Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare autosomal recessive urea cycle disorder characterized by hyperammonaemia. The biochemical measurement of the intermediate metabolites is h Show more
Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare autosomal recessive urea cycle disorder characterized by hyperammonaemia. The biochemical measurement of the intermediate metabolites is helpful for CPS1D diagnosis; it however cannot distinguish CPS1D from N-acetylglutamate synthetase deficiency. Therefore, next-generation sequencing (NGS) is often essential for the accurate diagnosis of CPS1D. NGS was performed to identify candidate gene variants of CPS1D in a Asian neonatal patient presented with poor feeding, reduced activity, tachypnea, lethargy, and convulsions. The potential pathogenicity of the identified variants was predicted by various types of bioinformatical analyses, including evolution conservation, domain and 3D structure simulations. Compound heterozygosity of CPS1D were identified. One was in exon 24 with a novel heterozygous missense variant c.2947C > T (p.P983S), and another was previously reported in exon 20 with c.2548C > T (p.R850C). Both variants were predicted to be deleterious. Conservation analysis and structural modeling showed that the two substituted amino acids were highly evolutionarily conserved, resulting in potential decreases of the binding pocket stability and the partial loss of enzyme activity. In this study, two pathogenic missense variants were identified with NGS, expanding the variants pectrum of the Show less
S-adenosyl-l-homocysteine (SAH), an amino acid derivative, is a key intermediate metabolite in methionine metabolism, which is normally considered as a harmful by-product and hydrolyzed quickly once f Show more
S-adenosyl-l-homocysteine (SAH), an amino acid derivative, is a key intermediate metabolite in methionine metabolism, which is normally considered as a harmful by-product and hydrolyzed quickly once formed. AHCY (adenosylhomocysteinase) converts SAH into homocysteine and adenosine. There are two other members in the AHCY family, AHCYL1 (adenosylhomocysteinase like 1) and AHCYL2 (adenosylhomocysteinase like 2). Here we define AHCYL1 function as a SAH sensor to inhibit macroautophagy/autophagy through PIK3C3. The C terminus of AHCYL1 interacts with SAH specifically and the interaction with SAH promotes the binding of the N terminus to the catalytic domain of PIK3C3, resulting in inhibition of PIK3C3. More importantly, this observation was further validated Show less
Fat deposition is a complex economic trait regulated by polygenic genetic basis and environmental factors. Therefore, integrating multi-omics data to uncover its internal regulatory mechanism has attr Show more
Fat deposition is a complex economic trait regulated by polygenic genetic basis and environmental factors. Therefore, integrating multi-omics data to uncover its internal regulatory mechanism has attracted extensive attention. Here, we performed genomics and transcriptomics analysis to detect candidates affecting subcutaneous fat (SCF) deposition in beef cattle. The association of 770K SNPs with the backfat thickness captured nine significant SNPs within or near 11 genes. Additionally, 13 overlapping genes regarding fat deposition were determined via the analysis of differentially expressed genes and weighted gene co-expression network analysis (WGCNA). We then calculated the correlations of these genes with BFT and constructed their interaction network. Finally, seven biomarkers including ACACA, SCD, FASN, ACOX1, ELOVL5, HACD2, and HSD17B12 were screened. Notably, ACACA, identified by the integration of genomics and transcriptomics, was more likely to exert profound effects on SCF deposition. These findings provided novel insights into the regulation mechanism underlying bovine fat accumulation. Show less
As a member of the PIKs family, PIK3C3 participates in autophagy and plays a central role in liver function. Several studies demonstrated that the complete suppression of PIK3C3 in mammals can cause h Show more
As a member of the PIKs family, PIK3C3 participates in autophagy and plays a central role in liver function. Several studies demonstrated that the complete suppression of PIK3C3 in mammals can cause hepatomegaly and hepatosteatosis. However, the function of PIK3C3 overexpression on the liver and other organs is still unknown. In this study, we successfully generated PIK3C3 transgenic pigs through somatic cell nuclear transfer (SCNT) by designing a specific vector for the overexpression of PIK3C3. Plasmid identification was performed through enzyme digestion and transfected into the fetal fibroblasts derived from Show less
To explore whether acupuncture combined with moxibustion could inhibit epithelialmesenchymal transition in Crohn's disease by affecting the transforming growth factor β 1 (TGF- β 1)/Smad3/Snail pathwa Show more
