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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 regulatory role of MACF1 and its upstream transcriptional control in focal adhesion remodeling and tumor progression in lung adenocarcinoma (LUAD). We employed in vitro loss- and gain-of-function assays using shRNA-mediated knockdown and ectopic overexpression of MACF1 and NR2F1 in LUAD cell lines (H1299 and Calu-3). Cell proliferation, adhesion, and migration were assessed by CCK-8, EdU, crystal violet, and Transwell assays. In vivo tumor growth and metastasis were evaluated using subcutaneous and tail vein xenograft models in nude mice. RNA-seq and GSEA were performed to identify MACF1-regulated pathways, followed by nuclear-cytoplasmic fractionation, dual-luciferase reporter assays, and immunofluorescence to assess WNT/β-catenin activity. ChIP-qPCR and ChIP-seq data from ENCODE were used to validate NR2F1 binding to the MACF1 promoter. MACF1 knockdown significantly suppressed LUAD cell proliferation, DNA replication, adhesion, and migration, and reduced tumor burden and lung metastases in vivo. Mechanistically, MACF1 activated WNT/β-catenin signaling by promoting CTNNB1 nuclear translocation, which upregulated focal adhesion genes (Paxillin, FAK, ITGB1). CTNNB1 agonist TWS119 restored focal adhesion in MACF1-deficient cells. Bioinformatic prediction and ChIP validation identified NR2F1 as a transcription factor directly targeting the MACF1 promoter. NR2F1 deficiency reduced MACF1 expression and phenocopied its functional loss, while MACF1 overexpression rescued the impaired phenotype. Our study uncovers a previously unrecognized NR2F1-MACF1-WNT axis that drives focal adhesion formation and LUAD progression. Targeting this regulatory circuit may offer new avenues for anti-metastatic therapy in lung adenocarcinoma. 1. NR2F1 is identified as a direct upstream transcription factor that activates MACF1 expression in LUAD. 2. MACF1 promotes LUAD cell proliferation, adhesion, and migration by enhancing focal adhesion assembly. 3. MACF1 activates the WNT/CTNNB1 signaling cascade, facilitating CTNNB1 nuclear translocation and downstream target expression. 4. Loss of MACF1 impairs focal adhesion formation and metastatic potential both in vitro and in xenograft and tail vein models. 5. The NR2F1-MACF1-WNT axis represents a novel regulatory circuit driving LUAD metastasis and offers potential therapeutic targets. Show less

Apolipoproteins as an integral part of lipoproteins are crucial for the transport and metabolism of lipids. However, there is a lack of longitudinal studies to quantify the concentrations of maternal apolipoproteins from preconception to postpartum and their associations with maternal metabolic health and offspring birth outcomes. Quantification of apolipoproteins was performed on maternal plasma samples (N = 243 trios) collected at preconception, 26-28 weeks' pregnancy, and three months postpartum in the Singapore PREconception Study of long-Term maternal and child Outcomes (S-PRESTO) cohort study. Linear regression models and network analysis were implemented to investigate the association of apolipoproteins with maternal genetic variants, biochemical measures, metabolic risk factors, and offspring birth outcomes. The concentrations of ApoC-III, ApoB and ApoL1 substantially increased in pregnancy compared to preconception and postpartum. Genome-wide association studies (GWAS) identified multiple single-nucleotide polymorphisms (SNPs) associated with plasma apolipoproteins (P < 5.00E-08), including APOE-rs7412 for ApoE, LPA-rs56393506 for Apo(a), APOM-rs707921 for ApoM, ABCC4-rs117797426 for ApoJ, THSD7B-rs575613 for ApoA-II, and LOC102724443-rs140433245 for ApoA-IV. Plasma apolipoproteins were strongly associated with biochemical measures including lipidomic profiles, lipoprotein features and fat-soluble vitamins, as well as metabolic risk factors including glycaemic traits, liver enzymes, inflammatory markers, albumin, and blood pressure. Integrative network analysis of apolipoproteins and their correlates/determinants revealed both shared and specific associations, with the strongest relationships observed among apolipoproteins, cholesterol, triglycerides, alpha tocopherol, and GlycA (P We describe the longitudinal landscape of maternal circulating apolipoproteins from preconception to postpartum and their associations with maternal metabolic risk factors and offspring birth outcomes. This multi-omics characterisation of biochemical correlates and genetic determinants of maternal apolipoproteins will deepen our understanding of the molecular basis of metabolic flexibility in expectant mothers, leading to better assessment of pregnancy-related outcomes. This research was supported by the Singapore National Research Foundation under its Translational and Clinical Research (TCR) Flagship Programme and administered by the Singapore Ministry of Health's National Medical Research Council (NMRC), Singapore- NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014. The Singapore Lipidomics Incubator (SLING) is supported by grants from the National University of Singapore via the Life Sciences Institute, the National Research Foundation (NRF, NRFI2015-05 and NRFSBP-P4) and A∗STAR IAF-ICP I1901E0040. Additional funding is provided by Institute for Human Development and Potential (IHDP)-Agency for Science, Technology and Research (A∗STAR), Singapore. Show less

