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Forensic taphonomy in fluvial water: A systematic review.

Human remains are frequently recovered from fluvial (lotic) water environments. Rivers, streams, canals and other flowing water bodies pose distinct challenges in forensic practice, particularly due to their current. Compared to other aquatic contexts, fluviatile taphonomy is underrepresented in the forensic literature and the last comprehensive summary was written over a decade ago. Therefore, a systematic review was performed to collect and summarise the current knowledge in forensics about fluvial taphonomy, including decomposition of remains, transport characteristics, search, postmortem submersion interval (PMSI) estimation, taphonomic alterations, and differences to other water bodies. 92 reports met the inclusion criteria for this review, most of them showed a moderate risk of bias. Their main findings were summarised and two major challenges identified. First, predictions about fluvial transport of human bodies pose a tremendous issue in forensic practice, leading to later detection and lower recovery rate of remains, complicating various subsequent analyses. Second, PMSI estimations are difficult particularly due to variable environmental conditions in fluviatile systems. Recommendations for future research in the area of fluvial forensic taphonomy include that case-related data such as the detailed decomposition state and river characteristics need to be made available. More standardised research protocols are required for a facilitated comparison between studies, environments and regions. This review provides forensic practitioners with a comprehensive, updated resource for the investigation of fluvial remains. It also guides future research towards a more efficient practice to build the basis for a broader, more robust and comprehensive synthesis, subsequently supporting analyses in forensic casework.

Humans

Artificial intelligence-assisted detection and optical differentiation of colorectal lesions in Lynch syndrome surveillance (CADLY2): a multicentre, open-label, randomised controlled superiority trial.

BACKGROUND: Artificial intelligence (AI)-based computer-aided detection (CADe) systems improve adenoma detection in average-risk colorectal cancer screening. Meanwhile, evidence in Lynch syndrome surveillance is sparse and inconsistent. We assessed the effect of CADe on adenoma detection during Lynch syndrome surveillance. Computer-aided optical diagnosis (CADx) performance for optical differentiation of colorectal lesions was evaluated as a secondary aim. METHODS: CADLY2 was an international, multicentre, open-label, randomised controlled superiority trial at nine specialised hereditary cancer surveillance centres in Belgium, Germany, the Netherlands, and Spain. Adults aged 18 years or older with genetically confirmed Lynch syndrome scheduled for surveillance colonoscopy were randomly assigned (1:1) to high-definition white-light (HD-WL) colonoscopy alone or to HD-WL colonoscopy with computer-aided assistance from CAD EYE (Fujifilm, Tokyo, Japan). CAD EYE was used for CADe during withdrawal and for CADx after lesion detection. Randomisation was done centrally through a secure web-based system using Pocock's minimisation algorithm with a stochastic component and was stratified by centre, sex, previous colorectal cancer, underlying pathogenic variant, and interval since previous colonoscopy. Allocation concealment was ensured through the centralised web-based system. Patients were masked to group allocation until the start of withdrawal in procedures with mild sedation, or until completion of the procedure in procedures with propofol-based sedation. Endoscopists were not masked. The primary outcome was adenoma detection rate, defined as the proportion of patients with at least one histopathologically confirmed adenoma, analysed in the full analysis set (defined as all randomly allocated patients with available data for the primary outcome). The diagnostic performance of the CADx system was evaluated as a secondary outcome. The safety analysis set comprised all randomly allocated patients who underwent a study colonoscopy. This study is registered with the German Clinical Trials Register, DRKS00030695, and is completed. FINDINGS: Between May 9, 2023, and Oct 30, 2025, 757 patients were randomly allocated to HD-WL colonoscopy (377 patients) or to AI-assisted colonoscopy (380 patients); 733 patients were included in the full analysis set (369 HD-WL and 364 AI-assisted). The median age was 49 years (IQR 38-59) in the HD-WL group and 50 years (38-59) in the AI-assisted group; 213 (58%) were female and 156 (42%) male in the HD-WL group, and 207 (57%) were female and 157 (43%) male in the AI-assisted group. The adenoma detection rate was 30·9% (114 of 369 patients) with HD-WL versus 33·8% (123 of 364 patients) with CADe assistance (odds ratio 1·14 [95% CI 0·83-1·57], p=0·41). For CADx differentiation of neoplastic versus non-neoplastic lesions in the paired lesion-level analysis, with histopathology as the reference standard and sessile serrated lesions and traditional serrated adenomas classified as non-neoplastic, CADx sensitivity was 85·9% (95% CI 82·0-89·1) and specificity was 91·4% (89·4-93·0). Three adverse events occurred in the AI-assisted group: two mild post-polypectomy bleedings and one serious pulmonary embolism or deep venous thrombosis unrelated to the procedure. No adverse events occurred in the HD-WL group. INTERPRETATION: CADe-assisted colonoscopy did not show the absolute improvement in adenoma detection rate that was assumed in the prespecified sample-size calculation. CADx did not clearly improve lesion differentiation beyond expert optical diagnosis in expert Lynch syndrome surveillance settings. FUNDING: Third-party research funding of the National Center for Hereditary Tumor Syndromes, University Hospital Bonn.

