👤 Shaowei Qiu

The intramuscular fat (IMF) content, as an important meat quality trait, can directly affect the tenderness, juiciness, and flavor of pork. Reasonably increasing the IMF content can improve the palatability of pork. Therefore, identification of important factors for the lipid accumulation among muscles is the breakthrough point for improving meat quality. FGF21, identified as a novel metabolic regulator, has been found to regulate glucose and lipid metabolism in 3T3-L1 adipocytes, but its function in porcine adipocytes remains unclear. In this study, we discovered that the administration of recombinant FGF21 protein promotes adipogenic differentiation and increases triglyceride accumulation in porcine adipocytes. While the expression of FGFR1 in adipocytes under muscle conditions is inhibited, affecting the signal transduction of FGF21. This inhibitory effect is accompanied by activation of the AhR signaling pathway. When treated with the AhR antagonist CH223191, there was a partial restoration of FGFR1 expression levels. This indicates that muscle cells suppress the expression of FGFR1 in adipocytes by activating the AhR signaling pathway, thereby affecting the signal transduction of FGF21. Our results reveal the regulatory role of FGF21 in pig adipocyte differentiation and the regulatory mechanism of muscle environment on FGFR1 expression, providing new theoretical basis for IMF content improvement from the perspective of FGF21-FGFR1 signaling transduction. Show less

Wound healing is a complex physiological process fundamentally dependent on angiogenesis for effective tissue repair. Endothelial progenitor cells (EPCs) have shown significant potential in promoting angiogenesis, primarily through their secretome, rich in proteins and extracellular vesicles (EVs) essential for cell signaling and tissue regeneration. This study investigates the effect of a collagen-bound proteoglycan mimetic (LXW7-DS-SILY or LDS), that binds to the αvβ3 integrin receptor, on the EPC secretome, with a dual focus on the proteomic content and the functional properties of EVs. Utilizing high-resolution two-dimensional liquid chromatography-tandem mass spectrometry (LC-MS/MS) alongside bioinformatic analysis, we identified significant alterations in protein expression profiles, particularly in angiogenesis and wound healing pathways. The functional impact of these changes was validated through biological assays, where the whole secretome and the EV fraction from EPCs seeded on collagen-bound LDS markedly enhanced vascular network formation, driven by the increase of growth factors and angiogenic regulators such as FGFR1, NRP1, and ANGPT2 within the EV fraction. Gene Ontology (GO) enrichment analysis further highlighted the enrichment of proteins within the EVs driving biological processes, including 'response to wounding' and 'positive regulation of cell motility'. These results underscore that LDS modulates the EPC secretome and significantly enhances its angiogenic potential, offering a promising therapeutic strategy for non-healing and ischemic wounds and suggesting that biomaterials can be modified to control the EV secretome to enhance tissue repair. Functional assays validating the omics data highlight the robustness of LDS as a targeted therapeutic for enhancing angiogenesis and tissue repair in clinical settings. Moreover, the pivotal role of EVs in mediating pro-angiogenic effects offers insights into developing biomaterial therapies that exploit key regulators within the EPC secretome for wound healing. STATEMENT OF SIGNIFICANCE: This manuscript explores how a proteoglycan mimetic that binds to both collagen and the α Show less

Cancer-targeted therapies are progressively pivotal in oncological care. Observational studies underscore the emergence of cancer therapy-related cardiovascular toxicity (CTR-CVT), impacting patient outcomes. We aimed to investigate the causal relationship between different types of cancer-targeted therapies and cardiovascular disease (CVD) outcomes through a two-sample Mendelian randomization (MR) study. This genome-wide association study was conducted using a two-sample Mendelian randomization framework. Genetic instruments for drug target gene expression were extracted from the eQTLGen consortium (31684 individuals, 37 cohorts). Genome-wide association study (GWAS) summary statistics for 19 cardiovascular diseases were derived from the FinnGen database. Primary analysis was carried out using the summary-data-based MR (SMR) method, with sensitivity analysis for validation. Colocalization analysis identifies shared causal variants between exposure eQTLs and CVD-associated single-nucleotide polymorphisms (SNPs). Among the 39 drug target genes, 8 were identified with detectable cis-eQTLs and were subsequently validated through positive control analysis for further investigation. In the SMR and sensitivity analyses, genetically proxied VEGFA inhibition showed significantly strong association with stroke (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.09-1.26, p = 1.33 × 10 This genetic association study revealed evidence supporting the genetic association between the use of VEGFA inhibitors and increased stroke risk, highlighting the need for enhanced pharmacovigilance. These findings underscore the delicate balance between cardiovascular toxicity risk and the benefits of cancer-targeted therapy. Show less

