👤 Zicheng Shao

Lung adenocarcinoma (LUAD) remains the leading cause of cancer deaths worldwide. Apurinic/apyrimidinic endonuclease 1 (APE1), an enzyme integral to DNA repair and redox signaling, is notably upregulated in LUAD. Here we reveal that APE1 amplification, primarily via allele duplication, strongly correlates with poor prognosis in LUAD patients. Using human LUAD cell lines and a Show less

This study aims to explore the association between plasma metabolites and chronic kidney disease progression in individuals with type 2 diabetes. We performed a comprehensive metabolomic analysis in a prospective cohort study of 5144 multi-ancestral individuals with type 2 diabetes in Singapore, using eGFR slope as the primary outcome of kidney function decline. In addition, we performed genome-wide association studies on metabolites to assess how these metabolites could be genetically influenced by metabolite quantitative trait loci and performed colocalisation analysis to identify genes affecting both metabolites and kidney function. Elevated levels of 61 lipids with long unsaturated fatty acid chains such as phosphatidylethanolamines, triacylglycerols, diacylglycerols, ceramides and deoxysphingolipids were prospectively associated with more rapid kidney function decline. In addition, elevated levels of seven amino acids and three lipids in the plasma were associated with a slower decline in eGFR. We also identified 15 metabolite quantitative trait loci associated with these metabolites, within which variants near TM6SF2, APOE and CPS1 could affect both metabolite levels and kidney functions. Our study identified plasma metabolites associated with prospective renal function decline, offering insights into the underlying mechanism by which the metabolite abnormalities due to fatty acid oversupply might reflect impaired β-oxidation and associate with future chronic kidney disease progression in individuals with diabetes. Show less

Diabetic kidney disease (DKD) is a severe global complication of diabetes, yet its molecular mechanisms remain incompletely understood. This study aimed to investigate the role of protein glycosylation in DKD pathogenesis and its association with gene expression changes, with the goal of identifying diagnostic biomarkers and personalized therapeutic targets. Integrated bioinformatics and machine learning approaches were applied to analyze multiple gene expression datasets. Differentially expressed glycosylation-related genes were identified, followed by unsupervised clustering to define molecular subtypes. Functional enrichment, immune cell infiltration analysis, and machine learning algorithms (including feature selection for hub genes) were employed. qPCR validation was performed on clinical DKD and normal kidney tissues, and ROC curves were generated to assess diagnostic potential. Unsupervised clustering of glycosylation-related genes revealed two distinct DKD molecular subtypes with differential pathway activation (e.g., extracellular matrix remodeling) and immune infiltration patterns. Six hub genes (S100A12, EXT1, SBSPON, ADAMTS1, FMOD, SPTB) were identified as critical to DKD pathogenesis through machine learning. Immune infiltration analysis showed significant differences in macrophage and neutrophil activity between DKD and controls and Immunohistochemical results confirmed the occurrence of immune infiltration. qPCR validation confirmed dysregulation of hub genes in DKD tissues compared to normal samples. ROC analysis demonstrated high diagnostic accuracy for these genes. This study highlights abnormal protein glycosylation as a key player in DKD and identifies six hub genes with potential as diagnostic biomarkers. The molecular subtypes and immune infiltration patterns provide insights into disease heterogeneity, paving the way for personalized therapies. Future studies should validate these findings in larger cohorts with explicit sample sizes to strengthen clinical applicability. 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 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