Humans

Genome-wide characterization of the TGF-β superfamily identifies bmp15, gdf9, and gsdf as sex-biased candidate regulators of gonadal differentiation in the synchronous hermaphrodite Plectropomus leopardus.

The transforming growth factor-β (TGF-β) superfamily plays conserved roles in vertebrate reproduction and gonadal sex differentiation. However, its genomic repertoire and sex-biased expression patterns remain unclear in the leopard coral grouper (Plectropomus leopardus), a species with synchronous hermaphroditism. Here, we performed a genome-wide identification of the TGF-β superfamily, identifying 42 genes from the chromosome-level genome. Phylogenetic and synteny analyses indicated that segmental duplication under purifying selection contributed to family expansion. Expression profiling across multiple tissues and four gonadal developmental stages (undifferentiated, 120 dph; early differentiated, 15 months; mature testis, 3 years; mature ovary, 3 years) identified eight gonad-enriched genes, among which bmp15 and gdf9 exhibited pronounced female-biased expression, with transcripts localized exclusively to the oocyte cytoplasm, particularly in stage II-III oocytes. In contrast, gsdf showed male-biased expression and was localized in spermatogenic cells of the testis. These reciprocal expression patterns indicate that bmp15/gdf9 and gsdf are candidate factors associated with gonadal sex differentiation. Our study provides the first comprehensive characterization of the TGF-β superfamily in P. leopardus and highlights bmp15, gdf9, and gsdf as candidate sex-differentiation factors in this hermaphroditic species.

Animals

Comparative analysis of DDR-related genes and microRNA expression during rice germination: Implications for salinity susceptibility screening.

Soil salinity poses a significant threat to the agri-food sector and particularly to rice cultivation. High salinity during germination induces overproduction of reactive oxygen species (ROS) that cause lesions in the DNA resulting in reduced vigor. MicroRNAs (miRNAs) are known to modulate stress response in plants, however, studies focusing on its relation with the expression of the DNA damage response (DDR)-related genes are not thoroughly explored. In this regard, the aim of this work was to investigate the link between the expression of miRNAs and putative targeted DDR-related genes in response to salinity stress during germination. Eight varieties representative of indica and japonica rice subspecies were categorized into clusters through a principal component analysis (PCA) based on their germination performance and stress tolerance index under varying concentrations of NaCl. Subsequently, the expression patterns of six miRNAs and their putative targeted DDR genes were measured in two contrastive cultivars through quantitative real-time PCR (qRT-PCR) while correlations were examined through Pearson's analysis. Results showed distinct expression profiles between halotolerant and sensitive cultivars. Two miRNAs were further investigated in mature dry seeds of all the cultivars to verify their earliest, seed-specific discriminative potential. The distinct miR414 expression pattern may represent a potential biomarker for identifying salinity-susceptible cultivars during early-stage breeding screening.

Oryza

Proteomic responses of the oil palm pest Metisa plana (Psychidae) to farnesyl acetate exposure.