To explore whether acupuncture combined with moxibustion could inhibit epithelialmesenchymal transition in Crohn's disease by affecting the transforming growth factor β 1 (TGF- β 1)/Smad3/Snail pathway. Sixty-three patients with Crohn's disease were randomly divided into an observation group (31 cases) receiving moxibustion at 43 °C combined with acupuncture, and a control group (32 cases) receiving moxibustion at 37 °C combined with sham acupuncture using a random number table. Patients were treated for 12 weeks. Crohn's Disease Activity Index (CDAI) was used to evaluate disease activity. Hematoxylin-eosin staining and transmission electron microscopy were utilized to observe the morphological and ultrastructural changes. Immunohistochemistry was used to detect the expression of transforming growth factor β 1 (TGF-β 1), T β R1, T β R2, Smad3, Snail, E-cadherin and fibronectin in intestinal mucosal tissues. The decrease of the CDAI score, morphological and ultrastructural changes were more significant in observation group. The expression levels of TGF- β 1, Tβ R2, Smad3, and Snail in the observation group were significantly lower than those before the treatment (P<0.05 or P<0.01). After treatment, the expression levels of TGF-β 1, TβR2, and Snail in the observation group were significantly lower than those in the control group (all P<0.05); compared with the control group, the expression of fibronectin in the observation group was significantly decreased, and the expression of E-cadherin was significantly increased (all P<0.05). Moxibustion at 43 °C combined with acupuncture may suppress TGF-β 1/Smad3/Snail pathway-mediated epithelial-mesenchymal transition of intestinal epithelial cells in Crohn's disease patients by inhibiting the expression levels of TGF-β 1, Tβ R2, Smad3, and Snail. (Registration No. ChiCTR-IIR-16007751). Show less
REVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major coronary events. Show more
REVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major coronary events. We now report results from extended follow-up beyond the scheduled study treatment period. A total of 30 449 adults with prior atherosclerotic vascular disease were randomly allocated to anacetrapib 100 mg daily or matching placebo, in addition to open-label atorvastatin therapy. After stopping the randomly allocated treatment, 26 129 survivors entered a post-trial follow-up period, blind to their original treatment allocation. The primary outcome was first post-randomization major coronary event (i.e. coronary death, myocardial infarction, or coronary revascularization) during the in-trial and post-trial treatment periods, with analysis by intention-to-treat. Allocation to anacetrapib conferred a 9% [95% confidence interval (CI) 3-15%; P = 0.004] proportional reduction in the incidence of major coronary events during the study treatment period (median 4.1 years). During extended follow-up (median 2.2 years), there was a further 20% (95% CI 10-29%; P < 0.001) reduction. Overall, there was a 12% (95% CI 7-17%, P < 0.001) proportional reduction in major coronary events during the overall follow-up period (median 6.3 years), corresponding to a 1.8% (95% CI 1.0-2.6%) absolute reduction. There were no significant effects on non-vascular mortality, site-specific cancer, or other serious adverse events. Morbidity follow-up was obtained for 25 784 (99%) participants. The beneficial effects of anacetrapib on major coronary events increased with longer follow-up, and no adverse effects emerged on non-vascular mortality or morbidity. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomized trials of lipid-modifying agents to assess their full benefits and potential harms. International Standard Randomized Controlled Trial Number (ISRCTN) 48678192; ClinicalTrials.gov No. NCT01252953; EudraCT No. 2010-023467-18. Show less
Accumulated studies have pointed out the striking association between variants in or near This study aims to decipher the complex relevance between gene polymorphisms, clinical parameters, and NAFLD b Show more
Accumulated studies have pointed out the striking association between variants in or near This study aims to decipher the complex relevance between gene polymorphisms, clinical parameters, and NAFLD by association study and mediation analysis. Eight SNPs (rs2854116, rs2854117, rs780093, rs780094, rs1260362, rs738409, rs2294918, and rs2281135) within The genotypic frequencies of rs1260326 and rs780094 were significantly different between NAFLD and control (rs1260326: Our results identified a prominent relationship between Show less
Ying Wang, Jun Liu, Chizuru Akatsu+18 more · 2022 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-24
Elimination of autoreactive developing B cells is an important mechanism to prevent autoantibody production. However, how B cell receptor (BCR) signaling triggers apoptosis of immature B cells remains Show more
Elimination of autoreactive developing B cells is an important mechanism to prevent autoantibody production. However, how B cell receptor (BCR) signaling triggers apoptosis of immature B cells remains poorly understood. We show that BCR stimulation up-regulates the expression of the lysosomal-associated transmembrane protein 5 (LAPTM5), which in turn triggers apoptosis of immature B cells through two pathways. LAPTM5 causes BCR internalization, resulting in decreased phosphorylation of SYK and ERK. In addition, LAPTM5 targets the E3 ubiquitin ligase WWP2 for lysosomal degradation, resulting in the accumulation of its substrate PTEN. Elevated PTEN levels suppress AKT phosphorylation, leading to increased FOXO1 expression and up-regulation of the cell cycle inhibitor p27Kip1 and the proapoptotic molecule BIM. In vivo, LAPTM5 is involved in the elimination of autoreactive B cells and its deficiency exacerbates autoantibody production. Our results reveal a previously unidentified mechanism that contributes to immature B cell apoptosis and B cell tolerance. Show less