Mammalian scent glands mediate species-specific chemical communication, yet the mechanistic basis for convergent musk production remain incompletely understood. Forest musk deer and muskrat have independently evolved specialized musk-secreting glands, representing a striking case of convergent evolution. Through an integrated multi-omics approach, this study identified cyclopentadecanone as a shared key metabolic precursor in musk from both forest musk deer and muskrat, although downstream metabolite profiles diverged between the two lineages. Single-cell RNA sequencing revealed that these specialized apocrine glands possessed unique secretory architecture and exhibited transcriptional profiles associated with periodic musk production, distinct from those in conventional apocrine glands. Convergent features were evident at the cellular level, where acinar, ductal, and basal epithelial subtypes showed parallel molecular signatures across both taxa. Notably, acinar cells in both species expressed common genes involved in fatty acid and glycerolipid metabolism (e.g., Show less

Studies have indicated that COVID-19 infection may accelerate the aging process in organisms. However, it remains unknown whether contracting COVID-19 affects life expectancy. Furthermore, the underlying biological mechanisms behind these findings are still unclear. We conducted a prospective cohort study on 56,504 participants of European ancestry from the UK Biobank who reported the time and number of COVID-19 infection between January 2020 and September 2023. The parental average longevity was used as a proxy for their own longevity. Linear regression was used to assess the relationship between COVID-19 infection and longevity. Furthermore, we investigated the shared genetic basis between COVID-19 and longevity using large-scale genome-wide association studies (GWAS) for COVID-19 (122,616 cases and 2,475,240 controls) and longevity (3,484 cases and 25,483 controls). Mendelian randomization (MR) and mediation analysis were utilized to assess causal relationships and potential mediators between COVID-19 susceptibility and longevity. Shared genetic loci between the two phenotypes were identified using conjunctional false discovery rate (conjFDR) statistical frameworks. After controlling for relevant covariates, COVID-19 infection might not be significantly correlated with longevity. In all MR methods, generalized summary-data-based Mendelian randomization (GSMR) analysis revealed a significant decrease in longevity due to severe COVID-19 infection (OR = 0.91, 95%CI: 0.84-0.98, P = 0.015). Mediation analysis identified stroke and myocardial infarction as potential mediators between COVID-19 susceptibility and reduced longevity. At conjFDR < 0.05, we identified rs62062323 (KANSL1) and rs9530111 (PIBF1) as shared loci between COVID-19 and longevity. Together, our findings provided preliminary evidence for the shared genetic basics between COVID-19 and aging. This discovery may have implications for personalized medicine and preventive strategies, helping identify individuals who may be more vulnerable to severe outcomes from COVID-19 due to their genetic makeup. Show less

Does preconception mental health status in either partner affect fertility and infertility, and is this association modified by socioeconomic status (SES)? Preconception mental health problems in both partners are associated with lower couple fertility, with the synergistic impact being most pronounced among couples with low SES status. Mental health problems are rising among young adults, and fertility rates are declining. Women's preconception mental health has been linked to lower fertility, but few studies have examined the combined impact of both partners' mental health. The modifying role of SES in these associations is also poorly understood. This couple-based prospective cohort study included 966 preconception couples who sought preconception care and were followed for 12 months in the Shanghai Birth Cohort between 2013 and 2015. The couples' mental health status was evaluated at enrolment using the Center for Epidemiological Studies-Depression Scale, Zung Self-Rating Anxiety Scale, and Perceived Stress Scale. The outcomes included couple fecundability (measured by the TTP) and infertility (i.e. TTP >12 menstrual cycles). In the partner-specific model, Cox proportional hazards models and logistic regression were used to evaluate the associations between each partner's depression, anxiety, and stress levels and couples' fertility. In the couple-based model, cross-classification and quantile g-computation were first applied to identify couples' joint exposure to specific psychological conditions in relation to fertility. Latent profile analysis (LPA) was then conducted to characterize distinct latent profiles of couples' overall mental health statuses, followed by Cox proportional hazards models and logistic regression to examine the corresponding associations. Key symptoms in the couples' depression, anxiety, and stress scales were determined by elastic net regression and least absolute shrinkage and selection operator. To assess the potential effect modification of SES on the association between couples' mental health and fertility, we conducted stratified analyses by male and female partner education levels and household income. In the female partner-specific model, a 1 SD increase in depression score was associated with 10% lower fecundability (FOR = 0.90, 95% CI: 0.82, 0.99). Likewise, a 1 SD increase in the stress score was associated with 13% lower fecundability (FOR = 0.87, 95% CI: 0.79, 0.96). Male anxiety was associated with a higher risk of infertility (OR = 1.19, 95% CI: 1.01, 1.42). Stratified analyses showed that depression, anxiety, and stress were significantly associated with lower fecundability among males with an education level Show less