Metisa plana Walker (Lepidoptera: Psychidae) is a major defoliator of oil palm in Malaysia, causing substantial economic losses. Farnesyl acetate (FA), a sesquiterpenoid compound, has been proposed as a potential insecticidal agent against M. plana, yet its molecular impact on larval physiology remains poorly understood. Here, we employed label-free quantitative proteomics, functional enrichment analysis, and targeted transcript assessment to characterize the temporal proteomic response of M. plana larvae at 7 and 14 days after treatment (DAT) with FA. Principal component analysis revealed robust separation between treated and control samples at both time points, indicating sustained treatment-driven proteomic restructuring. Early exposure (7 DAT) elicited a heterogeneous response involving stress-associated proteins, redox enzymes, and cytoskeletal regulators, whereas later exposure (14 DAT) produced a consolidated profile characterized by metabolic reprogramming, downregulation of ribosomal proteins, induction of heat shock proteins, and enrichment of RNA surveillance and mitochondrial pathways. Targeted transcript analysis qualitatively supported proteomic trends for HSP83 and aldehyde dehydrogenase X, although limited amplification precluded quantitative inference. Collectively, these findings demonstrate that FA exposure drives a shift from acute proteomic perturbation toward a maintenance-oriented physiological state, prioritizing proteostasis, energy management, and stress adaptation over growth and development. This integrated molecular perspective provides mechanistic insight into the chronic effects of FA, highlighting its potential to suppress larval performance and informing the development of biorational, physiology-based pest management strategies in non-model insects.

Animals

A genome-wide coverage-based pipeline for the identification of host-derived candidate DNA biomarkers from cell-free blood.

We have created a new data-analysis pipeline for the discovery of host-specific candidate DNA biomarkers derived from sequencing data of cell-free blood. Unlike approaches that rely on specific molecular or genetic signatures, our method leverages the coverage distribution of cell-free DNA sequences mapped to a reference genome, applying statistical analyses to identify informative short genomic regions for biomarker discovery. The pipeline is applicable to diverse diseases and can be used to analyze cell-free DNA sequences from plasma or serum to identify candidate biomarkers that are characteristic of disease states in mammals. Core functionalities were developed in Java and integrated with open-source software tools for the preprocessing of raw sequencing data, complemented by Python scripts for the machine-learning analysis and statistical validation. The pipeline is designed for HPC use and users can access the pipeline through a Galaxy workflow, which offers a user-friendly web interface for input selection prior to execution and analysis progress monitoring. Performance tests, carried out using duplicate sets of COVID-19 samples and controls, showed linear scalability of execution time with an increasing dataset size, as well as a substantial reduction in execution time through parallelized computation, whereby each HPC node is used to process the data of one chromosome. Further statistical tests confirmed the quality of the pipeline's results by showing that the set of identified candidate biomarkers remained stable across varying dataset sizes.

Biomarkers

Synaptic vesicle glycoprotein 2A PET imaging in parkinsonian α-synucleinopathies: a systematic review.

Synaptic dysfunction is increasingly recognized as an early and biologically relevant component of α-synucleinopathies. However, conventional imaging biomarkers mainly assess dopaminergic dysfunction, glucose metabolism, or structural damage rather than presynaptic density itself. Synaptic vesicle glycoprotein 2A (SV2A) PET enables in vivo assessment of presynaptic terminal integrity and may provide complementary information in Parkinson's disease (PD), Parkinson's disease dementia/dementia with Lewy bodies (PDD/DLB), and multiple system atrophy (MSA). This systematic review synthesized the available evidence on SV2A-targeted PET in parkinsonian α-synucleinopathies, focusing on regional imaging patterns, clinical associations, longitudinal findings, and methodological determinants of interpretation. Seventeen reports were included. In PD, the most recurrent finding was reduced SV2A binding in the substantia nigra, although additional involvement of brainstem, caudate, striatal, thalamic, raphe, or cortical regions was reported in selected cohorts. In PDD/DLB, abnormalities appeared broader and more cortical, with evidence of association between cortical SV2A binding and cognitive performance. In MSA, one study suggested a distinct infratentorial and cerebellar pattern with potential relevance for phenotypic stratification. SV2A PET is a promising research biomarker for biological characterization of synucleinopathies. However, the field remains limited by small cohorts, methodological heterogeneity, variable quantification strategies, limited longitudinal evidence, and potential cohort overlap. Multicentre validation and harmonized protocols are required before clinical translation.