The effects of cholamine, a raw material for synthesis of some active lipids, are unknown in poultry. To address this, 180 52-wk-old Hyline laying hens were randomly divided into 3 groups (20 replicat Show more
The effects of cholamine, a raw material for synthesis of some active lipids, are unknown in poultry. To address this, 180 52-wk-old Hyline laying hens were randomly divided into 3 groups (20 replicates per group with three hens per replicate). The control group and the treatment groups (treatment 1 and 2) were fed basal diet and the diet supplemented with 500 or 1,000 mg of cholamine per kilogram of the diet for 35 d, respectively. The data showed that supplementary cholamine significantly lowered egg production, daily feed intake, serum high-density lipoprotein cholesterol level, liver index, and the percentages of C15:0 and C20:0 in fatty acid composition of liver, significantly elevated hepatic triglyceride content, the ratio of villus height to crypt depth (P < 0.05), and the percentage of C18:2n-6 and the ratio of n-6 to n-3 polyunsaturated fatty acids in liver fat (P < 0.10). Moreover, supplementary cholamine altered the relative abundance of some intestinal bacteria with a decrease in the alpha biodiversity (P < 0.10). Additionally, transcriptome analysis on the livers of the treatment vs. the control groups identified 1,151 up- and 914 down-regulated differentially expressed genes (DEGs), and pathway analysis revealed that the suppressed Notch signaling pathway and the enhanced Oxidative phosphorylation pathway were enriched with DEGs. Particularly, fat absorption, transport and oxidative phosphorylation-related DEGs (e.g., FABP1, APOA4, and PCK1) were significantly induced, but fatty acid synthesis, and lipid package and secretion-related DEGs (e.g., FASN, SCD, and MTTP) were not. In conclusion, supplementary cholamine may lower egg production by promoting hepatic lipid deposition and reducing abundances of beneficial intestinal bacteria and microfloral biodiversity in laying hens. Show less
Advanced glycation end products (AGEs) are stable products produced by the reaction of macromolecules such as proteins, lipids or nucleic acids with glucose or other reducing monosaccharides, which ca Show more
Advanced glycation end products (AGEs) are stable products produced by the reaction of macromolecules such as proteins, lipids or nucleic acids with glucose or other reducing monosaccharides, which can be identified by immunohistochemistry in the senile plaques and neurofibrillary tangles of Alzheimer's disease (AD) patients. Growing evidence suggests that AGEs are important risk factors for the development and progression of AD. 1,8-cineole (CIN) is a monoterpenoid compound which exists in many plant essential oils and has been proven to have neuroprotective activity, but its specific effect and molecular mechanisms are not clear. In this study, AGEs-induced neuronal injury and intracerebroventricular-AGE animals as the possible models for AD were employed to investigate the effects of CIN on AD pathology as well as the molecular mechanisms involved both in vivo and in vitro. Our study demonstrated that CIN could ameliorate tau phosphorylation by down-regulating the activity of GSK-3β and reducing Aβ production by inhibiting the activity of BACE-1 both in vivo and in vitro. It is suggested that CIN has certain therapeutic value in the treatment of AD. Show less
Lung cancer is the most common malignancy, and its mortality ranks first among malignancies. Non-small cell lung carcinoma (NSCLC) is the most common pathological subtype of lung cancer. It is reporte Show more
Lung cancer is the most common malignancy, and its mortality ranks first among malignancies. Non-small cell lung carcinoma (NSCLC) is the most common pathological subtype of lung cancer. It is reported that circular RNAs (circRNAs) feature prominently in the occurrence and metastasis of NSCLC. This study aims to decipher the biological functions of circ₀₀₀₆₂₂₀ in NSCLC and the underlying mechanism. The microarray data (GSE101586) were downloaded from the Gene Expression Omnibus database, and differentially expressed circRNAs in NSCLC tissues were screened using the GEO2R tool. Quantitative real-time polymerase chain reaction was used for detecting the expression of circ₀₀₀₆₂₂₀, miR-203-3p, and regulator of G-protein signaling 17 (RGS17) mRNA in NSCLC tissues and cells. The connection between circ₀₀₀₆₂₂₀ expression and clinicopathological indicators was analyzed through the chi-square test. EdU and cell counting kit-8 assays were carried out to detect cell growth. Cell migration and invasion were detected by transwell assays. Bioinformatics was used to predict, and RNA immunoprecipitation assay and dual-luciferase reporter gene assay were conducted for verifying, the targeted relationship among circ₀₀₀₆₂₂₀, miR-203-3p, and RGS17. The expression of circ₀₀₀₆₂₂₀ was elevated in NSCLC cells and tissues, and high circ₀₀₀₆₂₂₀ expression was significantly associated with unfavorable clinicopathological indicators. In addition, it was revealed that circ₀₀₀₆₂₂₀ overexpression facilitated NSCLC cell growth, migration, and invasion, whereas knocking down circ₀₀₀₆₂₂₀ had contrary effects. Furthermore, miR-203-3p was identified as a downstream target of circ₀₀₀₆₂₂₀, and circ₀₀₀₆₂₂₀ could sponge miR-203-3p; RGS17 was identified as a downstream target of miR-203-3p and was positively modulated by circ₀₀₀₆₂₂₀. Circ₀₀₀₆₂₂₀ up-regulates RGS17 expression by adsorbing miR-203-3p to promote NSCLC development. Show less
