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PubMed2000

Experimental radiosurgery simulations using a theoretical model of cerebral arteriovenous malformations.

BACKGROUND AND PURPOSE: A novel biomathematical arteriovenous malformation (AVM) model based on electric network analysis was used to investigate theoretically the potential role of intranidal hemodynamic perturbations in elevating the risk of rupture after simulated brain AVM radiosurgery. METHODS: The effects of radiation on 28 interconnected plexiform and fistulous AVM nidus vessels were simulated by predefined random or stepwise occlusion. Electric circuit analysis revealed the changes in intranidal flow, pressure, and risk of rupture at intervals of 3 months during a 3-year latency period after simulated partial/complete irradiation of the nidus using doses <25 and >/=25 Gy. An expression for risk of rupture was derived on the basis of the functional distribution of the critical radii of component vessels. The theoretical effects of radiation were also tested on AVM nidus vessels with progressively increasing elastic modulus (E:) and wall thickness during the latency period, simulating their eventual fibrosis. RESULTS: In an AVM with E=5. 0x10(4) dyne/cm(2), 4 (14.3%) of a total 28 sets of AVM radiosurgery simulations revealed theoretical nidus rupture (risk of rupture >/=100%). Three of these were associated with partial nidus coverage and 1 with complete treatment. All ruptures occurred after random occlusion of nidus vessels in AVMs receiving low-dose radiosurgery. Intranidal hemodynamic perturbations were observed in all cases of AVM rupture; the occlusion of a fistulous component resulted in intranidal rerouting of flow and escalation of the intravascular pressure in adjacent plexiform components. Risk of rupture was found to correlate with nidus vessel wall strength: a low E: of 1.9x10(4) dyne/cm(2) resulted in a 92.8% incidence of AVM rupture, whereas a higher E: of 7.0x10(4) dyne/cm(2) resulted in only a 3.6% incidence of AVM rupture. A dramatic reduction in rupture incidence was observed when increasing fibrosis of the nidus was modeled during the latency period. CONCLUSIONS: It was found that the theoretical occurrence of AVM hemorrhage after radiosurgery was low, particularly when radiation-induced fibrosis of nidus vessels was considered. When rupture does occur, it would appear from a theoretical standpoint that the occlusion of intranidal fistulas or larger-caliber plexiform vessels could be a significant culprit in the generation of critical intranidal hemodynamic surges resulting in nidus rupture. The described AVM model should serve as a useful research tool for further theoretical investigations of cerebral AVM radiosurgery and its hemodynamic sequelae.

Cerebral Hemorrhage↗

PubMed2020

Metabolic Dysregulation of the Lysophospholipid/Autotaxin Axis in the Chromosome 9p21 Gene SNP rs10757274.

BACKGROUND: Common chromosome 9p21 single nucleotide polymorphisms (SNPs) increase coronary heart disease risk, independent of traditional lipid risk factors. However, lipids comprise large numbers of structurally related molecules not measured in traditional risk measurements, and many have inflammatory bioactivities. Here, we applied lipidomic and genomic approaches to 3 model systems to characterize lipid metabolic changes in common Chr9p21 SNPs, which confer ≈30% elevated coronary heart disease risk associated with altered expression of ANRIL, a long ncRNA. METHODS: Untargeted and targeted lipidomics was applied to plasma from NPHSII (Northwick Park Heart Study II) homozygotes for AA or GG in rs10757274, followed by correlation and network analysis. To identify candidate genes, transcriptomic data from shRNA downregulation of ANRIL in HEK-293 cells was mined. Transcriptional data from vascular smooth muscle cells differentiated from induced pluripotent stem cells of individuals with/without Chr9p21 risk, nonrisk alleles, and corresponding knockout isogenic lines were next examined. Last, an in-silico analysis of miRNAs was conducted to identify how ANRIL might control lysoPL (lysophosphospholipid)/lysoPA (lysophosphatidic acid) genes. RESULTS: Elevated risk GG correlated with reduced lysoPLs, lysoPA, and ATX (autotaxin). Five other risk SNPs did not show this phenotype. LysoPL-lysoPA interconversion was uncoupled from ATX in GG plasma, suggesting metabolic dysregulation. Significantly altered expression of several lysoPL/lysoPA metabolizing enzymes was found in HEK cells lacking ANRIL. In the vascular smooth muscle cells data set, the presence of risk alleles associated with altered expression of several lysoPL/lysoPA enzymes. Deletion of the risk locus reversed the expression of several lysoPL/lysoPA genes to nonrisk haplotype levels. Genes that were altered across both cell data sets were DGKA, MBOAT2, PLPP1, and LPL. The in-silico analysis identified 4 ANRIL-regulated miRNAs that control lysoPL genes as miR-186-3p, miR-34a-3p, miR-122-5p, and miR-34a-5p. CONCLUSIONS: A Chr9p21 risk SNP associates with complex alterations in immune-bioactive phospholipids and their metabolism. Lipid metabolites and genomic pathways associated with coronary heart disease pathogenesis in Chr9p21 and ANRIL-associated disease are demonstrated.