This study aims to identify and characterize daily activity accumulation patterns (bouts of physical activity and sedentary behavior) among adolescents and then to explore the associations between these groups and depressive symptoms. A total of 521 adolescents aged 13-18 years from Wuhan and Changsha, China, were included. Bouts of physical activity (PA) and sedentary behavior (SED) were measured using accelerometers. The Center for Epidemiologic Studies Depression Scale was used to assess participants' depressive symptoms. Latent profile analysis was employed to identify distinct groups based on their activity patterns. Three distinct groups were identified: "Prolonged sitters" ( The synergistic effect of strategies to reduce total SED duration by limiting SED bouts to 30 min or less and increasing light physical activity (LPA) may also be effective in alleviating depressive symptoms in adolescents. Show less

Evidence has linked self-reported sedentary behaviors with dementia and cognitive impairment; however, the underlying mechanisms remain poorly understood. We investigated the associations of accelerometer-measured sedentary behavior patterns with gray matter atrophy patterns in rural-dwelling older adults, while taking into account the manner in which sedentary time is accrued (in short or long bouts). This community-based study involved 911 dementia-free older adults (age ≥ 60 years, 59% women) who participated in both ActiGraph and brain MRI substudies within MIND-China (2018-2020). Sedentary behavior parameters (total sedentary time, mean sedentary bout duration, and sedentary breaks) were recorded with accelerometers. Regional gray matter volumes (GMV) were measured using voxel-based morphometry (VBM) methods. Data were analyzed using the general linear regression models, restricted cubic spline curves, and VBM analysis. There was an inverted U-shaped association between daily sedentary time and GMV in temporal, cingulate, and medial temporal cortex, while longer mean sedentary bout duration was linearly related to decreased GMV in total, frontal, temporal, insula, cingulate, and medial temporal cortex. Greater daily time spent in light or moderate-to-vigorous physical activity (LPA and MVPA) was correlated with larger insula GMV. The VBM analysis suggested that prolonged daily total sedentary time and mean sedentary bout duration were significantly associated with smaller GMV in extensive brain regions, especially in thalamus and insula. In conclusion, gray matter atrophy associated with sedentary behavior in older adults is characterized by reduced GMV in global, frontal, temporal, medial temporal, and cingulate cortex, especially in the insula and thalamus regions. Show less

Lanthanides-doped luminescent materials have gathered considerable attention due to their application potential in stress sensing, lighting and display, anti-counterfeiting technology and so forth. However, existing materials mainly cover the 380-1540 nm range, with slight extension to the UV region, impeding their applications in solar-blind imaging, background-free tracking, concealed communication, etc. To address this challenge, here we propose guidelines for far-UVC (200-230 nm) optical design. Accordingly, we achieve multi-stimulated far-UVC luminescence at ~222 nm in Pr Show less

Approximately 95% of lymphoplasmacytic lymphomas (LPL) are IgM secreting and are characterized as Waldenstrom Macroglobulinemia (WM). Conversely, non-IgM secreting LPL are rare. As part of the 12th International Workshop on WM (IWWM-12), a consensus panel of experts was tasked to develop recommendations for the management and response assessment of non-IgM LPL. The panel considered that in view of available molecular, pathological and clinical data, non-IgM LPL should be considered as a separate sub-entity of LPL. The panel further recommended that the IWWM-2 consensus criteria used for IgM LPL (WM) treatment initiation, should also be used for non-IgM LPL and be independent of IgG or IgA paraprotein level unless symptomatic hyperviscosity is present. The panel agreed that based on current evidence, there is insufficient data to support a different clinical management for non-IgM vs IgM (WM) LPL. Moreover, the panel advised that patients with non-IgM LPL should be treated in a similar manner to patients with IgM LPL independent of MYD88 mutation status until more is known about its impact on treatment outcomes for non-IgM LPL patients. The panel therefore recommends the use of the IWWM-11 IgM LPL (WM) response criteria for cases of non-IgM LPL with a monoclonal IgA or IgG paraprotein component, but creating a specific panel to develop formal response criteria for this LPL subset was also recommended. Show less