While heterozygous Through collaborative efforts, we assembled a cohort of 10 affected individuals from 8 unrelated families with either biallelic or monoallelic non-GAR domain Clustering revealed two distinct phenotypic signatures, suggesting domain-specific effects. Variants outside the GAR domain associate with broader neurodevelopmental phenotypes and variable craniofacial and skeletal expressivity. Additionally, enrichment analysis (p < 0.001) using OMIM HPO sets supported these findings. In contrast to the GAR domain's strong correlation with lissencephaly and brainstem malformations, biallelic non-GAR domain These results expand the phenotypic spectrum of Show less

To investigate the genetic etiology of ventriculomegaly (VM) in fetuses by analyzing chromosomal aberrations and genetic variations through high-throughput sequencing. Clinical data and samples (amniotic fluid or miscarriage tissue) were collected from fetuses with ventricular width >10 mm, diagnosed at Shanxi Children's Hospital between 2020 and 2023. All samples underwent copy number variation sequencing (CNV-seq), and those with negative CNV-seq result were further analyzed by whole exome sequencing (WES) to identify single-gene variants. Chromosomal abnormalities and monogenic variants were classified according to the American College of Medical Genetics and Genomics guidelines. Statistical analysis was performed using SPSS 26.0, and pregnancy outcomes were tracked. Among 73 VM fetuses, 23 (31.5%) cases exhibited chromosomal aberrations via CNV-seq, including 4 aneuploidies, 12 pathogenic CNVs, 2 likely pathogenic CNVs, and 8 variants of unknown significance. The incidence of chromosomal abnormalities was significantly higher in non-isolated VM fetuses compared to isolated VM (p < 0.05). WES analysis of 33 CNV-negative cases identified single-gene defects in 16 (48.5%) fetuses, including SPATA5, PDHA1, TRIM71, PIK3R2, TUBB, CRB2, PIDD1, RTTN, FGFR3, AIMP1, POGZ, MYH7, CNOT3, MACF1, and PURA gene, with 10 novel variants reported. Fetal VM is associated with heterogeneous neurodevelopmental outcomes, and genetic etiology plays an important role in its pathogenesis. WES enhances the efficiency of diagnosis, particularly for VM fetuses without detectable aneuploidy or CNVs. Identifying the genetic etiology of fetal VM is is crucial for informing birth defect prevention strategies and improving the overall health of the newborn population. Show less

Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by compromised neuromuscular signal transmission due to pathogenic germline variants in genes expressed at the neuromuscular junction (NMJ). A total of 40 genes have been reported in CMS (AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DES, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MACF1, MUSK, MYO9A, PLEC, PREPL, PTPN11, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TEFM, TOR1AIP1, UNC13A, UNC50 and VAMP1). The 40 genes are putatively classified into 13 subtypes by pathomechanical, clinical, and therapeutic features. A unique feature shared by recently identified genes is that CMS is concomitantly recognized in other mostly severer diseases. For example, four recently identified genes exhibit the following phenotypes: PURA-CMS, developmental delay; TEFM-CMS, mitochondrial disease; PTPN11-CMS, Noonan syndrome/Leopard syndrome; and DES-CMS, desmin myopathy. Conversely, these diseases are not always associated with CMS, although genetic and/or environmental factors that determine the involvement of the NMJ remain to be identified. In this review, particular emphasis will be placed on five recently identified genes (MACF1, TEFM, PTPN11, DES and UNC50). Show less

