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Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored 1 , 2 . FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P  < 2.6 × 10 –11 ) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants. Genome-wide association studies of individuals from an isolated population (data from the Finnish biobank study FinnGen) and consequent meta-analyses facilitate the identification of previously unknown coding variant associations for both rare and common diseases.

Although nanomaterials have shown promising biomedical application potential, incomplete understanding of their molecular interactions with biological systems prevents their inclusion into mainstream clinical applications. Here we show that black phosphorus (BP) nanomaterials directly affect the cell cycle’s centrosome machinery. BP destabilizes mitotic centrosomes by attenuating the cohesion of pericentriolar material and consequently leads to centrosome fragmentation within mitosis. As a result, BP-treated cells exhibit multipolar spindles and mitotic delay, and ultimately undergo apoptosis. Mechanistically, BP compromises centrosome integrity by deactivating the centrosome kinase polo-like kinase 1 (PLK1). BP directly binds to PLK1, inducing its aggregation, decreasing its cytosolic mobility and eventually restricting its recruitment to centrosomes for activation. With this mechanism, BP nanomaterials show great anticancer potential in tumour xenografted mice. Together, our study reveals a molecular mechanism for the tumoricidal properties of BP and proposes a direction for biomedical application of nanomaterials by exploring their intrinsic bioactivities.Understanding the fundamental nano–bio interactions of nanomaterials intended for biomedical use might unlock potential alternative applications. Here the authors reveal a tumoricidal mechanism of black phosphorus nanomaterials where these nanomaterials directly affect the mitotic centrosome machinery by suppressing polo-like kinase 1, suggesting that nanomaterials can be applied in targeted cancer therapy with their intrinsic nano–bio properties.

Porous carbon holds great potential for application in supercapacitors due to its rich pore structure and high specific surface area. In this research, lignin served as the starting material for the production of lignin-derived carbon materials via a carbonization-activation process. The resulting porous carbon materials underwent rigorous characterization using SEM, BET, Raman, XRD, and XPS to uncover their morphological and structural intricacies. Notably, the optimal product, achieved with a mass ratio of lignin to KOH and KCl at 1:2:0.5 and activation temperature at 700 °C, emerges as an excellent electrode material for high-performance supercapacitors. This superior carbon material boasts a remarkable specific surface area of 2730 m2 g−1, demonstrating an electrochemical capacitance up to 406 F/g at 1 A/g, its high performance surpasses many existing carbon materials. To further investigate the potential application of ELC in electric double-layer capacitors, the electrochemical properties of ELC in 6 M KOH, 1 M Na2SO4, and 1 M Et4NBF4/PC electrolytes were investigated, the reasons for the differences in ELC’s electrochemical performance in different electrolytes are discussed and analyzed in detail, and the advantages and disadvantages of ELC’s performance in capacitor devices of different systems are compared and analyzed. This was performed to compare the electrochemical performance of ELC and commercial YP-50F capacitor carbon in an electric double-layer capacitor, and to investigate the potential application of ELC.

Dengue virus (DENV) is a mosquito-borne pathogen that causes a spectrum of diseases including life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Vascular leakage is a common clinical crisis in DHF/DSS patients and highly associated with increased endothelial permeability. The presence of vascular leakage causes hypotension, circulatory failure, and disseminated intravascular coagulation as the disease progresses of DHF/DSS patients, which can lead to the death of patients. However, the mechanisms by which DENV infection caused the vascular leakage are not fully understood. This study reveals a distinct mechanism by which DENV induces endothelial permeability and vascular leakage in human endothelial cells and mice tissues. We initially show that DENV2 promotes the matrix metalloproteinase-9 (MMP-9) expression and secretion in DHF patients’ sera, peripheral blood mononuclear cells (PBMCs), and macrophages. This study further reveals that DENV non-structural protein 1 (NS1) induces MMP-9 expression through activating the nuclear factor κB (NF-κB) signaling pathway. Additionally, NS1 facilitates the MMP-9 enzymatic activity, which alters the adhesion and tight junction and vascular leakage in human endothelial cells and mouse tissues. Moreover, NS1 recruits MMP-9 to interact with β-catenin and Zona occludens protein-1/2 (ZO-1 and ZO-2) and to degrade the important adhesion and tight junction proteins, thereby inducing endothelial hyperpermeability and vascular leakage in human endothelial cells and mouse tissues. Thus, we reveal that DENV NS1 and MMP-9 cooperatively induce vascular leakage by impairing endothelial cell adhesion and tight junction, and suggest that MMP-9 may serve as a potential target for the treatment of hypovolemia in DSS/DHF patients.

