Neurexin-3 (Nrxn3) has been genetically associated with obesity, but the underlying neural mechanisms remain poorly understood. This study aimed to investigate the role of Nrxn3 in the paraventricular Show more
Neurexin-3 (Nrxn3) has been genetically associated with obesity, but the underlying neural mechanisms remain poorly understood. This study aimed to investigate the role of Nrxn3 in the paraventricular nucleus of the hypothalamus (PVN) in regulating energy balance and glucose homeostasis. We found that Nrxn3 expression in the PVN was upregulated in response to metabolic stressors, including cold exposure and fasting. Using Cre-loxP technology, we selectively ablated Nrxn3 in CaMKIIα-expressing neurons of the PVN in male mice. This genetic manipulation resulted in marked weight gain attributable to increased adiposity and impaired glucose tolerance, without affecting food intake. Our findings identify PVN CaMKIIα-expressing neurons as a critical locus where Nrxn3 modulates energy balance by regulating adipogenesis and glucose metabolism, independently of appetite. These results reveal a novel neural mechanism potentially linking Nrxn3 dysfunction to obesity pathogenesis, suggesting that targeting PVN Nrxn3-dependent neural pathways may inform new therapeutic approaches for obesity prevention and treatment. Show less
To explore the patterns of differentially expressed genes (DEGs) associated with different growth rates in rock carp (Procypris rabaudi), transcriptome sequencing was performed on the muscle, liver, a Show more
To explore the patterns of differentially expressed genes (DEGs) associated with different growth rates in rock carp (Procypris rabaudi), transcriptome sequencing was performed on the muscle, liver, and brain tissues of rock carp. Subsequently, bioinformatics analysis was conducted, and 2129, 1380, and 415 DEGs were identified in the muscle, liver, and brain tissues, respectively. GO enrichment and KEGG pathway analysis revealed that genes related to appetite regulation, protein degradation and digestion, lipid transport and metabolisms, and glycolysis/gluconeogenesis were upregulated in individuals with slower growth rates. Differential expression analysis identified 21 genes associated with feeding and metabolism across three tissues, including mc4r, npy, and npry in brain tissue; fatp, fabp, pparα, and apo in liver tissue; and prss, ctrl, and cela in muscle tissue. All these genes were upregulated in the slow-growing fish. Furthermore, weighted gene co-expression network analyses, including three modules (yellow, turquoise, and brown), significantly associated with growth. A network map that included these three modules enabled the identification of a series of hub genes, including rp13a, ube2o, h6pd, etc. These genes may be key candidate genes regulating the growth of rock carp. This study contributes to a deeper understanding of the growth control mechanism in rock carp and offers a scientific basis for efficient breeding and species improvement. Show less
Inactivation of phosphatase and tensin homolog (PTEN) is prevalent in human prostate cancer and causes high-grade adenocarcinoma with a long latency. Cancer-associated fibroblasts (CAFs) play a pivota Show more
Inactivation of phosphatase and tensin homolog (PTEN) is prevalent in human prostate cancer and causes high-grade adenocarcinoma with a long latency. Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor progression, but it remains elusive whether and how PTEN-deficient prostate cancers reprogram CAFs to overcome the barriers for tumor progression. Here, we report that PTEN deficiency induced Krüppel-like factor 5 (KLF5) acetylation and that interruption of KLF5 acetylation orchestrated intricate interactions between cancer cells and CAFs that enhance FGF receptor 1 (FGFR1) signaling and promote tumor growth. Deacetylated KLF5 promoted tumor cells to secrete TNF-α, which stimulated inflammatory CAFs to release FGF9. CX3CR1 inhibition blocked FGFR1 activation triggered by FGF9 and sensitized PTEN-deficient prostate cancer to the AKT inhibitor capivasertib. This study reveals the role of KLF5 acetylation in reprogramming CAFs and provides a rationale for combined therapies using inhibitors of AKT and CX3CR1. Show less
Large-for-gestational-age (LGA) neonates have increased risk of adverse pregnancy outcomes and adult metabolic diseases. We aimed to investigate the relationship between plasma angiopoietin-like prote Show more