Significant associations exist between major depressive disorder (MDD), metabolic syndrome (MetS), and cardiovascular disease, potentially attributable to heightened atherogenicity. This study aimed to ascertain if MDD, depression severity, suicidal behaviors, and neuroticism associate with elevated pro-atherogenic indices and reduced anti-atherogenic indices, including a reverse cholesterol transport (RCT) index. This study comprised 34 healthy controls and 33 MDD patients without MetS, and 35 controls and 31 MDD patients with MetS. It assessed total cholesterol (TC) and free cholesterol (FC), high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), triglycerides (TG), apolipoprotein (ApoA), ApoB, cholesterol esterification rate, and a RCT composite. No significant associations between MDD and lipids were seen in the total study group that combined individuals with and without MetS. In individuals devoid of MetS, MDD is significantly correlated with (a) elevated FC, TG, ApoB, Castelli risk index 1, and ApoB/ApoA, and (b) diminished HDLc, ApoA, and RCT index. In individuals without MetS, there are notable correlations between the severity of depression, suicidal tendencies, neuroticism, and ApoB/ApoA, Castelli risk, and RCT indices. The link between lipids and MDD features cannot be adequately estimated by combining participants with and without MetS. It should be examined in a study sample that excludes subjects with MetS. The depression phenome, suicidal behaviors, and neuroticism correlate with diminished RCT and heightened atherogenicity, which are likely implicated in the pathophysiology of MDD. Increased atherogenicity and lowered RCT may represent novel drug targets for the treatment and prevention of MDD, neuroticism, and suicidal behaviors. 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 expression, single-cell sequencing and genotype-phenotype correlation were analysed to explore the role of Two de novo heterozygous and eight biallelic Show less

A ketogenic diet is used in children with drug-resistant epilepsy but predictors for efficacy are largely lacking. Our aim was to evaluate if causative genetic variants could predict seizure response to the ketogenic diet. A cohort study of 226 children with refractory epilepsy and classic ketogenic diet treatment for at least 3 months (76.9% of the 294 who started) was performed. The median age at diet start was 5.1 years (range 0.1-17.8), 118 were girls and 108 boys. They had previous trials of a median of 6.0 anti-seizure medications (range 0-12) and intellectual disability was found in 87%. Seizure response (≥50% reduction) was found in 138/226 patients (61.1%) at 3 months, 121 (53.5%) at 6 months, 107 (47.3%) at 1 year and in 80 (37.0%) at 2 years follow-up of ketogenic diet. Age of epilepsy onset was lower and combined epilepsy type less common in responders compared to non-responders but no differences were found for specific seizure types, ketogenic ratio or beta-hydroxybutyric acid blood levels. A causative pathogenic/likely pathogenic variant was detected in 107/153 = 69.9% in 48 different genes. Next generation sequencing was used in 91/226 (40%) cases with a diagnostic yield of 58.2% (53/91). In comparison with cases without a revealed genetic aetiology, patients with a causative genetic variant had less atonic seizures and epileptic spasms and a better seizure response with 17.3% seizure free and 25% with >90% seizure reduction at 2-year follow-up. Causative variants in Show less

Microtubule-actin cross-linking factor 1 (MACF1), also known as actin cross-linking family protein 7 (ACF7), is a giant cytolinker protein with multiple conserved domains that can orchestrate cytoskeletal networks of actin and microtubules. MACF1 is involved in various biological processes, including cell polarity, cell-cell connection, cell proliferation, migration, vesicle transport, signal transduction, and neuronal development. In this review, we updated the physiological and pathological roles of MACF1, highlighting the components and signaling pathways involved. Novel evidence showed that MACF1 is involved in diverse human diseases, including multiple neuronal diseases, congenital myasthenic syndrome, premature ovarian insufficiency, spectraplakinopathy, osteoporosis, proliferative diabetic retinopathy, and various types of cancer. We also reviewed the physiological roles of MACF1, including its involvement in adhesome formation, bone formation, neuronal aging, and tooth development. In addition, MACF1 plays other roles, functioning as a biomarker for the prediction of infections in patients with burns and as a marker for genome selection breeding. These studies reinforce the idea that MACF1 is a bona fide versatile, multifaceted giant protein. Identifying additional MACF1 functions would finally help with the treatment of diseases caused by MACF1 defects. Show less

The liver, and more precisely hepatocytes, can be infected by several hepatotropic viruses, including HBV, HDV, HCV and HEV, with chronic infection leading to end-stage liver diseases. Since no HuH7.5-NTCP cells were cultured with 2% DMSO (dimethyl sulfoxide) for 1 week to allow partial differentiation into hepatocytes (dHuH7.5-NTCP) before infection with the different viruses and treatment with known antiviral molecules. We observed increased expression of liver specific transcripts and production of ApoB containing VLDL in dHuH7.5-NTCP cells and replication of HBV, HDV, HCV and HEV for at least 4 weeks after mono or multiple infections. We recapitulated the known antiviral effect of sofosbuvir on HCV and HEV (>90% reduction in the levels of intracellular viral RNAs, We set-up the first Hepatitis virus infections caused by HBV, HCV, HDV, and HEV represent a global health threat. Treatment options remain limited, notably due to the lack of knowledge about molecular virus-host interactions. Moreover, the interplay between these four viruses in the context of co-infections remains unknown. In this study, we report the first Show less

