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Tumor budding (TB) is a well-established prognostic indicator in various epithelial malignancies. Chordoma, although a rare mesenchymal tumor, paradoxically exhibits prominent epithelial-like characteristics, as demonstrated in previous studies. In particular, it remains unclear whether TB-like (TBL) structures are present in chordoma, as well as the molecular mechanisms driving their formation and their functional impact on tumor progression, representing a critical gap in current knowledge. Tumor budding-like grades were defined and evaluated in tumor specimens from 481 chordoma patients across 4 large cohorts using hematoxylin-eosin and immunohistochemical staining. Multi-omics profiling, encompassing GeoMx digital spatial profiling, spatial transcriptomics, bulk RNA sequencing, single-cell RNA sequencing, single-cell ATAC sequencing, and multiplex quantitative immunofluorescence, was integrated to delineate TBL cell subpopulations (TBLCs) and their interactions with cholesterol-metabolic tumor-associated macrophages (CM-TAMs). Organoid models and in vitro/in vivo functional assays were employed for mechanistic investigation and validation. Tumor budding-like structures were prevalent in chordoma, and higher TBL grades were associated with unfavorable clinical outcomes and aggressive phenotypes. Mechanistically, BACH1 in CM-TAMs drove ANGPTL4 secretion, which targeted the SDC4 receptor on TBLCs, thereby enhancing stem-like properties, promoting cholesterol accumulation, and accelerating malignant progression. Pharmacological inhibition of cholesterol metabolism or disruption of the BACH1-ANGPTL4-SDC4 signaling axis markedly reduced tumor invasiveness in both preclinical models and chordoma organoids. BACH1-driven CM-TAMs activate TBLCs via the ANGPTL4-SDC4 signaling axis, promoting stemness and cholesterol accumulation, ultimately driving malignant progression in chordoma. These findings uncover a previously unrecognized tumor-immune-metabolic interaction and suggest potential therapeutic targets for this disease. Show less

Aberrant differentiation of keratinocytes has been implicated in various skin diseases. However, the impact of lncRNA on keratinocyte differentiation and RNA alternative splicing remains poorly understood. The primary aim of this study was to delineate the landscape of differentially expressed lncRNAs in keratinocytes undergoing differentiation and to elucidate the underlying molecular mechanisms. Primary human keratinocytes (HKEn) were subjected to comprehensive microarray analysis to identify the differentially expressed lncRNAs upon calcium stimulation. Loss-of-function experiments were carried out to explore the role of NR037661 in keratinocyte differentiation. RNA sequencing analysis was performed to study the potential target genes of NR037761. RNA pull-down assay, SDS-PAGE, silver staining and mass spectrometry analysis were utilized to explore the potential proteins that interacted with NR037761 and participated in NR037761-mediated keratinocyte differentiation. The effects of NR037761 on the alternative splicing and expression of Angiopoietin-like 4 (ANGPTL4) were analyzed by RT-PCR and Western blot. NR037661 specifically interacts with the splicing factor Serine/arginine repetitive matrix protein 2 (SRRM2), facilitating its nuclear localization. This interaction modulates the alternative splicing (AS) of ANGPTL4 mRNA, ultimately influencing keratinocyte differentiation. Our findings illuminate a novel regulatory mechanism underlying keratinocyte differentiation, potentially revealing new therapeutic targets for skin diseases. Show less

Hypertriglyceridemia (HTG) and mixed dyslipidemia are significant risk factors for cardiovascular diseases. Despite the widespread use of traditional therapies, many patients continue to experience elevated triglycerides and residual cardiovascular risk. Small interfering RNA (siRNA) therapies represent a novel approach to lipid-lowering treatment. A systematic review and meta-analysis were conducted on randomized controlled trials comparing siRNA versus placebo for hypertriglyceridemia or mixed dyslipidemia. The search included PubMed, Cochrane Library, Web of Science, and Embase databases from inception to 1 October 2025, limited to English-language publications. Data extraction was performed independently by two authors. Eight RCTs involving 2,671 participants met the inclusion criteria. siRNA therapies significantly reduced triglycerides (TG) (MD, -52%; 95%, -57.9 to -46.2), non-high-density lipoprotein cholesterol (non-HDL-C) (MD, -21.9%; 95%, -26 to -17.7), very low-density lipoprotein cholesterol (VLDL-C) (MD, -49.5%; 95%, -60.1 to -38.9), apolipoprotein B (apoB) (MD, -12.6%; 95%, -16.4 to -8.8), and remnant cholesterol (MD, -64.8%; 95%, -81.7 to -47.9)compared with placebo. The reduction in TG was particularly notable. Subgroup analysis revealed that ANGPTL3-targeted therapies resulted in more substantial reductions in low-density lipoprotein cholesterol (MD, -13.2%; 95% CI, -20.1 to -6.2), while APOC3-targeted therapies had a neutral effect on LDL-C levels (MD, 0.6%; 95% CI, -5.7-6.9) ( siRNA therapies demonstrate significant efficacy in reducing triglycerides and improving lipid profiles in patients with HTG and mixed dyslipidemia. APOC3-targeted treatments primarily reduce triglycerides while increasing HDL-C, whereas ANGPTL3-targeted therapies offer broader lipid modulation, including substantial reductions in LDL-C. Both therapies demonstrate favorable safety profiles. Show less

