Sertoli cells are highly polarized testicular cells that provide a nurturing environment for germ cell development and maturation during spermatogenesis. The class III phosphatidylinositol 3-kinase (P Show more
Sertoli cells are highly polarized testicular cells that provide a nurturing environment for germ cell development and maturation during spermatogenesis. The class III phosphatidylinositol 3-kinase (PtdIns3K) plays core roles in macroautophagy in various cell types; however, its role in Sertoli cells remains unclear. Here, we generated a mouse line in which the gene encoding the catalytic subunit, Show less
Antimicrobial peptides (AMPs) are important mediators of intestinal immune surveillance. However, the regional heterogeneity of AMPs and its regulatory mechanisms remain obscure. Here, we clarified th Show more
Antimicrobial peptides (AMPs) are important mediators of intestinal immune surveillance. However, the regional heterogeneity of AMPs and its regulatory mechanisms remain obscure. Here, we clarified the regional heterogeneity of intestinal AMPs at the single-cell level, and revealed a cross-lineages AMP regulation mechanism that bile acid dependent transcription factors (BATFs), NR1H4, NR1H3 and VDR, regulate AMPs through a ligand-independent manner. Bile acids regulate AMPs by perturbing cell differentiation rather than activating BATFs signaling. Chromatin accessibility determines the potential of BATFs to regulate AMPs at the pre-transcriptional level, thus shaping the regional heterogeneity of AMPs. The BATFs-AMPs axis also participates in the establishment of intestinal antimicrobial barriers of fetuses and the defects of antibacterial ability during Crohn's disease. Overall, BATFs and chromatin accessibility play essential roles in shaping the regional heterogeneity of AMPs at pre- and postnatal stages, as well as in maintenance of antimicrobial immunity during homeostasis and disease. Show less
Acetate is associated with adipocyte differentiation and lipid deposition. To further develop this scientific point, obese mice on a high-fat diet were given an intragastric administration of acetate Show more
Acetate is associated with adipocyte differentiation and lipid deposition. To further develop this scientific point, obese mice on a high-fat diet were given an intragastric administration of acetate for 8 weeks and mouse adipose mesenchymal stem cells (mAMSCs) were treated with acetate for 24 h. The results showed that the body weight, food intake, Lee's index, adipose tissue coefficient, liver index, blood lipid levels, insulin resistance, pro-inflammatory factors levels and fatty lesions in liver and adipose tissue in obese mice treated with acetate increased markedly, while anti-inflammatory factors levels and liver function decreased significantly ( Show less
As a widely used lipid-lowering drug in clinical practice, atorvastatin is widely recognized for its role in protecting vascular endothelium in the cardiovascular system. However, a clear mechanistic Show more
As a widely used lipid-lowering drug in clinical practice, atorvastatin is widely recognized for its role in protecting vascular endothelium in the cardiovascular system. However, a clear mechanistic understanding of its action is lacking. Here, we found that atorvastatin counteracted angiotensin II-induced vascular endothelial injury in mice with hypertension. Mechanistically, atorvastatin up-regulated WWP2, a E6AP C-terminus (HECT)-type E3 ubiquitin ligase with an essential role in regulating protein ubiquitination and various biological processes, thereby rescuing vascular endothelial injury. By ubiquitinating ATP5A (ATP synthase mitochondrial F1 complex subunit alpha), WWP2 degraded ATP5A via the proteasome pathway, stabilizing Bcl-2/Bax in the mitochondrial pathway of apoptosis. Moreover, atorvastatin further ameliorated death of vascular endothelial cells and improved vascular endothelial functions under WWP2 overexpression, whereas WWP2 knockout abrogated these beneficial effects of atorvastatin. Furthermore, we generated endothelial cell-specific WWP2 knockout mice, and this WWP2-mediated mechanism was faithfully recapitulated in vivo. Thus, we propose that activation of a WWP2-dependent pathway that is pathologically repressed in damaged vascular endothelium under hypertension is a major mechanism of atorvastatin. Our findings are also pertinent to develop novel therapeutic strategies for vascular endothelial injury-related cardiovascular diseases. Show less
Neural progenitor cells (NPCs) are essential for in vitro drug screening and cell-based therapies for brain-related disorders, necessitating well-defined and reproducible culture systems. Current stra Show more
Neural progenitor cells (NPCs) are essential for in vitro drug screening and cell-based therapies for brain-related disorders, necessitating well-defined and reproducible culture systems. Current strategies employing protein growth factors pose challenges in terms of both reproducibility and cost. In this study, we developed a novel DNA-based modulator to regulate FGFR signaling in NPCs, thereby facilitating the long-term maintenance of stemness and promoting neurogenesis. This DNA-based FGFR-agonist effectively stimulated FGFR1 phosphorylation and activated the downstream ERK signaling pathway in human embryonic stem cell (HESC)-derived NPCs. We replaced the basic fibroblast growth factor (bFGF) in the culture medium with our DNA-based FGFR-agonist to artificially modulate FGFR signaling in NPCs. Utilizing a combination of cell experiments and bioinformatics analyses, we showed that our FGFR-agonist could enhance NPC proliferation, direct migration, and promote neurosphere formation, thus mimicking the functions of bFGF. Notably, transcriptomic analysis indicated that the FGFR-agonist could specifically influence the transcriptional program associated with stemness while maintaining the neuronal differentiation program, closely resembling the effects of bFGF. Furthermore, our culture conditions allowed for the successful propagation of NPCs through over 50 passages while retaining their ability to efficiently differentiate into neurons. Collectively, our approach offers a highly effective method for expanding NPCs, thereby providing new avenues for disease-in-dish research and drug screening aimed at combating neural degeneration. Show less