Large-for-gestational-age (LGA) neonates have increased risk of adverse pregnancy outcomes and adult metabolic diseases. We aimed to investigate the relationship between plasma angiopoietin-like protein 4 (ANGPTL4), a protein involved in lipid and glucose metabolism during pregnancy, placental function, growth factors, and the risk of LGA. We conducted a prospective cohort study and recruited women with singleton pregnancies at the National Taiwan University Hospital between 2013 and 2018. First trimester maternal plasma ANGPTL4 concentrations were measured. Among 353 pregnant women recruited, the LGA group had higher first trimester plasma ANGPTL4 concentrations than the appropriate-for-gestational-age group. Plasma ANGPTL4 was associated with hemoglobin A1c, post-load plasma glucose, plasma triglyceride, plasma free fatty acid concentrations, plasma growth hormone variant (GH-V), and birth weight, but was not associated with cord blood growth factors. After adjusting for age, body mass index, hemoglobin A1c, and plasma triglyceride concentrations, plasma ANGPTL4 concentrations were significantly associated with LGA risk, and its predictive performance, as measured by the area under the receiver operating characteristic curve, outperformed traditional risk factors for LGA. Plasma ANGPTL4 is associated with glucose and lipid metabolism during pregnancy, plasma GH-V, and birth weight, and is an early biomarker for predicting the risk of LGA. Show less
To investigate the serum lipid profiles of patients with localized osteosarcoma around the knee joint before and after neoadjuvant chemotherapy. After retrospectively screening the data of 742 patient Show more
To investigate the serum lipid profiles of patients with localized osteosarcoma around the knee joint before and after neoadjuvant chemotherapy. After retrospectively screening the data of 742 patients between January 2007 and July 2020, 50 patients aged 13 to 39 years with Enneking stage II disease were included in the study. Serum lipid levels, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), lipoprotein-α [Lp(a)], and apolipoprotein A1, B, and E (ApoA1, ApoB, and ApoE), and clinicopathological characteristics were collected before and after neoadjuvant chemotherapy. The mean levels of TC, TG, and ApoB were significantly increased following neoadjuvant chemotherapy (16%, 38%, and 20%, respectively, vs. pretreatment values; P<0.01). The mean levels of LDL-C and ApoE were also 19% and 16% higher, respectively (P<0.05). No correlation was found between the pretreatment lipid profile and the histologic response to chemotherapy. An increase in Lp(a) was strongly correlated with the Ki-67 index (R=0.31, P=0.023). Moreover, a trend toward longer disease-free survival (DFS) was observed in patients with decreased TG and increased LDL-C following chemotherapy, although this difference was not statistically significant (P=0.23 and P=0.24, respectively). Significant elevations in serum lipids were observed after neoadjuvant chemotherapy in patients with localized osteosarcoma. There was no prognostic significance of pretreatment serum lipid levels on histologic response to neoadjuvant chemotherapy. The scale of increase in serum Lp(a) might have a potential prognostic role in osteosarcoma. Patients with increased LDL-C or reduced TG after chemotherapy seem to exhibit a trend toward favorable DFS. Show less
The goat breeding industry on the Tibetan Plateau faces strong selection pressure to enhance fertility. Consequently, there is an urgent need to develop goat lines with higher fertility and adaptabili Show more
The goat breeding industry on the Tibetan Plateau faces strong selection pressure to enhance fertility. Consequently, there is an urgent need to develop goat lines with higher fertility and adaptability. The ovary, as a key organ determining reproductive performance, is regulated by a complex transcriptional network involving numerous protein-coding and non-coding genes. However, the molecular mechanisms of the key mRNA-miRNA-lncRNA regulatory network in goat ovaries remain largely unknown. This study focused on the histology and differential mRNA/miRNA/lncRNA between Chuanzhong black goat (CBG, high productivity, multiple births) and Tibetan goat (TG, strong adaptability, single birth) ovaries. Histomorphological analysis showed that the medulla proportion in CBG ovaries was significantly reduced compared to TG. RNA-Seq and small RNA-Seq analysis identified 1218 differentially expressed (DE) mRNAs, 100 DE miRNAs, and 326 DE lncRNAs, which were mainly enriched in ovarian steroidogenesis, oocyte meiosis, biosynthesis of amino acids and protein digestion, and absorption signaling pathways. Additionally, five key mRNA-miRNA-lncRNA interaction networks regulating goat reproductive performance were identified, including Show less
Accurate molecular representation of compounds is a fundamental challenge for prediction of drug targets and molecular properties. In this study, we present a molecular video-based foundation model, n Show more