BACKGROUNDMetabolic dysfunction-associated steatotic liver disease (MASLD) has a substantial inherited component. Rare variants in apolipoprotein B gene (APOB) have been implicated in susceptibility to liver steatosis, but their role in disease progression and outcomes is unclear.METHODSWe investigated APOB rare variants in a case-control cohort of people with advanced MASLD versus healthy controls (n = 510 and 261, respectively), a family-based study (n = 43 and literature meta-analysis), the Million Veteran Program (MVP) cohort (n = 94,885), and the UK Biobank (UKBB) (n = 417,657).RESULTSIn the clinical cohort, APOB variants were enriched in people with advanced MASLD (OR 13.8, 95% CI: 2.7-70.7, P = 0.002) and associated with lower circulating lipids, but higher MASLD activity and fibrosis (P < 0.05). In the family study, APOB variants segregated with hepatic steatosis and fibrosis (P < 0.05). Cross-ancestry meta-analysis of the study cohorts yielded pooled ORs for cirrhosis and hepatocellular carcinoma (HCC) of 1.82, 95% CI: 1.33-2.49 and 3.53, 95% CI: 2.09-5.98, respectively. Variants affecting specifically ApoB100 had a 3-fold greater effect on hepatic lipid metabolism compared with those impairing also ApoB48 and were specifically protective against coronary artery disease (P < 0.05). The variants affected cirrhosis risk similarly, but ApoB48/100 had a larger effect on HCC (P < 0.05).CONCLUSIONSRare APOB variants predispose individuals to advanced MASLD and HCC, with distinct contributions from disrupted VLDL and chylomicrons secretion. These findings highlight the interplay between hepatic and intestinal lipid handling, suggesting that APOB genotyping may enhance MASLD risk stratification and patient identification.FUNDINGEuropean Union, Italian Ministry of Health, Swedish Research Council, Veterans Health Administration, NIH. Show less

Drusen and subretinal drusenoid deposits, the pathognomonic lesions for age-related macular degeneration (AMD), are rich in cholesterol. Yet, AMD is not consistently linked to plasma lipids. Here wild-type and human apolipoprotein B100-expressing (APOB100) mice were put on a Western type of diet for 13 months and then assessed for plasma lipid profile, high-density lipoprotein (HDL) heterogeneity, status of intraretinal and choroidal vasculatures, retinal structure, function, levels of cholesterol and other sterols, lipid and cholesterol distribution and expression of cholesterol-related genes. The dietary effects were more pronounced in APOB100 mice, which had human-like hyperlipidemia and different subpopulations of HDL Show less

Hypothyroidism, the most prevalent endocrine disorder globally, is associated with increased cardiovascular risk. This study aims to evaluate cardiovascular risk factors-including serum oxidized low-density lipoprotein (ox-LDL), serum homocysteine (Hcy), and lipid profiles-and their correlations with thyroid-stimulating hormone (TSH) levels. Early identification of these risk predictors may reduce the incidence and mortality of cardiovascular disease in hypothyroid patients. This cross-sectional study included 676 participants. Subjects were stratified into four groups: three corresponding to TSH quartiles within the reference range and a fourth comprising subclinical hypothyroidism (SCH) patients with TSH levels above this range. All participants underwent physical examinations and provided fasting blood samples for measurement of TSH, free thyroxine (FT4), free triiodothyronine (FT3), blood glucose, triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), lipoprotein(a) [Lp(a)], ox-LDL, and Hcy. Across the four subgroups, LDL-C, ApoB, ox-LDL, and Hcy levels exhibited significant increasing trends (all The observed correlations between ox-LDL, Hcy, and dyslipidemia in subclinical hypothyroidism may indicate a proatherogenic state. Elevated ox-LDL and Hcy emerge as independent factors associated with accelerated atherosclerosis in this condition. Show less