Increasing evidence supports the involvement of the peripheral immune system in the pathogenesis of Alzheimer's disease (AD). In the present study, we found that B lymphocytes could mitigate beta-Amyl Show more
Increasing evidence supports the involvement of the peripheral immune system in the pathogenesis of Alzheimer's disease (AD). In the present study, we found that B lymphocytes could mitigate beta-Amyloid (Aβ) pathology and memory impairments in a transgenic AD mouse model. Specifically, in young 5 × FAD mice, we evidenced increased B cells in the frontal cortex and meningeal tissues; depletion of mature B cells aggravated these mice's Aβ load and memory deficits. The increased B cells produced more interleukin-35 (IL-35) in the front cortex. We further found IL-35 neutralization exacerbated Aβ pathology, while injecting IL-35 mitigated Aβ load and cognitive dysfunction in 5 × FAD mice with or without mature B cell deficiency. Mechanistically, IL-35 inhibited neuronal BACE1 transcription through modulating the SOCS1/STAT1 pathway, and reduced Aβ production accordingly. Reanalysis of the single-cell RNA sequencing data from blood samples of AD patients suggested an increased population of IL-35-producing B cells. Together, the present study revealed a novel effect of B lymphocyte-derived IL-35 on inhibiting Aβ production in the frontal cortex, which may serve as a potential target for future AD treatment. Show less
Proopiomelanocortin (POMC) is a hormone precursor, and has been reported to participate in domestication. However, its effects on feeding habit domestication in fish are poorly understood. Mandarin fi Show more
Proopiomelanocortin (POMC) is a hormone precursor, and has been reported to participate in domestication. However, its effects on feeding habit domestication in fish are poorly understood. Mandarin fish (Siniperca chuatsi) feeds solely on live prey fish since first-feeding. In the present study, the high expression of pomc in mandarin fish, both the pomc siRNA and MC4R inhibitor treatments increased the success rate of domestication from live prey fish to dead prey fish and food intake of dead prey fish, suggesting the role of pomc on the special feeding habit of live prey fish in mandarin fish. In addition, one c-fos binding site was identified in the region that from -1053 bp to -931 bp upstream of the transcription start site of pomc, and this region exhibited positive promoter activity. The mandarin fish brain cells treated with c-fos siRNA displayed suppressed pomc mRNA expression, indicating that c-fos positively regulated pomc expression. Furthermore, the mRNA expression of c-fos was higher in the mandarin fish which were more difficult to domesticate. The results of ChIP assay and inhibitor treatment confirmed that the activation of c-fos gene by histone H3K4me3 was catalyzed by Setd1b in mandarin fish. Three open peaks were found at the upstream regulatory region of setd1b by ATAC-seq, and the mRNA expression of setd1b was higher in the mandarin fish which were more difficult to domesticate. These results indicated that Setd1b could methylate histone H3K4 to activate the c-fos transcription, maintaining the high expression of pomc, which might contribute to the special feeding habit of mandarin fish. Show less
Lupus nephritis (LN) refers to the injury caused by systemic lupus erythematosus (SLE) involving the kidneys. A previous study identified angiopoietin-like protein 4 (ANGPTL4) as a novel urinary bioma Show more
Lupus nephritis (LN) refers to the injury caused by systemic lupus erythematosus (SLE) involving the kidneys. A previous study identified angiopoietin-like protein 4 (ANGPTL4) as a novel urinary biomarker for tracking disease activity in LN. To investigate the detailed role and regulatory mechanism of ANGPTL4 in experimental models of LN. MRL/lpr mice 11-week-old were injected with adeno-associated virus (AAV)-mediated ANGPTL4 short hairpin RNA (shRNA). At 16 and 20 weeks of age, 24-h urine samples were harvested to measure proteinuria levels. After the mice were sacrificed, blood and kidney tissues were harvested to examine serum creatinine (cr) and blood urea nitrogen (BUN) levels, kidney histological changes, and pro-inflammatory cytokine production. Additionally, the levels of NLRP3 inflammasome-associated molecules in mouse renal tissues were detected to clarify the underlying mechanism. The AAV-sh-ANGPTL4 injection significantly reduced the proteinuria, cr, and BUN levels in MRL/lpr mice. ANGPTL4 silencing ameliorated glomerular, tubular, and interstitial damage in mice, mitigating the pathological alternations of LN. In addition, ANGPTL4 knockdown repressed pro-inflammatory cytokine production in the kidneys. Mechanically, ANGPTL4 suppression inhibited NLRP3 inflammasome expression in renal tissues of mice. ANGPTL4 silencing inhibits the NLRP3 inflammasome-mediated inflammatory response, thereby ameliorating LN in MRL/lpr mice. Show less