The heat shock response (HSR) is a conserved cellular mechanism critical for adaptation to environmental and physiological stressors, with broad implications for cell survival, immune responses, and cancer biology. While the HSR has been extensively studied at the proteomic and transcriptomic levels, the role of lipid metabolism and membrane reorganization remains underexplored. Here, we integrate mass spectrometry-based lipidomics with RNA sequencing to characterize global lipidomic and transcriptomic changes in HeLa cells exposed to three conditions: control, heat shock (HS), and HS with eight hours of recovery. Heat shock-induced extensive lipid remodeling, including significant increases in fatty acids, glycerophospholipids, and sphingolipids, with partial normalization during recovery. Transcriptomic analysis identified over 2700 upregulated and 2300 downregulated genes under heat shock, with GO enrichment suggesting potential transcriptional contributions to lipid metabolism. However, transcriptional changes alone did not fully explain the observed lipidomic shifts, suggesting additional layers of regulation. Joint pathway analysis revealed enrichment in glycerophospholipid and sphingolipid metabolism, while network analysis identified lipid transport regulators (STAB2, APOB), stress-linked metabolic nodes (KNG1), and persistent sphingolipid enrichment during recovery. These findings provide a comprehensive framework for understanding lipid-mediated mechanisms of the HSR and highlight the importance of multi-omics integration in stress adaptation and disease biology. Show less

Avian leukosis (AL), a major vertically transmitted infectious disease, poses a significant challenge to the conservation and industrial development of indigenous chicken breeds in China. In this study, Chengkou mountain chickens were used as a model to systematically identify genetic markers associated with resistance to avian leukosis virus subgroup J (ALV-J) through a genome-wide association study (GWAS). Genomic DNA was extracted from 500 hens at 300 days of age, and cloacal swabs, plasma, and egg white samples were collected to assess the ALV-J infection status. A total of 325 ALV-positive (ALV+) and 175 ALV-negative (ALV-) individuals were identified. Based on 10× whole-genome resequencing and stringent quality control, 12,644,463 high-quality SNPs were obtained. GWAS revealed a significant enrichment of SNPs on chromosome 6 (Chr6), from which 218 SNPs significantly associated with ALV-J resistance and 49 candidate genes were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that many of these genes, including Show less

Split-hand/foot malformation (SHFM) is a rare congenital limb anomaly defined by the absence or hypoplasia of the central rays of the autopod. SHFM occurs as an isolated entity or part of genetic syndromes with several causative copy-number variations or monogenic alterations known to be involved in the disease pathomechanism. On the other hand, cleft lip/palate (CL/P) usually results from polygenic and environmental factors, with the complex interplay of both leading to this malformation. Pathogenic variants in We conducted targeted next-generation sequencing (NGS) in the proband with SHFM, followed by segregation analysis in the family members. In this study, we report an index patient presenting with isolated SHFM and his brother with CL and facial dysmorphism, as well as their father with isolated hyposmia. Targeted next-generation sequencing revealed a previously reported heterozygous missense pathogenic variant in This study expands the phenotypic spectrum associated with Show less

This study used whole-genome sequence data on 406 beef cattle (203 Hanwoo and 203 Angus) to detect signatures of selection using four different methods; integrated haplotype score (iHS), Rsb, XP-EHH, and runs of homozygosity (ROH). Based on Rsb and XP-EHH analysis, 36 and 21 genomic regions differed significantly between Angus and Hanwoo breeds. Within breeds, we identified 108 regions (76 in Hanwoo and 32 in Angus) with the ROH analysis and 331 regions with the iHS method (298 in Hanwoo and 33 in Angus). The candidate genes related to meat quality, such as HSPA9 and LPL, were found within Hanwoo, while genes associated with growth and meat quantity traits, including ACTC1 and TMEM68, were identified within Angus. This study can assist in understanding the selection history of these breeds and identifying the genomic regions associated with the traits selected for in the breeding programs for these cattle breeds. Show less

Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder caused by impaired insulin secretion from pancreatic β-cells and insulin resistance in target tissues. Genome-wide association studies have identified over 50 genetic variants linked to T2DM, including polymorphisms associated with the disease. This study investigates the impact of the Show less

Impaired glucose tolerance (IGM) and type 2 diabetes mellitus (T2DM) are associated with less optimal time spent in 24-hour movement behaviors (24 h-MBs) compared to people with normoglycemia (NG). We aimed to investigate how 24 h-MBs change over time and whether changes in 24 h-MBs differ between adults according to glycemic trajectories over time. Participants ( The online version contains supplementary material available at 10.1038/s41598-025-33099-z. Show less

Neuronal Ceroid Lipofuscinoses (NCLs), also known as Batten disease, are a group of inherited neurodegenerative disorders that mostly arise in childhood. Each of the NCLs is a genetically distinct disease caused by variants in at least 13 different genes (CLN1-CLN14). NCLs are neurodegenerative, and symptoms can include a combination of childhood dementia, epileptic seizures, motor decline and vision loss, and eventually lead to premature death. There is currently no cure for any subtype of NCL, however, enzyme replacement therapy is available for CLN2 disease, and several treatment strategies are being explored for other NCL subtypes. Early diagnosis and initiation of supportive services (e.g. health, education, social services) are essential to preserve quality of life. Only a few studies have investigated family experiences with NCL, many of which are international in scope. A mixed-method research study was conducted in the UK to understand family experiences in CLN2 and CLN3 disease. It involved an initial literature review, followed by in-depth qualitative interviews. Interview data were analysed using a thematic analysis. Thirteen families (n = 13) participated in the interviews. This represented 16 parents (11 mothers and 5 fathers) of 18 children (10 diagnosed with CLN3 disease and 8 diagnosed with CLN2 disease). Findings were analysed jointly across CLN2 and CLN3 disease. Six overarching themes emerged from the analysis: difficulty in recognising early symptoms; the shock of a diagnosis; the demands of caring for complex and ever-changing needs; a constant battle to access appropriate and timely support services; the extensive impact on the unaffected sibling; and the all-encompassing impact on the family. This study contributes novel UK specific data on family experiences and unmet needs in CLN2 and CLN3 disease. More needs to be done to ensure NCLs are diagnosed early, and timely local support services are made available to protect quality of life for both the affected children and their families. Show less

Despite the well-established association between the apolipoprotein B/apolipoprotein A1 (apoB/apoA1) ratio and ischemic stroke, its specific relationship with the underlying vascular pathologies contributing to stroke remains poorly understood. This study aims to investigate the association between the apoB/apoA1 ratio and intracranial or extracranial atherosclerosis. We enrolled 408 patients with acute ischemic stroke who had never been treated with statins or fibrates. Based on the images from computed tomography angiography (CTA), the patients were categorized into four groups: intracranial atherosclerosis stenosis (ICAS, n = 136), extracranial carotid atherosclerosis stenosis (ECAS, n = 45), combined intracranial and extracranial atherosclerosis stenosis (COAS, n = 73), and non-cerebral atherosclerosis stenosis (NCAS, n = 154). Demographic characteristics, clinical factors, and serum lipid levels were collected and then compared across groups. The apoB/apoA1 ratio was significantly higher in patients with ICAS, ECAS and COAS compared to those in the NCAS group. Multivariable logistic regression analysis demonstrated that the ApoB/ApoA1 ratio was independently associated with ICAS, but not with ECAS. ROC curve analysis showed that the ApoB/ApoA1 ratio had a good diagnostic ability for ICAS, with an area under the curve (AUC) of 0.764, an optimal cut-off value of 0.8122, a sensitivity of 81.3%, and a specificity of 59.8%. An higher apoB/apoA1 ratio is associated with ICAS in ischemic stroke patients. Show less

Our previous studies have shown that miR-130b can significantly inhibit subcutaneous fat deposition in pigs. This study aims to further investigate its effect on lipid accumulation at early-stage (24 and 48 h) and late-stage (7 d) adipogenic differentiation and to clarify potential mechanisms using primary rat intramuscular preadipocytes (IMAs). Results showed that at 24 h and 48 h, miR-130b overexpression significantly reduced lipid deposition by inhibiting proliferation and inducing apoptosis. Furthermore, miR-130b overexpression significantly inhibited the expression of cell cycle and apoptosis marker genes. Specifically, the mRNA expression of Show less