Humans

Urban stormwater infrastructure as a microplastic superhighway: a critical review of transport dynamics, modelling, and mitigation across pavements and drainage networks.

This review examines the transport, fate, modelling, and mitigation of Microplastics (MPs) in urban stormwater infrastructure, with emphasis on pavements, runoff pathways, micro-drainage, and macro-drainage systems. Following a systematic review approach, more than 1000 records were screened and approximately 50 core studies were retained when they addressed urban stormwater or drainage-related MP transport with adequate methodological reporting; marine-only studies and biological-effect studies without direct relevance to transport processes were excluded. The evidence shows that stormwater systems function not merely as passive conduits but as dynamic reactive transport systems with temporary storage, where particle mobilisation, sedimentation, resuspension, and temporary retention regulate MP export. Road surfaces, especially high-traffic areas, are major reservoirs of tyre wear, road-marking, atmospheric, and litter-derived particles that are rapidly mobilised during rainfall. Conventional grab sampling may underestimate MP loads, which in some cases exceed treated wastewater effluent loads by up to six-fold. Drainage structures such as manholes can immobilise up to 17.3% of near-neutrally buoyant particles, while biofouling and aggregation may shift buoyant polymers from wash-load to bedload. Mitigation systems, including permeable pavements, bioretention, wetlands, and technical inserts, can achieve high removal of coarse MPs, but performance declines for fine particles below 100 µm. The review highlights the need for standardised flow-proportional sampling, physically informed modelling, and treatment-train strategies targeting both surface sources and in-network storage.

Microplastics

Understanding Dynamics: A Systematic Review of the Attitudes, Knowledge, and Competencies of European Frontline Professionals Toward Domestic Abuse.

There remains a paucity of European research on attitudes and responses to domestic abuse from frontline workers and professionals who regularly encounter domestic abuse or engage with domestic abuse legislation. This systematic review synthesized qualitative, quantitative, and mixed-method peer-reviewed studies that explored professionals' knowledge, attitudes, and competencies related to domestic abuse. The professionals included medical staff (doctors, nurses, midwives), social care professionals, police officers, and criminal justice practitioners. The review was conducted on current European studies published between 2014 and 2025 and was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Databases consulted included APA PsycInfo, Scopus, Web of Science, PubMed, Sociological Abstracts, International Bibliography of the Social Sciences, Social Services Abstracts, and Google Scholar. Full-text review was performed on 273 articles, of which 36 were deemed appropriate for inclusion. The review included 8 multi-country studies spanning the United Kingdom (England, Scotland, and Wales), and 28 single-country studies conducted in England, Sweden, Turkey, Portugal, the Republic of Ireland, Wales, Bosnia, Spain, Italy, Slovenia, and Hungary. A narrative and thematic synthesis categorized professional attitudes toward domestic abuse into four emergent themes: attitudes toward engagement and responsibility, attitudes toward victims, knowledge and understanding of domestic abuse, and attitudes as predictors of professional practice. This review addresses a dearth of research and provides recommendations for promoting proactive practice among professionals most likely to receive disclosures of abuse.

Humans

Genome-guided stage- and tissue-resolved transcriptome analysis of Serrodes campana identifies sex-biased antennal expression and candidate chemosensory-related genes.

Serrodes campana is an erebid moth of ecological and forestry relevance; its larvae are mainly associated with the soapberry tree, Sapindus mukorossi, whereas adults exhibit fruit-piercing behavior. However, stage- and tissue-resolved transcriptomic resources for this species remain limited. Here, using a chromosome-level reference genome, we performed a genome-guided transcriptome analysis of S. campana based on 12 RNA-seq libraries representing major developmental stages and key adult tissues. Global transcriptomic analyses revealed pronounced transcriptional differentiation across developmental stages and tissue types. Tissue-enriched gene sets and functional enrichment analyses identified distinct molecular signatures associated with developmental, sensory, and pheromone-associated tissues. Comparative analysis of female and male antennae further revealed sex-biased expression of several candidate chemosensory-related genes. Among 153 curated chemosensory-related candidate genes, most odorant receptor genes showed strong antennal enrichment, whereas other major chemosensory gene families displayed broader but still tissue-preferential expression patterns. In addition, an exploratory comparison of female terminal abdominal gland tissue and male terminal abdominal coremata revealed divergent expression profiles and highlighted candidate genes potentially associated with pheromone-related physiology, reproduction, and tissue-specific signaling. Together, this study provides the first genome-guided stage- and tissue-resolved transcriptomic resource for S. campana and offers a useful foundation for future studies of chemosensory detection, sex-biased gene expression, and pheromone-associated biology in this species.