Shuai Yuan, Yuying Li, Lijuan Wang+13 more · 2023 · medRxiv : the preprint server for health sciences · Cold Spring Harbor Laboratory · added 2026-04-24
The study aimed to discover novel genetic loci for atrial fibrillation (AF), explore the shared genetic etiologies between AF and other cardiovascular and cardiometabolic traits, and uncover AF pathog Show more
The study aimed to discover novel genetic loci for atrial fibrillation (AF), explore the shared genetic etiologies between AF and other cardiovascular and cardiometabolic traits, and uncover AF pathogenesis using Mendelian randomization analysis. We conducted a genome-wide association study meta-analysis including 109,787 AF cases and 1,165,920 controls of European ancestry and identified 215 loci, among which 91 were novel. We performed Genomic Structural Equation Modeling analysis between AF and four cardiovascular comorbidities (coronary artery disease, ischemic stroke, heart failure, and vneous thromboembolism) and found 189 loci shared across these diseases as well as a universal genetic locus shared by atherosclerotic outcomes (i.e., rs1537373 near This genome-wide association study and trans-omic Mendelian randomization analysis provides insights into disease risk prediction, pathophysiology and downstream sequelae. Show less
Wnt/β-catenin signaling is a conserved pathway crucially governing development, homeostasis, and oncogenesis. Discoveries of its regulators hold great values in both basic and translational research. Show more
Wnt/β-catenin signaling is a conserved pathway crucially governing development, homeostasis, and oncogenesis. Discoveries of its regulators hold great values in both basic and translational research. Through screening, we identified a deubiquitinase, USP10, as a critical modulator of β-catenin. Mechanistically, USP10 binds to key scaffold Axin1 via conserved motifs and stabilizes Axin1 through K48-linked deubiquitination. Surprisingly, USP10 physically tethers Axin1 and β-catenin and promotes the phase separation for β-catenin suppression regardless of the enzymatic activity. Function-wise, USP10 enzymatic activity preferably regulates embryonic development and both the enzymatic activity and physical function jointly control intestinal homeostasis by antagonizing β-catenin. In colorectal cancer, USP10 substantially represses cancer growth mainly through physical promotion of phase separation and correlates with Wnt/β-catenin magnitude clinically. Collectively, we discovered USP10 functioning in multiple biological processes against β-catenin and unearthed the enzyme-dependent and -independent "dual-regulating" mechanism. These two functions of USP10 work in parallel and are context dependent. Show less
Retinal Müller glial dysfunction and intracellular edema are important mechanisms leading to diabetic macular edema (DME). Aquaporin 11 (AQP11) is primarily expressed in Müller glia with unclear funct Show more
Retinal Müller glial dysfunction and intracellular edema are important mechanisms leading to diabetic macular edema (DME). Aquaporin 11 (AQP11) is primarily expressed in Müller glia with unclear functions. This study aims to explore the role of AQP11 in the pathogenesis of intracellular edema of Müller glia in diabetic retinopathy (DR). Here, we found that AQP11 expression, primarily located at the endfeet of Müller glia, was down-regulated with diabetes progression, accompanied by intracellular edema, which was alleviated by intravitreal injection of lentivirus-mediated AQP11 overexpression. Similarly, intracellular edema of hypoxia-treated rat Müller cell line (rMC-1) was aggravated by AQP11 inhibition, while attenuated by AQP11 overexpression, accompanied by enhanced function in glutamate metabolism and reduced cell death. The down-regulation of AQP11 was also verified in the Müller glia from the epiretinal membranes (ERMs) of proliferative DR (PDR) patients. Mechanistically, down-regulation of AQP11 in DR was mediated by the HIF-1α-dependent and independent miRNA-AQP11 axis. Overall, we deciphered the AQP11 down-regulation, mediated by miRNA-AQP11 axis, resulted in Müller drainage dysfunction and subsequent intracellular edema in DR, which was partially reversed by AQP11 overexpression. Our findings propose a novel mechanism for the pathogenesis of DME, thus targeting AQP11 regulation provides a new therapeutic strategy for DME. Show less
Branched-chain keto-acid dehydrogenase kinase (BCKDK) is the rate-limiting enzyme of branched-chain amino acid (BCAA) metabolism. In the last six years, BCKDK has been used as a kinase to promote tumo Show more
Branched-chain keto-acid dehydrogenase kinase (BCKDK) is the rate-limiting enzyme of branched-chain amino acid (BCAA) metabolism. In the last six years, BCKDK has been used as a kinase to promote tumor proliferation and metastasis. Renal cell carcinoma (RCC) is a highly vascularized tumor. A high degree of vascularization promotes tumor metastasis. Our objective is to explore the relationship between BCKDK and RCC metastasis and its specific mechanism. In our study, BCKDK is highly expressed in renal clear cell carcinoma and promotes the migration of clear cell renal cell carcinoma (ccRCC). Exosomes from ccRCC cells can promote vascular permeability and angiogenesis, especially when BCKDK is overexpressed in ccRCC cells. BCKDK can also augment the miR-125a-5p expression in ccRCC cells and derived exosomes, thereby decreasing the downstream target protein VE-cadherin level, weakening adhesion junction expression, increasing vascular permeability, and promoting angiogenesis in HUVECs. The novel BCKDK/Exosome-miR-125a-5p/VE-cadherin axis regulates intercellular communication between ccRCC cells and HUVECs. BCKDK plays a critical role in renal cancer metastasis, may be used as a molecular marker of metastatic ccRCC, and even may become a potential target of clinical anti-vascular therapy for ccRCC. Show less