Although septal myectomy is the preferred treatment for medication-refractory hypertrophic obstructive cardiomyopathy (HOCM), the procedure remains subjective. A preoperative planning procedure is proposed using computational fluid dynamics simulations and shape optimization to assist in the objective assessment of the adequacy of the resection. 3 patients with HOCM were chosen for the application of the proposed procedure. The geometries of the preoperative left ventricular outflow tract (LVOT) of patients in the systolic phase were reconstructed from medical images. Computaional fluid dynamics (CFD) simulations were performed to assess hemodynamics within LVOT. Sensitivity analysis was performed to determine the resection extent on the septal wall, and the depth of the resection was optimized to relieve LVOT obstruction while minimizing damage to the septum. The optimized resection was then transferred from systole to diastole to provide surgeons with instructive guidance for septal myectomy. Comparison between preoperative and postoperative hemodynamics showed an evident improvement with respect to the pressure gradient throughout the LVOT. The resected myocardium in the diastolic phase is more extended and thinner than its state in the systolic phase. The proposed preoperative planning procedure may be a viable addition to the current preoperative assessment of patients with HOCM.

Precision medicine requires accurate identification of clinically relevant patient subgroups. Electronic health records provide major opportunities for leveraging machine learning approaches to uncover novel patient subgroups. However, many existing approaches fail to adequately capture complex interactions between diagnosis trajectories and disease-relevant risk events, leading to subgroups that can still display great heterogeneity in event risk and underlying molecular mechanisms. To address this challenge, we implemented VaDeSC-EHR, a transformer-based variational autoencoder for clustering longitudinal survival data as extracted from electronic health records. We show that VaDeSC-EHR outperforms baseline methods on both synthetic and real-world benchmark datasets with known ground-truth cluster labels. In an application to Crohn’s disease, VaDeSC-EHR successfully identifies four distinct subgroups with divergent diagnosis trajectories and risk profiles, revealing clinically and genetically relevant factors in Crohn’s disease. Our results show that VaDeSC-EHR can be a powerful tool for discovering novel patient subgroups in the development of precision medicine approaches. Longitudinal data in electronic health records could be used to improve definitions of patient clusters and therefore inform precision medicine interventions. Here, the authors introduce VaDeSC-EHR , a machine learning model that uses patient longitudinal trajectories and time-to-event data to define clusters.

Background Colorectal cancer (CRC) is a prevalent malignancy worldwide, characterized by high morbidity and mortality rates. The notch signaling pathway plays a dual role as both a tumor suppressor and promoter during embryonic development. However, the precise role and underlying mechanisms of notch signal pathway-related genes in CRC remain unclear. Methods In this study, a prognostic signature for CRC was established using CRC datasets from The Cancer Genome Atlas (TCGA) as the training datasets and two Gene Expression Omnibus (GEO) datasets for external validation. The limma R package was first used to screen the differentially expressed genes (DEGs) of the Notch pathway in CRC from TCGA datasets. The univariate Cox regression analysis identified 12 Notch pathway related genes (NPRG) that were significantly associated with overall survival (OS) in CRC. Next, the least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis were used to establish a 2-gene prognostic signature (HEYL & WNT5A). Receiver operating characteristic (ROC) curve showed that the 2-gene prognostic signature could effectively predict the 1-, 2-, and 3-year survival time of CRC patients. In addition, the prognostic value of the 2-gene signature was validated in two GEO CORD&READ cohorts. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to explore the signaling pathways and cellular processes associated with the 2-gene signature. A nomogram for predicting the OS of CRC patients was constructed by integrating clinical characteristics and the 2-gene NPRG signature, followed by validation using calibration curves and decision curve analysis (DCA) plots. Results The NPRG prognostic signature for CRC was established. HEYL and WNT5A were identified as hub genes of the Notch pathway in CRC. HEYL was significantly up-regulated in the high-risk group, while WNT5A was significantly up-regulated in the low-risk group. High expression of HEYL was associated with a poorer prognosis of CRC. Furthermore, Knockout of HEYL significantly inhibited the proliferation of CRC cells in HCT116 and RKO cell lines in vitro experiments. Conclusions Our research suggests that the 2-gene signature described here can serve as a reliable prognostic biomarker for predicting the prognosis of CRC patients.