Chromosomes, Human, Pair 9↗

PubMed2026

The investigation of human cerebrospinal fluid exosome in spinal cord injury.

Spinal cord injury (SCI) leads to severe neurological and functional impairments, yet reliable biomarkers for assessing injury severity and predicting recovery remain limited. Cerebrospinal fluid (CSF) is in direct contact with the central nervous system and provides a valuable source for detecting molecular changes after SCI. Although exosomal microRNAs (miRNAs) and proteins are increasingly recognized as mediators of intercellular communication, the role of human CSF exosomes in SCI has not been systematically investigated. To identify exosome-based biomarkers and potential therapeutic targets, we analyzed CSF and serum exosomes from patients with acute SCI using RNA sequencing and proteomic profiling. Weighted gene co-expression network analysis identified 6 gene modules significantly associated with injury severity and neurological recovery at 3 months. Proteomic analysis revealed a 5-protein panel that distinguished complete from incomplete SCI and a 4-protein panel that predicted neurological improvement. Additionally, 15 CSF-specific and 9 serum-specific exosomal miRNAs were identified independent of injury severity. Among 10 tested miRNAs associated with neurological recovery, 7 regulated astrocyte proliferation, and 6 promoted neurite extension and synapse formation. Overall, this study provides a comprehensive characterization of CSF exosomal miRNAs and proteins in human SCI and identifies molecular signatures associated with injury severity and recovery.

Humans↗

PubMed2003

Autocracy bias in informal groups under need for closure.

Two experiments investigated the tendency of groups with members under high (vs. low) need for cognitive closure to develop an autocratic leadership structure in which some members dominate the discussion, constitute the "hubs" of communication, and influence the group more than other members. The first experiment found that high (vs. low) need for closure groups, as assessed via dispositional measure of the need for closure, manifested greater asymmetry of conversational floor control, such that members with autocratic interactional style were more conversationally dominant and influential than less autocratic members. The second experiment manipulated the need for closure via time pressure and utilized a social network analysis. Consistent with expectation, groups under time pressure (vs. no pressure) showed a greater asymmetry of participation, of centrality, and of prestige among the group members, such that the more focal members were perceived to exert the greater influence over the groups' decisions.

Analysis of Variance↗

PubMed2005

Gendered elder care exchanges in a Caribbean village.

Caregiver gender research often translates into caregiver accounts of the care they provide for an elder parent or spouse, limiting an understanding of other community members'involvement and the actual gendered elder care activities performed and caregiver benefits received. This article describes women's and men's actual involvement in elder care. These findings are part of a four-phase ethnographic community study that includes in-depth network analysis of elder households. One-hundred and forty-three informal adult caregivers assisted 15 elders in obtaining the things they needed to live, providing 244 care activities. One-hundred and three women provided 194 care activities, and 40 men performed 50 care activities. In exchange, the frail elders gave the women caregivers 132 benefits and the men 54 benefits. Women and men differed in the amount and type of care involvement, as well as their motivational mechanisms for involvement in elder care.