Chromobox (CBX) proteins are essential components of the Polycomb group and play pivotal roles in tumor onset, progression, and metastasis. However, the prognostic significance and functions of CBXs in the advancement of breast cancer (BC) have not been sufficiently investigated. A comprehensive analysis of the expression and prognostic relevance of CBX1-8 in BC was conducted comprehensively using The Cancer Genome Atlas (TCGA) and multiple databases. High mRNA expression of CBX2, CBX3, and CBX5 in BC patients was significantly associated with reduced overall survival (OS). Results from univariate and multivariate Cox regression analysis revealed that the mRNA expression level of CBX2 in BC patients served as an independent prognostic factor. In Luminal A and Luminal B BC subtypes, high expression of CBX2 correlated with unfavorable prognosis. Subsequent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated a strong association between CBX2 and the cell cycle as well as DNA replication processes. CCK-8 and EdU assays demonstrated that silencing CBX2 inhibited the proliferation of T47D and MCF7 cell lines. Moreover, the cell cycle assay indicated that CBX2 silencing led to cell cycle arrest, accompanied by a significant decrease in the levels of CDK4 and CyclinD1. Elevated CBX2 expression significantly correlated with the infiltration of T cells, B cells, macrophages, and dendritic cells in BC. Our findings could provide new perspectives for identifying potential prognostic markers within the CBX family in BC. Targeting CBX2 may present a promising approach to address endocrine resistance in BC therapy. Show less

Susceptibility to metabolic dysfunction-associated fatty liver diseases (MAFLD) shows a large inter-ethnic variability. Currently, large-scale genome-wide association studies (GWAS) on MAFLD in a Korean population are limited. This study aimed to investigate genes underlying MAFLD in a Korean population. A total of 13,457 Korean adults (4061 cases and 9396 controls) who underwent abdominal ultrasonography, biochemical testing, and genetic studies at a comprehensive health promotion center from 2019 to 2023 were included. Genome-wide genotyping was conducted using Infinium Asian Screening Array and an iSCAN system (Illumina, San Diego, CA, USA). Gene-based approach was conducted with Multi-Marker Analysis for Genomic Annotation (MAGMA) and Functional Mapping and Annotation (FUMA). Expression quantitative trait loci (eQTLs) mapping was done using GTEx v8 data. The 22q13.3, 19p13.11, and 2p23.3 loci were associated with MAFLD after adjusting for age, sex, and body mass index (p < 5 × 10 This is the largest-scale GWAS of MAFLD in a Korean adult population. Genotyping PARVB as well as PNPLA3 might help us identify individuals with the highest risk of MAFLD in Korean adults. These findings would contribute to our understanding of genetic pathogenesis of MAFLD in the Korean population. Show less

Liver hepatocellular carcinoma (LIHC) is a common cancer worldwide. Mitogen-activated protein kinase kinase (MAP2Ks) are related to the occurrence and development of a variety of tumors. However, the expression pattern, role, and prognostic value of the 7 MAP2K family members in LIHC have not yet been elucidated. We used the Oncomine, UALCAN, Human Protein Atlas, GeneMANIA, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, TIMER, and Kaplan-Meier Plotter databases. On August 7, 2021, we searched these databases for the terms MAP2K1, MAP2K2, MAP2K3, MAP2K4, MAP2K5, MAP2K6, MAP2K7, and "liver cancer." The exposure group comprised LIHC patients, and the control group comprised normal patients (those with noncancerous liver tissue). All patients shown in the retrieval language search were included. We compared the mRNA expression of these proteins in LIHC and control patients to examine the potential role of MAP2K1 to 7 in LIHC. Relative to the normal liver tissue, mRNA expression of MAP2K1/3 was significantly downregulated (P < .001), MAP2K4 was downregulated (P < .05), and that of MAP2K2/5/6/7 significantly upregulated (P < .001), in LIHC. MAP2K mRNA expression varied with gender (P < .0001), cancer stage (P < .05), tumor grade (P < .05), and with node metastasis status (P < .05), except for MAP2K4. Based on Kyoto Encyclopedia of Genes and Genomes enrichment analysis, these genes were associated with the following pathways: MAPK signaling pathway, GnRH signaling pathway, Fc epsilon RI signaling pathway (P < .05). The MAP2Ks were significantly associated with purity (P < .05), except for MAP2K1/2, with B cell (P < .05), except for MAP2K3, and that all significantly associated withCD8+ T cell, CD4+ T cell, macrophage, neutrophil, and dendritic cell infiltration (P < .05). High mRNA expression of MAP2K1/3/4/5 (P < .05) and low expression of MAP2K6 (P < .05) indicated overall survival, the high expression of MAP2K3/4/5 were related to relapse free survival and progression free survival; the high expression of MAP2K3/5/7 were related to disease free survival. We identified MAP2K1 to 7 as potential diagnostic markers, and MAP2K2 to 7 as prognostic markers, of LIHC. Our future work will promote the use of MAP2Ks in the diagnosis and treatment of LIHC. Show less