Accurate molecular representation of compounds is a fundamental challenge for prediction of drug targets and molecular properties. In this study, we present a molecular video-based foundation model, named VideoMol, pretrained on 120 million frames of 2 million unlabeled drug-like and bioactive molecules. VideoMol renders each molecule as a video with 60-frame and designs three self-supervised learning strategies on molecular videos to capture molecular representation. We show high performance of VideoMol in predicting molecular targets and properties across 43 drug discovery benchmark datasets. VideoMol achieves high accuracy in identifying antiviral molecules against common diverse disease-specific drug targets (i.e., BACE1 and EP4). Drugs screened by VideoMol show better binding affinity than molecular docking, revealing the effectiveness in understanding the three-dimensional structure of molecules. We further illustrate interpretability of VideoMol using key chemical substructures. Show less
Familial hypercholesterolemia (FH) is a genetically inherited disorder caused by monogenic mutations or polygenic deleterious variants. Patients with FH innate with significantly elevated risks for co Show more
Familial hypercholesterolemia (FH) is a genetically inherited disorder caused by monogenic mutations or polygenic deleterious variants. Patients with FH innate with significantly elevated risks for coronary heart disease (CHD). FH prevalence based on genetic testing in Chinese CHD patients is missing. Whether classical index of coronary atherosclerosis severity can be used as indicators of FH needs to be explored. To investigate the FH prevalence in Chinese CHD patients and the association of SYNTAX I score with FH genotype. The monogenic and polygenic FH related genes were genotyped in 400 consecutively enrolled CHD patients. The clinical characteristics and SYNTAX I scores were analyzed in a retrospective nested case-control study. The prevalence of genetically confirmed FH in our CHD cohort was 8.75%. The cLDL-C level, SYNTAX I scores and incidences of triple vessel lesions in FH patients were significantly higher, while cLDL-C and SYNTAX I scores were independent risk factors for FH. Furthermore, cLDL-C levels of polygenic FH were significantly lower than monogenic FH, while their severity of coronary atherosclerosis was comparable. Our study revealed that the SYNTAX I score was an independent risk factor for FH. Besides, polygenic origin of FH should be taken into consideration for CHD patients suspected of FH. Show less
To investigate the correlation of apolipoprotein B/A1 (Apo B/A1) ratio with hemodynamics and degree of hearing impairment in elderly patients with sudden sensorineural hearing loss (SSNHL). A total of Show more
To investigate the correlation of apolipoprotein B/A1 (Apo B/A1) ratio with hemodynamics and degree of hearing impairment in elderly patients with sudden sensorineural hearing loss (SSNHL). A total of 82 elderly patients with SSNHL diagnosed and treated in our hospital from July 2019 to September 2022 were retrospectively selected as the research group. The patients were divided into the mild group (22 cases), the moderate group (45 cases), and the severe group (15 cases) according to the degree of hearing impairment. 82 elderly people who underwent physical examination in our hospital during the same period were selected as the control group. The ApoB/A1 ratio and hemodynamic [whole blood low-shear viscosity (LSV), whole blood high-shear viscosity (HSV) and plasma viscosity (PV)] were measured in the two groups. The correlation of ApoB/A1 ratio with hemodynamics and degree of hearing impairment was analyzed. The predictive value of ApoB/A1 ratio and hemodynamics for the severity of SSNHL in elderly patients was analyzed. Compared with the control group, the ApoB/A1 ratio, and the levels of LSV, HSV and PV were higher in the research group ( The contents of ApoB/A1, HSV, LSV and PV were significantly increased in elderly patients with SSNHL, and their levels are significantly related to the degree of hearing impairment. The combined detection has high value in evaluating the severity of the disease. Show less
In this study, we aimed to investigate the relationship between the intraocular levels of inflammatory factors and myopia-related retinal vascular and neuronal degeneration. One hundred and forty-seve Show more