The gut microbiota influences host immunity and metabolism, and changes in its composition and function have been implicated in several non-communicable diseases. Here, comparing germ-free (GF) and specific pathogen-free (SPF) mice using spatial transcriptomics, single-cell RNA sequencing, and targeted bile acid metabolomics across multiple organs, we systematically assessed how the gut microbiota's absence affected organ morphology, immune homeostasis, bile acid, and lipid metabolism. Through integrated analysis, we detect marked aberration in B, myeloid, and T/natural killer cells, altered mucosal zonation and nutrient uptake, and significant shifts in bile acid profiles in feces, liver, and circulation, with the alternate synthesis pathway predominant in GF mice and pronounced changes in bile acid enterohepatic circulation. Particularly, autophagy-driven lipid droplet breakdown in ileum epithelium and the liver's zinc finger and BTB domain-containing protein (ZBTB20)-Lipoprotein lipase (LPL) (ZBTB20-LPL) axis are key to plasma lipid homeostasis in GF mice. Our results unveil the complexity of microbiota-host interactions in the crosstalk between commensal gut bacteria and the host. Show less

There has been remarkable progress over the past 80 years since Jan Waldenstrom first described patients with a hyperviscosity syndrome related to IgM paraprotein in 1944. The definition of Waldenstrom macroglobulinemia (WM) has evolved from a clinical syndrome to a distinct clinicopathologic entity with characteristic morphology, immunophenotype and molecular features. The landmark discovery of MYD88 mutation among most WM cases in 2012 marked the dawning of an era of molecular genomic exploration that led to a paradigm shift in clinical practice. In the current World Health Organization (WHO) classification of hematologic neoplasms, WM is included in the category of lymphoplasmacytic lymphoma (LPL) of which WM represents over 90% of cases. LPL/WM is also better defined, resolving ambiguity in many cases that would have been classified as "low-grade B-cell lymphoma with plasmacytic differentiation" a decade before. Nevertheless, challenges still face pathologists because criteria for distinguishing LPL/WM from other types of low-grade B-cell lymphoma, particularly marginal zone lymphoma (MZL), remain imperfect. In this review, we highlight the current understanding of LPL and WM brought to light by new discoveries, which in turn are increasingly translated to improved diagnosis and personalized therapy. Key concepts in the diagnosis and their clinical implications are emphasized. Controversies and challenges are also discussed. Show less

Accurate skin lesion classification is crucial for the early detection of malignant lesions, including melanoma, as well as improved patient outcomes. While convolutional neural networks (CNNs) excel at capturing local morphological features, they struggle with global context modeling essential for comprehensive lesion assessment. Vision transformers address this limitation but suffer from quadratic computational complexity O(n Show less

To investigate the genetic etiology of six adult patients with Dilated cardiomyopathy (DCM), and analyze the structure of the identified variants, for providing reference for the diagnosis of DCM. Six adult patients with DCM (patients 1-6) admitted to the Department of Cardiology of Zhumadian Central Hospital from January 2023 to December 2023 were recruited. Clinical data of the patients were retrospectively collected. And 5 mL of peripheral blood was collected from each patient. Pathogenic variants of the patients were detected by whole exome sequencing (WES), and candidate variants were verified by Sanger sequencing. The possible functional significance of the identified missense variants was evaluated using software including SIFT, PolyPhen-2 and Mutation Taster. Specific regions of the MYBPC protein encoded by the MYBPC3 gene from different species were aligned using Mutation Taster. The wild-type and mutant MYBPC proteins were constructed using homologous modeling software MODELLER v10.4 and three-dimensional structures were visualized using PyMOL software. The molecular interaction between MYBPC-C5 domain and myosin with or without the mutation was further analyzed using ZDOCK module in Discovery Studio 2019 software. Pathogenicity ratings for the detected variant sites were performed in accordance with the Standards and Guidelines for the Interpretation of Sequence variants by the American College of Medical Genetics and Genomics (ACMG) (hereafter referred to as the ACMG Guidelines). This study was reviewed and approved by the Ethics Committee of Zhumadian Central Hospital (Approval No. 2022092007). The six DCM patients had typical symptoms of heart failure, and echocardiography showed whole-heart dilation and decreased ventricular wall motion, left ventricular end-diastolic dimension (LVEDD) was 59-74 mm, left ventricular ejection fraction (LVEF) was 35%-43%, and left ventricular fractional shortening (LVFS) was 17%-28%. Variations of the DCM related genes, including a c.98473A>T (p.Lys32825*) variation of the TTN gene and a c.1976T>C (p.Ile659Thr) variation of the MYBPC3 gene, were identified in two patients. Multiple software predicted that both mutations were deleterious. MYBPC3-Ile659Thr mutation affected the highly conserved residue within the C5 domain of MYBPC. Three-dimensional structural analysis of homologous modeling revealed the alterations in amino acid properties and interactions with surrounding amino acids caused by the MYBPC3-Ile659Thr mutation. Further molecular docking analysis showed that the Ile659Thr mutation altered both the hydrogen bond and salt-bridge interactions between the MYBPC-C5 domain and the ligand myosin. Two mutations associated with DCM were identified in this study. The abnormal conformation of the mutant protein further affected its interaction with the ligand myosin, resulting in the phenotype of DCM. Show less

