Search Results (275)

Orthorhombic normal fault networks in sedimentary basins and their formation mechanisms are of significant geological importance. Orthorhombic normal fault networks and planar H-shaped normal fault networks (HNF) developed in distinct locations along the Linshang dextral transtensional fault, with the HNF on the eastern hanging wall and the orthorhombic normal fault networks on the western footwall. Using 2D and 3D seismic data, we investigated the geometry, evolution, and formation mechanisms of these fault networks within the regional tectonic context. The HNF consists of systematically arranged E–W-trending normal faults and N–S-trending cross normal faults. The orthorhombic normal fault networks comprise four sets of normal faults. Expansion indices and balanced cross-section analyses indicate that both these networks formed contemporaneously during the E₂s³ stage. Mechanical analysis suggests that differences in the local stress field led to the development of these networks in different segments of the Linshang Fault. The HNF formed sequentially within a single tectonic phase. In contrast, the orthorhombic normal fault networks developed within a 3D strain field driven by the combined effects of dextral transtension along the Linshang Fault and footwall tilting. Hydrocarbon exploration results confirm that these normal fault networks exert significant control on hydrocarbon migration pathways and accumulation patterns. Full article

Hepatocyte nuclear factor 4α (HNF4A) is a critical transcription factor that regulates the differentiation and metabolism of intestinal epithelial cells. However, its role in piglet growth remains unclear. In this study, the tissue expression of HNF4A was examined using RT-qPCR, and the putative functional SNPs were analyzed by integrating bioinformatics and DNA sequencing. Association analysis was performed in 156 Min pigs and 160 Landraces, and the biological function of the identified genetic variant was explored using a dual-luciferase reporter assay. The results showed that HNF4A was widely expressed in liver, kidney and gastrointestinal tissues, with significantly higher expression in the liver of adult pigs than in newborn piglets (p < 0.05). A 20 bp InDel was identified in the first intron of porcine HNF4A. Allele frequency analysis showed that the Del allele (20 bp deletion) was dominant in Landrace and Duroc pigs, while the In allele (20 bp insertion) was dominant in Min and Jinhua pigs. Association analysis revealed that Min pigs with the In/Del genotype had significantly higher body weights at 14, 21, 28 and 35 days and higher average daily gain (ADG) than those of the In/In animals (p < 0.05). Landrace piglets with the Del/Del genotype exhibited significantly higher body weight at 21 and 28 days than those of the In/Del genotype (p < 0.05). The dual-luciferase reporter assay suggested that the plasmid carrying the In allele exhibited higher transcriptional activity than the Del allele (p < 0.05). Notably, the genotype associated with superior growth performance differed between the two breeds. Collectively, a 20 bp InDel within HNF4A was identified, which might affect piglet growth partially by modulating its transcription, and further study in other populations with different genetic backgrounds is needed before its application in pig breeding. Full article

Interpreting HNF1B variants is challenging in clinical practice. We aimed to integrate functional, clinical, and family data to improve variant classification, describe clinical features of carriers and report registry-level prevalence of HNF1B alterations. Clinical, genetic, and family data were analyzed from the Norwegian MODY Registry (NMR) and the Norwegian Childhood Diabetes Registry (NCDR). Clinical features of sequence variant and 17q12 deletion (17q12del) carriers were summarized, and variants were classified using ACMG-AMP-ClinGen criteria. Registry-level prevalence was reported with 95% confidence intervals. HNF1B sequence variants were functionally assessed, showing that lower transactivation (TA) was associated with higher clinical severity. Eleven variants demonstrated impaired functional activity, with TA inversely correlated with clinical burden (ρ = −0.701, p = 0.002). We identified 28 individuals with 17q12del (21 in NMR, seven in NCDR) and 15 individuals carrying 14 unique pathogenic/likely pathogenic (P/LP) sequence variants, all detected in the NMR. Overall, 36/486 probands (7.4%) with genetically confirmed monogenic diabetes in the NMR carried a P/LP HNF1B sequence variant or 17q12del. In the NCDR, ~0.2% carried 17q12del (7/3583; 3/7 GADA/IA-2A-positive). Functional data enabled reclassification of three variants. Since many pediatric 17q12del carriers in the NMR were referred for testing due to structural renal anomalies without diabetes, HNF1B screening should be considered in children with renal/extra-renal features, irrespective of diabetes or autoantibody status. Full article