Nelumbo nucifera (N. nucifera), a kind of edible Chinese herbal, has been studied in treating hyperlipidemia. However, the hypolipidemic mechanism of N. nucifera remains unknown. Aims of this review: Show more
Nelumbo nucifera (N. nucifera), a kind of edible Chinese herbal, has been studied in treating hyperlipidemia. However, the hypolipidemic mechanism of N. nucifera remains unknown. Aims of this review: We aimed to screen the effective constituent of N. nucifera alkaloids and elucidated the potential mechanism for treating hyperlipidemia. A triple combination strategy of UHPLC-MS We comprehensively investigated the characterization of N. nucifera alkaloids by using UHPLC-LTQ-Orbitrap MS 35 compounds were identified from N. nucifera alkaloid extraction by UHPLC-LTQ-Orbitrap MS O-nornuciferine and N. nucifera alkaloids had exibited significant effects in hyperlipidemia. The candidate genes were LDLR, LPL and ANGPTL4, etc. It was most likely that they adjusted lipid metabolism by modulating expression levels of various key factors which were involved in bile secretion, glycerolipid metabolism, sphingolipid metabolism and PPAR signaling pathway, and so on. This study clarified the hypolipidemic mechanism of the alkaloids in N. nucifera, and laid a foundation for the subsequent development of clinical application and better quality of N. nucifera. Show less
Malignant meningiomas often show invasive growth that makes complete tumor resection challenging, and they are more prone to recur after radical resection. Invasive meningioma associated transcript 1 Show more
Malignant meningiomas often show invasive growth that makes complete tumor resection challenging, and they are more prone to recur after radical resection. Invasive meningioma associated transcript 1 (IMAT1) is a long noncoding RNA located on Show less
MicroRNAs (miRNAs) play an important role in the pathogenesis of atrial fibrillation (AF). Exosomal miRNAs may develop as promising biomarkers for AF. To explore significant exosomal miRNAs in AF, pla Show more
MicroRNAs (miRNAs) play an important role in the pathogenesis of atrial fibrillation (AF). Exosomal miRNAs may develop as promising biomarkers for AF. To explore significant exosomal miRNAs in AF, plasma exosomes were extracted from 3 patients with AF and 3 patients with sinus rhythm (SR), respectively. Differential expression of exosomal miRNAs were screened by high-throughput sequencing analysis and verified by qRT-PCR from 40 patients with AF and 40 patients with SR. The target genes prediction, biological function, and signaling pathways analysis were conducted by miRanda software, gene ontology (GO), and KEGG analysis. The results showed that there were 40 differently expressed exosomal miRNAs from AF patients compared with SR patients, of which 13 miRNAs were upregulated and 27 miRNAs were downregulated. qRT-PCR validation demonstrated that miR-124-3p, miR-378d, miR-2110, and miR-3180-3p were remarkably upregulated, while miR-223-5p, miR-574-3p, miR-125a-3p, and miR-1299 were downregulated. To explore the function of miR-124-3p associated with AF, plasma exosomes derived from AF patients were co-incubated with rat myocardial fibroblasts. The expression of miR-124-3p was upregulated in myocardial fibroblasts. The viability and proliferation of myocardial fibroblasts were elevated by transfecting with miR-124-3p overexpression plasmids using CCK8 and immunofluorescence-staining methods. AXIN1 was verified to be the target of miR-124-3p by luciferase assay in vitro. Expression of AXIN1 was reduced, while β-catenin, Collagen 1, and α-SMA were increased in myocardial fibroblasts with miR-124-3p overexpression. In conclusion, these findings suggested that circulating exosomal miRNAs may serve as novel biomarkers for AF, and miR-124-3p promotes fibroblast activation and proliferation through regulating WNT/β-catenin signaling pathway via AXIN1. Show less
Delta-5 desaturase (D5D), encoded by the fatty acid desaturase 1 (FADS1) gene, is a rate-limiting enzyme in polyunsaturated fatty acid (PUFA) synthesis that influences the PUFA levels in milk fat. How Show more
Delta-5 desaturase (D5D), encoded by the fatty acid desaturase 1 (FADS1) gene, is a rate-limiting enzyme in polyunsaturated fatty acid (PUFA) synthesis that influences the PUFA levels in milk fat. However, the function and molecular mechanism of FADS1 in milk fat metabolism remain largely unknown. The Show less
The high heterogeneity of ovarian cancer (OC) brings great difficulties to its early diagnosis and prognostic forecast. There is an urgent need to establish a prognostic model of OC based on clinicopa Show more