Jun Li, Ying Xia, Shumin Kong+6 more · 2023 · Journal of the European Academy of Dermatology and Venereology : JEADV · Blackwell Publishing · added 2026-04-24
Actinic keratosis (AK) represents an intraepidermal malignant neoplasm with the proliferation of atypical keratinocytes. AK lesions are regarded as early in situ squamous cell carcinomas (SCCs) having Show more
Actinic keratosis (AK) represents an intraepidermal malignant neoplasm with the proliferation of atypical keratinocytes. AK lesions are regarded as early in situ squamous cell carcinomas (SCCs) having the potential to progress into invasive SCC (iSCC) and metastasize, causing death. This study aimed to investigate the heterogeneity of keratinocytes and how this heterogeneity promoted AK development and progression. We employed single-cell RNA sequencing (scRNA-seq) to examine the heterogeneity of keratinocytes and dermal fibroblast clusters in AKs and adjacent normal skins. Cell clustering, pseudotime trajectory construction, gene ontology enrichment analysis, transcription factor network analysis, and cell-cell communication were used to investigate the heterogeneity of keratinocytes in AK. The cellular identity and function were verified by immunohistochemical and immunofluorescence staining. Using scRNA-seq, we revealed 13 keratinocyte subgroups (clusters 0-12) in AK tissues and characterized 2 AK-specific clusters. Cluster 9 displayed high levels of IL1R2 and WFDC2, and cluster 11 showed high levels of FADS2 and FASN. The percentages of cells in these two clusters significantly increased in AK compared with normal tissues. The existence and spatial localization of AK-specific IL1R2+WFDC2+ cluster were verified by immunohistochemical and immunofluorescence staining. Functional studies indicated that the genes identified in the IL1R2+WFDC2+ cluster were crucial for epithelial cell proliferation, migration, and angiogenesis. Further immunofluorescent staining revealed the interactions between AK-specific keratinocytes and secretory-papillary fibroblasts mainly through ANGPTL4-ITGA5 signalling pathway rarely seen in normal tissues. The findings of this study might help better understand AK pathogenesis. Show less
Antibiotic misuse has been a severe problem in animal husbandry. It is meaningful to replace antibiotics with Bacillus, as feed additives are indeed a research hotspot. Bacillus pumilus plays a certai Show more
Antibiotic misuse has been a severe problem in animal husbandry. It is meaningful to replace antibiotics with Bacillus, as feed additives are indeed a research hotspot. Bacillus pumilus plays a certain role in promoting the growth performance and immunological indicators of animals. There are few reports about the function of goat-derived B. pumilus in animals until now. This study aimed to investigate the effects of B. pumilus fsznc-09 on growth performance and immune function of Jintang black goats. B. pumilus-treated group was fed with 1 ml freeze-dried agent of B. pumilus fsznc-09 at a concentration of 109 cfu/ml every 2 days. The growth performance, serum biochemical indexes, the expressions of muscle development and metabolism related genes of Jintang black goats were measured after 30 days. The results showed that the average daily gain and average daily feed intake were significantly increased, and feed conversion ratio was significantly decreased. The activities of total superoxide dismutase, alkaline phosphatase, immunoglobulin G and interferon-γ in serum of goats were significantly increased. However, the activity of malondialdehyde in serum was significantly decreased. The diameters and areas in longissimus dorsi fibre and gluteus fibre of goats were significantly decreased, while the densities in gluteus fibre of goats were significantly increased. The expressions of FAS, LPL, PPAR-γ, CAT, MYOD1, MYOG, MYF5 and MyHCI in longissimus dorsi and gluteus of goats were significantly improved. The expressions of TGFβ1, SREBP-1, MyHCIIb and MyHCIIx in longissimus dorsi and gluteus of goats were significantly increased. The expressions of FN1 in longissimus dorsi and MyHCIIa in gluteus of goats were significantly decreased. In conclusion, B. pumilus fsznc-09 can effectively improve the growth performance, immunological indicators and the expressions of muscle development and metabolism related genes of Jintang black goat. Show less
Globally, lung adenocarcinoma (LUAD) is the most common type of lung cancer. The secreted protein angiopoietin-like 4 (ANGPTL4) has been implicated in a number of physiological and pathological proces Show more