The statins remain the foundation of lipid management because they lower low-density lipoprotein cholesterol (LDL-C) and prevent cardiovascular events, and guidelines recommend stepwise intensification, often with ezetimibe first, when targets are not met or when intolerance limits dosing. This review introduces a mechanism-first, phenotype-guided framework that links add-on therapies to the dominant driver of residual risk, LDL-C, triglyceride-rich lipoproteins, elevated lipoprotein(a), or inherited dyslipidemia while integrating trial evidence with clinical practicality. Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies remain the best-validated add-on for very high-risk patients. FOURIER and ODYSSEY OUTCOMES demonstrated event reduction with evolocumab or alirocumab on background statin therapy. For patients who cannot tolerate adequate statin doses, bempedoic acid provides liver-selective inhibition of adenosine triphosphate (ATP)-citrate lyase, and CLEAR Outcomes showed fewer major cardiovascular events in statin-intolerant populations. Inclisiran extends PCSK9 pathway suppression through hepatic small interfering RNA (siRNA) and enables durable LDL-C reduction with twice-yearly maintenance dosing, offering an adherence-oriented alternative while outcomes data mature. Angiopoietin-like protein 3 (ANGPTL3)-directed therapies (evinacumab and investigational RNAi agents such as zodasiran) lower atherogenic lipoproteins through largely LDL receptor independent biology. They expand options for refractory disease, including homozygous familial hypercholesterolemia. Apolipoprotein C-III (ApoC-III) inhibitors (olezarsen and plozasiran) drive large triglyceride reductions that can be decisive in severe hypertriglyceridemia and pancreatitis-prone syndromes. Next-generation cholesteryl ester transfer protein (CETP) inhibition (notably obicetrapib) has re-emerged as an oral strategy with substantial lipid effects as outcomes programs progress. High-dose eicosapentaenoic acid (EPA) (icosapent ethyl) has the clearest triglyceride-focused outcomes signal; REDUCE-IT showed significant ischemic event reduction in statin-treated patients with persistent hypertriglyceridemia. Early Show less

AI literacy is increasingly important in college students' academic achievement, daily life, and future employability. However, current research predominantly overlooks the heterogeneity in students' AI literacy, especially how individual psychological characteristics and features of AI technology contribute to this variation. This oversight limits the formulation of tailored strategies to meet the students' various demands in an era shaped by rapid AI advancement. This study aims to adopt an individual-centered approach to identify distinct AI literacy profiles among college students. In addition, it investigates, based on affordance theory, how positive emotions, instrumental motivation, perceived ease of use, and psychological anthropomorphism predict assignment to different profiles. A total of 808 Chinese college students participated in this survey. Latent profile analysis (LPA) was employed to classify students into distinct AI literacy profiles. Multinomial logistic regression was conducted to examine how psychological and technological factors predict profile classification. This study identified four distinct AI literacy profiles among college students: preliminary contact type, ethical orientation type, balanced development type, and behavioral conservatism type. These profiles showed significant differences in positive emotions, instrumental motivation, perceived ease of use, and psychological anthropomorphism, highlighting diverse psychological and technological characteristics inherent to each group. This study underscores the heterogeneity of AI literacy within the college student population and detects four distinct AI literacy profiles with unique psychological and technological traits. The findings indicate that students' AI literacy is profoundly affected by emotional tendencies, motivational drives, and technological variables, highlighting the need for tailored educational strategies that address the distinct psychological and technological drivers of each literacy profile. Show less

The gut microbiota is a diverse and abundant microbial community in animals; it plays a key role in nutrient absorption and immune defense and is an important factor affecting chicken health and growth performance. Understanding the composition of chicken gut microbiota and its influencing factors can provide a theoretical foundation for maintaining the diversity and microecological balance of beneficial microbial communities in the chicken intestinal tract. This review aimed to explore the recent advancements in understanding the non-genetic e.g. environmental and host genetic factors that influence the chicken gut microbiome, focusing on the gut microbial composition including host genetic kinship, heritability, microbial quantitative loci, and candidate genes. Studies on host genetic factors have identified several genes associated with gut microbial composition including lipid droplet associated hydrolase (LDAH) and apolipoprotein B (APOB) associated with Staphylococcus; TOX high mobility group box family member 2 (TOX2) significant locus linked to Veillonella, and reelin (RELN), lumican (LUM), and S-phase cyclin A associated protein in the ER (SCAPER) associated with intestinal microbial abundance. These factors are involved in host growth, development, and immune system regulation, collectively indicating that host genes play a significant role in regulating chicken gut microbiota. Furthermore, a comprehensive exploration of both non-genetic and host genetic factors could provide a solid foundation and practical strategies for improving chicken health and production performance by regulating the gut microbiota. Show less

