Neurodevelopmental disorders such as attention deficit and disruptive behaviour disorders (ADHD), autism spectrum disorder (ASD), and schizophrenia have been increasingly prevalent recently. Previous Show more
Neurodevelopmental disorders such as attention deficit and disruptive behaviour disorders (ADHD), autism spectrum disorder (ASD), and schizophrenia have been increasingly prevalent recently. Previous research has demonstrated that inflammatory activity from autoimmune diseases is involved in neurological diseases. However, some studies question the association between inflammatory activities and neurodevelopmental disorders. Herein, we attempt to clarify this relationship using Mendelian randomization (MR) analysis. We used systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes mellitus (T1D) to represent autoimmune diseases. First, we conducted MR analysis to examine associated SNPs between autoimmune and neurodevelopmental disorders. Second, we performed bidirectional MR analysis to identify 429 types of signalling peptides and proteins or relevant receptors with causality reported diseases. Finally, we compared the genes with the gene loci identified in the available TWAS-hub site. The MR results of autoimmune diseases on neurodevelopmental disorders did not present any significant association in all models. However, we identified 20-45 factors in ADHD, ASD, and schizophrenia, including semaphorin 3, IL-27 receptor subunit alpha, and fibroblast growth factor 16, which were considered clinically significant pro-inflammatory mediators. GO and KEGG enrichment analyses revealed unequal integrities among the three neurodevelopmental diseases, and we failed to identify a shared pathway linking autoimmune diseases and neurodevelopmental disorders. TWAS analysis indicated that CHRNA5 potentially mediates inflammatory activities in schizophrenia. According to our data, we failed to identify an association between autoimmune diseases and neurodevelopmental disorders. However, we demonstrated that some pro-inflammatory factors are involved in neurodevelopmental disorders. Show less
Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of estrogen receptor, progesterone receptor, and HER2 expression, which limits the availability of targeted t Show more
Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of estrogen receptor, progesterone receptor, and HER2 expression, which limits the availability of targeted therapies and results in poor prognosis. Immune checkpoint blockade (ICB) therapies have emerged as promising treatments by enhancing anti-tumor immunity; however, a substantial proportion of patients with TNBC exhibit primary or acquired resistance. This resistance is largely influenced by the tumor microenvironment (TME). This study uses integrated single-cell and spatial transcriptomics to elucidate key cellular mechanisms of resistance, with particular emphasis on lipid-mediated stromal-immune interactions within the TNBC TME. This investigation encompassed analysis of single-cell RNA sequencing (scRNA-seq) data from three TNBC datasets and spatial transcriptomic data from 43 TNBC samples. Spatial niches and cell-cell interactions were identified using the Multimodal Intersection Analysis (MIA) algorithm. Experimentally, adipose-derived mesenchymal stem cells (AD-SCs) were co-cultured with MDA-MB-231 TNBC cells to generate lipid-processing CAFs (lpCAFs) and subsequently co-cultured with THP-1 macrophages. Lipid metabolism and M2 polarization of macrophages were assessed using BODIPY staining, Oil Red O, qPCR, flow cytometry and Western blotting techniques. ABCA8 ABCA8 Show less
Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent type of heart failure, but effective treatments are lacking. Cardiac lymphatics play a crucial role in maintaining Show more
Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent type of heart failure, but effective treatments are lacking. Cardiac lymphatics play a crucial role in maintaining heart health by draining fluids and immune cells. However, their involvement in HFpEF remains largely unexplored. We examined cardiac lymphatic alterations in mice with HFpEF with comorbid obesity and hypertension, and in heart tissues from patients with HFpEF. Using genetically engineered mouse models and various cellular and molecular techniques, we investigated the role of cardiac lymphatics in HFpEF and the underlying mechanisms. In mice with HFpEF, cardiac lymphatics displayed substantial structural and functional anomalies, including decreased lymphatic endothelial cell (LEC) density, vessel fragmentation, reduced branch connections, and impaired capacity to drain fluids and immune cells. LEC numbers and marker expression levels were also decreased in heart tissues from patients with HFpEF. Stimulating lymphangiogenesis with an adeno-associated virus expressing an engineered variant of vascular endothelial growth factor C (VEGFC Our study provides evidence that cardiac lymphatic disruption, driven by impaired BCAA catabolism in LECs, is a key factor contributing to HFpEF. These findings unravel the crucial role of BCAA catabolism in modulating lymphatic biology, and suggest that preserving cardiac lymphatic integrity may present a novel therapeutic strategy for HFpEF. Show less
Sustained activation of hepatic stellate cells (HSCs) drives liver fibrosis in response to chronic liver injury and inflammation. It is reported that profibrogenic signals released from stressed/injur Show more