In this study, we aimed to investigate the relationship between the intraocular levels of inflammatory factors and myopia-related retinal vascular and neuronal degeneration. One hundred and forty-seven patients with Implantable Collamer Lens (ICL) implantation were enrolled and all participants received comprehensive ophthalmic examination. About 100~150 ul of aqueous humor was collected immediately before ICL surgery. The levels of inflammatory factors including Aggrecan, April, BAFF, CCL5, CD163, Chi3l1, gp130, IL-6Rα, IL-8, IL-10, IL-11, IL-12, IL-19, IL-27, IL-28A, IL-34, IFN-β, IFN-γ, MMP-1, MMP-2, MMP-3 and PTX3 in the aqueous humor were measured using the Luminex Multiplexing system. Results showed that aqueous humor levels of pro-inflammatory factors Chi3l1, IL-6Rα, IL-8, IL-12, IL-27, inflammation-related cytokines April, BAFF and IL-34 progressively increased from the progression of myopic retinopathy. Conversely, the aqueous levels of IL-11 and Aggrecan gradually decreased from the progression of myopic retinopathy. Correlation analysis showed that the intraocular levels of Chi3l1, IL-6Rα, IL-8, IL-27 and BAFF were negatively correlated with retinal vascular density. The intraocular level of IL-6Rα was negatively correlated with retinal neuronal thickness. Protein-Protein Interaction (PPI) analysis revealed that Chi3l1 and Aggrecan were the upstream cytokines that affect IL-10 and IL-8 in the pathological myopic eyes. KEGG pathway analysis showed that cytokine-cytokine receptor interaction, JAK-STAT signaling pathway, rheumatoid arthritis, and chagas disease were influenced by these altered inflammatory factors (adjusted p-value<0.001). The production of inflammatory factors in the eyes of individuals with high myopia and pathological myopia was altered, and the elevated levels of intraocular pro-inflammatory factors such as Chi3l1, IL-6Rα, and IL-8 were closely associated with myopia-related retinal microvascular and neurodegeneration. Show less
The acquisition of ectopic fibroblast growth factor receptor 1 (FGFR1) expression is well documented in prostate cancer (PCa) progression, notably in conferring tumor growth advantage and facilitating Show more
The acquisition of ectopic fibroblast growth factor receptor 1 (FGFR1) expression is well documented in prostate cancer (PCa) progression, notably in conferring tumor growth advantage and facilitating metastasis. However, how FGFR1 contributes to PCa progression is not fully revealed. Here we report that ectopic FGFR1 in PCa cells promotes transferrin receptor 1 (TFR1) expression and expands the labile iron pool (LIP), and vice versa. We further demonstrate that FGFR1 stabilizes iron regulatory proteins 2 (IRP2) and therefore, upregulates TFR1 via promoting IRP2 binding to the IRE of TFR1. Deletion of FGFR1 in DU145 cells decreases the LIP, which potentiates the anticancer efficacy of iron chelator. Intriguingly, forced expression of IRP2 in FGFR1 depleted cells reinstates TFR1 expression and LIP, subsequently restoring the tumorigenicity of the cells. Together, our results here unravel a new mechanism by which FGFR1 drives PCa progression and suggest a potential novel target for PCa therapy. Show less
Structural variations (SVs) have significant impacts on complex phenotypes by rearranging large amounts of DNA sequence. We present a comprehensive SV catalog based on the whole-genome sequence of 106 Show more
Structural variations (SVs) have significant impacts on complex phenotypes by rearranging large amounts of DNA sequence. We present a comprehensive SV catalog based on the whole-genome sequence of 1060 pigs (Sus scrofa) representing 101 breeds, covering 9.6% of the pig genome. This catalog includes 42,487 deletions, 37,913 mobile element insertions, 3308 duplications, 1664 inversions, and 45,184 break ends. Estimates of breed ancestry and hybridization using genotyped SVs align well with those from single nucleotide polymorphisms. Geographically stratified deletions are observed, along with known duplications of the KIT gene, responsible for white coat color in European pigs. Additionally, we identify a recent SINE element insertion in MYO5A transcripts of European pigs, potentially influencing alternative splicing patterns and coat color alterations. Furthermore, a Yorkshire-specific copy number gain within ABCG2 is found, impacting chromatin interactions and gene expression across multiple tissues over a stretch of genomic region of ~200 kb. Preliminary investigations into SV's impact on gene expression and traits using the Pig Genotype-Tissue Expression (PigGTEx) data reveal SV associations with regulatory variants and gene-trait pairs. For instance, a 51-bp deletion is linked to the lead eQTL of the lipid metabolism regulating gene FADS3, whose expression in embryo may affect loin muscle area, as revealed by our transcriptome-wide association studies. This SV catalog serves as a valuable resource for studying diversity, evolutionary history, and functional shaping of the pig genome by processes like domestication, trait-based breeding, and adaptive evolution. Show less
The Butuo Black Sheep (BBS) is well-known for its ability to thrive at high altitudes, resist diseases, and produce premium-quality meat. Nonetheless, there is insufficient data regarding its genetic Show more