Globally, lung adenocarcinoma (LUAD) is the most common type of lung cancer. The secreted protein angiopoietin-like 4 (ANGPTL4) has been implicated in a number of physiological and pathological processes, including angiogenesis and lipid metabolism. But the role of ANGPTL4 in LUAD remains unknown. The expression of ANGPTL4 and miR-133a-3p was confirmed by public database analysis. Xenograft model, MTT, Clone formation and EdU analysis were used to confirm the effects of miR-133a-3p/ANGPTL4 on LUAD cell proliferation and growth. Wound healing and Transwell analysis were used to elucidate the role of miR-133a-3p/ANGPTL4 in LUAD cell migration and invasion. Oil red O staining was used to confirm ANGPTL4 in LUAD lipids production. Dual-luciferase reporter gene analysis was used to demonstrate miR-133a-3p could directly bind ANGPTL4 3'-UTR. WB and PCR were used to confirm the protein expression of ANGPTL4. ANGPTL4 was significantly increased in LUAD samples, which could promote LUAD cell proliferation, migration, invasion, growth and lipid production. miR-133a-3p could directly bind to ANGPTL4 mRNA, and repress the expression ANGPTL4, resulting in suppressing LUAD proliferation and metastasis. In conclusion, miR-133a-3p/ANGPTL4 axis might be a potential biomarker and therapeutic target for LUAD patients. Show less
The relationships of the rs17782313 polymorphism near melanocortin 4 receptor gene (MC4R) and the rs8192678 polymorphism in peroxisome proliferator-activated receptor gamma coactivator 1 alpha gene (P Show more
The relationships of the rs17782313 polymorphism near melanocortin 4 receptor gene (MC4R) and the rs8192678 polymorphism in peroxisome proliferator-activated receptor gamma coactivator 1 alpha gene (PGC1α) with metabolic abnormalities have been explored in many populations around the world, but the findings were not all consistent and sometimes even a bit contradictory. Electronic databases including Medline, Scopus, Embase, Web of Science, CNKI and Google Scholar were checked for studies that met the inclusion criteria. Data were carefully extracted from eligible studies. Standardized mean differences (SMDs) were calculated by using a random-effects model to examine the differences in the indexes of obesity, glucometabolic disorder and dyslipidemia between the genotypes of the rs17782313 and rs8192678 polymorphisms. Cochran's Q-statistic test and Begg's test were employed to identify heterogeneity among studies and publication bias, respectively. Fifty studies (58,716 subjects) and 51 studies (18,660 subjects) were respectively included in the pooled meta-analyses for the rs17782313 and rs8192678 polymorphisms. The C-allele carriers of the rs17782313 polymorphism had a higher average level of body mass index (SMD = 0.21 kg/m The meta-analysis demonstrates that the C allele of the MC4R rs17782313 polymorphism confers a higher risk of obesity and hyperglycemia, and the PGC1α rs8192678 polymorphism is weakly correlated with glucometabolic disorder. These findings may partly explain the relationships between these variants and diabetes as well as cardiovascular disease. https://www.crd.york.ac.uk/prospero/, identifier CRD42022373543. Show less
Diabetes has been regarded as an independent risk factor for Alzheimer's disease (AD). Our previous study found that diabetes activated autophagy, but lysosome function was impaired. Autophagy-lysosom Show more
Diabetes has been regarded as an independent risk factor for Alzheimer's disease (AD). Our previous study found that diabetes activated autophagy, but lysosome function was impaired. Autophagy-lysosome dysfunction may be involved in Aβ deposition in diabetic cognitive impairment. In the present study, we used STZ-induced diabetic rats and SH-SY5Y cells to investigate whether diabetes inhibits autophagosome fusion with lysosomes. We found that in the in vivo study, STZ-induced diabetic rats exhibited cognitive dysfunction, and the lysosome function-related factors CTSL, CTSD, and Rab7 were decreased (P < 0.05). In an in vitro study, the mRFP-GFP-LC3 assay showed that the fusion of autophagosomes with lysosomes was partly blocked in SH-SY5Y cells. High glucose treatment downregulated the number of autophagolysosomes, downregulated CTSD, CTSL, and Rab7 expression (P < 0.05), and then influenced the function of ACP2 to partly block the fusion of autophagosomes and lysosomes to inhibit Aβ clearance. These findings indicate that high glucose treatment affected lysosome function, interfered with the fusion of autophagosomes with lysosomes, and partly blocked autophagic flux to influence Aβ clearance. Show less
Pancreatic cancer is associated with high mortality and is one of the most aggressive of malignancies, but studies have not fully evaluated its molecular subtypes, prognosis and response to immunother Show more
Pancreatic cancer is associated with high mortality and is one of the most aggressive of malignancies, but studies have not fully evaluated its molecular subtypes, prognosis and response to immunotherapy of different subtypes. The purpose of this study was to explore the molecular subtypes and the key genes associated with the prognosis of pancreas cancer patients and study the clinical phenotype, prognosis and response to immunotherapy using single-cell seq data and bulk RNA seq data, and data retrieved from GEO and TCGA databases. Single-cell seq data and bioinformatics methods were used in this study. Pancreatic cancer data were retrieved from GEO and TCGA databases, the molecular subtypes of pancreatic cancer were determined using the six cGAS-STING related pathways, and the clinical phenotype, mutation, immunological characteristics and pathways related to pancreatic cancer were evaluated. Pancreatic cancer was classified into 3 molecular subtypes, and survival analysis revealed that patients in Cluster3 (C3) had the worst prognosis, whereas Cluster1 (C1) had the best prognosis. The clinical