The high heterogeneity of ovarian cancer (OC) brings great difficulties to its early diagnosis and prognostic forecast. There is an urgent need to establish a prognostic model of OC based on clinicopathological features and genomics. We identified hypoxia-related differentially expressed genes (DEGs) between OC tissues from The Cancer Genome Atlas (TCGA) and normal tissues from the Genotype-Tissue Expression (GTEx). LASSO Cox regression analysis was applied for building a prognostic model in the TCGA-GTEx cohorts, and its predictive value was validated in the GEO-OC cohort. Functional enrichment analysis was performed to investigate the underlying mechanisms. By constructing a hypoxia model of the SKOV3 cell line and applying qRT-PCR, we investigated the relationship between hypoxia with two novel genes in the prognostic model (ISG20 and ANGPTL4). Twelve prognostic hypoxia-related DEGs were identified, and nine of them were selected to establish a prognostic model. OC patients were stratified into two risk groups, and the high-risk group showed reduced survival time compared to the low-risk group upon survival analysis. Univariate and multivariate Cox regression analysis demonstrated that the risk score was an independent risk factor for overall survival. The biological function of the identified prognostic hypoxia-related gene signature was involved in immune cell infiltration. Low expression of ISG20 was observed in the CoCl Our findings showed that this hypoxia-related gene signature could serve as a satisfactory prognostic classifier for OC and will be beneficial to the research and development of targeted therapeutic strategies. Show less
Biofilm-immobilized continuous fermentation is a novel fermentation strategy that has been utilized in ethanol fermentation. Continuous fermentation contributes to the self-proliferation of Saccharomy Show more
Biofilm-immobilized continuous fermentation is a novel fermentation strategy that has been utilized in ethanol fermentation. Continuous fermentation contributes to the self-proliferation of Saccharomyces cerevisiae biofilms. Previously, we successfully described the cell cycle differences between biofilm-immobilized fermentation and calcium alginate-immobilized fermentation. In the present study, we investigated the relationship between biofilm formation and the cell cycle. We knocked down Show less
Genetic factors play a critical role in the pathogenesis of osteoporosis. The imbalance of WNT/β-catenin will cause the occurrence of osteoporosis. LRP5 and AXIN1 play an important role in the classic Show more
Genetic factors play a critical role in the pathogenesis of osteoporosis. The imbalance of WNT/β-catenin will cause the occurrence of osteoporosis. LRP5 and AXIN1 play an important role in the classical Wnt/β-catenin signaling pathway. Our study was aimed to determine the association between five candidate single nucleotide polymorphisms (SNPs) of LRP5 or AXIN1 and osteoporosis susceptibility in Chinese Han population. A total of 599 osteoporosis patients and 599 healthy individuals were recruited for this case-control study. Agena MassARRAY was used to genotype SNPs. The association between SNPs and osteoporosis susceptibility in different genetic models was analyzed by PLINK software. We used false-positive report probability (FPRP) analysis to detect whether the positive results were just chance or noteworthy observations. Multifactor dimension reduction (MDR) was used to analyze the interaction of SNP-SNP in the osteoporosis risk. Finally, haplotype analysis was performed by plink1.07 and Haploview software. We found that LRP5 rs11228240, AXIN1 rs2301522, and rs9921222 were significantly associated with the osteoporosis susceptibility. The results of subgroup analysis showed that LRP5 rs11228240 (protective factor) and AXIN1 rs2301522 (risk factor) were associated with the susceptibility of osteoporosis among participants who were age >60 years, female or BMI ≤ 24; AXIN1 rs9921222 significantly increased the risk of osteoporosis among participants with BMI ≤ 24. The genotype A The LRP5-rs11228240, AXIN1-rs2301522, and AXIN1- rs9921222 were associated with osteoporosis susceptibility in Chinese Han population. Show less
Yu Zhang, Yuming Zhu, Mo Zhang+9 more · 2022 · European heart journal. Quality of care & clinical outcomes · Oxford University Press · added 2026-04-24
In the clinical practice, the right ventricular (RV) manifestations have received less attention in hypertrophic cardiomyopathy (HCM). This paper aimed to evaluate the risk prediction value and geneti Show more
In the clinical practice, the right ventricular (RV) manifestations have received less attention in hypertrophic cardiomyopathy (HCM). This paper aimed to evaluate the risk prediction value and genetic characteristics of RV involvement in HCM patients. A total of 893 patients with HCM were recruited. RV hypertrophy, RV obstruction, and RV late gadolinium enhancement were evaluated by echocardiography and/or cardiac magnetic resonance. Patients with any of the above structural abnormalities were identified as having RV involvement. All patients were followed with a median follow-up time of 3.0 years. The primary endpoint was cardiovascular death; the secondary endpoints were all-cause death and heart failure (HF)-related death. Survival analyses were conducted to evaluate the associations between RV involvement and the endpoints. Genetic testing was performed on 669 patients. RV involvement was recognized in 114 of 893 patients (12.8%). Survival analyses demonstrated that RV involvement was an independent risk factor for cardiovascular death (P = 0.002), all-cause death (P = 0.011), and HF-related death (P = 0.004). These outcome results were then confirmed by a sensitivity analysis. Genetic testing revealed a higher frequency of genotype-positive in patients with RV involvement (57.0% vs. 31.0%, P < 0.001), and the P/LP variants of MYBPC3 were more frequently identified in patients with RV involvement (30.4% vs. 12.0%, P < 0.001). Logistic analyses indicated the independent correlation between RV involvement and these genetic factors. RV involvement was an independent risk factor for cardiovascular death, all-cause death and HF-related death in HCM patients. Genetic factors might contribute to RV involvement in HCM. Show less