The Butuo Black Sheep (BBS) is well-known for its ability to thrive at high altitudes, resist diseases, and produce premium-quality meat. Nonetheless, there is insufficient data regarding its genetic diversity and population-specific Single nucleotide polymorphisms (SNPs). This paper centers on the genetic diversity of (BBS). The investigation conducted a whole-genome resequencing of 33 BBS individuals to recognize distinct SNPs exclusive to BBS. The inquiry utilized bioinformatic analysis to identify and explain SNPs and pinpoint crucial mutation sites. The findings reveal that reproductive-related genes (GHR, FSHR, PGR, BMPR1B, FST, ESR1), lipid-related genes (PPARGC1A, STAT6, DGAT1, ACACA, LPL), and protein-related genes (CSN2, LALBA, CSN1S1, CSN1S2) were identified as hub genes. Functional enrichment analysis showed that genes associated with reproduction, immunity, inflammation, hypoxia, PI3K-Akt, and AMPK signaling pathways were present. This research suggests that the unique ability of BBS to adapt to low oxygen levels in the plateau environment may be owing to mutations in a variety of genes. This study provides valuable insights into the genetic makeup of BBS and its potential implications for breeding and conservation efforts. The genes and SPNs identified in this study could serve as molecular markers for BBS. Show less
Endothelial-mesenchymal transition (EndMT) disrupts vascular endothelial integrity and induces atherosclerosis. Active integrin β1 plays a pivotal role in promoting EndMT by facilitating TGFβ/Smad sig Show more
Endothelial-mesenchymal transition (EndMT) disrupts vascular endothelial integrity and induces atherosclerosis. Active integrin β1 plays a pivotal role in promoting EndMT by facilitating TGFβ/Smad signaling in endothelial cells. Here, we report a novel anthraquinone compound, Kanglexin (KLX), which prevented EndMT and atherosclerosis by activating MAP4K4 and suppressing integrin β1/TGFβ signaling. First, KLX effectively counteracted the EndMT phenotype and mitigated the dysregulation of endothelial and mesenchymal markers induced by TGFβ1. Second, KLX suppressed TGFβ/Smad signaling by inactivating integrin β1 and inhibiting the polymerization of TGFβR1/2. The underlying mechanism involved the activation of FGFR1 by KLX, resulting in the phosphorylation of MAP4K4 and Moesin, which led to integrin β1 inactivation by displacing Talin from its β-tail. Oral administration of KLX effectively stimulated endothelial FGFR1 and inhibited integrin β1, thereby preventing vascular EndMT and attenuating plaque formation and progression in the aorta of atherosclerotic Apoe Show less
To investigate the correlation between serum angiopoietin-like protein 4 (ANGPTL4) levels, white matter hyperintensity (WMH), and cognitive impairment (CI) in patients with cerebral small vessel disea Show more
To investigate the correlation between serum angiopoietin-like protein 4 (ANGPTL4) levels, white matter hyperintensity (WMH), and cognitive impairment (CI) in patients with cerebral small vessel disease (CSVD). This cross-sectional study enrolled 171 patients with CSVD who attended the First Affiliated Hospital of Xinxiang Medical University from December 2021 to July 2022. All subjects underwent a 3.0T head magnetic resonance imaging, neuropsychology assessment, and blood sampling. Serum ANGPTL4 levels were detected by enzyme-linked immunosorbent assay and the severity of WMH was assessed by the Fazekas scale. According to the Montreal Cognitive Assessment (MoCA) scale, subjects were divided into normal cognition group (NC, n = 80) and CI group (n = 91). According to the total Fazekas scores, subjects were divided into a mild WMH group (n = 84), a moderate WMH group (n = 70), and a severe WMH group (n = 17). Serum ANGPTL4 levels were significantly higher in the CI group than in the NC group (p < .05) and were negatively correlated with mini-mental state examination scores and MoCA scores (r = -0.26, -0.341, p < .05). Serum ANGPTL4 levels increased significantly in the mild to moderate WMH group but tended to decrease in the severe WMH group. Binary logistic regression analysis showed that ANGPTL4 was an independent influencing factor for CSVD-CI (OR = 2.062, 95% CI (1.591-2.674), p < .001). The area under curve of ANGPTL4 for CSVD-CI was 0.847 (0.791-0.903). ANGPTL4 may be involved in the process of white matter damage and CI in CSVD patients and shows a diagnostic value for CSVD-CI. Show less
Atrial fibrillation is the most common clinical arrhythmia and may be due in part to metabolic stress. Atrial specific deletion of the master metabolic sensor, AMP-activated protein kinase (AMPK), ind Show more
Atrial fibrillation is the most common clinical arrhythmia and may be due in part to metabolic stress. Atrial specific deletion of the master metabolic sensor, AMP-activated protein kinase (AMPK), induces atrial remodeling culminating in atrial fibrillation in mice, implicating AMPK signaling in the maintenance of atrial electrical and structural homeostasis. However, atrial substrate preference for mitochondrial oxidation and the role of AMPK in regulating atrial metabolism are unknown. Here, using LC-MS/MS methodology combined with infusions of [ Show less