Animals

PPRC1 is a prognostic biomarker and key regulator of mitochondrial oxidative phosphorylation in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) remains an incurable haematological malignancy, underscoring the need for novel prognostic biomarkers and therapeutic targets. This study aimed to investigate the clinical and biological significance of peroxisome proliferator-activated receptor gamma coactivator-related protein 1 (PPRC1) in MM. METHODS: Expression and clinical data were obtained from public databases and an independent local cohort. Kaplan-Meier and Cox regression analyses were performed to evaluate prognostic value. Differential expression analysis, pathway enrichment analysis and single-cell RNA-seq data analysis were used to explore biological functions. PPRC1 was silenced in MM cell lines using siRNA to assess its effects on cell survival and oxidative phosphorylation. RESULTS: PPRC1 was significantly upregulated in MM and was associated with advanced disease stage and poor overall survival. Multivariate Cox analysis identified PPRC1 as an independent prognostic factor. A nomogram incorporating PPRC1 and revised-ISS improved survival prediction. Functional analyses revealed that PPRC1 was positively correlated with oxidative phosphorylation and oncogenic signalling pathways. A potential connection between PPRC1 expression and immune cell infiltration was observed. PPRC1 knockdown inhibited cell proliferation, induced cell cycle arrest and apoptosis and impaired oxidative phosphorylation in MM. CONCLUSIONS: PPRC1 acts as a prognostic biomarker and metabolic regulator in MM by sustaining mitochondrial oxidative phosphorylation. These findings highlight PPRC1 as a potential therapeutic target in MM.

Humans

The co-existence of Ehlers-Danlos syndrome and postural orthostatic tachycardia syndrome: A systematic review of the literature.

There is a growing body of literature evaluating both postural orthostatic tachycardia syndrome (POTS) and Ehlers-Danlos syndrome (EDS). We conducted a systematic review to evaluate what is currently known about the co-existence of both conditions. A search of MEDLINE and EMBASE was performed in December 2025 and data were collected in tables and pooled to determine the prevalence of POTS in EDS and EDS in POTS. A total of 30 studies were included with 8421 patients with EDS and 12,983 patients with POTS. The average age across 16 studies that reported mean age was 33.3 years. POTS in patients with EDS ranges from 17.5% to 92.7% depending on the population. EDS in patients with POTS ranges from 17.9% to 50.0% depending on the population. One study suggested that patients with EDS and POTS had greater medication use, pain medications and greater number of clinic visits compared to POTS alone while another suggests that these patients have greater gastrointestinal symptoms and the odds were greatest for postprandial distress syndrome, chronic nausea and vomiting syndrome, vomiting and post-prandial fullness. We conclude that EDS and POTS frequently co-occur, and proportions of patients with POTS and EDS depends on the population evaluated. Overall, more research is needed to better understand how to effectively manage patients living with both EDS and POTS.

Humans

Peripheral inflammation and executive function among community samples across the lifespan: A systematic review and meta-analysis.