Background: Long-read, single-CpG-resolution sequencing is redefining the information-to-depth ratio in epigenomics. While conventional methylome analysis often requires high coverage, we propose a scalable pipeline designed to extract high-density regulatory logic from shallow sequencing data. Methods: By utilizing the progenitor-like HepaRG cell line as a model for liver plasticity, we validated this framework across two divergent developmental trajectories: hepatic maturation and sphere-induced retrodifferentiation. Our technical approach combines CpG-centric enrichment and regional methylation aggregation to reconstruct regulatory landscapes from sparse data. Using long-read Nanopore sequencing, we mapped the dynamics of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). Results: Our pipeline revealed that these trajectories are not inverse processes but engage distinct epigenetic strategies. Hepatic maturation is characterized by the accumulation of 5hmC that partially targets repressive heterochromatin (H3K9me3, H4K20me3) and pioneer factors such as FOXA2. In contrast, retrodifferentiation increases 5mC, potentially silencing adult regulators such as HNF1A via Polycomb-associated networks. In addition, aggregation-based analysis can distinguish widespread focal perturbations from a restricted subset of transcription factors that translate epigenetic changes into regional accessibility. Conclusions: This study provides a scalable computational framework for investigating cellular fate transitions, proving that high-value epigenetic insights are attainable even at reduced sequencing depths. Full article

Random integer lattices are fundamental to lattice-based cryptography and algorithmic number theory. A new random integer lattice model, free of any restrictions on the Hermite Normal Form (HNF), was introduced by in 2016. It was also observed that the probability of such a lattice being in a simple HNF form is approximately 44%. In this paper, the gap between general random integer lattices and those in a simple HNF is bridged by introducing the concept of the $(n,k)$-simple random integer lattice, where the first k diagonal entries of the HNF are fixed to 1. We derive the asymptotic counting formula for such lattices and compute their density among all integer lattices. Furthermore, a generation algorithm for the $(n,k)$-simple random integer lattice based on rejection sampling and inverse sampling methods are proposed, with the analysis showing that it achieves $O\left(n^2\right)$ expected running time. This work provides a theoretical foundation and practical toolkit for constructing structured random lattices with controlled HNF forms. Full article

The combination of thiopurine and methotrexate (MTX) is a standard co-therapy regimen for acute lymphoblastic leukemia (ALL). Despite its efficacy, this regimen is constrained by a narrow therapeutic window and considerable inter-individual variability, which heightens the risk of drug-induced liver injury (DILI). MTX-induced metabolic strain further destabilizes cytokine-sensitive thiopurine detoxification pathways during systemic inflammation. Conventional pharmacogenetic (PGx) testing for TPMT and NUDT15 variants is effective in predicting myelosuppression, but often fails to detect hepatotoxicity as an adverse effect, suggesting a clinically significant genotype-phenotype difference. This review examines the molecular determinants of DILI, emphasizing the role of secondary metabolic pathways and transporter dynamics as key modulators of risk. The study describes cytokine-mediated (IL-6, TNF-α) transcriptional suppression of cytochrome P450 enzymes and hepatic transporters (SLCO1B1, ABCC2/4) not merely as secondary modulators, but as the primary determinants of localized, tissue-specific drug exposure through disrupted nuclear receptor signaling (PXR, CAR, HNF4α). This mechanism promotes functional phenoconversion and toxic molecular shunting, leading to increased intrahepatic drug exposure. It synthesizes the current knowledge on the metabolism of thiopurine and MTX, focusing on the genetic and non-genetic factors influencing toxicity and their interactions. The review also critically evaluates the limitations of static PGx-guided dosing. It highlights the need for comprehensive, real-time risk assessment that integrates gene-environment interactions, multi-omics data, and clinical monitoring to improve precision therapy for ALL. This approach combines extended PGx profiling, transcriptomic monitoring, and clinical biomarker assessment to provide a transformative strategy for precision drug delivery. Full article