The metabolic reprogramming of macrophages is a potential therapeutic strategy for sepsis treatment, but the mechanism underlying this reprogramming remains unclear. Since glycolysis can drive macroph Show more
The metabolic reprogramming of macrophages is a potential therapeutic strategy for sepsis treatment, but the mechanism underlying this reprogramming remains unclear. Since glycolysis can drive macrophage phenotype switching, the rate-limiting enzymes in glycolysis may be key to treating sepsis. Here, we found that, compared with other isoenzymes, the expression of 6-phosphofructokinase, muscle type (PFKM) was the most upregulated in monocytes from septic patients. Recombinant thrombomodulin (rTM) treatment downregulated the protein expression of PFKM in macrophages. Both rTM treatment and Pfkm knockout protected mice from sepsis and reduced the production of the proinflammatory cytokines IL-1β, IL-6, TNF-α, and IL-27, whereas PFKM overexpression increased the production of these cytokines. Mechanistically, rTM treatment inhibited glycolysis in macrophages by decreasing PFKM expression in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. HIF-1α overexpression increased methyltransferase-like 3 (METTL3) expression, elevated the m Show less
Lung squamous cell carcinoma (LUSC) is the second most common pathological type of non-small cell lung cancer (NSCLC). However, compared with lung adenocarcinoma (LUAD), the incidence of driver gene m Show more
Lung squamous cell carcinoma (LUSC) is the second most common pathological type of non-small cell lung cancer (NSCLC). However, compared with lung adenocarcinoma (LUAD), the incidence of driver gene mutations in LUSC is relatively lower and treatment options for LUSC patients are very limited. We described a LUSC patient with a novel FGFR3-IER5L fusion revealed by next generation sequencing in this report. The patient refused surgery, radiotherapy or chemotherapy and received anlotinib treatment. Anlotinib is a small molecular multi-target tyrosine kinase inhibitor, which can inhibit the activity of kinases including vascular endothelial growth factor receptor 2/3 (VEGFR2/3), fibroblast growth factor receptor 1-4 (FGFR1-4), platelet-derived growth factor receptor α/β (PDGFRα/β), and c-Kit. The patient achieved partial response and the progression-free survival was 3.8 months. Show less
Obesity, a multifactorial disease with many complications, has become a global epidemic. Weight management, including dietary supplementation, has been confirmed to provide relevant health benefits. H Show more
Obesity, a multifactorial disease with many complications, has become a global epidemic. Weight management, including dietary supplementation, has been confirmed to provide relevant health benefits. However, experimental evidence and mechanistic elucidation of dietary supplements in this regard are limited. Here, the weight loss efficacy of MHP, a commercial solid beverage consisting of mulberry leaf aqueous extract and Show less
Cyclic dipeptides (CDPs), known for their diverse biological activities, have potential therapeutic applications in mental and behavioral disorders (MBDs), particularly schizophrenia. This study explo Show more
Cyclic dipeptides (CDPs), known for their diverse biological activities, have potential therapeutic applications in mental and behavioral disorders (MBDs), particularly schizophrenia. This study explores the CDPs' therapeutic potential using bibliometric analysis, network pharmacology, molecular docking, and experimental verification, focusing on the interactions with the SIGMA1 receptor. A literature review over three decades utilizing the Web of Science Core Collection (WOSCC) was conducted to identify the emerging trends in CDPs research. A compound library was constructed from the PubChem database, and target prediction using SwissTargetPrediction revealed 800 potential protein targets. A compound-target network highlighted the key interactions with kinases, G protein-coupled receptors, and chromatin-modifying enzymes. Enrichment analysis revealed significant associations with schizophrenia and other MBDs. Schizophrenia-related targets among the potential protein targets were identified using the GEO database. Molecular docking results showed interactions of MC4R, OPRK1, SIGMA1, and CDK5R1 with various CDPs compounds, with SIGMA1 being especially noteworthy. Most CDPs exhibited lower binding energies than the control compounds NE-100 and duloxetine. Experimental validation demonstrated that CDPs such as Cyclo(Ala-Gln), Cyclo(Ala-His), and Cyclo(Val-Gly) exhibited IC Show less