Molecular genetic testing was performed on a fetus with ectrodactyly of the right foot to clarify the pathogenic cause and provide evidence for prenatal counseling. Trio whole-exome sequencing (trio-WES) was performed on the fetus and his parents to identify the underlying genetic cause. Candidate variants were validated by Sanger sequencing, and their molecular effects were analyzed through minigene assays. Trio-WES identified a novel heterozygous variant (c.1977+1G>C) in FGFR1, which is consistent with FGFR1-related Hartsfield syndrome (HS; OMIM#615465). Sanger sequencing confirmed that this variant was de novo. The minigene assay revealed that all variants (c.1977+1G>C, c.1977+1G>A, and c.1977+1G>T) at the splice site generated two aberrant splicing events: (1) complete retention of intron 14, leading to a frameshift and premature termination codon; and (2) skipping of exon 14, causing an in-frame deletion of 41 amino acids. These events collectively impaired the function of the FGFR1 protein's tyrosine kinase domain. To our knowledge, prenatal reports of FGFR1-related HS remain extremely limited, and this is the first molecularly confirmed prenatal diagnosis of HS in China. The findings not only expand the mutational spectrum of HS but also provide genetic counseling and reproductive guidance for this family. Show less

Oxidized phospholipids (OxPL) are bioactive lipid species that circulate bound to apolipoprotein B-100 [apoB] and apolipoprotein(a) [apo(a)] and have been widely studied as biomarkers of oxidative lipid burden. When bound to apolipoprotein B-100 [OxPL-apoB] and apolipoprotein(a) [OxPL-apo(a)], they serve as informative biomarkers for CVD risk prediction, risk reclassification, and therapeutic monitoring, particularly in studies involving RNA-targeted therapies against lipoprotein(a). To date, measurement of OxPL-apoB and OxPL-apo(a) has been limited to research-use assays performed in an academic laboratory without formal clinical laboratory validation. Here we report the first full CLIA-compliant analytical validation of chemiluminescent ELISA methods for OxPL-apoB and OxPL-apo(a), enabling their implementation in a regulated clinical reference laboratory setting. The OxPL-apoB ELISA employs murine monoclonal IgG antibody MB47 to capture apoB-100-containing lipoproteins, while the OxPL-apo(a) employs murine monoclonal IgG antibody LPA4 to capture apo(a)-containing particles. In both assays, OxPL is detected by murine monoclonal IgM antibody biotin-E06. The concentration of OxPL is determined against a standard curve of phosphocholine (PC) equivalents using PC-modified bovine serum albumin. The analytical measuring range of both assays is 1.48-148.48 nmol/L PC-OxPL. Serum and plasma matrices showed minimal bias and were analytically equivalent. In healthy donors, OxPL-apoB levels ranged from <1.48 to 25.23 nmol/L PC-OxPL (mean 4.18, median 1.79 nmol/L), while OxPL-apo(a) levels ranged from <1.48 to 126.94 nmol/L PC-OxPL (mean 31.04, median 6.90 nmol/L), with strong correlation to Lp(a) concentrations (R Show less

Sepsis is a syndrome caused by the host's inflammatory response to an infection with an unknown mechanism. This study aimed to identify differentially expressed genes (DEGs) potentially involved in the development and recovery of tracheal injury from septic shock. Nine New Zealand white rabbits were randomized to control (CON), septic shock model (SS), and septic shock norepinephrine treatment (SSNE) groups (each group n = 3). The SS and SSNE groups were injected with lipopolysaccharide to induce septic shock. The SSNE group was administered Ringer lactate with norepinephrine to maintain normal blood pressure. All animals underwent cuffed endotracheal intubation for 2 h. The injured tracheal segment was harvested. RNA sequencing was performed to identify the DEGs, followed by bioinformatics analysis, and pathological staining (both HE and Masson) was performed for pathological evaluation. Bioinformatics analysis included principal component analysis (PCA), gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) network construction. Key findings were validated by qRT-PCR and immunohistochemistry. We obtained 124 upregulated and 28 downregulated DEGs in SS vs. CON groups, along with 60 upregulated and 178 downregulated DEGs in SSNE vs. SS groups. The pathological score showed that trachea tissue in the SS group had the highest score. The protein-protein interaction (PPI) prediction identified APOB and CD36 as the hub genes. The molecular experiments further confirmed that at mRNA and protein levels, APOB was significantly upregulated, while CD36 was significantly downregulated. Subsequent qRT-PCR and immunohistochemical analyses confirmed that APOB expression was significantly upregulated while CD36 was downregulated in the septic shock group, a trend partially reversed by norepinephrine treatment. Our study results suggest that APOB and CD36 may be involved in the pathogenesis of tracheal injury recovery in septic shock patients treated with NE. Not applicable. Show less