Background: Long noncoding RNAs (lncRNAs) have emerged as critical regulators of hepatic metabolism and disease progression. The hepatocyte nuclear factor 1 alpha antisense 1 (HNF1A-AS1) lncRNA modulates liver-specific transcription factors; however, its physiological role in diet-dependent lipid homeostasis remains poorly defined. Methods: In this study, we investigated the mouse ortholog, Hnf1a opposite strand 1 (Hnf1aos1), using AAV-mediated knockdown in C57BL/6J mice fed either a chow diet (10% kcal from fat) or a high-fat diet (HFD; 60% kcal from fat) for 12 weeks. Metabolic phenotyping included hepatic lipid quantification, histological analysis, serum biochemistry, and quantitative gene expression profiling. Results: Loss of Hnf1aos1 produced distinct, diet-dependent alterations in hepatic lipid handling. Under chow conditions, knockdown mice exhibited selective hepatic cholesterol accumulation (6.10 ± 2.9 mg/g tissue vs. 3.51 ± 1.1 mg/g in controls), accompanied by dysregulation of cholesterol clearance pathways. In contrast, under HFD conditions, knockdown precipitated severe macrovesicular degeneration, with hepatic triglyceride levels approximately doubled relative to HFD-fed controls (51.72 ± 19.8 mg/g vs. 26.34 ± 11.9 mg/g) and a numerically elevated triglyceride-to-cholesterol ratio (TG:TC ≈ 6.1:1; p = 0.0621, trend). Chow/Kd mice gained significantly less weight than chow-fed controls, whereas HFD/Kd mice exhibited weight gain comparable to HFD controls despite severe hepatic steatosis. This paradoxical phenotype suggests impaired metabolic feedback at the post-transcriptional level, in which compensatory upregulation of Hnf1a mRNA is insufficient to suppress lipid-associated genes such as Cd36, despite profound lipid overload; however, HNF1A protein levels were not directly measured in this study. Conclusion: Collectively, these findings identify Hnf1aos1 as a regulator of hepatic lipid homeostasis whose loss produces a phenotype consistent with inappropriate lipid accumulation during nutrient excess, without defining the underlying molecular mechanism. Our results support a role for Hnf1aos1 in shaping hepatic metabolic plasticity and provide insight into lncRNA-associated MASLD phenotypes. Full article

Electromagnetic hydrodynamic (EMHD) mixed convective flow of tetra hybrid nanofluid (TeHNF) in a Darcy-Forchheimer porous medium in a vertical channel with thermal radiation is considered in the paper. The electric and magnetic fields are homogeneous, magnetic perpendicular to the walls of the channel, and electric perpendicular to the plane formed by the directions of the magnetic field and the basic current. The channel walls are impermeable, and they are at constant but different temperatures. The basic equations that describe this problem are ordinary nonlinear differential equations (ODEs), and they are transformed into dimensionless ODEs by introducing dimensionless quantities, which are analytically solved using the homotopy perturbation method (HPM). The relations for velocity and temperature distributions, Nusselt numbers and shear stresses on the channel walls were determined. These relations are functions of introduced physical parameters that characterize the observed problem. For TeHNF, where the base fluid is water and the nanoparticles are made of aluminum oxide, titanium dioxide, magnesium oxide and magnetite, a part of the obtained results is given. Velocity and temperature plots are presented in the form of graphs, and Nusselt numbers and shear stresses are presented in the form of tables. Based on the analysis of the obtained results, appropriate conclusions were drawn. It was concluded that an increase in the Hartmann number as well as an increase in the porosity factor decrease the fluid velocity and shear stress, and increase the fluid temperature and Nusselt numbers. Higher values of the Forchheimer factor and higher heat radiation correspond to lower fluid velocities, lower temperatures, lower values of shear stresses and Nusselt numbers. By increasing the value of the Grashof number, the velocity of the fluid increases, and so do the shear stresses. TeHNF shows advantages over simpler hybrid nanofluids and commercial fluids. Full article

Cystathionine β-synthase (CBS) deficiency causes classical homocystinuria with severe hyperhomocysteinemia (HHcy) that is inadequately controlled by current therapies. We tested whether liver-targeted CBS gene therapy provides durable biochemical and phenotypic rescue. Using a Cre-inducible adult mouse model of whole-body CBS loss, a single intravenous dose of AAV-DJ-hCBS (3 × 10¹² or 3 × 10¹³ vg/kg) was administered, and the animals were followed for 12 months. Vector biodistribution showed ~100-fold hepatic enrichment over the kidney and spleen. Both doses rapidly normalized plasma homocysteine (<8 µM), maintaining correction throughout the study while preventing alopecia, weight loss, and loss of adiposity. Liver histology showed resolution of inflammation, and only 2 of 19 mice developed anti-hCBS antibodies. Liver proteomics (3998 proteins quantified) revealed CBS deficiency-associated suppression of tRNA aminoacylation and dysregulation of lipid and carbon metabolism with an HNF4A transcriptional signature, all normalized by therapy. Liver metabolomics demonstrated accumulation of S-adenosylmethionine and S-adenosylhomocysteine and disruption of phosphatidylcholine synthesis, also corrected by treatment. Plasma metabolomics revealed systemic disturbances fully normalized by hepatic CBS restoration. These findings identify the liver as the central metabolic control point in CBS deficiency and support liver-targeted gene therapy as a durable corrective strategy. Full article