phenotype and gene mutation were statistically different among the three molecular subtypes. Analysis of immunotherapy response revealed that most immune checkpoint genes were differentially expressed in the three subtypes. A lower risk of immune escape was observed in Cluster1 (C1), indicating higher sensitivity to immunotherapeutic drugs and subjects in this Cluster are more likely to benefit from immunotherapy. The pathways related to pancreatic cancer were differentially enriched among the three subtypes. Five genes, namely SFRP1, GIPR, EMP1, COL17A and CXCL11 were selected to construct a prognostic signature. Single-cell seq data were to classify pancreatic cancer into three molecular subtypes based on differences in clinical phenotype, mutation, immune characteristics and differentially enriched pathways. Five prognosis-related genes were identified for prediction of survival of pancreatic cancer patients and to evaluate the efficacy of immunotherapy in various subtypes. Show less
Tendinopathy is a disease with surging prevalence. Lacking understanding of molecular mechanisms impedes the development of therapeutic approaches and agents. Lysine lactylation (Kla) is a newly disco Show more
Tendinopathy is a disease with surging prevalence. Lacking understanding of molecular mechanisms impedes the development of therapeutic approaches and agents. Lysine lactylation (Kla) is a newly discovered post-translational modification related to glycolysis. It has long been noted that manipulation of glycolysis metabolism could affect tendon cell function, tendon homeostasis, and healing process of tendon. However, protein lactylation sites in tendinopathy remain unexplored. Here, we conducted the first proteome-wide Kla analysis in tendon samples harvested from patients with rotator cuff tendinopathy (RCT), which identified 872 Kla sites across 284 proteins. Compared with normal counterparts, 136 Kla sites on 77 proteins were identified as upregulated in the pathological tendon, while 56 sites on 32 proteins were downregulated. Function enrichment analysis demonstrated that the majority of proteins with upregulated Kla levels functioned in organization of the tendon matrix and cholesterol metabolism, accompanied by lower expression levels which meant impaired cholesterol metabolism and degeneration of the tendon matrix, indicating potential cross-talk between protein lactylation and expression levels. At last, by western blotting and immunofluorescence, we verified the correlation between high lactylation and the downregulation of matrix and cholesterol-related proteins including BGN, MYL3, TPM3, and APOC3. ProteomeXchange: PXD033146. Show less
The Yangtze River Delta white goats are the sole goat breed producing brush hair of high quality. Owing to the particularities of its wool production, a higher demand is placed on breeding efforts for Show more
The Yangtze River Delta white goats are the sole goat breed producing brush hair of high quality. Owing to the particularities of its wool production, a higher demand is placed on breeding efforts for this animal. Studies on the developmental mechanisms of the aligned hair follicle stem cells (HFSCs) provide a theoretical basis for molecular breeding. In the present study, HFSCs were isolated using the technique of immunohistochemistry from the cervical spinal skin tissue samples from the fetal sheep, and the miR-133a-3p expression was confirmed using quantitative reverse-transcription PCR (RT-qPCR) and western blotting experiments from the isolated HFSCs. Additionally, the effects on the proliferation and apoptosis of HFSCs were detected using flow cytometry and 5-ethynyl-2'-deoxyuridine assays, along with other methods, following the overexpression of miR-133a-3p or its inhibition. The experimental results revealed that miR-133a-3p overexpressed could inhibit the proliferation of HFSCs and promote apoptosis by specifically targeting DUSP6. While the miR-133a-3p knockdown could promote the proliferation but inhibit the apoptosis of the HFSCs. Meanwhile, the miR-133a-3p knockdown experiments showed opposite outcomes. These results illustrate the presence of a relevant network between Show less
Nanoplastics and di(2-ethylhexyl) phthalate (DEHP) are ubiquitous emerging contaminants that are transferred among organisms through food chain in the ecosystem. This study evaluated the trophic trans Show more
Nanoplastics and di(2-ethylhexyl) phthalate (DEHP) are ubiquitous emerging contaminants that are transferred among organisms through food chain in the ecosystem. This study evaluated the trophic transfer of polystyrene nanoplastics (PSNPs) and DEHP in a food chain including Chlorella pyrenoidosa, Daphnia magna and Micropterus salmoides (algae-crustacean-fish) and lipid metabolism at a higher trophic level in fish. Our results showed that the PSNPs and DEHP accumulated in C. pyrenoidosa or D. magna were transferred to the M. salmoides, of which the DEHP were not biomagnified, while the PSNPs were trophically amplified by the food chain. It is suggested that more PSNPs might be accumulated by higher level consumers in a longer food chain. Additionally, the trophic transfer of PSNPs and DEHP resulted in antioxidant response and histopathological damage in M. salmoides. Moreover, the lipid biochemical parameters and lipid metabolism related genes (fasn, hsl, cpt1a, atgl, apob, fabp1, lpl, cetp) of M. salmoides were significantly affected, which indicated disturbance of lipid metabolism. This study offers great insight into the transfer of contaminants by trophic transfer and their negative effects on organisms at higher trophic levels, which cause human exposure to MNPs and organic contaminants in the ecosystem. Show less