Sustained activation of hepatic stellate cells (HSCs) drives liver fibrosis in response to chronic liver injury and inflammation. It is reported that profibrogenic signals released from stressed/injured hepatocytes evoke fibrogenic responses in HSCs. However, intrahepatocyte players that modulate such cell-to-cell communications remain poorly defined. In this study, hepatic ChREBPΞ± is found to be reduced in mouse models of chemical-induced liver fibrosis as well as in three groups of human patients with liver fibrosis. ChrebpΞ±-LKO mice are highly sensitive to both chemical (CCL4 and TAA) and bile duct ligation (BDL)-induced liver injury and developed more advanced liver fibrosis without affecting liver lipid content. Hepatocyte ChREBPΞ± overexpression suppressed the activation of HSCs in an in vitro medium transfer experiment in part via inhibiting the expression of profibrogenic factors THBS1 and CTGF. RNA-Seq analysis revealed that E2F1, a novel effector of TGFΞ²-mediated fibrogenic pathway, is highly induced in the liver of ChrebpΞ±-LKO mice. Hepatic knockdown of E2F1 ameliorated the increased liver fibrosis in mice with hepatic ChrebpΞ± deficiency while reducing the expression of hepatic THBS1 and CTGF. Show less
Citrin deficiency (CD) is caused by the inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People wit Show more
Citrin deficiency (CD) is caused by the inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. Here we show that SLC25A13 loss causes the accumulation of glycerol-3-phosphate (G3P), which activates the carbohydrate response element-binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol and to transcribe key genes driving lipogenesis. Mouse and human data suggest that G3P-ChREBP is a mechanistic component of the Randle Cycle that contributes to metabolic-dysfunction-associated steatotic liver disease and forms part of a system that communicates metabolic states from the liver to the brain in a manner that alters food and alcohol choices. The data provide a framework for understanding FGF21 induction in varied conditions, suggest ways to develop FGF21-inducing drugs and suggest potential drug candidates for lean metabolic-dysfunction-associated steatotic liver disease and support of urea cycle function in CD. Show less
Perioperative neurocognitive disorder (PND) is a common complication following thoracic surgery and often leading to poor outcomes. Despite ongoing research, effective treatments for late PND remain l Show more
Perioperative neurocognitive disorder (PND) is a common complication following thoracic surgery and often leading to poor outcomes. Despite ongoing research, effective treatments for late PND remain limited. Identifying reliable biomarkers for early diagnosis is, therefore, essential. A prospective cohort study was conducted with 60 elderly patients undergoing thoracic surgery. Serum samples were collected within 10Β minutes prior to anesthesia and following extubation to measure adiponectin (APN), cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), aquaporin-4 (AQP4) and brain-derived neurotrophic factor (BDNF). Among PND patients, serum APN, PKA, AQP4, and BDNF levels were markedly decreased compared with the normal group. While serum cAMP (HRβ=β1.087, pβ=β0.695, 95% CI [0.284-4.166]) and PKA (HRβ=β0.996, pβ=β0.09, 95% CI [0.491-0.947]) were not significantly correlated with PND, serum APN (HRβ=β0.307, 95% CI [0.113-0.835], pβ=β0.021), AQP4 (HRβ=β0.204, 95% CI [0.060-0.697], pβ=β0.011), and BDNF (HRβ=β0.382, 95% CI [0.177-0.823], pβ=β0.014) were protective factors against PND. ROC analysis demonstrated that APN (AUCβ=β0.68, 95% CI [0.51-0.87]), AQP4 (AUCβ=β0.73, 95% CI [0.59-0.87]), BDNF (AUCβ=β0.73, 95% CI [0.59-0.87]), and the model of combining those biomarkers (AUCβ=β0.91, 95% CI [0.83-0.99]) could predict PND. PND patients exhibited a lower protective stress response to surgical trauma. High serum APN, AQP4, and BDNF levels were independent protective factors for PND, and a combined model of these biomarkers showed predictive potential for PND. Show less
Lipokines are a class of lipid-derived signaling molecules, playing essential roles in regulating metabolic homeostasis and systemic metabolism. In this review, we first comprehensively describe six m Show more
Lipokines are a class of lipid-derived signaling molecules, playing essential roles in regulating metabolic homeostasis and systemic metabolism. In this review, we first comprehensively describe six major lipokines, including palmitoleic acid (C16:1n7), 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), fatty acid esters of hydroxy fatty acids (FAHFAs), 12-hydroxyeicosapentaenoic acid (12-HEPE), lysophosphatidic acid (LPA), and 15-hydroxyeicosatetraenoic acid (15-HETE), focusing on their mechanistic roles in energy metabolism and inflammatory modulation as well as their cross-talk within different signaling pathways. These lipokines collectively contribute to metabolic homeostasis by regulating multiple pathways, including insulin signaling, AMPK activation, inflammatory modulation, and G-protein-coupled receptor-mediated pathways. Furthermore, we clarify the associations between lipokines and various diseases such as obesity, type 2 diabetes, cardiovascular diseases, non-alcoholic fatty liver disease, inflammatory disorders, and cancer, and discuss their potential as biomarkers and therapeutic targets. Despite current challenges, including functional complexity, limitations of model systems, and difficulties in clinical translation, lipokines demonstrate promising prospects in the prevention and treatment of metabolic diseases and application in precision medicine. Future research should prioritize the elucidation of the specific action mechanisms of different lipokines, development of highly sensitive detection methodologies, and large-scale clinical trials to facilitate the translation of the research results into practical medical applications. Show less