Higher levels of peripheral inflammatory markers are proposed to disrupt cognitive processes; however, the extent to which this relationship applies to executive functions, specifically, has yet to be systematically evaluated. The current meta-analysis synthesizes all available literature measuring the association between peripheral inflammation and executive functions among community individuals across the lifespan. This systematic review searched Web of Science, PubMed, and PsycINFO for published and unpublished studies, in the English language, that assessed the association between markers of peripheral inflammation and self-report and behavioral measures of executive function. In addition to methodological and demographic information, correlation/beta coefficients were extracted from included studies to quantify the association between inflammation and executive functions. This review included 58 studies, 41 of which were included in the random-effects meta-analysis (N = 255,539). Among community individuals, higher levels of CRP and IL-6 were associated with poorer executive functioning. These results did not differ when models accounted for potential confounding variables. Meta-regressions revealed that the relationship between inflammatory biomarkers and executive function did not differ as a function of age, adiposity, or percentage of the sample who identified as female. Results of the present review indicate that higher levels of specific inflammatory markers are associated with lower performance on executive function measures; however, we observed significant heterogeneity in the study design and measurement of both inflammation and executive functioning, suggesting important considerations for future research.

Humans

Exploratory identification and cellular functional characterization of ppiabl as a candidate gene associated with growth traits in Paralichthys olivaceus.

The Japanese flounder (Paralichthys olivaceus) is an important mariculture species. However, the genetic mechanisms underlying its growth traits remain poorly understood. To explore the genetic basis of growth variation, whole-genome resequencing was performed in a cultured cohort of 60 individuals, followed by exploratory genome-wide association analysis and candidate-gene prioritization. The results revealed heritability estimates of 0.40 for body weight and 0.24 for body length, with substantial overlap in associated loci between the two traits. Exploratory association and variant-annotation analyses prioritized ppiabl, which carries a nonconservative missense variant, as a candidate gene for further investigation. Tissue expression analysis showed that ppiabl was highly expressed in muscle tissue. This gene encodes a protein belonging to the conserved peptidyl-prolyl cis-trans isomerase family. In Japanese flounder primary muscle cells, ppiabl knockdown was associated with altered expression of growth-related genes and an increased G1-phase fraction, whereas overexpression produced changes in the opposite direction. In line with this, fast-growing individuals were found to have significantly larger muscle fiber areas than slow-growing ones. These findings suggest that ppiabl may be involved in muscle-related cellular processes associated with growth variation in Japanese flounder, although its contribution to whole-animal growth requires further validation. Overall, this exploratory study prioritizes ppiabl as a candidate gene potentially associated with growth-related cellular processes in Japanese flounder, although validation in larger independent populations and in vivo models is required.

Animals

Mitigating pH-induced instability in deruxtecan-based ADCs: an onboard-mixing icIEF approach for robust charge heterogeneity characterization.

Accurate charge variant analysis of antibody-drug conjugates (ADCs) is essential for understanding product heterogeneity and ensuring quality control. However, Deruxtecan (DXd)-based ADCs present a unique analytical challenge due to the intrinsic instability of the payload, where the lactone ring readily undergoes hydrolysis under alkaline conditions, resulting in time-dependent shifts in charge distribution during imaged capillary isoelectric focusing (icIEF). In this study, we describe the development of an onboard-mixing icIEF method designed to minimize pH-induced degradation during sample preparation. By separating ADC samples from carrier ampholytes (CAs) prior to injection and enabling real-time mixing within the instrument, this approach effectively suppresses premature lactone ring opening and stabilizes charge variant profiles. Comparative studies between conventional premixing and onboard-mixing approach demonstrated that the latter significantly enhances reproducibility, particularly for acidic variants that are highly sensitive to structural conversion. Comprehensive method validation confirmed excellent precision, linearity, and sensitivity, with consistent performance across run-to-run and intra-day analyses. The results underscore the importance of controlling microenvironmental pH exposure in the analysis of chemically instable ADCs. The proposed onboard-mixing strategy provides a robust and efficient solution for icIEF-based characterization, reducing analytical artifacts while simplifying method development. This approach is broadly applicable to ADCs and other biotherapeutics containing pH-sensitive functional groups.

Hydrogen-Ion Concentration

Reinforcement learning-based dynamic ensemble for missense variant effect prediction and tiered prioritization of VUS.