It remains controversial whether the long-term use of statins or newer nonstatin drugs has a positive effect on human longevity. Therefore, this study aimed to investigate the genetic associations bet Show more
It remains controversial whether the long-term use of statins or newer nonstatin drugs has a positive effect on human longevity. Therefore, this study aimed to investigate the genetic associations between different lipid-lowering therapeutic gene targets and human longevity. Two-sample Mendelian randomization analyses were conducted. The exposures comprised genetic variants that proxy nine drug target genes mimicking lipid-lowering effects (LDLR, HMGCR, PCKS9, NPC1L1, APOB, CETP, LPL, APOC3, and ANGPTL3). Two large-scale genome-wide association study (GWAS) summary datasets of human lifespan, including up to 500,193 European individuals, were used as outcomes. The inverse-variance weighting method was applied as the main approach. Sensitivity tests were conducted to evaluate the robustness, heterogeneity, and pleiotropy of the results. Causal effects were further validated using expression quantitative trait locus (eQTL) data. Genetically proxied LDLR variants, which mimic the effects of lowering low-density lipoprotein cholesterol (LDL-C), were associated with extended lifespan. This association was replicated in the validation set and was further confirmed in the eQTL summary data of blood and liver tissues. Mediation analysis revealed that the genetic mimicry of LDLR enhancement extended lifespan by reducing the risk of major coronary heart disease, accounting for 22.8% of the mediation effect. The genetically proxied CETP and APOC3 inhibitions also showed causal effects on increased life expectancy in both outcome datasets. The lipid-lowering variants of HMGCR, PCKS9, LPL, and APOB were associated with longer lifespans but did not causally increase extreme longevity. No statistical evidence was detected to support an association between NPC1L1 and lifespan. This study suggests that LDLR is a promising genetic target for human longevity. Lipid-related gene targets, such as PCSK9, CETP, and APOC3, might potentially regulate human lifespan, thus offering promising prospects for developing newer nonstatin therapies. Show less
The poor prognosis of serous ovarian cancer (SOC) is due to its high invasive capacity and cisplatin resistance of SOC cells, whereas the molecular mechanisms remain poorly understood. In the present Show more
The poor prognosis of serous ovarian cancer (SOC) is due to its high invasive capacity and cisplatin resistance of SOC cells, whereas the molecular mechanisms remain poorly understood. In the present study, the expression and function of non-muscle myosin heavy chain IIB (MYH10) in SOC are identified by immunohistochemistry, in vitro, and in vivo studies, respectively. The mechanism of MYH10 is demonstrated by co-immunoprecipitation, GST pull-down, confocal laser assays, and so on. The results show that the knockdown of MYH10 suppressed SOC cell proliferation, migration, invasion, metastasis, and cisplatin resistance both in vivo and in vitro. Further studies confirm that the MYH10 protein functional domain combines with non-muscle myosin heavy chain IIA (MYH9) to recruit the deubiquitinating enzyme Ubiquitin-specific proteases 45 and deubiquitinates snail to inhibit snail degradation, eventually promoting tumorigenesis, progression, and cisplatin resistance in SOC. In clinical samples, MYH10 expression is significantly elevated in SOC samples compared to the paratumor samples. And the expression of MYH10 is positively correlated with MYH9 expression. MYH10+/MYH9+ co-expression is an independent prognostic factor for predicting SOC patient survival. These findings uncover a key role of the MYH10-MYH9-snail axis in SOC carcinogenesis, progression, and cisplatin resistance, and provide potential novel therapeutic targets for SOC intervention. Show less
Heterosis, also known as hybrid vigor, is widely used in aquaculture, but the molecular causes for this phenomenon remain obscure. Here, we conducted a transcriptome analysis to unveil the gene expres Show more
Heterosis, also known as hybrid vigor, is widely used in aquaculture, but the molecular causes for this phenomenon remain obscure. Here, we conducted a transcriptome analysis to unveil the gene expression patterns and molecular bases underlying thermo-resistant heterosis in Crassostrea gigas ♀ × Crassostrea angulata ♂ (GA) and C. angulata ♀ × C. gigas ♂ (AG). About 505 million clean reads were obtained, and 38,210 genes were identified, of which 3779 genes were differentially expressed between the reciprocal hybrids and purebreds. The global gene expression levels were toward the C. gigas genome in the reciprocal hybrids. In GA and AG, 95.69% and 92.00% of the differentially expressed genes (DEGs) exhibited a non-additive expression pattern, respectively. We observed all gene expression modes, including additive, partial dominance, high and low dominance, and under- and over-dominance. Of these, 77.52% and 50.00% of the DEGs exhibited under- or over-dominance in GA and AG, respectively. The over-dominance DEGs common to reciprocal hybrids were significantly enriched in protein folding, protein refolding, and intrinsic apoptotic signaling pathway, while the under-dominance DEGs were significantly enriched in cell cycle. As possible candidate genes for thermo-resistant heterosis, GRP78, major egg antigen, BAG, Hsp70, and Hsp27 were over-dominantly expressed, while MCM6 and ANAPC4 were under-dominantly expressed. This study extends our understanding of the thermo-resistant heterosis in oysters. Show less