Women with autoimmune diseases (AIDs) experience chronic immune dysregulation and hormonal fluctuations, both of which may influence breast cancer risk. However, it remains unclear whether this risk i Show more
Women with autoimmune diseases (AIDs) experience chronic immune dysregulation and hormonal fluctuations, both of which may influence breast cancer risk. However, it remains unclear whether this risk is driven mainly by its treatment or the underlying disease, highlighting the need for integrating real-world data and genetic evidence. The FDA Adverse Event Reporting System (FAERS) were utilized to identify breast cancer safety signals among women with AIDs, analyzing 11,479 reports from 2004 to 2024. Disproportionality analyses using Reporting Odds Ratio (ROR) and Information Component (IC) were conducted. Then, we mapped these drugs to their target genes and performed mendelian randomization (MR) to assess their causal relationships with breast cancer. Finally, we investigated shared genetic architecture between breast cancer and AIDs using global and local genetic correlation, cross-trait meta-analysis, and transcriptome-wide association studies. We identified 13 immunosuppressive drugs (TNF inhibitors, interleukin inhibitors, and monoclonal antibodies), 3 immunostimulants and 16 adjunctive drugs associated with increased breast cancer reporting in patients with AIDs. The drugs with the highest case reports for positive disproportionality analysis were interferon beta-1a (N: 1731, IC [IC025] 1.56 [1.49]), natalizumab (798, 0.65 [0.54]), and infliximab (741, 0.64 [0.53]). MR results revealed causal links between 9 drug targets and breast cancer risk, such as FDPS (OR: 0.66, p: 1.33E-08), CALCRL (OR: 0.887, p: 4.77E-06) and PARP1 (OR: 1.051, p: 3.50E-06). Global genetic correlation identified significant shared heritability between breast cancer and 3 specific AIDs, including type 1 diabetes mellitus (rg: -0.242, p: 0.95E-4), ulcerative colitis (rg: 0.125, p: 0.29E-2), and migraine (rg: 0.078, p: 0.79E-2). Specifically, the most notable genetic overlap was observed between breast cancer and type 1 diabetes mellitus, with significant shared risk SNPs (rs12046289 and rs6679677) and susceptibility genes (ADCY3 and CENPO). Our study uncovered several immune-related drugs associated with increased breast cancer reporting in women with AIDs. This risk may be explained by several potential drug targets with causal roles, or by the shared genetic comorbidity between specific AIDs and breast cancer. These insights emphasize the need for tailored breast cancer surveillance and highlight potential molecular targets for intervention in vulnerable populations. Show less
Accelerated population aging and rising incidence of bone defects have intensified the need for advanced bone regeneration strategies. While tissue-engineered scaffolds fabricated via 3D printing offe Show more
Accelerated population aging and rising incidence of bone defects have intensified the need for advanced bone regeneration strategies. While tissue-engineered scaffolds fabricated via 3D printing offer promising alternatives to conventional grafts, most techniques fail to replicate the multi-scale fibrous architecture of native bone extracellular matrix, limiting their biofunctionality. To address this, we developed a hybrid manufacturing strategy integrating low-temperature thermally induced phase separation with extrusion-based 3D printing of polylactic acid (PLA) scaffolds. By optimizing solvent ratios (THF: DMFΒ =Β 3:1) and freezing temperatures (-196Β Β°C-4Β Β°C), we produced scaffolds with tunable micro-nano fibrous surfaces and macroporous structures. Key findings revealed that scaffolds processed at -196Β Β°C (PLA-196) exhibited the highest porosity (pore size: 6.01Β Β±Β 2.06Β ΞΌm), superior hydrophilicity, and enhanced compressive modulus. These scaffolds significantly promoted BMSC adhesion, proliferation, and osteogenic differentiation via activation of Show less
Pancreatic cancer has a complex immunosuppressive tumor microenvironment (TME), which is highly resistant to conventional therapies and emerging cancer immunotherapies. Oncolytic viruses are multiface Show more
Pancreatic cancer has a complex immunosuppressive tumor microenvironment (TME), which is highly resistant to conventional therapies and emerging cancer immunotherapies. Oncolytic viruses are multifaceted killers of malignant tumors, which can selectively infect, replicate in and lyse tumor cells, release tumor-associated antigens to stimulate specific antitumor immune responses, and recruit immune cells into the TME, turning "cold" tumors "hot". Here, we report a novel A novel oncolytic VV with deletion of the TK, N1L, and A41L genes, and expression of the red fluorescent protein (RFP) gene (VVL-TD-RFP) was constructed using CRISPR-Cas9-based homologous recombination. This virus was armed with IL-27, creating VVL-TD-IL-27. The characteristics of these viruses were evaluated VVL-TD-RFP cured 71.4% of tumor-bearing mice, compared with 14.3% of animals treated with VVLΞTKΞN1L that does not have an A41L gene deletion. Efficacy was mainly dependent on elevated dendritic cell (DC) populations, activation of DC, CD86 VVL-TD-mIL-27 is a potential immunotherapy agent for the treatment of pancreatic cancer, and a clinical study of this virus is warranted. Show less
