressed by JMJD1C silencing both in vivo and in vitro. The overexpression of STAT3 reversed the inhibitory effect of JMJD1C depletion on proliferation and glycolysis in PASMCs under hypoxia. Thus, JMJD1C induces glycolytic processes by activating STAT3 signaling to promote PASMC proliferation and pulmonary vascular remodeling, suggesting the potential role of JMJD1C in regulating the metabolic program and vascular remodeling in PAH. Show less

Myelination contributes not only to the rapid nerve conduction but also to axonal insulation and protection. In the central nervous system (CNS), the initial myelination features a multistep process where oligodendrocyte precursor cells undergo proliferation and migration before differentiating into mature oligodendrocytes. Mature oligodendrocytes then extend processes and wrap around axons to form the multilayered myelin sheath. These steps are tightly regulated by various cellular and molecular mechanisms, such as transcription factors (Olig family, Sox family), growth factors (PDGF, BDNF, FGF-2, IGF), chemokines/cytokines (TGF-β, IL-1β, TNFα, IL-6, IFN-γ), hormones (T3), axonal signals (PSA-NCAM, L1-CAM, LINGO-1, neural activity), and intracellular signaling pathways (Wnt/β-catenin, PI3 K/AKT/mTOR, ERK/MAPK). However, the fundamental mechanisms for initial myelination are yet to be fully elucidated. Identifying pivotal mechanisms for myelination onset, development, and repair will become the focus of future studies. This review focuses on the current understanding of how CNS myelination is initiated and also the regulatory mechanisms underlying the process. Show less

Alpine Merino Sheep is a novel breed reared from Australian Merino Sheep as the father and Gansu Alpine Fine-Wool Sheep as the mother, living all year in cold and arid alpine areas with exceptional wool quality and meat performance. Body weight is an important economic trait of the Alpine Merino Sheep, but there is limited research on identifying the genes associated with live weight in the 14th month for improving the accuracy of the genomic prediction of this trait. Therefore, this study's sample comprised 1310 Alpine Merino Sheep ewes, and the Fine Wool Sheep 50K Panel was used for genome-wide association study (GWAS) analysis to identify candidate genes. Moreover, the trial population (1310 ewes) in this study was randomly divided into two groups. One group was used as the population for GWAS analysis and screened for the most significant top 5%, top 10%, top 15%, and top 20% SNPs to obtain prior marker information. The other group was used to estimate the genetic parameters based on the weight assigned by heritability combined with different prior marker information. The aim of this study was to compare the accuracy of genomic breeding value estimation when combined with prior marker information from GWAS analysis with the optimal linear unbiased prediction method for genome selection (GBLUP) for the breeding value of target traits. Finally, the accuracy was evaluated using the five-fold cross-validation method. This research provides theoretical and technical support to improve the accuracy of sheep genome selection and better guide breeding. The results demonstrated that eight candidate genes were associated with GWAS analysis, and the gene function query and literature search results suggested that Show less

Fusion genes are considered to be one of the major drivers behind cancer initiation and progression. Meanwhile, non-acute promyelocytic leukemia (APL) pediatric patients with acute myeloid leukemia (AML) in children had limited treatment efficacy. Hence, we developed and validated a simple clinical scoring system for predicting outcomes in non-APL pediatric patients with AML. A total of 184 non-APL pediatric patients with AML who were admitted to our hospital and an independent dataset (318 patients) from the TARGET database were included. Least absolute shrinkage and selection operation (LASSO) and Cox regression analysis were used to identify prognostic factors. Then, a nomogram score was developed to predict the 1, 3, and 5 years overall survival (OS) based on their clinical characteristics and fusion genes. The accuracy of the nomogram score was determined by calibration curves and receiver operating characteristic (ROC) curves. Additionally, an internal verification cohort was used to assess its applicability. Based on Cox and LASSO regression analyses, a nomogram score was constructed using clinical characteristics and OS-related fusion genes ( Our model based on the fusion gene is a prognostic biomarker for non-APL pediatric patients with AML. The nomogram score can provide personalized prognosis prediction, thereby benefiting clinical decision-making. Show less

Hypertrophic cardiomyopathy is the most common cause of sudden death in the young. Because the disease exhibits variable penetrance, there are likely nongenetic factors that contribute to the manifestation of the disease phenotype. Clinically, hypertension is a major cause of morbidity and mortality in patients with HCM, suggesting a potential synergistic role for the sarcomeric mutations associated with HCM and mechanical stress on the heart. We developed an Show less