Demyelination diseases are characterized by injury to large (A-type) myelinated nerve fibers, and by secondary damage to small (C-type) sensory fibers, which leads to chronic pain symptoms, such as allodynia. The mechanisms underlying the interactions between the two fiber types are not clear. This study aims to investigate the role of lysophosphatidic acid (LPA) signaling in satellite glial cells (SGCs) within the dorsal root ganglia (DRG) in demyelination-induced chronic pain. A demyelination model was established by injecting cobra venom into the tibial nerve of 8-10-week-old Sprague-Dawley rats to selectively damage A-fiber myelin. Myelin morphology was observed via transmission electron microscopy (TEM) at 1, 3, 7, and 14 days post-injection. Pain behaviors (mechanical hypersensitivity, thermal hyperalgesia, and spontaneous pain) were assessed to evaluate progression. In vivo electrophysiology was performed to analyze sensory conduction and excitability changes in A- and C-type neurons. Immunofluorescence staining assessed SGC activation, LPA1 receptor (LPA1R) expression, and connexin 43 (Cx43) dynamics in the L4 DRG over time. Pharmacological interventions targeting LPA1R and SGC activation were applied to evaluate their effects on pain behaviors, cytokine release, and neuronal excitability using RT-PCR, ELISA, and spinal electrophysiology. Cobra venom induced a selective A-fiber demyelination and persistent pain in rats. It also upregulated the expression of LPA1R on SGCs that surround large DRG neurons, which normally mediate non-noxious input, and increased gap junction-mediated coupling via Cx43, leading to the activation of SGCs surrounding small nociceptive neurons. The activated SGCs released inflammatory mediators that increased nociceptive neuron excitability, driving chronic pain. In support of these results, pharmacological inhibition of LPA1R-mediated SGCs activation reversed this process. Our study demonstrates that LPA-LPA1R signaling in SGCs drives A-fiber demyelination-induced neuropathic pain by promoting Cx43-mediated SGC-neuron crosstalk and cytokine release. Targeting this pathway may represent a promising strategy to alleviate demyelination-associated chronic pain. Show less

ObjectiveRespect for older adults (ROA) is shaped by multiple ecological systems and personal factors. However, little is known about the potential subgroups that may differ in their constellation of influencing factors and their association with ROA.MethodsThis cross-sectional study included 1,476 community-dwelling Chinese adults aged 18-83 years ( Show less

Lymphoplasmacytic Lymphoma (LPL) with immunoglobulin (Ig)A paraprotein is rare. When plasma cells dominate, the diagnosis becomes more challenging. We reported a case of a 71-year-old male with elevated creatinine, splenomegaly, monoclonal IgA, and MYD88 mutation. Only monoclonal plasma cells were detected first, leading to a misdiagnosis of multiple myeloma. When progressive spleen enlargement was observed, re-evaluation revealed the emergence of monoclonal lymphocytes and the diagnosis was revised to LPL. The addition of rituximab to DVD regimen led to a partial response. For cases where an initial definitive diagnosis cannot be established, close follow-up is required for timely diagnosis revision and therapeutic adjustment. Show less

At present, studies on tadpole nutrition and metabolism are scarce. This study aimed at comparing the influence of two protein sources, fishmeal (FM) and dried whole egg powder (DWEP), on tadpoles from the perspective of growth, the metamorphosis rate, lipid metabolism, antioxidant properties and the intestinal flora. In this experiment, the control diet was set to contain no FM or DWEP. Based on the control diet, 5% and 10% FM or DWEP were included, respectively. The results of the experiment indicated that FM or DWEP inclusion significantly enhanced the growth performance and metamorphosis rate ( Show less

The micropapillary (MIP) pattern is a high-grade histological subtype of lung adenocarcinoma (LUAD) with poor prognosis. In this study, surgically resected tumor samples from 101 patients with stage I-III MIP-LUAD (MIP ≥30%) were microdissected to separate MIP components from non-MIP components, all of which underwent RNA and DNA whole-exome sequencing (WES). The genomic and transcriptomic landscapes of MIP and non-MIP components within MIP-enriched tumor tissues demonstrated remarkable similarities, notably marked by high epidermal growth factor receptor (EGFR) alteration frequencies. However, when compared to MIP-naïve LUAD tissues, MIP components showed higher chromosomal instability and revealed 18 enriched alterations, encompassing EGFR mutations, EGFR amplifications, and CDKN2A/CDKN2B deletions, which all linked to upregulation of cell proliferation pathways and downregulation of immune pathways. Shared mutations were observed in 97.8% (91/93) of patients with paired DNA WES data for MIP and non-MIP components within the same tissues, suggesting a common origin. The recurrence-free survival analysis identified MACF1, PCLO, ADGRV1, and Fanconi Anemia pathway mutations as negative indicators. In all, we conducted an in-depth analysis of the molecular characteristics and transformation mechanisms of MIP-LUAD, employing microdissection techniques to investigate the genomic and transcriptomic levels within a substantial cohort, providing insights for precision medicine of this aggressive cancer subtype. © 2025 The Pathological Society of Great Britain and Ireland. Show less