Biomarker profiling from biofluids such as blood are widely measured in clinical research, using for example Olink proteomics panels. One such research focus area is cardiovascular disease (CVD), for Show more
Biomarker profiling from biofluids such as blood are widely measured in clinical research, using for example Olink proteomics panels. One such research focus area is cardiovascular disease (CVD), for which chronic sleep restriction (SR) is a risk factor. However, it remains unclear whether blood levels of commonly measured CVD biomarkers are sensitive to acute dynamic factors such as SR, physical exercise (PEx), and time of day. In this crossover design, 16 normal-weight, healthy men underwent three highly standardized in-lab nights of SR (4.25 h/night) and normal sleep (NS, 8.5 h/night) in randomized order, with 88 CVD blood protein biomarkers quantified using the Olink technology (and selected validation using ELISA) in the morning, evening, and immediately before and repeatedly after 30 min of high-intensity exercise. We found significant time-of-day-dependent changes in several CVD biomarkers. Whereas several proteins were exercise-induced across sleep conditions (such as the canonical exerkines IL- 6 and BDNF), exercise-induced proteomic dynamics differed in response to recurrent SR, compared with following NS. Moreover, SR compared with NS resulted in a biomarker profile previously associated with increased prospective risk of several CVDs across large-scale cohorts (such as higher circulating levels of IL-27 and LGALS9). Our findings highlight how dynamic physiology can modulate CVD biomarker levels. These results also underscore the need to consider sleep duration as a key determinant of cardiovascular health-an emphasis reflected in recent American Heart Association guidelines. Further studies in women, older individuals, and patients with prior CVD, andΒ across different chronotypes and dietary schedules are warranted. Show less
Tumorigenesis is typically accompanied by cellular dedifferentiation and the acquisition of stem cell-like attributes. However, few studies have comprehensively evaluated the putative relationships be Show more
Tumorigenesis is typically accompanied by cellular dedifferentiation and the acquisition of stem cell-like attributes. However, few studies have comprehensively evaluated the putative relationships between these characteristics and various cancers. Here, we integrated gene expression and DNA methylation quantitative trait loci (cis-eQTL and cis-mQTL) data from the blood to perform multi-omics Mendelian randomization analysis. Our analyses revealed 967 stem cell-associated genes (PΒ <Β 0.05) and 11,262 methylation sites (PΒ <Β 0.01) significantly related to 12 cancers. SMAD7 (cg14321542) in colon cancer, IGF2 (cg13508136) in prostate cancer, and FADS1 (cg07005513) in rectal cancer were prioritized as candidate causal genes and regulatory elements. Notably, using cis-eQTL data from the corresponding tissue sites, we detected 16 stem cell-associated genes dramatically causally associated with six cancers (FDR<0.2). The gene THBS3 was particularly common in both blood and stomach tissues and exhibited prognostic significance. Furthermore, it was markedly associated with one microbial metabolic pathway and four immunophenotypes. Functional validation using the ECC12 gastric cancer cell line revealed that the inhibition of its expression could accelerate oxidative phosphorylation and reactive oxygen species production, reduce clonal proliferation ability, and promote the apoptosis of stomach tumor cells. Additionally, based on spatial transcriptomic data from gastrointestinal cancers, the results demonstrated the clusters enriched with the most stem cell-associated genes exhibited significantly enhanced tumor-promoting potency, and the THBS3-expressing cells displayed suppressed oxidative phosphorylation. Overall, this study enhances our understanding of tumorigenic mechanisms and aids in the identification of therapeutic targets. Show less
Acupuncture has been proposed as a therapeutic intervention for stroke recovery, yet the underlying molecular mechanisms remain poorly understood. In this study, we used a mouse model of hemorrhagic s Show more
Acupuncture has been proposed as a therapeutic intervention for stroke recovery, yet the underlying molecular mechanisms remain poorly understood. In this study, we used a mouse model of hemorrhagic stroke induced by autologous blood injection to investigate the effects of acupuncture on post-stroke recovery at the cellular and molecular levels, utilizing single-cell RNA sequencing. Our findings revealed that acupuncture modulates the gene expression of microglia, astrocytes, and oligodendrocytes, three major glial cell types, which may contribute to the improvement of stroke-induced phenotypes. Notably, we identified a potential role of the APOE-TREM2 signaling axis, with ligand-binding interactions enhancing microglia activation and promoting their neuroprotective functions. These findings also suggested that acupuncture may promote microglia-astrocyte interactions, leading to enhanced neuroinflammation resolution and tissue repair. Our study provided new insights into the cellular mechanisms underlying acupuncture's therapeutic effects in stroke recovery and highlighted the potential of targeting glial cell-mediated pathways, including APOE-TREM2, as a strategy for improving post-stroke rehabilitation. Show less