Adult↗

PubMedDate not supplied

CA 125: the past and the future.

Over the last 15 years, substantial progress has been made in understanding the potential and the limitations of the CA 125 assay. More than 2000 papers have been published concerning laboratory and clinical studies of CA 125. The original CA 125 assay utilized the OC 125 antibody that recognizes the CA 125 epitope on a high molecular weight glycoprotein. Despite repeated attempts, the gene encoding the peptide component has not yet been cloned. Monoclonal antibodies have been raised against other epitopes expressed by this molecule, leading to the development of the CA 125-II assay that exhibits less day-to-day variation. Using either assay, elevated levels of CA 125 are detected in a number of benign conditions, including endometriosis. CA 125 is most consistently elevated in epithelial ovarian cancer, but can be expressed in a number of gynecologic (endometrial, fallopian tube) and non-gynecologic (pancreatic, breast, colon and lung) cancers. The best established application of the CA 125 assay is in monitoring ovarian cancer. The rate of decline in CA 125 during primary chemotherapy has been an important independent prognostic factor in several multivariate analyses. Persistent elevation of CA 125 at the time of a second look surgical surveillance procedure predicts residual disease with > 95% specificity. Rising CA 125 values have preceded clinical detection of recurrent disease by at least 3 months in most, but not all studies. Given the modest activity of salvage chemotherapy, this information has not yet impacted on survival. Rising CA 125 during subsequent chemotherapy has been associated with progressive disease in more than 90% of cases. CA 125 may serve as an effective surrogate marker for clinical response in phase II trials of new drugs. CA 125 levels can aid in distinguishing malignant from benign pelvic masses, permitting effective triage of patients for primary surgery. Early detection of ovarian cancer remains the most promising application of CA 125. An algorithm has been developed that estimates the risk of ovarian cancer (ROC) based upon the level and trend of CA 125 values. A major trial has been initiated that uses the ROC algorithm to trigger transvaginal sonography and/or subsequent laparotomy. Such a trial could demonstrate improvement in survival through early detection. This strategy should provide adequate specificity, but sensitivity for early stage disease may not be optimal. In the future, improved sensitivity may be attained using multiple markers and neural network analysis. Most serum tumor markers have been proteins or carbohydrates, but lipid markers such as lysophosphatidic acid deserve evaluation. Genomic and proteonomic technologies should identify additional novel markers.

Antibodies↗

PubMed2006

Identification of contrastive and comparable school neighborhoods for childhood obesity and physical activity research.

UNLABELLED: The neighborhood social and physical environments are considered significant factors contributing to children's inactive lifestyles, poor eating habits, and high levels of childhood obesity. Understanding of neighborhood environmental profiles is needed to facilitate community-based research and the development and implementation of community prevention and intervention programs. We sought to identify contrastive and comparable districts for childhood obesity and physical activity research studies. We have applied GIS technology to manipulate multiple data sources to generate objective and quantitative measures of school neighborhood-level characteristics for school-based studies. GIS technology integrated data from multiple sources (land use, traffic, crime, and census tract) and available social and built environment indicators theorized to be associated with childhood obesity and physical activity. We used network analysis and geoprocessing tools within a GIS environment to integrate these data and to generate objective social and physical environment measures for school districts. We applied hierarchical cluster analysis to categorize school district groups according to their neighborhood characteristics. We tested the utility of the area characterizations by using them to select comparable and contrastive schools for two specific studies. RESULTS: We generated school neighborhood-level social and built environment indicators for all 412 Chicago public elementary school districts. The combination of GIS and cluster analysis allowed us to identify eight school neighborhoods that were contrastive and comparable on parameters of interest (land use and safety) for a childhood obesity and physical activity study. CONCLUSION: The combination of GIS and cluster analysis makes it possible to objectively characterize urban neighborhoods and to select comparable and/or contrasting neighborhoods for community-based health studies.