Based on the special role of mitochondria in tumour energy metabolism. We hope to explore the pathogenesis and potential therapeutic targets of Hepatocellular carcinoma by analysing the expression of 1136 mitochondrial proteins in hepatocellular carcinoma and their mechanisms in the Human.MitoCarta3.0 database. The expression of 1136 mitochondrial proteins in HCC was analysed by the TCGA database. We selected the top eight mitochondrial proteins among the highly expressed mitochondrial proteins that had not been studied in HCC and were statistically (P < 0.05) significant, according to fold change. Protein expression was verified by real-time quantitative reverse transcription polymerase chain reaction in tumours and adjacent paracancerous tissues of 34 pairs of HCC patients. Further in HCC cells, the expression of FDPS, DNA2 and MYO19 was verified. Clinical correlations of FDPS, DNA2 and MYO19 were analysed by UALCAN and KM-plot databases. Immune correlation of FDPS, DNA2 and MYO19 was analysed by TIMER2.0 and Sangerbox3.0 online databases. Mitochondrial proteins were expressed on all 24 chromosomes. More than 2/3 of the mitochondria were 100-600 bp long, of which 204 were secondary transmembrane proteins. 1136 mitochondrial proteins, of which 202 are not included in the TCGA database. Of the 934 mitochondrial proteins included in the TCGA database, 706 were highly expressed and 228 were poorly expressed in HCC. Further validated by HCC tissues and cells, the study found that significantly high expression of FDPS, DNA2 and MYO19 was negatively correlated with the prognosis of HCC patients. The results of the immune correlation analysis showed that DNA2 and MYO19 may be involved in regulating the infiltration of immune cells. 934 out of 1136 mitochondrial proteins in the Human.MitoCarta3.0 database were differentially expressed in HCC, suggesting that mitochondrial proteins play an important biological role in the development of HCC. Further experimental validation and bioinformatics analyses showed that functional mitochondrial proteins are potential pathophysiological mechanisms for malignant progression of HCC. Mitochondrial proteins, in the future, have the potential to be valuable therapeutic targets for HCC. Show less

Hyperlipidemia and chronic kidney disease (CKD) are well-established risk factors for cardiovascular disease and act synergistically to promote vascular inflammation and disease progression. However, the mechanisms underlying this synergetic effect remain largely unknown. Using a mouse model combining hyperlipidemia (via high-fat diet feeding, HFD) with 5/6 nephrectomy-induced CKD, we made the following significant findings: 1) HFD + CKD upregulated 1179 genes in mouse aortas and induced prominent reactive oxygen species (ROS), far more than either HFD or CKD alone. 2) HFD + CKD upregulated 86 CRISPRi-identified mitochondrial ROS regulators, 36 CRISPRi-identified cellular ROS regulators, and 19 GSEA-collected ROS regulators. These changes were associated with the upregulations of 48 cytokines, 7 highest toxicity uremic toxin receptors-including CD1D, FCGRT, AHR, IL6RA AGER, NR1H3 and NPY5R-in aortas. 3) These uremic toxin receptors emerged as novel promoters of inflammation and trained immunity. Deficiencies in CD1D, AHR, AGER, and the trained immunity promoter SET7 each downregulated up to 5.5 % of the genes upregulated by HFD + CKD. Conversely, activation of NR1H3 using an agonist upregulated up to 12.2 % of these genes. 4) The expression of 46 cytokine genes was strongly associated with NR1H3 upregulation. 5) The NR1H3 agonist also induced the expression of 28 ROS regulators, including YBX2, a novel anti-ROS transcription factor and RNA-binding protein, suggesting a potential negative feedback mechanism. YBX2 deficiency increased the cellular ROS level, while YBX2 overexpression suppressed 27 proinflammatory genes induced by HFD + CKD. Our findings provide novel insights into the role of the NR1H3-YBX2 axis in regulating inflammation accelerated by hyperlipidemia and CKD. Show less