Interleukin-27 receptor alpha (IL27RA), a key subunit of the interleukin-27 receptor, plays an essential role in T cell-mediated immunity. However, its relevance in breast cancer and response to immun Show more
Interleukin-27 receptor alpha (IL27RA), a key subunit of the interleukin-27 receptor, plays an essential role in T cell-mediated immunity. However, its relevance in breast cancer and response to immunotherapy remains unexplored. We integrated bulk and single-cell RNA sequencing data from TCGA, GEO, and scRNA-seq datasets to analyze IL27RA expression, prognosis, immune infiltration, and treatment response. TIDE and immune checkpoint-treated clinical cohorts were used to assess immunotherapy responsiveness. Chemotherapy sensitivity was predicted using GDSC data, and IL27RA protein expression was validated by Western blot. IL27RA was downregulated in breast cancer but high expression correlated with favorable survival. It was primarily expressed in T cells, particularly CD8βΊ subsets, and associated with enriched immune infiltration and elevated checkpoint gene expression. IL27RA high-expression patients showed lower TIDE scores, better outcomes in ICI-treated cohorts, and higher sensitivity to multiple chemotherapeutic agents. IL27RA is a potential immune biomarker that reflects an inflamed tumor microenvironment and predicts benefit from immunotherapy and chemotherapy in breast cancer. These findings provide novel insights into immune-based stratification using single-cell transcriptomic data. Show less
The microtubule actin crosslinking factor 1 ( Trios-based whole-exome sequencing was performed on a cohort with generalised epilepsy from the China Epilepsy Gene 1.0 project. The spatial-temporal expr Show more
The microtubule actin crosslinking factor 1 ( Trios-based whole-exome sequencing was performed on a cohort with generalised epilepsy from the China Epilepsy Gene 1.0 project. The spatial-temporal expression, single-cell sequencing and genotype-phenotype correlation were analysed to explore the role of Two de novo heterozygous and eight biallelic Show less
Phenotypic transformation of Schwann cells (SCs) plays a crucial role in nerve regeneration. Previous studies have demonstrated that Runx2 significantly influences the biological behavior of SCs. None Show more
Phenotypic transformation of Schwann cells (SCs) plays a crucial role in nerve regeneration. Previous studies have demonstrated that Runx2 significantly influences the biological behavior of SCs. Nonetheless, the regulatory mechanisms that govern its epigenetic regulation are not yet fully elucidated. To facilitate this investigation, an adenovirus for the overexpression of Runx2 was constructed. Healthy adult Sprague-Dawley rats, weighing between 100 and 150Β g and irrespective of sex, were randomly selected for the study. After establishing a model of sciatic nerve crush injury, tissue samples were harvested for histological analysis at both 4 and 7Β days post-injury. In vitro, an Runx2-overexpressing SC line was established. Thorough analysis of transcriptome data, coupled with CUT&Tag sequencing of histones and transcription factors in SCs following Runx2 overexpression, was conducted. Additionally, single-cell RNA sequencing data from GSE216665 were incorporated to elucidate the mechanistic role of Runx2. The findings were subsequently validated through dual-luciferase assays. Following nerve crush injury, Runx2-positive SCs were identified at the injury site. Through comprehensive multiomics analysis, we discovered that lipid metabolism was disrupted in Runx2-overexpressing SCs. Further investigation established a detailed super-silencer landscape in these cells, revealing that elevated Runx2 levels form a super-silencer within the transcriptional regulatory region of the Lpl gene, thereby downregulating Lpl expression. Runx2 can modulate the biological behavior of SCs by forming super-silencers that interfere with the expression of lipid metabolism genes, such as Lpl, thereby altering the metabolic capacity of SCs. Show less
Diabetic cardiomyopathy (DCM) in type 2 diabetes (T2D) may lead to heart failure and patient death. Fibroblast growth factor 21 (FGF21) is a therapeutic candidate for treating this disease. However, o Show more
Diabetic cardiomyopathy (DCM) in type 2 diabetes (T2D) may lead to heart failure and patient death. Fibroblast growth factor 21 (FGF21) is a therapeutic candidate for treating this disease. However, one impediment to its clinical use is its weak ability to activate downstream signaling pathways. In this study, based on our in-depth understanding of the binding properties of fibroblast growth factor receptor 1c (FGFR1c) with paracrine FGF1 and endocrine FGF21, we engineered a novel FGF21 analog named FGF21 Show less
The existing evidence regarding the impact of tamoxifen on lipoprotein(a) and apolipoproteins remains inconsistent. Therefore, this updated meta-analysis of randomized controlled trials (RCTs) aims to Show more