Familial hypercholesterolemia (FH) is a genetic disorder characterised by elevated plasma LDL-cholesterol, predisposing to premature atherosclerotic cardiovascular disease. Most cases follow an autosomal dominant pattern (ADH) caused by pathogenic variants in LDLR, APOB or PCSK9. In contrast, the rare autosomal recessive form (ARH) results from biallelic mutations in LDLRAP1, leading to defective LDL receptor-mediated endocytosis. Despite the high rate of consanguinity in Tunisia, LDLRAP1 variants have not yet been reported in this population. In this study, Whole Exome Sequencing of two consanguineous Tunisian families, identified distinct pathogenic variants. In the first family (FH-A), a recurrent LDLR splice-site variant (c.1845+1G>A) was detected in both heterozygous and homozygous states, consistent with an autosomal dominant inheritance pattern. In the second family (FH-B), a novel homozygous LDLRAP1 missense variant (c.161G>A; p.Gly54Asp) was identified, confirming autosomal recessive inheritance. In silico analyses using MutationTaster, DynaMut2, MUpro, DDGun, NetSurfP-2.0, ConSurf and PyMOL predicted that the p.Gly54Asp substitution destabilises the PTB domain of LDLRAP1 by disrupting key hydrogen bonds and hydrophobic interactions, thereby likely impairing LDLR internalisation. According to ACMG guidelines, this variant is classified as likely pathogenic. Clinically, ARH patients exhibited early-onset xanthomas and an unusual quadricuspid aortic valve (QAV). Targeted analysis of valvulogenesis genes (NOTCH1, GATA4, NKX2-5, TBX5, AGTR1, BMP2) revealed no co-segregating pathogenic variants, suggesting that QAV may result from embryonic LDL accumulation disrupting Notch1 signalling rather than a monogenic defect. Comparison with other ADH Tunisian families carrying the same LDLR mutation showed phenotypic variability, likely influenced by genetic modifiers, treatment response and environmental factors. These findings provide the first evidence of LDLRAP1-associated ARH in Tunisia and highlight the genetic heterogeneity of FH, emphasising the importance of integrating molecular, structural and functional analyses for accurate diagnosis, personalised management and early prevention. Show less

Lipoprotein(a) (Lp(a)) is an independent cardiovascular risk factor, primarily determined by genetic factors. This study assessed Lp(a) concentrations in presumably healthy subjects and evaluated its association with age, sex, and cardiometabolic risk factors. The study included presumably healthy 1046 adults and 276 children. Laboratory parameters: lipid profile, Lp(a), apolipoprotein B (apoB), glucose, HbA1c, C-reactive protein and creatinine were measured. Contributions of Lp(a)-apoB to apoB (%Lp(a)/apoB) and of Lp(a)-cholesterol to LDL-cholesterol (%Lp(a)-C/LDL-C) were calculated. Lipoprotein(a) concentrations were significantly higher in adults than in children (P = 0.014) and in women than in girls (P = 0.003), but showed no overall sex differences. In women, Lp(a) was higher after age 50, while in men a slight rise occurred after age 60. Lipid indices %Lp(a)/apoB and %Lp(a)-C/LDL-C declined in men until their 40s and was higher after 50 in both sexes. In a multivariable logistic regression model increased LDL-C concentration was a significant predictor of Lp(a) ≥ 0.30 g/L in women (odds ratio, OR = 1.77; P = 0.021) and children (OR = 2.83; P = 0.009). Boys had twofold higher probability of Lp(a) ≥ 0.30 g/L than girls (OR = 2.17; P = 0.024). Lipoprotein(a) concentrations increase with age, especially after 50 in women and 60 in men, and are significantly associated with LDL-C. Rising %Lp(a)/apoB and %Lp(a)-C/LDL-C alongside falling apoB and LDL-C suggest greater atherogenicity in older individuals, particularly men. These findings support including Lp(a) in lipid profile for better cardiovascular risk assessment. Show less