Mesenchymal cells constitute the primary structural support elements within endometriotic lesions, yet their pivotal roles in endometriotic pathogenesis remain largely uncharted. This study aimed to construct a single-cell atlas of endometriosis using samples from three ovarian tissues affected by endometriosis and three normal ovarian tissues. Through the utilization of scRNA-seq, we have unveiled six distinct mesenchymal subclusters in normal and endometriosis-afflicted ovaries, elucidating the diverse functions of mesenchymal populations in endometriosis. Our comprehensive analysis has revealed that mesenchymal cells predominantly engage in three key functions: ribosome-mediated protein synthesis and processing, cell adhesion facilitating intercellular support and communication, and a range of metabolic processes. Furthermore, our findings have identified several pivotal differentially expressed genes (e.g. C3, FN1, COL3A1, COL1A1, NRXN3), primarily associated with the complement and coagulation cascades, extracellular matrix (ECM) regulation, ECM receptor interactions, and cell adhesion molecules. In essence, our study provides a comprehensive transcriptomic dataset and novel insights into adhesive molecule and integrin networks within mesenchymal subclusters in endometriosis. This, in effect, has deepened the understanding of the pathomechanisms governing this condition. Show less

Steroid-resistant nephrotic syndrome (SRNS) is insensitive to steroid therapy and overwhelmingly progresses to kidney failure (KF), the known pathogenic genes of which include key subunits of the nuclear pore complex (NPC), a less-recognized contributor to glomerular podocyte injury. After analyzing their clinical characterizations and obtaining parental consent, whole-exome sequencing (WES) was performed on patients with SRNS. Several nucleoporin (NUP) biallelic pathogenic variants were identified and further analyzed by cDNA-PCR sequencing from white cells of peripheral blood, minigene assay, immunohistochemical (IHC) staining, and electron microscopy (EM) ultrastructure observation of kidney biopsy, as well as multiple in silico prediction tools, including 3D protein modeling. Here, in six families with SRNS, we identified pathogenic mutations in NUP85/93/107/160 genes. Specifically, the patient with NUP93 mutation developed KF six months after diagnosis at 1 year 2 months. Two missense mutations, c.1655A > G and c.1604A > C, disrupted the protein stability of NUP93 by IHC staining of kidney biopsy. Ultrastructurally, the above mutations led to severe vacuolization and deformed nucleus in podocytes, torn and dissolved glomerular basement membrane, and diffuse foot process effacement. The patient with NUP85 mutation reached chronic kidney disease (CKD) stage 3 after 4 years follow-up, with exons 2-5 in-frame loss and a missense variant at c.511C > T, not affecting NUP85 expression but possibly weakened interaction with Seh1. Additionally, an extended endoplasmic reticulum (ER) tubule was readily observed under EM. Meanwhile, dilated ER was also found in two children with NUP160 mutations (c.3330 delA and c.2407 G > A; c.2241 + 1 (IVS17) G > T and c.3656 T > G), one of which has undergone kidney transplantation. Compound heterozygous variants in NUP107, c.1695 G > C and c.1360 C > T, were found in a 14-year-old girl initially diagnosed with CKD stage 5, with the former variant causing exon 19 skipping and early translation termination. c.1311 + 1(IVS15) G > A and c.1790 C > T were identified in the second affected girl, with the former causing exon 15 skipping and an in-frame loss of aa417-438, which disrupted the stability of NUP107 and interaction with NUP133. Our findings expand the spectrum of phenotypes and genotypes of NUPs-associated SRNS and suggest its possible pathogenic mechanism in nuclear and ER homeostasis. Show less

Based on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in Parkinson's disease. Here we show that VPS13C, a bridge-like lipid-transport protein and a Parkinson's disease gene, is a sensor of lysosome stress or damage. Following lysosome membrane perturbation, VPS13C rapidly relocates from the cytosol to the surface of lysosomes where it tethers their membranes to the ER. This recruitment depends on Rab7 and requires a signal at the damaged lysosome surface that releases an inhibited state of VPS13C, which hinders access of its VAB domain to lysosome-bound Rab7. Although another Parkinson's disease protein, LRRK2, is also recruited to stressed or damaged lysosomes, its recruitment occurs at much later stages and by different mechanisms. Given the role of VPS13 proteins in bulk lipid transport, these findings suggest that lipid delivery to lysosomes by VPS13C is part of an early protective response to lysosome damage. Show less