Background: Psoriasis frequently relapses after treatment withdrawal, consistent with persistent epigenetic programs in lesional immune cells. Lysine acetylation is a reversible regulatory layer linking chromatin accessibility, transcription factor activity, and immune-cell effector programs; yet, its cell-type-resolved landscape and clinical stratification value in psoriasis remain incompletely defined. Methods: We integrated four bulk transcriptome cohorts of psoriatic and healthy skin (746 psoriasis, 515 controls) with two public skin scRNA-seq datasets. A diagnostic acetylation-regulator signature was derived from 33 curated acetylation regulators, and acetylation endotypes were defined by unsupervised clustering. The cell-type-specific expression was mapped at the single-cell resolution. Key regulators were validated by quantitative real-time polymerase chain reaction (qRT-PCR) in an imiquimod-induced psoriasis-like mouse model, and further verified in an independent dataset (GSE136757). Motif enrichment and drug–target mining were used to prioritize transcriptional regulators and candidate epigenetic therapeutics. Results: Sixteen acetylation regulators were differentially expressed in bulk skin, with histone deacetylase (HDAC1) showing the strongest upregulation and lysine acetyltransferase (KAT2A) the strongest downregulation. A 13-gene acetylation signature discriminated psoriasis from controls (area under the curve, AUC 0.886) and separated lesional samples into two acetylation endotypes with divergent pathway states (hypoxia–glycolysis versus oxidative-stress-dominated programs). Single-cell mapping demonstrated immune-restricted acetylation modules, including CREB binding protein (CREBBP)-enriched neutrophils, histone deacetylase 1 (HDAC1)-high cluster of differentiation (CD)8⁺ T cells, and lysine acetyltransferase 6A (KAT6A)/lymphoid enhancer binding factor (LEF1)-enriched CD4⁺ and regulatory T cell (Treg) subsets, coincident with interleukin (IL)-17-related inflammatory programs. In mice, qRT-PCR confirmed the coordinated dysregulation of hub genes and highlighted Hnf1a and Kat6a as reproducible candidates. External validation using the GSE136757 dataset further supports their robust diagnostic performance. Motif analysis nominated interferon regulatory factor (IRF4), YY transcription factor (YY2), and zinc finger protein (ZNF404) as putative transcriptional mediators downstream of acetylation programs, and drug–target mining prioritized epigenetic compounds with subtype-relevant potential, including histone deacetylase (HDAC) inhibitors (e.g., entinostat) and the p300/CREB binding protein (CBP) inhibitor A485. Conclusions: This integrative atlas links acetylation regulators to specific immune compartments, defines acetylation endotypes associated with distinct inflammatory programs, and provides a rationale for stratified epigenetic target selection in psoriasis. Full article

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute the most common underlying cause of chronic kidney disease in pediatric populations. Maternal hypovitaminosis D links to mesoderm-related birth defects, leading to our hypothesis that maternal vitamin D deficiency (VDD) impairs renal development (a mesoderm-derived process) and induces offspring CAKUT. To investigate whether a low-vitamin D level can cause CAKUT, we used vitamin D-free diets to induce a maternal vitamin D deficiency mice model. The maternal vitamin D deficiency (VDD) mice models and normal vitamin D status (CON) were successfully established by administering a vitamin D-free or vitamin D-sufficient diet for 4 weeks prior to pregnancy. The overall incidence of CAKUT was significantly increased in VDD neonatal mice (19.4% vs. 2.44%; p = 0.0006), with a higher incidence of early duplicated budding in E11.5. E11.5 ureteric bud tissue revealed significantly increased activity of Gdnf-Ret-p-Erk1/2 signaling in the VDD group. In vivo intervention with the p-Erk1/2 antagonist U0126 in the pregnant VDD mice model at E10.5 improved CAKUT occurrence in offspring with p-Erk1/2 expression decreasing toward normal levels. Early metanephric ureteric bud H3K4me3 CUT&TAG analysis at E12.5 revealed chromatin activation patterns, which revealed that the downregulation of Hnf1β promoter region peaks was accompanied by reduced Hnf1β expression, and Robo2 promoter region peak was upregulated with increased Robo2 expression in the VDD group. Maternal vitamin D deficiency in mice significantly increased offspring CAKUT incidence. This phenotype was mediated by enhanced Gdnf-Ret-p-Erk1/2 signaling and reversed by p-Erk1/2 inhibition, with VDD inducing epigenetic remodeling of Hnf1β and Robo2 promoters. Full article