The existing evidence regarding the impact of tamoxifen on lipoprotein(a) and apolipoproteins remains inconsistent. Therefore, this updated meta-analysis of randomized controlled trials (RCTs) aims to enhance the quality of evidence concerning the effects of tamoxifen on these lipid parameters. Eligible RCTs published up to October 2024 were meticulously selected through a comprehensive search. A meta-analysis was then performed using a random-effects model, and results were presented as the weighted mean difference (WMD) with a 95% confidence interval (CI). Findings from the random-effects model revealed an increase in ApoA-I (WMD: 15.22βmg/dL, 95% CI: 6.43-24.01, Pβ=β0.001), alongside decreases in ApoB (WMD: -9.33βmg/dL, 95% CI: -15.46 to -3.19, Pβ=β0.003) and lipoprotein(a) (WMD: -3.35βmg/dL, 95% CI: -5.78 to -0.91, Pβ=β0.007) levels following tamoxifen treatment in women. Subgroup analyses indicated a more significant reduction in lipoprotein(a) levels in RCTs with a duration of β€24 weeks (WMD: -3.65βmg/dL) and in studies using tamoxifen doses of β₯20βmg/day (WMD: -4.53βmg/dL). This meta-analysis provides evidence that tamoxifen leads to a decrease in lipoprotein(a) levels, along with reductions in ApoB and increases in ApoA-I among women. Show less
The deer antler is a fully regenerable and the fastest-growing osseous organ. Circular RNA (circRNA), a novel member of the non-coding RNA family, has significant research potential and crucial roles Show more
The deer antler is a fully regenerable and the fastest-growing osseous organ. Circular RNA (circRNA), a novel member of the non-coding RNA family, has significant research potential and crucial roles in biological processes. This study aims to explore the impact and mechanisms of circRNA505 on antler chondrocytes. Functional experiments demonstrated that m5C-modified circRNA505 inhibits antler chondrocyte proliferation, enhances osteogenic differentiation, and facilitates cellular glycolysis. Mechanistically, dual luciferase and AGO2-RIP assays revealed a direct binding relationship between circRNA505, miR-127, and p53. Rescue assays further showed that circRNA505 affects cell proliferation and differentiation through the miR-127/p53 axis. Meanwhile, RNA Antisense Purification (RAP) screening and analysis of related proteins binding to circRNA505 demonstrated that circRNA505 binds to LDHA and increases the level of LDHA phosphorylation through FGFR1 to promote cellular glycolysis by FISH-IF, RIP, and Western blot experiments. Additionally, Me-RIP assays confirmed the m5C methylation modification of circRNA505. NSUN2 mediates the m5C modification of circRNA505, affecting its stability, while the m5C reader ALYREF promotes the nuclear export of circRNA505 in an ALYREF-dependent manner. This study provides new insights into the regulatory mechanisms underlying rapid antler development. Show less
Obesity-induced metabolic inflammation is a key driver of chronic kidney disease (CKD), with immune dysregulation, particularly among lymphocytes, contributing to early disease pathology. To explore t Show more
Obesity-induced metabolic inflammation is a key driver of chronic kidney disease (CKD), with immune dysregulation, particularly among lymphocytes, contributing to early disease pathology. To explore the role of apolipoprotein A4 (Apoa4) in regulating immune cell metabolism and function, we establish high-fat diet-induced obese (DIO) models using wild-type and Show less
Sarcopenia is a common age-related skeletal muscle disorder that lacks diagnostic and therapeutic options. Emerging evidence suggests that cuproptosis, a copper-dependent form of regulated cell death, Show more
Sarcopenia is a common age-related skeletal muscle disorder that lacks diagnostic and therapeutic options. Emerging evidence suggests that cuproptosis, a copper-dependent form of regulated cell death, contributes to muscle atrophy, yet the underlying associations remain poorly understood. To address this gap, we integrated two GEO datasets (GSE1428 and GSE25941) for differential expression analysis and applied weighted gene co-expression network analysis (WGCNA) to identify disease-related modules. Cuproptosis-related genes (CRGs) from GeneCards database were intersected with DEGs and WGCNA gene modules to obtain sarcopenia-associated cuproptosis DEGs (SAR-CUP DEGs). Functional enrichment was performed using GO, KEGG, GSEA and GSVA. Hub genes were further identified through three machine learning algorithms (LASSO, RF, and SVM). Regulatory networks were constructed via NetworkAnalyst and GeneMANIA database. A diagnostic model was also developed and later validated in an independent dataset (GSE136344). Experimental validation was performed in a D-galactose-induced sarcopenia cell model. We identified 367 DEGs and 7 co-expression modules, among which 14 SAR-CUP DEGs were mainly enriched in mitochondrial energy metabolism pathways. Machine learning methods highlighted Show less
Despite the increasing approval and ongoing clinical trials of FGFR-targeted therapies, accurately detecting FGFR fusions remains a challenge due to limited research, low incidence rates, complex fusi Show more