Based on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in Parkinson's disease (PD). Here we show that VPS13C, a bridge-like lipid transport protein and a PD gene, is a sensor of lysosome stress/damage. Upon lysosome membrane perturbation, VPS13C rapidly relocates from the cytosol to the surface of lysosomes where it tethers their membranes to the ER. This recruitment depends on Rab7 and requires a signal at the damaged lysosome surface that releases an inhibited state of VPS13C which hinders access of its VAB domain to lysosome-bound Rab7. While another PD protein, LRRK2, is also recruited to stressed/damaged lysosomes, its recruitment occurs at much later stages and by different mechanisms. Given the role of VPS13 proteins in bulk lipid transport, these findings suggest that lipid delivery to lysosomes by VPS13C is part of an early protective response to lysosome damage. Show less

Diabetes and obesity are momentous risk factors threatening people's lives and health. Currently available incretin analogue glucagon-like peptide 1 (GLP-1) possesses huge hypoglycemic effect with the unsatisfactory effect of weight loss. Co-agonists targeting GLP-1R plus glucagon receptor (GCGR) or gastric inhibitory polypeptide receptor (GIPR) show synergistic benefits in glycaemic control and weight loss. Here, we describe a novel dual GIP and GLP-1 receptor agonist, DR10627, and performed a preclinical assessment of it. The agonistic ability of DR10627 was indirectly assessed by inducing cAMP accumulation in Chinese hamster ovary (CHO) cells transfected with GLP-1R or GIPR in vitro. The plasma pharmacokinetics of DR10627 were analysed in cynomolgus monkeys. The OGTTs were performed in Sprague‑Dawley (SD) rats. The glucose lowering effects were evaluated by repeated administration of DR10627 in diabetic ( DR10627 had the capacity to activate both GLP-1R and GIPR in vitro. The terminal half-life of DR10627 was found to be approximately 4.19-5.8 h in cynomolgus monkeys. DR10627 had a great improvement in oral glucose tolerance in SD rats. Moreover, DR10627 had a potent glucose-lowering effect in Preclinical assessment demonstrated that administration of DR10627 resulted in glucose lowering in SD rats and Show less

Altered apolipoprotein kinetics play a critical role in promoting dyslipidemia and atherogenesis. Human apolipoprotein kinetics have been extensively evaluated, but similar studies in mice are hampered by the lack of robust methods suitable for the small amounts of blood that can be collected at sequential time points from individual mice. We describe a targeted liquid chromatography tandem mass spectrometry method for simultaneously quantifying the stable isotope enrichment of several apolipoproteins represented by multiple peptides in serial blood samples (15 μl each) obtained after retro-orbital injection of Show less