Fibroblast growth factor 21 (FGF21) is a hepatokine that regulates systemic metabolism. Here, we delineate a novel regulatory pathway for FGF21 orchestrated by the small GTPase Rab2A. Our previous findings demonstrated that liver-specific deficiency of Rab2A impairs very low-density lipoprotein lipidation and promotes apolipoprotein B (APOB) accumulation. We now show that accumulated APOB drives the cleavage and activation of cAMP-responsive element-binding protein H (CREBH), a key hepatic transcription factor for FGF21 expression. Mechanistically, hepatic Rab2A inhibition protected mice from high-fat diet-induced obesity and was associated with markedly elevated circulating FGF21, the phenotype largely rescued by adenovirus-mediated knockdown of either CREBH or APOB. Collectively, we define a Rab2A-APOB-CREBH axis that is potentially essential for the hepatic regulation of FGF21. Show less

Cerebral microbleeds (CMBs) have been found to promote Alzheimer's disease (AD) progression. Hypertension (HTN) is one of the major etiological factors for CMBs and an important risk factor for AD. However, the association between HTN-related CMBs and AD pathology remains undetermined. This study aims to identify the relationship between HTN-related CMBs and amyloid-β 42 (Aβ42) and β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) levels in plasma astrocyte-derived exosomes (ADEs). In total, 88 HTN participants including 30 with deep/infratentorial (D/I) CMBs, 30 with mixed CMBs, and 28 without CMBs were analyzed. Susceptibility-weighted imaging was performed to assess the location, presence, and number of CMBs. ELISA kits for BACE-1 and Aβ42 were employed to evaluate the levels of astrocyte-derived exosomal proteins. The results indicated that plasma ADE levels of Aβ42 were reduced in the HTN + D/I CMBs and HTN + Mixed CMBs groups relative to the HTN-CMBs group. Furthermore, the plasma ADE levels of Aβ42 were significantly associated with CMBs in patients with HTN. However, no significant differences were found in the plasma ADE levels of BACE-1 among the HTN + D/I CMBs, HTN + Mixed CMBs, and HTN-CMBs groups. The study revealed that reduced plasma ADE levels of Aβ42 were significantly associated with CMBs in HTN patients. This finding suggests a potential link between HTN-related CMBs and AD-related amyloid-β pathology, offering novel insights into the mechanisms by which HTN-related CMBs promote AD progression. Show less

Keratin 17 (K17) is a stress-responsive intermediate filament protein that is upregulated in chronic skin diseases and in several carcinomas. We previously showed that K17 is induced in epidermal keratinocytes following exposure to DNA-damaging agents, promoting keratinocyte survival and chemically induced papilloma formation in mouse skin. Molecularly, K17 is recruited to the nucleus, where it impacts nuclear architecture, gene expression, and the DNA damage response (DDR). Here, we report on efforts to delineate K17-dependent processes during DDR by focusing on its interacting partners. Using mass spectrometry, we identified a network of K17-interacting Rho GTPase signaling proteins, including Rac1 and its activator Dock7. Biochemically, we confirmed that Rac1 and K17 interact directly in vitro and in A431 tumor keratinocytes, both at baseline and after ionizing radiation. We show that Show less

Dysregulation of low-density lipoprotein (LDL) cholesterol is strongly correlated with the risk of metabolic dysfunction-associated steatotic liver disease. Endogenous molecules targeting LDL clearance play crucial roles in the progression of liver steatosis. Human cathelicidin LL-37 can form complexes with lipoproteins, but whether these complexes regulate lipoprotein-driven cholesterol metabolism is not clear. Here, we find that cathelicidin LL-37 binds to LDL via apolipoprotein (Apo)B-100 domains, enhancing the solubility of ApoB-100 and inhibiting the modifications and aggregation of LDL. LL-37-LDL interaction promotes LDL uptake through LDL receptor (LDLR) both in hepatocytes and macrophages. This interaction also promotes LDL cholesterol clearance by facilitating cholesterol excretion and cholesterol efflux. In Apoe Show less

Infiltration of T cell acute lymphoblastic leukemia (T-ALL) into the meninges worsens prognosis, underscoring the need to understand mechanisms driving meningeal involvement. Here, we show that T-ALL cells expressing CXCR3 exploit normal T cell function to infiltrate the inflamed meninges. CXCR3 deletion hampered disease progression and extramedullary dissemination by reducing leukemic cell proliferation and migration. Conversely, forced expression of CXCR3 facilitated T-ALL trafficking to the meninges. We identified the ubiquitin-specific protease 7 as a key regulator of CXCR3 protein stability in T-ALL. Furthermore, we discovered elevated levels of CXCL10, a CXCR3 ligand, in the cerebrospinal fluid from patients with T-ALL and leukemia-bearing mice. Our studies demonstrate that meningeal stromal cells, specifically pericytes and fibroblasts, induce CXCL10 expression in response to leukemia and that loss of CXCL10 attenuated T-ALL influx into the meninges. Moreover, we report that leukemia-derived proinflammatory cytokines, TNF-α, IL-27, and IFN-γ, induced CXCL10 in the meningeal stroma. Pharmacological inhibition or deletion of CXCR3 or CXCL10 reduced T-ALL cell migration and adhesion to meningeal stromal cells. Finally, we reveal that CXCR3 and CXCL10 upregulated VLA-4/VCAM-1 signaling, promoting cell-cell adhesion and thus T-ALL retention in the meninges. Our findings highlight the pivotal role of CXCR3-CXCL10 signaling in T-ALL progression and meningeal colonization. Show less