The treatment of ulcerative colitis (UC) remains challenging due to limited efficacy and significant side effects. Organosilicone Double-Long-Chain Diquaternary Ammonium Salt (JUC Spray Dressing) exhibits antibacterial, anti-inflammatory, and wound-healing properties. This study aimed to evaluate the therapeutic effects of JUC Spray Dressing in a Dextran Sulfate Sodium Salt (DSS)-induced UC mouse model and explore its potential mechanisms of action. A UC model was induced in mice using 3% DSS, followed by JUC Spray Dressing enema treatment. Disease activity index (DAI), histological scores, bacterial biofilms on the intestinal mucosa, and tight junction integrity were assessed. Inflammatory cytokine levels in peripheral blood were measured, and 16S rDNA amplicon sequencing was performed to analyze cecal microbiota composition. JUC Spray Dressing significantly alleviated UC symptoms and reduced colonic congestion, with no significant difference compared to other treatment groups (P > 0.05). All treatments significantly decreased the expression of inflammatory cytokines in peripheral blood (P < 0.0001), with no significant differences among the groups. Additionally, all treatments effectively reduced biofilm thickness and bacterial abundance, improving intestinal barrier integrity. JUC Spray Dressing inhibited harmful bacteria such as spp. without significantly altering overall microbial composition. JUC Spray Dressing effectively removes intestinal bacterial biofilms, reduces inflammation, and enhances barrier function to alleviate UC symptoms. Its efficacy appeared comparable to conventional treatments, suggesting potential as an alternative therapeutic option; however, the present study did not assess mucosal safety, and dedicated toxicology studies are required to establish safety for intraluminal use.

Abstract Dupuytren's disease is characterized by fingers becoming permanently bent in a flexed position. Whereas people of African ancestry are rarely afflicted by Dupuytren's disease, up to ∼30% of men over 60 years suffer from this condition in northern Europe. Here, we meta-analyze 3 biobanks comprising 7,871 cases and 645,880 controls and find 61 genome-wide significant variants associated with Dupuytren's disease. We show that 3 of the 61 loci harbor alleles of Neandertal origin, including the second and third most strongly associated ones (P = 6.4 × 10−132 and P = 9.2 × 10−69, respectively). For the most strongly associated Neandertal variant, we identify EPDR1 as the causal gene. Dupuytren's disease is an example of how admixture with Neandertals has shaped regional differences in disease prevalence.

Adult male germline stem cells (spermatogonia) proliferate by mitosis and, after puberty, generate spermatocytes that undertake meiosis to produce haploid spermatozoa. Germ cells are under evolutionary constraint to curtail mutations and maintain genome integrity. Despite constant turnover, spermatogonia very rarely form tumors, so-called spermatocytic tumors (SpT). In line with the previous identification of FGFR3 and HRAS selfish mutations in a subset of cases, candidate gene screening of 29 SpTs identified an oncogenic NRAS mutation in two cases. To gain insights in the etiology of SpT and into properties of the male germline, we performed whole-genome sequencing of five tumors (4/5 with matched normal tissue). The acquired single nucleotide variant load was extremely low (~0.2 per Mb), with an average of 6 (2-9) non-synonymous variants per tumor, none of which is likely to be oncogenic. The observed mutational signature of SpTs is strikingly similar to that of germline de novo mutations, mostly involving C>T transitions with a significant enrichment in the ACG trinucleotide context. The tumors exhibited extensive aneuploidy (50-99 autosomes/tumor) involving whole-chromosomes, with recurrent gains of chr9 and chr20 and loss of chr7, suggesting that aneuploidy itself represents the initiating oncogenic event. We propose that SpT etiology recapitulates the unique properties of male germ cells; because of evolutionary constraints to maintain low point mutation rate, rare tumorigenic driver events are caused by a combination of gene imbalance mediated via whole-chromosome aneuploidy. Finally, we propose a general framework of male germ cell tumor pathology that accounts for their mutational landscape, timing and cellular origin.