The integration of chemotherapy and immunotherapy as a first-line treatment for extensive-stage small cell lung cancer (ES-SCLC) has been adopted in clinical practice, yet the response to immune checkpoint inhibitors (ICIs) is variable, benefiting only a fraction of patients. The current absence of reliable biomarkers for predicting treatment response and prognosis represents a significant gap in knowledge, hindering the optimization of patient stratification and treatment planning. This retrospective cohort study aims to assess the potential predictive and prognostic significance of clinicopathological baseline features in ES-SCLC patients. Our study retrospectively analyzed the data of consecutive patients with ES-SCLC treated with first-line etoposide plus platinum chemotherapy ± immunotherapy at The Affiliated Lihuili Hospital of Ningbo University from April 2017 to April 2023. Data on clinical information, serum laboratory indicators, pathological immunohistochemical markers, and progression-free survival (PFS) times were collected. Univariate and multivariate Cox regression analyses were employed to determine whether these indicators could serve as independent prognostic factors for PFS. Further, potential predictive markers for treatment efficacy were identified using a Cox regression model that incorporated an interaction term between treatment modality and the indicator. A total of 121 patients with ES-SCLC were enrolled in the study, of whom 62 received chemotherapy alone, and 59 received chemotherapy in combination with immunotherapy. Compared to chemotherapy alone, the addition of immunotherapy to first-line chemotherapy significantly extended the PFS time [P<0.001; hazard ratio (HR) =0.42; 95% confidence interval (CI): 0.28, 0.64] of the ES-SCLC patients. The multivariate analysis revealed that an immunochemotherapy regimen (P<0.001, HR =0.40; 95% CI: 0.24, 0.68), a low-density lipoprotein (LDL) level of >1.8 mmol/L (P=0.02; HR =0.41; 95% CI: 0.20, 0.85) were independent prognostic factors of favorable PFS in the first-line treatment of all ES-SCLC, while a lactate dehydrogenase (LDH) level of >273 U/L (P=0.04; HR =1.78; 95% CI: 1.03, 3.07), a neuron-specific enolase (NSE) concentration of >102.6 ng/mL (P=0.009; HR =6.49; 95% CI: 1.60, 26.32), an apolipoprotein A1 (ApoA1) concentration of >0.9 g/L (P<0.001; HR =4.15; 95% CI: 1.98, 8.71), and an apolipoprotein B (ApoB) concentration of >0.8 g/L (P=0.002; HR =2.24; 95% CI: 1.34, 3.75) were independent prognostic factors of poorer PFS. Further, the interaction effect analysis demonstrated that an LDL level of >1.8 mmol/L and the absence of bone metastasis were potential predictors of an improved response to ICI therapy compared to chemotherapy alone. This study showed the survival benefit of receiving a chemoimmunotherapy regimen as the first-line treatment in a real-world scenario. It also suggests the prognostic significance of pre-treatment LDL, LDH, NSE, ApoA1, and ApoB with optimal cut-off values in the first-line treatment of all ES-SCLC, and the potential utility of baseline LDL level or the presence of bone metastasis in guiding first-line treatment strategies. Show less

Idiopathic pulmonary fibrosis (IPF) is a respiratory disorder of obscure etiology and limited treatment options, possibly linked to dysregulation in lipid metabolism. While several observational studies suggest that lipid-lowering agents may decrease the risk of IPF, the evidence is inconsistent. The present Mendelian randomization (MR) study aims to determine the association between circulating lipid traits and IPF and to assess the potential influence of lipid-modifying medications for IPF. Summary statistics of 5 lipid traits (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, apolipoprotein A, and apolipoprotein B) and IPF were sourced from the UK Biobank and FinnGen Project Round 10. The study's focus on lipid-regulatory genes encompassed PCSK9, NPC1L1, ABCG5, ABCG8, HMGCR, APOB, LDLR, CETP, ANGPTL3, APOC3, LPL, and PPARA. The primary effect estimates were determined using the inverse-variance-weighted method, with additional analyses employing the contamination mixture method, robust adjusted profile score, the weighted median, weighted mode methods, and MR-Egger. Summary-data-based Mendelian randomization (SMR) was used to confirm significant lipid-modifying drug targets, leveraging data on expressed quantitative trait loci in relevant tissues. Sensitivity analyses included assessments of heterogeneity, horizontal pleiotropy, and leave-one-out methods. There was no significant effect of blood lipid traits on IPF risk (all P＞0.05). Drug-target MR analysis indicated that genetic mimicry for inhibitor of NPC1L1, PCSK9, ABCG5, ABCG8, and APOC3 were associated with increased IPF risks, with odds ratios (ORs) and 95% confidence intervals (CIs) as follows: 2.74 (1.05-7.12, P = 0.039), 1.36 (1.02-1.82, P = 0.037), 1.66 (1.12-2.45, P = 0.011), 1.68 (1.14-2.48, P = 0.009), and 1.42 (1.20-1.67, P = 3.17×10 Serum lipid traits did not significantly affect the risk of idiopathic pulmonary fibrosis. Drug targets MR studies examining 12 lipid-modifying drugs indicated that PCSK9 inhibitors could dramatically increase IPF risk, a mechanism that may differ from their lipid-lowering actions and thus warrants further investigation. Show less