Lynch syndrome is a genetic cancer-predisposing syndrome caused by pathogenic mutations in DNA mismatch repair (path_MMR) genes. Due to the elevated cancer risk, novel screening methods, alongside current surveillance techniques, could enhance cancer risk stratification. Here we show how bi-omics integration could be utilized to pinpoint potential cancer-predicting biomarkers in Lynch syndrome. We studied which blood-based circulating microRNAs and metabolites could predict Lynch syndrome cancer occurrence within a 5.8-year prospective surveillance period. We used single- and bi-omics bioinformatic analyses and identified omics-level patterns and associations across these biological layers. Lasso Cox regression was used to highlight the most promising cancer-predicting biomarkers. Our findings revealed distinct circulating metabolite landscapes among path_MMR variant carriers and a circulating microRNA co-expression module significantly associated with future cancer incidence. These microRNAs regulate cancer-related pathways, including the PI3K/Akt signaling pathway. Additionally, a metabolite module consisting of ApoB-containing lipoproteins (low-, intermediate-, and very low-density lipoproteins) showed distinct levels across path_MMR variants. Notably, three biomarkers-hsa-miR-101-3p, hsa-miR-183-5p, and triglycerides in high-density lipoprotein particles (HDL_TG)-significantly predicted cancer risk, achieving a Harrel's Concordance Index (C-index) of 0.76 (p = .0007). Elevated levels of these biomarkers indicated increased cancer risk. Internal validation of the model yielded a C-index of 0.72. The bi-omics approach and the identified biomarkers offer promising insights for future studies regarding cancer risk identification in Lynch syndrome. Show less

MN-001 (tipelukast), a compound with lipid-modulating and anti-inflammatory properties, and its active metabolite MN-002, have been suggested to influence cholesterol metabolism. This study aimed to investigate whether MN-001 and MN-002 enhance cholesterol efflux via ABCA1 and ABCG1, thereby reducing foam cell formation. We also evaluated cholesterol efflux capacity in patients with diabetes before and after MN-001 administration. Cholesterol efflux was assessed in THP-1 macrophages treated with MN-001 and MN-002 in the presence of ApoA-I or HDL. ABCA1 and ABCG1 expression were evaluated using western blot and qPCR analyses. A 12-week observational study in patients with diabetes evaluated the cholesterol efflux capacity using ApoB-depleted serum and radiolabeled J774.1 macrophages. Molecular docking simulations were conducted to explore MN-002 binding affinities, aiming to identify potential target proteins and elucidate the molecular mechanisms underlying their effects on cholesterol metabolism. MN-002 enhanced ABCA1-mediated cholesterol efflux and upregulated ABCA1 expression independently of PKA. It also increased ABCG1 expression; however, neither MN-001 nor MN-002 influenced HDL-mediated efflux. MN-001 showed no significant improvement in cholesterol efflux capacity (p = 0.6507) in patients with diabetes. Molecular docking simulations indicated that MN-002 may bind to PPAR-alpha, suggesting a potential mechanism for its effects. MN-002 offers a novel therapeutic approach for atherosclerosis by upregulating ABCA1 and ABCG1 expression and enhancing ApoA-I-mediated cholesterol efflux. Further studies are required to clarify the underlying mechanisms and assess their clinical potential in atherosclerosis and metabolic disorders. Show less

Dietary fibre is an important regulator of the gut microbiome and is associated with many health benefits. However, high levels of fibre intake have also been reported to exacerbate some diseases. Here, we show that mice fed semi-synthetic diets supplemented with purified inulin fibre develop chronic infections with the parasitic whipworm Trichuris muris, concomitant with dysregulated innate antimicrobial defences, exacerbated mucosal inflammation, and altered tryptophan metabolism. Inhibition of tryptophan catabolism or neutralizing either IL-27 or IL-18 restored infection resistance. Inulin-fed mice developed gut microbiota dysbiosis during parasite infection, with Proteobacteria becoming dominant. However, despite drastic differences in gut microbiota compositions in control- and inulin-fed mice, microbiota transfer and depletion experiments demonstrated that dietary inulin triggered chronic T. muris infection in a microbiota-independent manner. Importantly, removing inulin from the diet within a critical immune development window rapidly restored anti-parasite immunity, indicating direct, time-dependent modulation of mucosal immune responses. These data reveal T. muris-induced dysbiosis as a consequence rather than a causative factor of diet-driven changes in host susceptibility, and establish a direct link between dietary fibre and host defence at mucosal surfaces. Video Abstract. Show less