BACKGROUND: Accurate classification of missense variants remains a challenging task despite major advances in genomics. Numerous computational models have been developed to assist in variant classification, but often require repeated integration and benchmarking efforts. Ensemble methods have been proposed to overcome the limitations of single predictors, but mostly rely on fixed, predefined weights that constrain their ability to capture interactions among predictive signals. METHODS: We present GenixRL, a dynamic ensemble framework that reformulates model fusion as a reinforcement learning optimization problem. GenixRL uses a Q-learning agent to learn a policy that dynamically weights the probabilistic outputs of complementary predictors, including BayesDel (addAF and noAF), ClinPred, and MetaRNN. Replacing static weighting with policy learning allows GenixRL to adaptively identify optimal weightings and substantially improve classification accuracy. RESULTS: In benchmark evaluation against 25 state-of-the-art predictors, GenixRL achieved an AUROC of 0.9644 on an independent ClinVar dataset. On saturation genome editing assays for BRCA1 and BRCA2, GenixRL achieved the best performance and ranked highest on 14 of 17 clinically significant genes in a zero-shot evaluation. Applied to uncertain and conflicting ClinVar variants, GenixRL enabled tiered, evidence-based prioritization of hundreds of thousands of variants as likely pathogenic or pathogenic with high confidence, supported by orthogonal population evidence from gnomAD. CONCLUSION: GenixRL advances pathogenicity prediction for missense variants and provides an adaptive ensemble that sorts variants of uncertain significance into tiered candidates for expert curation and functional validation.

Mutation, Missense

Genome-wide association study of estimated glomerular filtration rate using repeated measurements in the Taiwan Biobank.

BACKGROUND: Chronic kidney disease (CKD) is a major global public health issue, with genetic factors playing a significant role in kidney function. Although genome-wide association studies (GWAS) have identified numerous loci associated with estimated glomerular filtration rate (eGFR), most studies relied on a single time-point measurement, which limits the capacity to account for within-individual measurement variability. METHODS: We performed a repeated-measurement GWAS in the prospective Taiwan Biobank (Taiwanese ancestry; n = 25,004) using two repeated creatinine-based eGFR measurements. Repeated eGFR values were analyzed using a linear mixed-effects model with a subject-specific random intercept and time-varying covariates, providing a more precise estimate of eGFR level. Identified loci underwent functional annotation (expression quantitative trait locus, deleteriousness prediction, and epigenetic markers) and were compared with results from a single-measurement GWAS. RESULTS: Six loci associated with eGFR were identified, including four previously reported regions (1q22, 4q21.1, 11p14.1, and 17q21.2) and two additional loci (6p21.32 and 15q24.2). Functional annotation implicated several candidate genes-such as MUC1/EFNA1, SHROOM3, HLA-DQB1, MPPED2, NRG4, and PGAP3/FBXL20-in the regulation of kidney function. CONCLUSION: Incorporating repeated eGFR measurements into GWAS may improve phenotypic precision for identifying genetic associations with kidney function. This study identified eGFR-associated loci and biologically plausible candidate genes in a Taiwanese population, which require further replication and functional validation.

Chronic kidney disease

Biliary Cirrhosis in Myhre Syndrome: The First Case Report of Liver Transplantation and a Review of Reported Hepatic Findings.

Myhre syndrome is a rare autosomal-dominant disorder caused by gain-of-function pathogenic variants in SMAD4 and is now recognized as a progressive multisystem fibrotic disease. Although transforming growth factor-β (TGF-β) signaling plays a central role in hepatic fibrogenesis, hepatobiliary involvement in Myhre syndrome has not been systematically evaluated. We report the first case of Myhre syndrome complicated by rapidly progressive biliary cirrhosis requiring liver transplantation in a 15-year-old male with a confirmed SMAD4 p.Ile500Val variant. Following an infectious episode, the patient developed severe cholestasis with imaging and histopathologic findings consistent with fibro-obliterative cholangiopathy, ultimately necessitating living donor liver transplantation. A systematic review of 55 published reports comprising 217 patients with Myhre syndrome revealed that hepatic evaluation was rarely performed and that previously reported liver abnormalities were mild and secondary, most commonly related to right heart dysfunction or metabolic disease, with no prior cases of progressive biliary fibrosis. This case suggests that dysregulated SMAD4-TGF-β signaling may predispose selected organs to fibro-obliterative injury and that infection-driven inflammation may act as a critical trigger for hepatic fibrosis in Myhre syndrome, expanding the recognized spectrum of organ involvement in this disorder.

Humans