Methionine or lysine has been reported to influence DNA methylation and fat metabolism, but their combined effects in N6-methyl-adenosine (m The results showed that the addition of RML in a LP diet te Show more
Methionine or lysine has been reported to influence DNA methylation and fat metabolism, but their combined effects in N6-methyl-adenosine (m The results showed that the addition of RML in a LP diet tended to lower the concentrations of plasma leptin (P = 0.07), triglyceride (P = 0.05), and non-esterified FA (P = 0.08). Feeding a LP diet increased the enzyme activity or mRNA expression of lipogenic enzymes and decreased lipolytic enzymes compared with the NP diet. This effect was reversed by supplementation of RML with a LP diet. The inclusion of RML in a LP diet affected the polyunsaturated fatty acids (PUFA), n-3 PUFA, and n-6 PUFA in the liver but not in the muscle, which might be linked with altered expression of FA desaturase-1 (FADS1) and acetyl-CoA carboxylase (ACC). A LP diet supplemented with RML increased (P < 0.05) total m Our findings showed that the inclusion of RML in a LP diet could alter fat deposition through modulations of lipogenesis and lipolysis in the liver and muscle. These changes in fat metabolism may be associated with the modification of m Show less
Gliomas, the most prevalent brain tumors, account for nearly one-third of the all brain and central nervous system (CNS) tumors diagnosed in the USA. The purpose of this study was to discuss the impor Show more
Gliomas, the most prevalent brain tumors, account for nearly one-third of the all brain and central nervous system (CNS) tumors diagnosed in the USA. The purpose of this study was to discuss the important role of A kinase-interacting protein 1 (AKIP1) in glioma and reveal the potential mechanism. After prediction by CCLE, the expression of AKIP1 was determined by qRT-PCR and western blot. The impacts of AKIP1 knockdown on the proliferation, migration, and invasion were then measured by MTT, colony formation assay, wound healing, and transwell assays. Western blot was used to assess the protein levels of migration and epithelial-mesenchymal transition- (EMT-) related factors. Subsequently, the expression of Disks Large Homolog 2 (DLG2) was predicted by bioinformatics analyses, and the interaction between AKIP1 and DLG2 was confirmed by IP assay, qRT-PCR, and western blot. Finally, DLG2 was further downregulated in glioma cells to detect the association between AKIP1 and DLG2 in the cellular functions of glioma. It was demonstrated that AKIP1 exhibited a high level in glioma cells, and interference of AKIP1 led to reductions in the proliferation, migration, invasion, and EMT of glioma cells. DLG2, which was lowly expressed in glioma cells, demonstrated a negative link to AKIP2. Inhibition of both AKIP2 and DLG2 counteracted the inhibited cellular behaviors on account of AKIP1 interference. To be concluded, this study presented evidence that AKIP1 silencing suppressed the progression of glioma via targeting DLG2, which could provide novel insights to impede the development of glioma. Show less
Alzheimer's disease is a global public health problem and the most common form of dementia. Due to the failure of many single therapies targeting the two hallmarks, Aβ and Tau, and the multifactorial Show more
Alzheimer's disease is a global public health problem and the most common form of dementia. Due to the failure of many single therapies targeting the two hallmarks, Aβ and Tau, and the multifactorial etiology of AD, there is now more and more interest in nutraceutical agents with multiple effects such as Show less
Inhibition of the cholesteryl ester transfer protein (CETP) has been considered as a promising way for the treatment of cardiovascular disease (CVD) for three decades. However, clinical trials of seve Show more
Inhibition of the cholesteryl ester transfer protein (CETP) has been considered as a promising way for the treatment of cardiovascular disease (CVD) for three decades. However, clinical trials of several CETP inhibitors with various potencies have been marginally successful at best, raising doubts on the target drugability of CETP. The in-depth understanding of the glycosylated CETP structure could be beneficial to more definitive descriptions of the CETP function and the underlying mechanism. In this work, large-scale molecular dynamics simulations were performed to thoroughly explore the mechanism of glycans modulating CETP. Here, the extensive simulation results intensely suggest that glycan88 tends to assist CETP in forming a continuous tunnel throughout interacting with the upper-right region of the N-barrel, while it also could prevent the formation of a continuous tunnel by swinging toward the right-rear of the N-barrel. Furthermore, glycan240 formed stable H-bonds with Helix-B and might further stabilize the central cavity of CETP. Furthermore, the nonspecific involvement of the hydroxyl groups from the various glycans with protein core interactions and the similar influence of different glycans trapped at similar regions on the protein structure suggest that physiological glycan may lead to a similar effect. This study would provide valuable insights into devising novel methods for CVD treatment targeting CETP and functional studies about glycosylation for other systems. Show less