Despite the increasing approval and ongoing clinical trials of FGFR-targeted therapies, accurately detecting FGFR fusions remains a challenge due to limited research, low incidence rates, complex fusion partner distribution, and unique kinase domain distribution. We conducted a multicenter study to comprehensively profile FGFR fusions in the largest Chinese pan-cancer cohort to date, comprising 118 FGFR fusions from 114 individuals. Both DNA- and RNA-based sequencing approaches were utilized to reveal novel and fundamental features of FGFR fusion. Our research reveals an incidence rate of 0.96% for FGFR rearrangements within this Chinese cohort, including a high incidence rate of FGFR fusions (40%) in parotid gland carcinoma. However, this is based on a small sample size of 5 tumors and should be interpreted cautiously pending validation in larger cohorts. We also uncovered distinct breakpoint distribution patterns across various FGFR rearrangements. For example, a primary breakpoint in intron17 of FGFR2 was predominant (21/22), while FGFR1/3 breakpoints displayed substantial diversity. For the first time, we identified "hot" breakpoints in FGFR1 intron17, exon18, and FGFR3's 3' untranslated region. These findings underline the importance of incorporating these regions in targeted sequencing to ensure comprehensive detection of FGFR1/3 fusions. Notably, we observed a predilection for intrachromosomal distribution in common FGFR1/2/3 fusions. In contrast, most novel fusions (12/15) exhibited an interchromosomal distribution pattern, indicating variations in the fusion formation mechanism. Importantly, our study demonstrates the substantial incremental value of RNA-NGS or other orthogonal methods in confirming the functionality of FGFR rearrangements initially identified by DNA sequencing. In our cohort, 46% (6/13) of rare FGFR1/2/3 fusions lacked detectable RNA transcripts; however, this does not definitively indicate non-functionality as factors such as low RNA quality, expression below detection limits, or nonsense-mediated decay may contribute. Therefore, RNA-based validation is critical for accurately identifying potentially targetable FGFR fusions and guiding therapy. Our findings offer critical novel insights into functional FGFR fusions and bear considerable clinical implications for identifying individuals whose tumors are most likely to respond favorably to FGFR-targeted therapies. Show less
Dual-specificity protein phosphatase 6 (DUSP6), also known as mitogenactivated protein kinase phosphatase 3 (MKP-3), was considered as a functional candidate gene for white fat accumulation in mice. H Show more
Dual-specificity protein phosphatase 6 (DUSP6), also known as mitogenactivated protein kinase phosphatase 3 (MKP-3), was considered as a functional candidate gene for white fat accumulation in mice. However, the physiological function of the DUSP6 gene on white adipocyte adipogenesis in farm animals remains unknown. In this study, we aimed to clarify the effect of DUSP6 on porcine subcutaneous preadipocyte proliferation and differentiation. We first make clear that the patterns of DUSP6 expression is associated with fat contents in porcine fat deposition related tissues. Porcine subcutaneous preadipocytes were isolated and induced to differentiation. Small interfering RNAs were applied to deplete DUSP6. MTT assay, CCK-8 analysis, Oil Red O staining, triglyceride determination and reverse transcription quantitative polymerase chain reaction were applied to study the regulatory role of DUSP6 during adipocyte adipogenesis in pigs. We found that the expression levels of DUSP6 were significantly higher in backfat and longissimus dorsi tissues from fat-type pigs than in those from lean-type pigs. Consistently, the significantly induced expression of DUSP6 was also observed in differentiated adipocytes. In addition, knockdown of DUSP6 greatly inhibited preadipocytes proliferation, through the decreased cell viability and downregulated mRNA expressions of cell proliferation-associated genes, including PCNA, CDK1, CDK2. Furthermore, knockdown of DUSP6 significantly inhibited preadipocytes differentiation, as evidenced by markedly reduced lipid droplet formation, attenuated triglyceride accumulation and downregulated expression levels of adipogenic transcription masters (PPARΞ³, C/EBPΞ², FASN and FABP4) in DUSP6 knockdown cells. Our results demonstrate that DUSP6 is required for white adipocyte adipogenesis in pigs. Show less
Coronary heart disease (CHD) arises from a complex interplay of genetic and environmental factors. This study examines the influence of This retrospective case-control study enrolled 900 CHD patients Show more
Coronary heart disease (CHD) arises from a complex interplay of genetic and environmental factors. This study examines the influence of This retrospective case-control study enrolled 900 CHD patients and 900 control subjects. We evaluated associations between conventional cardiovascular risk factors and polymorphisms at the No significant differences were observed in the distribution of The Show less
Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer (BC), characterized by limited treatment options and poor clinical outcomes. Aberrant FGFR signaling has been implic Show more
Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer (BC), characterized by limited treatment options and poor clinical outcomes. Aberrant FGFR signaling has been implicated in TNBC; however, the therapeutic potential of targeting FGFRs for TNBC treatment remains unclear. This study investigated the anti-cancer activity of the selective pan-FGFR inhibitor Erdafitinib and its underlying mechanisms using both in vitro and in vivo models. The results demonstrated that Erdafitinib suppressed TNBC tumorigenicity by promoting FGFR1/4 degradation, generating reactive oxygen species (ROS), inducing DNA damage, and ultimately triggering cell death. Mechanistic analyses revealed that Erdafitinib facilitated FGFR1/4 degradation through ubiquitination, enhanced interaction between TRIM25 and FGFR1/4, and subsequent lysosomal degradation. Furthermore, RNA-seq data from the TCGA and GEO databases, along with paired tumor tissues from TNBC patients, indicated that FGFR4 was significantly upregulated in TNBC. Notably, co-knockdown of FGFR1 and FGFR4 induced cytotoxicity in MDA-MB-231 cells, highlighting the therapeutic relevance of FGFR1/4 degradation by Erdafitinib in TNBC. These findings provide novel insights into the mechanisms underlying the anti-cancer efficacy of Erdafitinib, supporting its potential as a promising therapeutic agent for TNBC. Show less