The pathogenesis of rheumatoid arthritis (RA) is an immune imbalance, in which various inflammatory immune cells and pro-inflammatory factors are involved. Interleukin-17 (IL-17), a potent pro-inflamm Show more
The pathogenesis of rheumatoid arthritis (RA) is an immune imbalance, in which various inflammatory immune cells and pro-inflammatory factors are involved. Interleukin-17 (IL-17), a potent pro-inflammatory cytokine, has been found to have increased expression in the joints of patients with RA compared to healthy individuals. However, the causal relationship between the expression level of IL-17 or IL-17 receptor (IL-17R) and RA remained unknown. In this study, two-sample Mendelian randomization (MR) was used to investigate the causal relationship between IL-17 and RA. Summary statistics for RA (14,361 RA cases and 43,923 healthy controls) and IL-17 (3,301 samples) were obtained from an available meta-analysis of published genome-wide association studies (GWAS). Relevant single nucleotide polymorphisms (SNPs) were selected by executing quality control steps from the GWAS summary results. Then we used bi-directional two-sample Mendelian randomization (MR) and multi-variable MR (MVMR) analysis to examine evidence of causality. MR and MVMR analyses progressed mainly using inverse variance weighted (IVW), weighted median (WM), and MR-Egger regression methods, which were applied to the genetic instrumental variables (IVs) of IL-17A/IL-17 RA, IL-17C/IL-17 RC, and IL-17D/IL-17RD and RA. For assessing the robustness of the results, we also carried out a sensitivity analysis to assess heterogeneity and pleiotropy, such as MR-Egger, leave-one-out, and MR pleiotropy residual sum and outlier (MR-PRESSO). Two-sample MR Analysis showed the causal relationship between IL-17A/IL-17RA and RA. The presence of genetically high IL-17A/IL-17RA may increase the risk of RA (IL-17A(OR = 1.095; 95% C.I., 0.990-1.210, p.adj = 0.013), IL-17RA(OR = 1.113, 95%CI = 1.006-1.231, p.adj = 0.006)). However, the results indicated that IL-17C/IL-17RC, and IL-17D/IL-17RD demonstrated no causal impact on RA (IL-17C(OR = 1.007, 95%CI = 0.890-1.139, p.adj = 0.152), IL-17RC(OR = 1.006, 95%CI = 0.904-1.119, p.adj = 0.152), IL-17D(OR = 0.979, 95%CI = 0.843-1.137, p.adj = 0.130), IL-17RD(OR = 0.983, 95%CI = 0.876-1.104, p.adj = 0.129)). Furthermore, MVMR analysis shown that IL-17RA(OR = 1.049, 95% CI: 0.997-1.102, p.adj = 0.014) was associated with increased risk of RA. Sensitivity analysis showed no heterogeneity and pleiotropy, suggesting that the above results were robust and reliable. The MR analysis provides evidence that IL-17A/IL-17RA are risk factors for RA. This emphasizes the importance of intervention on IL-17A/IL-17RA in patients with RA. Developing drugs that limit IL-17A may reduce the risk of RA. Show less
Our previous study found that increased serum IL-27 could promote rheumatoid arthritis (RA) B cell dysfunction via activating mTOR signaling pathway. This study aimed to explore the effects of IL-27 o Show more
Our previous study found that increased serum IL-27 could promote rheumatoid arthritis (RA) B cell dysfunction via activating mTOR signaling pathway. This study aimed to explore the effects of IL-27 on B cell metabolism and clarify the mechanisms via which IL-27 enhancing glycolysis to induce B cells hyperactivation. Peripheral CD19 Show less
Therapies for cholangiocarcinoma are largely limited and ineffective. Herein, we examined the role of the FGF and VEGF pathways in regulating lymphangiogenesis and PD-L1 expression in intrahepatic cho Show more
Therapies for cholangiocarcinoma are largely limited and ineffective. Herein, we examined the role of the FGF and VEGF pathways in regulating lymphangiogenesis and PD-L1 expression in intrahepatic cholangiocarcinoma (iCCA). The lymphangiogenic functions of FGF and VEGF were evaluated in lymphatic endothelial cells (LECs) and iCCA xenograft mouse models. The relationship between VEGF and hexokinase 2 (HK2) was validated in LECs by western blot, immunofluorescence, ChIP and luciferase reporter assays. The efficacy of the combination therapy was assessed in LECs and xenograft models. Microarray analysis was used to evaluate the pathological relationships of FGFR1 and VEGFR3 with HK2 in human lymphatic vessels. FGF promoted lymphangiogenesis through c-MYC-dependent modulation of HK2 expression. VEGFC also upregulated HK2 expression. Mechanistically, VEGFC phosphorylated components of the PI3K/Akt/mTOR axis to upregulate HIF-1α expression at the translational level, and HIF-1α then bound to the HK2 promoter region to activate its transcription. More importantly, dual FGFR and VEGFR inhibition with infigratinib and SAR131675 almost completely inhibited lymphangiogenesis, and significantly suppressed iCCA tumor growth and progression by reducing PD-L1 expression in LECs. Dual FGFR and VEGFR inhibition inhibits lymphangiogenesis through suppression of c-MYC-dependent and HIF-1α-mediated HK2 expression, respectively. HK2 downregulation decreased glycolytic activity and further attenuated PD-L1 expression. Our findings suggest that dual FGFR and VEGFR blockade is an effective novel combination strategy to inhibit lymphangiogenesis and improve immunocompetence in iCCA. Show less