Imprinted genes are epigenetically regulated in normal tissues to follow monoallelic expression according to the parent of origin of each allele. Some of these patterns are dysregulated in cancer. We developed a novel computational multi-omic pipeline to evaluate monoallelic and biallelic expression patterns based on matched RNA-seq expression data, whole-exome sequencing information, and copy number data. We analyzed allelic expression of the entire genes, individual isoforms, and each exon of 59,283 autosomal protein-coding and ncRNA genes, with a focus on 94 genes previously reported to be imprinted. We analyzed 108 cell lines from 9 different tumor histologies using molecular data from the DepMap Portal for the Cancer Cell Line Encyclopedia. Allelic expression patterns of imprinted genes and isoforms in tumor cells were variable. We also identified additional genes and isoforms with predominantly monoallelic expression due to a variety of potential mechanisms. We provide a novel public dataset of transcriptome-wide allelic expression patterns in cell lines from diverse tumor categories, which can serve as a resource for future cancer studies. We examined associations of in vitro cell line response to antitumor agents and repurposed drugs with allelic patterns and overall levels of isoform expression of imprinted genes and of additional genes with predominantly monoallelic expression. Drug response was associated with isoform expression patterns of multiple imprinted genes including CPA4, DGCR6, DNMT1, GNAS, GRB10, H19, NAA60, OSBPL5, PHACTR2, and ZFAT, predominantly monoallelically expressed MAP2K5 and BCLAF1, and additional predominantly monoallelically expressed genes. Multiple associations may be related to mechanisms of drug activity, including associations between the response to the DNA damaging agents and allelic expression of ZFAT, CDC27, and BCLAF1 isoforms, and the response to inhibitors of multiple signaling pathways with expression patterns of GNAS isoforms. Tumor cells have a range of monoallelic and biallelic expression patterns in both imprinted and non-imprinted genes and are likely affected by the complex interplay among changes in allelic expression, sequence variants, copy number changes, and expression changes of biologically important genes. Multiple isoform-specific patterns of allelic expression were associated with drug response, indicating complex mechanisms of cancer chemoresistance. Show less

Malignant melanoma is the deadliest skin cancer, with a poor prognosis in advanced stages. We reported that both Hedgehog-GLI (HH/GLI) and Mitogen-activated protein Kinase (MAPK) extracellular signal-regulated kinase 5 (ERK5) pathways promote melanoma growth, and that ERK5 activation is required for HH/GLI-dependent melanoma cell proliferation. Here, we explored whether ERK5 regulates HH/GLI signaling. Both genetic (using ERK5-specific shRNA) and pharmacologic (using the ERK5 inhibitors JWG-071 and AX15836, and the MAPK/ERK kinase 5, MEK5 inhibitors GW284543 and BIX02189) targeting approaches were used. Luciferase assay using the GLI-binding site luciferase reporter was performed to evaluate GLI transcriptional activity. A constitutively active form of MEK5 (MEK5DD) was used to induce ERK5 activation. 3D spheroid assays were performed in melanoma cells. Genetic and pharmacologic ERK5 inhibition reduces GLI1 and GLI2 protein levels and transcriptional activity of endogenous HH/GLI pathway induced by the agonist SAG in NIH/3T3 cells. In these cells, MEK5DD overexpression potentiates transcriptional activity of endogenous HH/GLI pathway induced by SAG, whereas ERK5 silencing prevents this effect. Consistently, MEK5DD overexpression increases GLI1 and GLI2 protein levels. In melanoma cells, ERK5 silencing reduces GLI1 and GLI2 mRNA and protein levels and inhibits GLI transcriptional activity. MEK5DD further increases the transcriptional activity of the HH/GLI pathway and GLI1 protein levels. Combination of GLI and MEK5 inhibitors is more effective than single treatments in reducing melanoma spheroid growth. MEK5-ERK5 is an activator of GLI transcription factors, and combined targeting of these pathways warrants further preclinical investigation as a potential innovative therapeutic approach for melanoma. Show less