Altered levels of human plasma metabolites have been implicated in the etiology of bipolar disorder (BD). However, the causality between metabolites and the disease was not well described. We performe Show more
Altered levels of human plasma metabolites have been implicated in the etiology of bipolar disorder (BD). However, the causality between metabolites and the disease was not well described. We performed a bidirectional metabolome-wide Mendelian randomization (MR) analysis to evaluate the potential causal relationships between 871 plasma metabolites and BD. We used DrugBank and ChEMBL to evaluate whether related metabolites are potential therapeutic targets. Finally, Bayesian colocalization analysis was performed to identify shared genomic loci BD and identified metabolites. Our MR results showed that six metabolites were significantly associated with a reduced risk of BD, including arachidonate (20:4n6) (OR: 0.90, 95% CI: 0.84-0.95) and sphingomyelin (d18:2/24:1, d18:1/24:2) (OR: 0.92, 95% CI: 0.87-0.96), while five metabolites were significantly associated with an increased risk of BD, including 1-palmitoyl-2-linoleoyl-GPE (16:0/18:2) (OR: 1.09, 95% CI: 1.05-1.13). However, our reverse MR analysis showed that BD was not associated with the levels of any metabolite. Additionally, the leave-one-out analysis revealed SNPs within chromosome 11 loci harboring MYRF, FADS1, and FADS2 as ones with the potential to influence partial causal effects. Druggability evaluation showed that 10 of the BD-related metabolites, such as sphingomyelin and cytidine, have been targeted by pharmacologic intervention. Colocalization analysis highlighted one colocalized region (chromosome 11q12) shared by 11 metabolites and BD and pointed to some genes as possible players, including FADS1, FADS2, FADS3, and SYT7. Our study supported a causal role of plasma metabolites in the susceptibility to BD, and the identified metabolites may provide a new avenue for the prevention and treatment of BD. Show less
Fibrotic remodeling of nucleus pulposus (NP) leads to structural and mechanical anomalies of intervertebral discs that prone to degeneration, leading to low back pain incidence and disability. Emergen Show more
Fibrotic remodeling of nucleus pulposus (NP) leads to structural and mechanical anomalies of intervertebral discs that prone to degeneration, leading to low back pain incidence and disability. Emergence of fibroblastic cells in disc degeneration has been reported, yet their nature and origin remain elusive. In this study, we performed an integrative analysis of multiple single-cell RNA sequencing datasets to interrogate the cellular heterogeneity and fibroblast-like entities in degenerative human NP specimens. We found that disc degeneration severity is associated with an enrichment of fibrocyte phenotype, characterized by CD45 and collagen I dual positivity, and expression of myofibroblast marker Ξ±-smooth muscle actin. Refined clustering and classification distinguished the fibrocyte-like populations as subtypes in the NP cells - and immunocytes-clusters, expressing disc degeneration markers HTRA1 and ANGPTL4 and genes related to response to TGF-Ξ². In injury-induced mouse disc degeneration model, fibrocytes were found recruited into the NP undergoing fibrosis and adopted a myofibroblast phenotype. Depleting the fibrocytes in CD11b-DTR mice in which myeloid-derived lineages were ablated by diphtheria toxin could markedly attenuate fibrous modeling and myofibroblast formation in the NP of the degenerative discs, and prevent disc height loss and histomorphological abnormalities. Marker analysis supports that disc degeneration progression is dependent on a function of CD45 Show less
Sow colostrum is rich in lactoferrin (LF), which can be orally administered to protect piglets from porcine epidemic diarrhea virus (PEDV) infection, thereby reducing piglet mortality. Previous study Show more
Sow colostrum is rich in lactoferrin (LF), which can be orally administered to protect piglets from porcine epidemic diarrhea virus (PEDV) infection, thereby reducing piglet mortality. Previous study has shown that sows fed with recombinant B. subtilis expressing 4,4-diaponeurosporene (B.S-Dia) have significantly higher LF levels in their colostrum compared to sows fed with B. subtilis. This suggests that 4,4-diaponeurosporene (DNP) produced by B.S-Dia may influence LF content in sow colostrum. In this study, we first extracted DNP expressed by the recombinant probiotic using acetone-hexane extraction. Flow cytometry, RT-qPCR, and ELISA analyses demonstrated that DNP promoted dendritic cell (DCs) maturation and increased the expression of IL-1Ξ² and IL-27. We then established a method for isolating neutrophils from sow colostrum and set up a co-culture system of neutrophils and DCs to investigate factors regulating LF secretion. The results indicated that DCs secretions enhanced LF expression in neutrophils. Finally, the application of IL-27 inhibitors confirmed that IL-27 produced by DCs upregulates LF secretion in neutrophils. These findings elucidate the mechanism by which DNP promotes LF production in colostrum and provide a theoretical foundation for using B.S-Dia to prevent and control PEDV infection in piglets. Show less