Tripartite motif-containing protein 59 (TRIM59) is a biomarker for multiple tumors with crucial roles. However, the specific role of TRIM59 in germ cells remains largely unknown. Here, we investigated the effects and underlying regulatory mechanisms of TRIM59 on germ cells using the mouse spermatogonial cell line GC-1. Our results demonstrated that TRIM59 promoted proliferation and inhibited apoptosis of GC-1 cells. Mechanistically, TRIM59 maintained GC-1 cell behaviors through ubiquitination of AXIN1 to activate β-catenin signaling. Furthermore, activation of β-catenin signaling reversed the effects mediated by Show less

Ageing increases susceptibility to neurodegenerative disorders, such as Alzheimer's disease (AD). Serum levels of sclerostin, an osteocyte-derived Wnt-β-catenin signalling antagonist, increase with age and inhibit osteoblastogenesis. As Wnt-β-catenin signalling acts as a protective mechanism for memory, we hypothesize that osteocyte-derived sclerostin can impact cognitive function under pathological conditions. Here we show that osteocyte-derived sclerostin can cross the blood-brain barrier of old mice, where it can dysregulate Wnt-β-catenin signalling. Gain-of-function and loss-of-function experiments show that abnormally elevated osteocyte-derived sclerostin impairs synaptic plasticity and memory in old mice of both sexes. Mechanistically, sclerostin increases amyloid β (Aβ) production through β-catenin-β-secretase 1 (BACE1) signalling, indicating a functional role for sclerostin in AD. Accordingly, high sclerostin levels in patients with AD of both sexes are associated with severe cognitive impairment, which is in line with the acceleration of Αβ production in an AD mouse model with bone-specific overexpression of sclerostin. Thus, we demonstrate osteocyte-derived sclerostin-mediated bone-brain crosstalk, which could serve as a target for developing therapeutic interventions against AD. Show less

Individuals with type 1 diabetes (T1D) generally have normal or even higher HDL (high-density lipoprotein)-cholesterol levels than people without diabetes yet are at increased risk for atherosclerotic cardiovascular disease (CVD). Human HDL is a complex mixture of particles that can vary in cholesterol content by >2-fold. To investigate if specific HDL subspecies contribute to the increased atherosclerosis associated with T1D, we created mouse models of T1D that exhibit human-like HDL subspecies. We also measured HDL subspecies and their association with incident CVD in a cohort of people with T1D. We generated LDL receptor-deficient ( Diabetic Our results suggest that the balance between APOB lipoproteins and the larger HDL subspecies contributes to atherosclerosis progression and incident CVD in the setting of T1D and that larger HDLs exert atheroprotective effects on endothelial cells rather than by promoting macrophage cholesterol efflux. Show less

Small extracellular vesicles (sEVs) act as a critical mediator in intercellular communication. Compared to sEVs derived from in vitro sources, tissue-derived sEVs can reflect the in vivo signals released from specific tissues more accurately. Currently, studies on the role of sEVs in the cochlea have relied on studying sEVs from in vitro sources. This study evaluates three cochlear tissue digestion and cochlear tissue-derived sEV (CDsEV) isolation methods, and first proposes that the optimal approach for isolating CDsEVs using collagenase D and DNase І combined with sucrose density gradient centrifugation. Furthermore, it comprehensively investigates CDsEV contents and cell origins. Small RNA sequencing and proteomics are performed to analyze the miRNAs and proteins of CDsEVs. The miRNAs and proteins of CDsEVs are crucial for maintaining normal auditory function. Among them, FGFR1 in CDsEVs may mediate the survival of cochlear hair cells via sEVs. Finally, the joint analysis of single CDsEV sequencing and single-cell RNA sequencing data is utilized to trace cellular origins of CDsEVs. The results show that different types of cochlear cells secrete different amounts of CDsEVs, with Kölliker's organ cells and supporting cells secrete the most. The findings are expected to enhance the understanding of CDsEVs in the cochlea. Show less

Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide. Catheter ablation has become a crucial treatment for AF. However, there is a possibility of atrial fibrillation recurrence after catheter ablation. Our study sought to elucidate the role of lncRNA‒mRNA regulatory networks in late AF recurrence after catheter ablation. We conducted RNA sequencing to profile the transcriptomes of 5 samples from the presence of recurrence after AF ablation (P-RAF) and 5 samples from the absence of recurrence after AF ablation (A-RAF). Differentially expressed genes (DEGs) and long noncoding RNAs (DE-lncRNAs) were analyzed using the DESeq2 R package. The functional correlations of the DEGs were assessed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. A protein‒protein interaction (PPI) network was constructed using STRING and Cytoscape. We also established a lncRNA‒mRNA regulatory network between DE-lncRNAs and DEGs using BEDTools v2.1.2 software and the Pearson correlation coefficient method. To validate the high-throughput sequencing results of the hub genes, we conducted quantitative real-time polymerase chain reaction (qRT‒PCR) experiments. A total of 28,528 mRNAs and 42,333 lncRNAs were detected. A total of 96 DEGs and 203 DE-lncRNAs were identified between the two groups. GO analysis revealed that the DEGs were enriched in the biological processes (BPs) of "regulation of immune response" and "regulation of immune system process", the cellular components (CCs) of "extracellular matrix" and "cell‒cell junction", and the molecular functions (MFs) of "signaling adaptor activity" and "protein-macromolecule adaptor activity". According to the KEGG analysis, the DEGs were associated with the "PI3K-Akt signaling pathway" and "MAPK signaling pathway." Nine hub genes (MMP9, IGF2, FGFR1, HSPG2, GZMB, PEG10, GNLY, COL6A1, and KCNE3) were identified through the PPI network. lncRNA-TMEM51-AS1-201 was identified as a core regulator in the lncRNA‒mRNA regulatory network, suggesting its potential impact on the recurrence of AF after catheter ablation through the regulation of COL6A1, FGFR1, HSPG2, and IGF2. The recurrence of atrial fibrillation after catheter ablation may be associated with immune responses and fibrosis, with the extracellular matrix playing a crucial role. TMEM51-AS1-201 has been identified as a potential key target for AF recurrence after catheter ablation. Show less

The fibroblast growth factor receptor (FGFR) signaling pathway plays important roles in cellular processes such as proliferation, differentiation, and migration. In this study, we highlighted the potential of FGFR inhibitors bearing the ( Show less

Lipid metabolism disorders are frequently noted in atopic dermatitis (AD) patients, prompting the long-term use of lipid-lowering drugs. However, the causal effects of circulating lipids and different lipid-lowering drugs on the risk of AD are not thoroughly understood. Using publicly available genome-wide association studies (GWAS) summary data from two different cohorts, a series of Mendelian randomization (MR) analyses were conducted to explore the causal effects of genetically proxied circulating lipids and lipid-lowering drugs on the risk of AD. Statistically, the random-effects inverse-variance-weighted (IVW) model was used as main analysis and several methods were conducted for sensitivity analysis to test the robustness of our results. Our findings revealed reduced risks of AD related to genetically proxied subtilisin/kexin type 9 (PCSK9) inhibition and lipoprotein lipase (LPL) agonist, while an increased AD risk associated with Niemann-Pick C1-like 1 (NPC1L1) inhibition. Circulating lipids and other drug targets did not show significant associations with AD risk. These results were replicated in the validation cohort; sensitivity analyses confirmed the robustness. This MR study suggests that, independent of circulating lipids, the use of PCSK9 inhibitors and LPL agonists may be associated with a decreased risk of AD, while inhibition of NPC1L1 is implicated in an increased risk. These findings may help optimize personalized selection of lipid-lowering drugs for AD patients and those at risk of AD. Show less

The intestinal microbiota of ruminants is an important factor affecting animal production and health. Research on the association mechanism between the intestinal microbiota and meat quality of ruminants will play a positive role in understanding the formation mechanism of meat quality in ruminants and improving production efficiency. In this study, the fatty acid composition and content, expression of related genes, and structural characteristics of the ileum microbiota of ewes of Tibetan sheep at different ages (4 months, 1.5 years, 3.5 years, and 6 years) were detected and analyzed. The results revealed significant differences in fatty acid composition and content in the muscle of Tibetan sheep at different ages ( Show less