Adolescent↗

PubMed2006

Defining rational hospital catchments for non-urban areas based on travel-time.

BACKGROUND: Cost containment typically involves rationalizing healthcare service delivery through centralization of services to achieve economies of scale. Hospitals are frequently the chosen site of cost containment and rationalization especially in rural areas. Socio-demographic and geographic characteristics make hospital service allocation more difficult in rural and remote regions. This research presents a methodology to model rational catchments or service areas around rural hospitals--based on travel time. RESULTS: This research employs a vector-based GIS network analysis to model catchments that better represent access to hospital-based healthcare services in British Columbia's rural and remote areas. The tool permits modelling of alternate scenarios in which access to different baskets of services (e.g. rural maternity care or ICU) are assessed. In addition, estimates of the percentage of population that is served--or not served--within specified travel times are calculated. CONCLUSION: The modelling tool described is useful for defining true geographical catchments around rural hospitals as well as modelling the percentage of the population served within certain time guidelines (e.g. one hour) for specific health services. It is potentially valuable to policy makers and health services allocation specialists.

British Columbia↗

PubMed2005

A network approach for researching partnerships in health.

BACKGROUND: The last decade has witnessed a significant move towards new modes of governing that are based on coordination and collaboration. In particular, local level partnerships have been widely introduced around the world. There are few comprehensive approaches for researching the effects of these partnerships. The aim of this paper is to outline a network approach that combines structure and agency based explanations to research partnerships in health. Network research based on two Primary Care Partnerships (PCPs) in Victoria is used to demonstrate the utility of this approach. The paper examines multiple types of ties between people (structure), and the use and value of relationships to partners (agency), using interviews with the people involved in two PCPs--one in metropolitan Melbourne and one in a rural area. RESULTS: Network maps of ties based on work, strategic information and policy advice, show that there are many strong connections in both PCPs. Not surprisingly, PCP staff are central and highly connected. Of more interest are the ties that are dependent on these dedicated partnership staff, as they reveal which actors become weakly linked or disconnected without them. Network measures indicate that work ties are the most dispersed and strategic information ties are the most concentrated around fewer people. Divisions of general practice are weakly linked, while local government officials and Department of Human Services (DHS) regional staff appear to play important bridging roles. Finally, the relationships between partners have changed and improved, and most of those interviewed value their new or improved links with partners. CONCLUSION: Improving service coordination and health promotion planning requires engaging people and building strong relationships. Mapping ties is a useful means for assessing the strengths and weaknesses of partnerships, and network analysis indicates concentration and dispersion, the importance of particular individuals, and the points at which they will fragment. A narrative approach adds an assessment of whether the partnerships are being used and valued. The approach outlined here, which examines structure and agency as separate but related explanations, has much to offer in examining partnerships.

Journal Article↗

PubMed2026

Integration of GWAS and WGCNA reveals novel candidate genes for cottonseed oil content in Gossypium hirsutum L.

Genetic improvement of cottonseed oil content represents a crucial strategy for enhancing the comprehensive utilization of cotton. Here, genome-wide association study (GWAS) and weighted gene co-expression network analysis (WGCNA) were integrated to elucidate the genetic control underlying oil content. Phenotypic evaluation of 159 cotton accessions revealed extensive genetic variation, with kernel oil content ranging from 17.81% to 39.50%. Population structure analysis based on 20,213 single nucleotide polymorphisms (SNPs) classified the accessions into two major subpopulations. A total of 18 SNPs exhibited significant associations with oil content, two of which were stably detected across multiple environments using the FarmCPU model. Further haplotype analysis within linkage disequilibrium (LD) blocks confirmed a favorable haplotype on chromosome A05 that was strongly correlated with elevated oil content. Integration of publicly available transcriptome data from 11 ovule developmental stages with WGCNA identified modules significantly linked to oil content. Of the 74 candidate genes within LD intervals, 17 were assigned to WGCNA modules. Functional annotation and enrichment analyses highlighted four putative candidate genes (GH_A05G1503, GH_A05G1506, GH_A05G1531, and GH_A10G2150) involved in oil biosynthesis. These findings deepen our understanding of the genetic mechanisms governing cottonseed oil biosynthesis and lay a foundation for breeding high-oil cotton varieties.