Childhood trauma is a well-established risk factor for poor clinical outcomes in bipolar disorder (BD), yet most studies have relied on cumulative trauma scores, potentially overlooking heterogeneity in trauma exposure and its differential impact on psychopathology. This study employed latent profile analysis (LPA) to identify distinct subtypes of childhood trauma based on the Childhood Trauma Questionnaire (CTQ) among 725 individuals with BD in a Chinese clinical sample. Differences across trauma profiles were examined in relation to demographic features, psychiatric symptoms (anxiety, depression, mania), and suicidal ideation (Beck Scale for Suicide Ideation, BSSI). A four-class solution was identified, and the relationship with mental health outcomes was analyzed. Class 4 group, characterized by the most severe emotional abuse and physical neglect, along with the lowest emotional neglect, reported the highest levels of anxiety (HAMA), depression (HAMD), and suicidal ideation (BSSI). In contrast, manic symptoms (YMRS) were present across all groups but did not differ significantly between trauma profiles. Logistic regression indicated that emotional abuse was the strongest predictor of trauma class membership. Distinct trauma profiles in BD are differentially associated with symptom severity and suicide risk. These findings highlight the clinical value of moving beyond cumulative trauma scores to identify trauma-specific subtypes. Early identification of high-risk trauma configurations may inform personalized assessment and intervention strategies for individuals with BD. Show less

Maternal immune activation (MIA) during pregnancy has been implicated as a key environmental risk factor in autism spectrum disorder (ASD). Interferon-alpha (IFN-α), a type I interferon, may disrupt fetal neurodevelopment, yet its mechanistic impact remains insufficiently understood. This study explores the effects of maternal IFN-α exposure on neurobehavioral and neurobiological outcomes in a Wistar rat model. Pregnant rats received IFN-α on gestational day 10, and offspring were evaluated through behavioral assays, neurochemical analyses, and histopathological assessments. IFN-α exposure resulted in significant reductions in GABA, 5-HIAA, and GAD-67 levels, particularly in male offspring, indicating neurotransmitter dysregulation. Histologically, neuronal loss was observed in the hippocampal CA1 and CA3 regions and cerebellar Purkinje cells. Astrocyte activation, reflected by increased GFAP immunoreactivity, was prominent, suggesting a neuroinflammatory response. Additionally, reduced brain-derived neurotrophic factor (BDNF) and elevated tumor necrosis factor-alpha (TNF-α) levels support the presence of inflammation-induced synaptic dysfunction and impaired neuroplasticity. Behaviorally, male offspring exhibited reduced sociability and impaired social novelty recognition. Both sexes demonstrated deficits in motor coordination and exploratory activity. These findings align with core ASD phenotypes and underscore a heightened male vulnerability. Overall, the study provides compelling evidence that prenatal IFN-α exposure leads to persistent neuroimmune, neurochemical, and structural alterations resembling ASD. The results highlight the need for further research into immune-mediated neurodevelopmental disruptions and sex-specific vulnerabilities, offering potential pathways for preventive and therapeutic interventions targeting MIA-related risk mechanisms. Show less

Fear memory generalization is a fundamental hallmark of post-traumatic stress disorder (PTSD) that enables animals to use past experience to adapt to changing conditions. The infralimbic cortex (IL) is implicated in suppressing generalized fear, but the underlying molecular mechanisms remain unknown. Here, we demonstrate that S-nitrosylation of Dexras1 (SNO-Dexras1) in the IL drives fear generalization. Dexras1 is activated by nitric oxide (NO) donors as well as by N-methyl-D-aspartic acid (NMDA) receptor-stimulated NO synthesis in cortical neurons. It is found that the level of SNO-Dexras1 is significantly increased in the IL of generalized mice and downregulation of SNO-Dexras1 attenuates fear generalization. Mechanistically, inhibition of SNO-Dexras1 increases the expression of phosphorylated extracellular regulated protein kinases (pERK) and brain derived neurotrophic factor (BDNF), implicating synaptic remodeling in the IL. Our study reveals a key role of SNO-Dexras1 in the fear generalization, which may provide a potential therapeutic strategy for PTSD. Show less