On-chip polarization-sensitive photodetectors are highly desired for ultra-compact optoelectronic systems. It has been demonstrated that polarization-sensitive photodetection can be realized using int Show more
On-chip polarization-sensitive photodetectors are highly desired for ultra-compact optoelectronic systems. It has been demonstrated that polarization-sensitive photodetection can be realized using intrinsic chiral and anisotropy materials. However, these photodetectors can only realize the detection of either circularly polarized light (CPL) or linear polarized light (LPL) and are not applicable to multiple-polarization-sensitive photodetection. Herein, we experimentally demonstrate a metasurface-integrated semiconductor to realize multiple-polarization-sensitive photodetection at visible wavelengths. This device is composed of a MoSe Show less
Few evidence is available in the early prediction models of behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease (AD). This study aimed to develop and validate a novel genet Show more
Few evidence is available in the early prediction models of behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease (AD). This study aimed to develop and validate a novel genetic-clinical-radiological nomogram for evaluating BPSD in patients with AD and explore its underlying nutritional mechanism. This retrospective study included 165 patients with AD from the Chinese Imaging, Biomarkers, and Lifestyle (CIBL) cohort between June 1, 2021, and March 31, 2022. Data on demographics, neuropsychological assessments, single-nucleotide polymorphisms of AD risk genes, and regional brain volumes were collected. A multivariate logistic regression model identified BPSD-associated factors, for subsequently constructing a diagnostic nomogram. This nomogram was internally validated through 1000-bootstrap resampling and externally validated using a time-series split based on the CIBL cohort data between June 1, 2022, and February 1, 2023. Area under receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) were used to assess the discrimination, calibration, and clinical applicability of the nomogram. Factors independently associated with BPSD were: CETP rs1800775 (odds ratio [OR] = 4.137, 95% confidence interval [CI]: 1.276-13.415, P = 0.018), decreased Mini Nutritional Assessment score (OR = 0.187, 95% CI: 0.086-0.405, P <0.001), increased caregiver burden inventory score (OR = 8.993, 95% CI: 3.830-21.119, P <0.001), and decreased brain stem volume (OR = 0.006, 95% CI: 0.001-0.191, P = 0.004). These variables were incorporated into the nomogram. The area under the ROC curve was 0.925 (95% CI: 0.884-0.967, P <0.001) in the internal validation and 0.791 (95% CI: 0.686-0.895, P <0.001) in the external validation. The calibration plots showed favorable consistency between the prediction of nomogram and actual observations, and the DCA showed that the model was clinically useful in both validations. A novel nomogram was established and validated based on lipid metabolism-related genes, nutritional status, and brain stem volumes, which may allow patients with AD to benefit from early triage and more intensive monitoring of BPSD. Chictr.org.cn , ChiCTR2100049131. Show less
Bihui Jin, Guanyu Su, Xiao Zhou+6 more · 2024 · Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics · added 2026-04-24
Papillary thyroid carcinoma (PTC) is the most prevalent malignancy of the thyroid. Fibroblast growth factor receptor 1 (FGFR1) is highly expressed in PTC and works as an oncogenic protein in this dise Show more
Papillary thyroid carcinoma (PTC) is the most prevalent malignancy of the thyroid. Fibroblast growth factor receptor 1 (FGFR1) is highly expressed in PTC and works as an oncogenic protein in this disease. In this report, we wanted to uncover a new mechanism that drives overexpression of FGFR1 in PTC. Analysis of FGFR1 expression in clinical specimens and PTC cells revealed that FGFR1 expression was enhanced in PTC. Using siRNA/shRNA silencing experiments, we found that FGFR1 downregulation impeded PTC cell growth, invasion, and migration and promoted apoptosis in vitro, as well as suppressed tumor growth in vivo. Bioinformatic analyses predicted the potential USP7-FGFR1 interplay and the potential binding between YY1 and the FGFR1 promoter. The mechanism study found that USP7 stabilized FGFR1 protein via deubiquitination, and YY1 could promote the transcription of FGFR1. Our rescue experiments showed that FGFR1 re-expression had a counteracting effect on USP7 downregulation-imposed in vitro alterations of cell functions and in vivo suppression of xenograft growth. In conclusion, our study identifies the deubiquitinating enzyme USP7 and the oncogenic transcription factor YY1 as potent inducers of FGFR1 overexpression. Designing inhibitors targeting FGFR1 or its upstream inducers USP7 and YY1 may be foreseen as a promising strategy to control PTC development. Show less