To investigate the influence of MEK5/ERK5 pathway on mitophagy in osteosarcoma (OS), as well as the involved molecular mechanisms. The overlapped genes of mitophagy-related genes from MSigDB database and DEGs between metastatic and primary OS groups from GSE32981 were identified. GSVA of mitophagy-related pathways between the metastatic and primary groups were analyzed. The relationships between Nur77 and mitophagy-related pathways, prognosis, immune infiltrating cells, immune response gene sets were investigated. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blotting were utilized to assess the expression levels of MEK5, ERK5, Nur77, PINK1, and Parkin. Cellular behaviors and mitochondrial potential were evaluated via CCK-8, Transwell assay and JC-1 staining. Total 4 overlapped genes were obtained as mitophagy-related DEGs, including GABARAPL1, HIF1A, PINK1, and RB1CC1. The activity scores of 3 mitophagy-related pathways exhibited significant differences between metastatic and primary groups. Importantly, Nur77 was significantly negatively correlated with a mitophagy-related pathway (GOBP MITOPHAGY: R = - 0.48, P = 0.02). The Nur77 expression in metastatic group was remarkedly higher than that in the primary group (P < 0.001). Patients with high Nur77 expression had poor prognosis, with AUC values all above 0.615 in predicting 1-, 3-, and 5-year survival. In addition, Nur77 was closely related to numerous immune cells, including activated dendritic cells, activated mast cells and M0 macrophages, and immune response gene sets chemokines and cytokines (all P < 0.05). In addition, MEK5/ERK5 pathway is activated in OS, and Nur77 is overexpressed in OS, and MEK5/ERK pathway promotes Nur77 expression, tumorigenesis and mitochondrial function in U2OS cells. Cytosporone B implement significantly increased the tumorigenesis of U2OS cells in sh-MEK5 group, and inhibited the weaken in mitochondrial membrane potential caused by MEK5 downregulation, and reversed the protein levels of mitophagy markers PINK1 and Parkin in sh-MEK5 group. MEK5-ERK5 pathway mediates mitophagy by regulating Nur77 to promote tumorigenesis of OS cells. These findings offered promising therapeutic targets for OS. Show less

The fibroblast growth factor receptor family members, FGFR1-4, are frequently overexpressed in various solid tumors, including breast cancer and sarcomas. This overexpression highlights the potential of the family of FGFRs as promising targets for cancer therapy. However, conventional FGFR kinase inhibitors often encounter challenges such as limited efficacy or drug resistance. In this study, we pursue an alternative strategy by designing a conjugate of the FGFR ligand FGF1 with the radioisotope Show less

This study provides an analysis of 37 ovarian Sertoli-Leydig cell tumors (SLCT), focusing on their morphological, immunohistochemical, and molecular features. The cohort was comprised of 9 well-differentiated, 25 moderately differentiated, and 3 poorly differentiated tumors. The immunohistochemical analysis was performed with 28 markers, including diagnostic markers and markers with possible predictive significance. The results showed high expression of sex cord markers (FOXL2, SF1, inhibin A, CD99, calretinin, ER, PR, AR), and variable expression of other markers such as CKAE1/3 (83%), CAIX (14%), and MUC4 (1%). Loss of PTEN expression was present in 14% of cases, and CTLA4 expression was seen in 43% of cases. All tumors were MMR proficient and HER2 and PD-L1 negative. The molecular analysis showed DICER1 mutations in 54.5% of cases, and a FOXL2 mutation in 6% of tumors. In addition, we detected 2 cases with TERT promoter mutation. RNA NGS sequencing identified significant differences in mRNA expression between DICER1 Show less

We have designed the first antigen-less pro-vaccine, named 8206, for treating autoimmune diseases. Composed of dexamethasone, rapamycin, and R848 at a mass ratio of 8:20:6, 8206 is a complete tolerogenic adjuvant that acts systemically to form an active vaccine in situ with endogenous pathogenic autoantigens. This active vaccine suppresses autoimmunity by expanding antigen-specific Treg cells in affected tissues. In a mouse model of atherosclerosis, 8206 successfully targeted all three analyzed pathogenic autoantigens (ApoB, HSP60, and HMGB1) and inhibited disease progression. These findings suggest that 8206 can potentially serve as a universal treatment vaccine for autoimmune diseases by eliminating the need for exogenous immunogens, with implications for broad applications in immunotherapy. Show less