To explore the clinical and genetic characteristics of eight children with Primary hypertrophic cardiomyopathy (HCM). Eight children with HCM admitted to the Department of Cardiology of Henan Children's Hospital from January 2018 to December 2021 were selected as the study subjects. Clinical data of the children were collected. Whole exome sequencing was carried out on two children, and trio whole exome sequencing was carried out on the remainder 6 children. Sanger sequencing was used to verify the candidate variants in the children and their parents, and the pathogenicity of the variants was evaluated based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). The patients had included 5 males and 3 females, with their ages ranging from 5 to 13 years old. The average age of diagnosis was (7.87 ± 4.8) years old, and the cardiac phenotype showed non-obstructive HCM in all of the patients. WES has identified variants of the MYH7 gene in 4 children, including c.2155C>T (p.Arg719Trp), c.1208G>A (p.Arg403Gln), c.1358G>A (p.Arg453His), and c.1498G>A (p.Glu500Lys). Based on the guidelines from the ACMG, the first 3 variants were classified as pathogenic, while c.1498G>A (p.Glu500Lys) was classified as likely pathogenic (PM1+PM2_Supporting+PM6+PP3), which was also unreported previously. The remaining four children had all harbored maternal variants, including MYL2: c.173G>A (p.Arg58Gln; classified as pathogenic), TPM1: c.574G>A (p.Glu192Lys) and ACTC1: c.301G>A (p.Glu101Lys)(both were classified as likely pathogenic), and MYBPC3: c.146T>G (p.Ile49Ser; classified as variant of uncertain significance). Seven children were treated with 0.5 ~ 3 mg/(kg·d) propranolol, and their symptoms had improved significantly. They were followed up until September 30, 2022 without further cardiac event. Genetic testing can clarify the molecular basis for unexplained cardiomyopathy and provide a basis for clinical diagnosis and genetic counseling. Discovery of the c.1498G>A (p.Glu500Lys) variant has also expanded the spectrum of MYH7 gene mutations underlying HCM. Show less

Paclitaxel (PTX) resistance is a key cause of chemotherapy failure in patients with triple negative breast cancer (TNBC). The aim of this study is to investigate the effect and mechanism of long non-coding RNA (lncRNA) on the PTX resistance of TNBC cells through autophagy. MDA-MB-231 cells are used to induce the PTX-resistant TNBC cell line MDA-MB-231.PR (MDR) by increasing dose intermittently. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the mRNA levels of phosphoinositide-3-kinase class 3 (PIK3C3), miR-361-5p and lncRNA PRKCQ-AS1 in the cells, and Western blot analysis was used to detect the protein expressions of PIK3C3, autophagy-related, drug-resistant and apoptosis-related genes. MDC staining detected the formation of autophagic vacuoles. The interactions between miR-361-5p and PIK3C3 and between lncRNA PRKCQ-AS1 and miR-361-5p were verified by dual-luciferase assay. Cell viability, apoptosis, migration and invasion were assessed by performing MTT, flow cytometry assay, and transwell assay. The mRNA level of miR-361-5p and the autophagy and drug resistance levels of TNBC PTX-resistant cells were significantly up-regulated. miR-361-5p could target autophagy-related gene PIK3C3, and overexpression of miR-361-5p could down-regulate PIK3C3 protein expression and autophagy level and PTX resistance of MDR cells. LncRNA PRKCQ-AS1 was selected through bioanalysis, and miR-361-5p could target lncRNA PRKCQ-AS1. In addition, lncRNA PRKCQ-AS1 level was up-regulated in TNBC PTX-resistant cells, and knockdown of lncRNA PRKCQ-AS1 could weaken autophagy and drug resistance level and could promote cell apoptosis. Overexpression of lncRNA PRKCQ-AS1 reversed the pro-apoptotic effect and down-regulation of autophagy and resistance levels was induced by miR-361-5p. In vivo experiments were performed to verify the role of lncRNA PRKCQ-AS1. We demonstrate that down-regulation of lncRNA PRKCQ-AS1 weakened PTX resistance and promoted cell apoptosis by miR-361-5p/PIK3C3 mediated autophagy. Show less

Adequate mass and function of adipose tissues (ATs) play essential roles in preventing metabolic perturbations. The pathological reduction of ATs in lipodystrophy leads to an array of metabolic diseases. Understanding the underlying mechanisms may benefit the development of effective therapies. Several cellular processes, including autophagy and vesicle trafficking, function collectively to maintain AT homeostasis. Here, we investigated the impact of adipocyte-specific deletion of the lipid kinase phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) on AT homeostasis and systemic metabolism in mice. We report that PIK3C3 functions in all ATs and that its absence disturbs adipocyte autophagy and hinders adipocyte differentiation, survival, and function with differential effects on brown and white ATs. These abnormalities cause loss of white ATs, whitening followed by loss of brown ATs, and impaired "browning" of white ATs. Consequently, mice exhibit compromised thermogenic capacity and develop dyslipidemia, hepatic steatosis, insulin resistance, and type 2 diabetes. While these effects of PIK3C3 largely contrast previous findings with the autophagy-related (ATG) protein ATG7 in adipocytes, mice with a combined deficiency in both factors reveal a dominant role of the PIK3C3-deficient phenotype. We have also found that dietary lipid excess exacerbates AT pathologies caused by PIK3C3 deficiency. Surprisingly, glucose tolerance is spared in adipocyte-specific PIK3C3-deficient mice, a phenotype that is more evident during dietary lipid excess. These findings reveal a crucial yet complex role for PIK3C3 in ATs, with potential therapeutic implications. Show less

The quadrilateral reassortant IAV A/(H1N1) pdm09 is the pathogen responsible for the first influenza pandemic of the 21st century. The virus spread rapidly among hosts causing high mortality within human population. Efficient accumulation of virions is known to be important for the rapid transmission of virus. However, the mechanism by which A/(H1N1) pdm09 promotes its rapid replication has not been fully studied. Here, we found the NS1 of A/(H1N1) pdm09 mediated complete macroautophagy/autophagy, and then facilitated self-replication, which may be associated with the more rapid spread of this virus compared with H1N1 Show less