The pivotal role of lysosomal function in preserving neuronal homeostasis is recognized, with its dysfunction being implicated in neurodegenerative processes, notably in Parkinson's disease (PD). Yet, Show more
The pivotal role of lysosomal function in preserving neuronal homeostasis is recognized, with its dysfunction being implicated in neurodegenerative processes, notably in Parkinson's disease (PD). Yet, the molecular underpinnings of lysosome-related genes (LRGs) in the context of PD remain partially elucidated. We collected RNA-seq data from the brain substantia nigra of 30 PD patients and 20 normal subjects from the GEO database. We obtained molecular classification clusters from the screened lysosomal expression patterns. The lysosome-related diagnostic model of Parkinson's disease was constructed by XGBoost and Random Forest. And we validated the expression patterns of signature LRGs in the diagnostic model by constructing a PD rat model. Finally, the linkage between PD and cancer through signature genes was explored. The expression patterns of the 33 LRGs screened can be divided into two groups of PD samples, enabling exploration of the variance in biological processes and immune elements. Cluster A had a higher disease severity. Subsequently, critical genes were sieved through the application of machine learning methodologies culminating in the identification of two intersecting feature genes (ACP2 and LRP2). A PD risk prediction model was constructed grounded on these signature genes. The model's validity was assessed through nomogram evaluation, which demonstrated robust confidence validity. Then we analyzed the correlation analysis, immune in-filtration, biological function, and rat expression validation of the two genes with common pathogenic genes in Parkinson's disease, indicating that these two genes play an important role in the pathogenesis of PD. We then selected ACP2, which had a significant immune infiltration correlation, as the entry gene for the pan-cancer analysis. The pan-cancer analysis revealed that ACP2 has profound associations with prognostic indicators, immune infiltration, and tumor-related regulatory processes across various neoplasms, suggesting its potential as a therapeutic target in a range of human diseases, including PD and cancers. Our study comprehensively analyzed the molecular grouping of LRGs expression patterns in Parkinson's disease, and the disease progression was more severe in cluster A. And the PD diagnosis model related to LRGs is constructed. Finally, ACP2 is a potential target for the relationship between Parkinson's disease and tumor. Show less
Fibroblast growth factor receptor 2 (FGFR2) represents an appealing therapeutic target for multiple cancers, yet no selective FGFR2 inhibitors have been approved for clinical use to date. Here, we rep Show more
Fibroblast growth factor receptor 2 (FGFR2) represents an appealing therapeutic target for multiple cancers, yet no selective FGFR2 inhibitors have been approved for clinical use to date. Here, we report the discovery of a series of new selective, irreversible FGFR2 inhibitors. The representative compound LHQ490 potently inhibited FGFR2 kinase activity with an IC Show less
Liver metastasis (LM) stands as a primary cause of mortality in metastatic colorectal cancer (mCRC), posing a significant impediment to long-term survival benefits from targeted therapy and immunother Show more
Liver metastasis (LM) stands as a primary cause of mortality in metastatic colorectal cancer (mCRC), posing a significant impediment to long-term survival benefits from targeted therapy and immunotherapy. However, there is currently a lack of comprehensive investigation into how senescent and exhausted immune cells contribute to LM. We gathered single-cell sequencing data from primary colorectal cancer (pCRC) and their corresponding matched LM tissues from 16 mCRC patients. In this study, we identified senescent and exhausted immune cells, performed enrichment analysis, cell communication, cell trajectory, and cell-based We identified senescent-like myeloid cells (SMCs) and exhausted T cells (TEXs) as the primary senescent and exhausted immune cells. Our findings indicate that SMCs and TEXs can potentially activate transcription factors downstream via ANGPTL4-SDC1/SDC4, this activation plays a role in regulating the epithelial-mesenchymal transition (EMT) program and facilitates the development of LM, the results of cell-based This study elucidates the potential molecular mechanisms underlying the occurrence of LM from various angles through single-cell multi-omics analysis in CRC. It also constructs a network illustrating the role of senescent or exhausted immune cells in regulating EMT. Show less