While multiple transcription factors (TFs) have been recognized to drive epithelial-mesenchymal transition (EMT) in cancer, their interdependence and context-dependent functions are poorly understood. Show more
While multiple transcription factors (TFs) have been recognized to drive epithelial-mesenchymal transition (EMT) in cancer, their interdependence and context-dependent functions are poorly understood. In this study, we show that FOXQ1 and SNAI1 act as independent TFs within the EMT program with a shared ability to upregulate common EMT TFs without reciprocally impacting the expression of one another. Despite this independence, human mammary epithelial cells (HMLE) with ectopic expression of either FOXQ1 or SNAI1 share a common gene set that is enriched for a DDR2 coexpression signature. Further analysis identified DDR2 as the most upregulated receptor tyrosine kinase and a shared downstream effector of FOXQ1 and SNAI1 in triple-negative breast cancer (TNBC) cell lines. Alteration of DDR2 expression in either FOXQ1 or SNAI1 driven EMT models or in TNBC cells resulted in a profound change of cell motility without significantly impacting EMT marker expression, cell morphology, or the stem cell population. Lastly, we demonstrated that knockdown of DDR2 in the FOXQ1-driven EMT model and TNBC cell line significantly altered the global metabolic profile, including glutamine-glutamate and Aspartic acid recycling. Show less
Pulmonary fibrosis initiates a pneumonic cascade that leads to fibroblast dysfunction characterized by excess proliferation. Anoikis is a physiological process that ensures tissue development and home Show more
Pulmonary fibrosis initiates a pneumonic cascade that leads to fibroblast dysfunction characterized by excess proliferation. Anoikis is a physiological process that ensures tissue development and homeostasis. Researchers have not clearly determined whether disruption of anoikis is involved in pulmonary fibrosis. Here, we investigated the mechanism by which silica induces fibroblast activation via anoikis resistance and subsequent fibrosis. Anoikis of lung fibroblasts, alveolar epithelial cells and endothelial cells during the process of fibrosis was detected using CCK-8, western blot, cell count and flow cytometry (FCM) assays. Although the three cell types showed similar increases in proliferation, the expression of NTRK2, a marker of anoikis resistance, was upregulated specifically in fibroblasts, indicating the unique proliferation mechanism of fibroblasts in pulmonary fibrosis, which may be related to anoikis resistance. Furthermore, the CRISPR/Cas9 system was used to investigate the molecular mechanism of anoikis resistance; the SiO The current study revealed a specific pattern of fibroblast proliferation, and strategies targeting anoikis resistance may inhibit the pathological process of pulmonary fibrosis. This result provides a new approach for treating pulmonary fibrosis and new insights into the potential application of ZC3H4 in the development of novel therapeutic strategies for mitigating pulmonary fibrosis. Show less
Regulator of ribosome synthesis 1 (RRS1) is a key factor in ribosome biosynthesis and other cellular functions. High level of RRS1 in breast cancer cell lines is associated with increased cell prolife Show more
Regulator of ribosome synthesis 1 (RRS1) is a key factor in ribosome biosynthesis and other cellular functions. High level of RRS1 in breast cancer cell lines is associated with increased cell proliferation, invasion and migration. RRS1 controls the assembly of the 60s subunit and maturation of 25S rRNA during ribosome biosynthesis. In this study, lentiviral transfection of sh‑RNA was used to knock down the level of RRS1, to detect the effect of RRS1 on cell function and to explore the specific mechanism of RRS1 affecting cell invasion and metastasis by COIP and dual‑luciferase reporter gene assays. The present study found that RRS1 knockdown reduced the accumulation of ribosome protein L11 (RPL11) in the nucleolus, which then migrated to the nucleoplasm and bound to c‑Myc. This inhibited trans‑activation of SNAIL by c‑Myc and eventually decreased the invasion and metastasis capacity of the human breast cancer cell line BT549. Taken together, RRS1 regulates invasion and metastasis of human breast cancer cells through the RPL11‑c‑Myc‑SNAIL axis. The findings are of great significance for exploring the mechanism of breast cancer invasion and metastasis and the corresponding regulatory factors. Show less
Many studies show that genetics play a major contribution to the onset of obesity. Human genome-wide association studies (GWASs) have identified hundreds of genes that are associated with obesity. How Show more
Many studies show that genetics play a major contribution to the onset of obesity. Human genome-wide association studies (GWASs) have identified hundreds of genes that are associated with obesity. However, the majority of them have not been functionally validated. Show less