Cholesterol-loaded macrophage foam cells are a key feature of atherosclerotic plaques. Oxysterol-binding protein-related protein 2 (ORP2) facilitates the transport of cholesterol from lysosomes to the plasma membrane in cultured cell lines. However, the role of ORP2 in macrophages and its involvement in atherosclerosis remain unclear. In this study, we found ORP2 expression was reduced in atherosclerotic vessels and in macrophages exposed to oxidized LDL (ox-LDL). Myeloid-specific human ORP2 overexpression (hORP2 Show less

Effective therapeutic drugs for calcific aortic valve disease (CAVD) are lacking, although its incidence has been increasing over the past decade and is predicted to continue rising in the future. This study aimed to explore the role and potential mechanisms of liver X receptor α (LXRα) in CAVD, which offers a promising approach for treating CAVD. Osteogenic stimulation was performed following which a substantial downregulation of LXRα was observed in human calcific aortic valves and valvular interstitial cells. Further functional investigations revealed that silencing LXRα exacerbated calcification both in vitro and in vivo. We showed that LXRα suppressed the protein kinase R-like endoplasmic reticulum kinase/eukaryotic initiation factor 2/activating transcription factor 4 pathway, which controls endoplasmic reticulum stress (ERS) and promotes osteogenic differentiation, thereby slowing the course of CAVD. Our research offers fresh perspectives on how LXRα controls the pathophysiology of CAVD via regulating ERS. The findings suggest that targeting LXRα is a potential treatment strategy for treating aortic valve calcification. Show less

Mutations in four genes encoding the outer ring complex of nuclear pore complexes (NPCs), NUP85, NUP107, NUP133 and NUP160, cause monogenic steroid-resistant nephrotic syndrome (SRNS). Knockout of NUP85, NUP107, or NUP133 in immortalized human podocytes activates CDC42, an important effector of SRNS pathogenesis. However, it is unknown whether or not loss of NUP160 dysregulates CDC42 in the podocytes. Here, we generated a podocyte-specific Nup160 knockout mouse model with double-fluorescent (mT/mG) Cre reporter genes using CRISPR/Cas9 and Cre/loxP technologies. We investigated nephrotic syndrome-associated phenotypes in the Nup160podo-/- mice, and performed single-cell transcriptomic and proteomic analysis of glomerular suspension cells and cultured primary podocytes, respectively. The Nup160podo-/- mice exhibited progressive proteinuria and fusion of podocyte foot processes. We found decreased Cdc42 protein and normal Cdc42 transcriptional level in the podocytes of the Nup160podo-/- mice using analysis of single-cell transcriptomes and proteomes. We subsequently observed that Cdc42 protein decreased in both kidney tissues and cultured primary podocytes of the Nup160podo-/- mice, although Cdc42 mRNA levels were elevated in the cultured primary podocytes of the Nup160podo-/- mice. We also found that Cdc42 activity was significantly reduced in the cultured primary podocytes of the Nup160podo-/- mice. In conclusion, loss of Nup160 dysregulated Cdc42 in the podocytes of the Nup160podo-/- mice with proteinuria and fusion of podocyte foot processes. Our findings suggest that the dysregulation of CDC42 may contribute to the pathogenesis of SRNS in patients with mutations in NUP160. Show less