Inflammation is widely viewed as a driver of hepatocellular carcinoma (HCC), yet inflammatory signaling also reshapes hepatic xenobiotic metabolism. Here, we established transgenic (Tg) IKKβ^Δhep mice (Tg-IKKβ^Δhep), which combine hepatocyte-specific IKKβ deletion with liver expression of a nuclear, kinase-inactive IKKβ mutant (NLS-IKKβKN). Tg-IKKβ^Δhep mice developed spontaneous chronic hepatitis and progressive fibrosis but were strikingly resistant to diethylnitrosamine (DEN)-induced hepatocarcinogenesis, with markedly reduced tumor multiplicity and total tumor burden. Despite persistent inflammatory injury, DEN-triggered oxidative DNA damage and p53 activation were markedly attenuated, compatible with reduced tumor initiation. Transcriptomic and biochemical analyses revealed broad repression of xenobiotic-metabolizing cytochrome P450 genes, including the pericentral enzyme CYP2E1, accompanied by reduced CYP2E1 protein abundance. This was associated with impaired HNF4α–PXR–CAR transcriptional output and reduced HNF4α occupancy at target promoters. Acute TNFα or IL-1β exposure recapitulated this repression, in part through reduced PGC-1α expression and decreased RNA polymerase II recruitment to target promoters. In parallel, pericentral xenobiotic metabolism was blunted, a change that could plausibly diminish DEN bioactivation and genotoxic stress. Together, these findings support a “metabolic gatekeeping” model in which chronic inflammation can constrain chemical hepatocarcinogenesis by attenuating carcinogen-metabolizing capacity. Full article

Globally, chronic kidney disease (CKD) affects over 800 million individuals and is characterized by significant genetic complexity. More than 600 genes are associated with hereditary kidney disease, which may manifest as isolated kidney issues or as part of a syndrome that also includes extrarenal manifestations. The aim of this study was to identify genetic variants in a group of ten patients who presented with clinical signs suggestive of genetic syndromes associated with CKD, or who were asymptomatic but had a positive family history of CKD. Extensive genetic testing (targeted gene panels and whole-exome sequencing—WES) identified a mutation in the PKD1 gene in 3 out of 10 cases. In one patient, a known mutation in the PKD2 gene was identified. Another four patients were diagnosed with Alport syndrome: three of these presented with de novo missense mutations in the COL4A5 gene, and one patient had a mutation in the COL4A3 gene. One patient was diagnosed with MODY5, caused by a known mutation in the HNF1B gene, and one patient was diagnosed with Bartter syndrome type 1, resulting from a known mutation in the SLC12A1 gene. We present genotype–phenotype correlations, highlighting the particularities of each patient within their family context. Our findings emphasize the importance of genotype–phenotype correlations in refining diagnosis, personalizing therapeutic management, and providing essential genetic counseling for at-risk relatives. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its consequences represent a growing global health burden that urgently requires physiologically relevant in vitro models beyond conventional 2D culture systems. In this study, we report the successful establishment of 45 patient-derived liver organoid lines. These organoids were generated from healthy, steatotic and cirrhotic tissues collected from 207 liver surgeries at RWTH University Hospital Aachen, with an initiation success rate of 82%. The organoids were propagated for at least six passages using an optimized protocol. Multiplex immunofluorescence analysis revealed highly proliferative structures with approximately 40% Ki-67-positive cells expressing hepatocyte (Albumin and HNF4α) and cholangiocyte (CK19) markers. Intermittent LGR5 staining suggested the presence of liver progenitor cell features. Quantitative PCR results confirmed variable HNF4α expression, indicating inter-patient heterogeneity in differentiation status. Time-lapse imaging combined with mathematical modeling uncovered a biphasic growth dynamic with an initial linear expansion in the first 15 h, followed by exponential growth (doubling time ≈ 20.6 h) between 30 and 72 h. Overall, our workflow produced genetically and phenotypically stable liver organoids that recapitulate essential features of various hepatic conditions. This provides a solid foundation for disease modeling, potential drug testing, and quantitative systems biology. Full article

Diabetic wounds remain a major clinical challenge due to delayed healing caused by chronic inflammation and impaired fibroblast activity. Here, we present a thermoresponsive gel composed of chitosan (CS) and poloxamers (POL) incorporating silk fibroin (SFB) and Aloe vera gel extract (AV), developed for topical application and, for the first time, evaluated using an inflammation-induced diabetic fibroblast model. The optimized formulation exhibited rapid sol–gel transition at physiological temperature and suitable rheological properties for effective wound coverage. In vitro evaluation using human normal fibroblasts (HNF) and human diabetic fibroblasts (HDF), under both basal and inflammation-induced conditions, demonstrated good cytocompatibility and a significant enhancement of fibroblast migration, particularly in an inflammatory microenvironment simulated by high glucose, lipopolysaccharide (LPS), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). These findings highlight the potential of the developed thermoresponsive gel as a promising biomaterial platform for improving diabetic wound healing under inflammation-relevant conditions. Full article