Two-pore domain potassium channels (K2P) are a large family of "background" channels that allow outward "leak" of potassium ions. The NALCN/UNC80/UNC79 complex is a non-selective channel that allows i Show more
Two-pore domain potassium channels (K2P) are a large family of "background" channels that allow outward "leak" of potassium ions. The NALCN/UNC80/UNC79 complex is a non-selective channel that allows inward flow of sodium and other cations. It is unclear how K2Ps and NALCN differentially modulate animal behavior. Here, we found that loss of function (lf) in the K2P gene twk-40 suppressed the reduced body curvatures of C. elegans NALCN(lf) mutants. twk-40(lf) caused a deep body curvature and extended backward locomotion, and these phenotypes appeared to be associated with neuron-specific expression of twk-40 and distinct twk-40 transcript isoforms. To survey the functions of other less studied K2P channels, we examined loss-of-function mutants of 13 additional twk genes expressed in the motor circuit and detected defective body curvature and/or locomotion in mutants of twk-2, twk-17, twk-30, twk-48, unc-58, and the previously reported twk-7. We generated presumptive gain-of-function (gf) mutations in twk-40, twk-2, twk-7, and unc-58 and found that they caused paralysis. Further analyses detected variable genetic interactions between twk-40 and other twk genes, an interdependence between twk-40 and twk-2, and opposite behavioral effects between NALCN and twk-2, twk-7, or unc-58. Finally, we found that the hydrophobicity/hydrophilicity property of TWK-40 residue 159 could affect the channel activity. Together, our study identified twk-40 as a novel modulator of the motor behavior, uncovered potential behavioral effects of five other K2P genes and suggests that NALCN and some K2Ps can oppositely affect C. elegans behavior. Show less
Breast cancer has become the malignancy with the highest mortality rate in female patients worldwide. The limited efficacy of immunotherapy as a breast cancer treatment has fueled the development of r Show more
Breast cancer has become the malignancy with the highest mortality rate in female patients worldwide. The limited efficacy of immunotherapy as a breast cancer treatment has fueled the development of research on the tumor immune microenvironment. In this study, data on breast cancer patients were collected from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohorts. Differential gene expression analysis, univariate Cox regression analysis, and least absolute shrinkage and selection operator (LASSO) Cox regression analysis were performed to select overall survival (OS)-related, tumor tissue highly expressed, and immune- and inflammation-related genes. A tumor immune-inflammation signature (TIIS) consisting of 18 genes was finally screened out in the LASSO Cox regression model. Model performance was assessed by time-dependent receiver operating characteristic (ROC) curves. In addition, the CIBERSORT algorithm and abundant expression of immune checkpoints were utilized to clarify the correlation between the risk signature and immune landscape in breast cancer. Furthermore, the association of IL27 with the immune signature was analyzed in pan-cancer and the effect of IL27 on the migration of breast cancer cells was investigated since the regression coefficient of IL27 was the highest. A TIIS based on 18 genes was constructed The TIIS represents a promising prognostic tool for estimating OS in patients with breast cancer and is correlated with immune status. Show less
As an acetylcholinesterase inhibitor (AChEI), Huperzine-A (Hup-A) is marketed for treatment of mild to moderate Alzheimer's disease (AD) for decades in China. However, Hup-A causes some side effects. Show more
As an acetylcholinesterase inhibitor (AChEI), Huperzine-A (Hup-A) is marketed for treatment of mild to moderate Alzheimer's disease (AD) for decades in China. However, Hup-A causes some side effects. To search for new analogs or derivatives of Hup-A, we produced five Lycopodium alkaloids and two analogues by chemical synthesis: Lyconadins A-E, H-R-NOB, and 2JY-OBZ4. To systematically evaluate the therapeutic effects of the seven compounds on AD cell models. We assessed the effects of the seven compounds on cell viability via CCK-8 kit and used HEK293-hTau cells and N2a-hAPP cells as AD cell models to evaluate their potential therapeutic effects. We examined their effects on cholinesterase activity by employing the mice primary neuron. All compounds did not affect cell viability; in addition, Lyconadin A and 2JY-OBZ4 particularly increased cell viability. Lyconadin D and Lyconadin E restored tau phosphorylation at Thr231, and H-R-NOB and 2JY-OBZ4 restored tau phosphorylation at Thr231 and Ser396 in GSK-3β-transfected HEK293-hTau cells. 2JY-OBZ4 decreased the level of PP2Ac-pY307 and increased the level of PP2Ac-mL309, supporting that 2JY-OBZ4 may activate PP2A. Lyconadin B, Lyconadin D, Lyconadin E, H-R-NOB, and 2JY-OBZ4 increased sAβPPα level in N2a-hAPP cells. 2JY-OBZ4 decreased the levels of BACE1 and sAβPPβ, thereby reduced Aβ production. Seven compounds exhibited weaker AChE activity inhibition efficiency than Hup-A. Among them, 2JY-OBZ4 showed the strongest AChE inhibition activity with an inhibition rate of 17% at 10μM. Among the seven Lycopodium compounds, 2JY-OBZ4 showed the most expected effects on promoting cell viability, downregulating tau hyperphosphorylation, and Aβ production and inhibiting AChE in AD. Show less