Distant metastasis and immune evasion are the major obstacles for successful colorectal cancer (CRC) treatment. The link between metastasis and immune evasion, as well as their therapeutic significance, remains unclear. Long non-coding RNAs from six paired CRC and normal tissues were screened by RNA sequencing (RNA-seq). LncRNA-CTD (CTD-2568A17.8) expression levels were determined using in situ hybridization and quantitative PCR analysis. In vitro and in vivo assays were performed to confirm the function of lncRNA-CTD. Flow cytometry was used to analyze the impact of lncRNA-CTD on immune cell infiltration and T-cell function. RNA-seq combined with RNA pull-down and RNA immunoprecipitation assay was used to identify the changes in downstream molecules induced by lncRNA-CTD. The therapeutic value of the combination of lncRNA-CTD and immune checkpoint inhibitors has been evaluated. In this study, we identified a novel long non-coding RNA, lncRNA-CTD, which is downregulated in CRC and correlates with both metastasis and immunotherapy response. Mechanistically, the interaction of lncRNA and smad2 prevented the phosphorylation and nuclear translocation of smad2, which inhibited the expression of snail1, thereby inhibiting the metastasis of CRC. LncRNA-CTD enhances major histocompatibility complex class I (MHC-I) expression on the cancer cell membrane by interacting with STUB1 to disrupt the interaction of STUB1 with the MHC-I activator NLRC5 and subsequent NLRC5 ubiquitination-mediated degradation, increasing the susceptibility of CRC cells to being killed by CD8 Collectively, our study reveals the role and mechanism of lncRNA-CTD in CRC metastasis and immune evasion. Overexpression of lncRNA-CTD suppresses CRC metastasis and improves the efficacy of immune checkpoint inhibitors.Cite Now. Show less

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a tendency to recur and a poor prognosis. Epithelial mesenchymal transition (EMT) and proliferation of nasal epithelial cells (NECs) play an important role in CRSwNP development. Secretogranin II (SCG2) is reported to be an EMT-related gene, but its role in CRSwNP has not been reported. In this study, human NECs were cultured in an air-liquid interface culture system and stimulated with IL-13 to maintain or promote the CRSwNP state. EMT-associated protein expression levels were examined by real-time quantitative PCR and Western blot. Dual luciferase, chromatin immunoprecipitation, and co-immunoprecipitation experiments were used to validate the regulatory relationship between SP1, SCG2, and ubiquitin-1 (UBQLN1). The nuclear translocation of Snail was examined by immunofluorescence assay. The results showed that the expression levels of SP1, SCG2, and UBQLN1 were all up-regulated in CRSwNP tissues. SCG2 knockdown inhibited EMT and proliferation of human NECs. Mechanistically, SP1 promoted the proliferation and EMT of human NECs by transcriptionally increasing SCG2 expression. SCG2 activated the AKT serine/threonine kinase (AKT)/glycogen synthase kinase-3 beta (GSK-3β)/Snail family transcriptional repressor 1 (Snail) pathway and promoted Snail nuclear translocation via UBQLN1. In short, SCG2, which is transcriptionally up-regulated by SP1, promotes the proliferation and EMT of human NECs by activating the AKT/GSK-3β/Snail pathway through binding to UBQLN1. Show less

Metastatic spread of cancer is the leading cause of death in patients with epithelial ovarian cancer (EOC), and elucidation of the molecular mechanisms underlying this process is a major focus of cancer research. Fibroblast growth factor-inducible 14 (Fn14) has been shown to regulate wound repair, inflammation, angiogenesis, and chemoresistance, but its functional role in metastasis in EOC is still unknown. Here it is reported that Fn14 is identified as a cancer metastasis suppressor that inhibits the migratory and invasive potential of EOC cells by down-regulating epithelial-mesenchymal transition (EMT). Mechanistically, it is identified that Fn14 promotes acetylation-dependent protein degradation of Slug, a key transcriptional factor associated with EMT. The deacetylase Sirtuin 2 (SIRT2) has been reported to be involved in the deacetylation of Slug protein to stabilize it and then prevent its degradation in the nucleus. The results showed that Fn14 alters the subcellular localization of (SIRT2) by interacting with SIRT2, leading to reduced SIRT2 shuttling into the nucleus and subsequently promoting the acetylated degradation of Slug. Collectively, the work has demonstrated for the first time that Fn14 inhibits EOC metastasis by regulating SIRT2-mediated Slug deacetylation, providing a new perspective and method for the development of future novel therapeutic strategies for the treatment of EOC metastasis. Show less

Cisplatin resistance in tongue squamous cell carcinoma (TSCC) correlates with poor prognosis, where natural killer (NK) cells in the tumor microenvironment (TME) play a crucial role. This study investigated the mechanism by which exosomes from cisplatin-resistant TSCC cells suppress NK cell function. We found that exosomal long non-coding RNA SNHG26, highly enriched in cisplatin-resistant TSCC cells and their exosomes, was transferred to NK cells. Within NK cells, SNHG26 acted as a scaffold promoting WWP2-mediated ubiquitination and degradation of the transcription factor SOX2, thereby inhibiting HLA-DRA transcription and subsequent IL-2/JAK-STAT5 signaling. Concurrently, SNHG26 competitively bound miR-515-5p, relieving its suppression of TGFB1 mRNA and activating the TGF-β1/Smad2 pathway. These dual mechanisms significantly impaired NK cell proliferation, activation, and cytotoxicity. SNHG26 depletion reversed NK cell suppression and cisplatin resistance in vitro and in vivo. Thus, our study identifies exosomal SNHG26 as a key mediator of cisplatin resistance and NK cell dysfunction in TSCC, suggesting its potential as a promising therapeutic target. Show less

Renal ischemia-reperfusion injury (RIRI) stands as an unavoidable complication arising from kidney surgery, profoundly intertwined with its prognosis. The role of differentially expressed in FDCP 6 homolog (DEF6) in RIRI remains elusive, despite its confirmation as a potential therapeutic target for diverse diseases. Here, we investigated the mechanism by which DEF6 regulated RIRI. RNA sequencing data and IP-MS were used to identify the expression and potential targets of DEF6 through bioinformatics analysis. To elucidate the impact of DEF6 on RIRI, both an in vivo model of RIRI in mice and an in vitro model of kidney cell hypoxia/reoxygenation were established. Biochemical and histological analyses were used to investigate the influence of DEF6 on kidney damage mediated by RIRI. We confirmed that DEF6 was upregulated during RIRI and had a close correlation with RIRI-related inflammation and apoptosis. Moreover, inhibition of DEF6 could mitigate RIRI-induced kidney damage, inflammation, and apoptosis. Through our comprehensive mechanistic investigation, we revealed that DEF6 interacts with poly ADP-ribose polymerase 1 (PARP1) and suppresses the ubiquitination of PARP1. Inhibition of DEF6 resulted in reduced cleaveage of PARP1, leading to a marked suppression of PARP1-mediated apoptosis activation. The aggravation effect on inflammation and apoptosis achieved through DEF6 was nullified by the inhibition of NF-κB and Bax/Bcl2 signaling activation through PARP1 deletion. The findings from our study indicate that DEF6 suppressed the WWP2 mediated ubiquitination of PARP1 and modulates the activation of NF-κB and Bax/Bcl2 pathway, thus involved in RIRI-induced inflammation and apoptosis. These results suggest that DEF6 holds promise as a potential therapeutic target for mitigating RIRI. Show less

Fetal growth restriction (FGR) is a common complication of pregnancy, which seriously endangers fetal health and still lacks effective therapeutic targets. Clostridium difficile (C. difficile) is associated with fetal birth weight, and its membrane vesicles (MVs) are pathogenic vectors. However, the role of C. difficile and its MVs in FGR remains unclear. Here we found that supplementation with C. difficile altered the characteristics of gut microbiota and reduced the birth weight in mice. Interestingly, C. difficile MVs entered placenta, inhibited trophoblast motility, and induced fetal weight loss in mice. Mechanistically, C. difficile MVs activated the PPAR pathway via enhancing the transcriptional activity of PPARγ promoter, consequently inhibiting trophoblast motility. Moreover, PPARγ expression was significantly elevated in FGR placenta, and negatively correlated with fetal birth weight. Together, our findings reveal the significance of C. difficile and its MVs in FGR, providing new insights into the mechanisms of FGR development. Show less

Familial chylomicronemia syndrome (FCS) comprises a group of ultrarare disorders caused by biallelic variants in LPL or, less frequently, by GPIHBP1, APOC2, APOA5, or LMF1. To evaluate the phenotypes and management of eight non-lipoprotein lipase (LPL)-FCS patients. Seven pediatric and one adult patients with non-LPL-FCS were enrolled. Clinical features, treatment outcomes, and genetic profiles were assessed. Among the 33 patients with FCS, 25 (76%) had LPL-FCS and eight (24%) had non-LPL-FCS; five had variants in GPIHBP1, one each in the LMF1, APOC2, and one with composite heterozygous variants in APOA5 and LPL. Twelve non-LPL variants were identified, five of which were novel variants in GPIHBP1 and two in LMF1. In silico predictions indicated that all novel variants might impact protein function. Elevated baseline triglyceride (TG) levels [22.9 (17.4-30.8) mmol/L, 2026.7 (1540.0-2728.5) mg/dL] were observed in all patients. Among the pediatric patients (7/7), chylomicronemia was the most common onset symptom. Acute pancreatitis was observed in only one patient with LMF1-FCS during pregnancy. The frequency of symptoms and lipid levels in the non-LPL-FCS group were slightly lower than those in the LPL-FCS group (P > 0.05). Dietary fat restriction reduced TG levels by 84.0% to 4.21 mmol/L (372.6 mg/dL, P < 0.01). Compared with other non-LPL-FCS patients, GPIHBP1-FCS patients experienced greater challenges in managing TG levels (P < 0.05). This study unveiled the genetic profile of the Chinese FCS cohort and enriched the mutation spectrum of non-LPL-FCS. The clinical characteristics and treatment outcomes of patients with non-LPL-FCS were delineated. Show less

Previous studies have shown an association between lipid-lowering drugs, circulating inflammatory factors, and atrial fibrillation (AF), but the specific effects of lipid-lowering drugs on AF and whether they can be mediated by circulating inflammatory factors remain unclear. We collected 10 genetic variants encoding lipid-lowering drug targets (LDLR, HMGCR, PCSK9, NPC1L1, APOB, APOB, ABCG5, ABCG8, LPL, APOC3, and PPARA) and AF based on genome-wide association study (GWAS) summary statistics. Drug target Mendelian randomization (MR) was used to explore the causal relationship between lipid-lowering drugs and AF. In addition, we performed a mediation analysis of 91 circulating inflammatory factors to explore potential mediators. Sensitivity analyses were performed to verify the reliability of the MR Results by MR-Egger intercept test, Cochran's Q test and leave-one-out test. The results of IVW method showed that LPL agonist had a protective effect on AF(OR = 0. 854, 95%CI: 0.816-0.894, Our study provides new insights into the complex interactions among lipid-lowering agents, circulating inflammatory factors and AF, and also identified a potential mediating role of FGF5 in the pathogenesis of AF. Our findings highlight the potential of LPL agonists and targeting specific inflammatory factors for therapeutic intervention in AF, providing promising avenues for future research and clinical strategies for the management and prevention of AF. Show less

Mutational signature analysis gained significant attention for providing critical insights into the underlying mutational processes for various DNA single base substitution (SBS) signatures and their associations with different cancer types. Recently, RNA single base substitution (RNA-SBS) signatures were defined and described by decomposing RNA variants found in non-small cell lung cancer. Through statistical association, they attributed Apolipoprotein B mRNA Editing Enzyme, Catalytic Polypeptide 3A (APOBEC3A) mutagenesis to the RNA-SBS2 signature. Here, we provide the first validation of an RNA-SBS mutational signature by decomposing novel exogenous and endogenous APOBEC3A RNA editing signatures into COSMICv3.4 RNA-SBS reference signatures. Additionally, we have identified novel RNA-SBS signatures for APOBEC1, APOBEC3B, and APOBEC3G. Show less

Triglycerides (TGs) associate with apolipoprotein B100 (apoB100) to form very low density lipoproteins (VLDLs) in the liver. The repertoire of factors that facilitate this association is incompletely understood. FITM2, an integral endoplasmic reticulum (ER) protein, was originally discovered as a factor participating in cytosolic lipid droplet (LD) biogenesis in tissues that do not form VLDL. We hypothesized that in the liver, in addition to promoting cytosolic LD formation, FITM2 would also transfer TG from its site of synthesis in the ER membrane to nascent VLDL particles within the ER lumen. Experiments were conducted using a rat hepatic cell line (McArdle-RH7777, or McA cells), an established model of mammalian lipoprotein metabolism, and mice. FITM2 expression was reduced using siRNA in cells and by liver specific cre-recombinase mediated deletion of the Fitm2 gene in mice. Effects of FITM2 deficiency on VLDL assembly and secretion in vitro and in vivo were measured by multiple methods, including density gradient ultracentrifugation, chromatography, mass spectrometry, stimulated Raman scattering (SRS) microscopy, sub-cellular fractionation, immunoprecipitation, immunofluorescence, and electron microscopy. 1) FITM2-deficient hepatic cells in vitro and in vivo secrete TG-depleted VLDL particles, but the number of particles is unchanged compared to controls; 2) FITM2 deficiency in mice on a high fat diet (HFD) results in decreased plasma TG levels. The number of apoB100-containing lipoproteins remains similar, but shift from VLDL to low density lipoprotein (LDL) density; 3) Both in vitro and in vivo, when TG synthesis is stimulated and FITM2 is deficient, TG accumulates in the ER, and despite its availability this pool is unable to fully lipidate apoB100 particles; 4) FITM2 deficiency disrupts ER morphology and results in ER stress. The results suggest that FITM2 contributes to VLDL lipidation, especially when newly synthesized hepatic TG is in abundance. In addition to its fundamental importance in VLDL assembly, the results also suggest that under dysmetabolic conditions, FITM2 may be an important factor in the partitioning of TG between cytosolic LDs and VLDL particles. Show less

This study aims to investigate the association between nine tag single nucleotide polymorphisms (SNPs) in the A case-control study was conducted to investigate the association between CAD and Results of the polymorphism study indicated that the The Show less