Gossypium↗

PubMed2026

Genes associated with translation and oxidative phosphorylation as components of the translational response in nodulated and water-restricted soybean.

BACKGROUND: Soybean primarily acquires nitrogen through symbiosis with nitrogen-fixing bacteria. Water deficit (WD) is a major stress limiting crop yield. Nodulation may enhance drought tolerance in legumes by modulating nitrogen and hormone metabolism, osmotic adjustment, and antioxidant defenses; however, the molecular basis underlying the differential WD responses between N-fix and N-fed plants remain unclear. Translational control of gene expression is a key regulatory mechanism during stress. RESULTS: We compared the transcriptome and translatome of soybean roots from N-fix and N-fed plants exposed to WD across four combined treatments. N-fix plants under WD exhibited more complex responses in terms of total differentially expressed genes (DEGs) compared to N-fed plants. This increased complexity was also evident among translationally regulated DEGs and differentially expressed transcription factors, whose involvement in WD responses of N-fix plants is novel. Co-expression network analysis identified modules associated with core biological processes encompassing nodulation, WD, and notably, their interplay was particularly prominent in Module 1, which was enriched in genes related to ribosomal protein synthesis and oxidative phosphorylation (OXPHOS). Guilt-by-Association analysis enabled the prediction of novel functions for differentially expressed, uncharacterized hub genes related to stress and/or nodulation responses. CONCLUSIONS: Translational regulation of genes involved in OXPHOS and translation initiation emerged as a central response in N-fix plants under WD. These findings reveal distinct molecular adaptations in N-fix soybean roots facing WD and highlight translational control as a key regulatory layer. We also identified promising candidate genes-including transcription factors and uncharacterized hub genes under translational regulation-that represent potential targets for improving drought tolerance in legumes once validated functionally.

Glycine max↗

PubMed2026

TMEM33 regulates the proliferation and migration of lung adenocarcinoma by promoting the PI3K/AKT/mTOR signaling pathway.

Lung adenocarcinoma is a common type of lung cancer with high incidence and mortality rates. TMEM33, a tumor-associated protein, has not been fully elucidated in lung adenocarcinoma. To explore the expression of TMEM33 in lung adenocarcinoma, its impact on tumor progression, and its role in the PI3K/AKT/mTOR signaling pathway. Key genes associated with lung adenocarcinoma were screened using the Gene Expression Omnibus (GEO) dataset GSE140797 in combination with a weighted correlation network analysis (WGCNA). Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed on these key genes. TMEM33 expression in Lung adenocarcinoma patients was validated using data from the TCGA database. The directly interactive molecules were screened through a bioinformatics method. Cellular assays (Western Blot, CCK8, colony formation, scratch assay, Trans well assay) and a nude mouse model were used to investigate the effects of TMEM33 on cell proliferation, migration, and tumor growth. TMEM33 is highly expressed in lung adenocarcinoma tissues (P < 0.05) and associated with poor prognosis. Overexpression of TMEM33 promotes cell proliferation and migration, and activates the PI3K/AKT/mTOR signaling pathway (P < 0.01). In the nude mouse model, TMEM33 overexpression increases tumor volume (P < 0.001), and PI3K/AKT pathway inhibition suppresses these effects (P < 0.05, P < 0.01). TMEM33 acts as an oncogene in lung adenocarcinoma by activating the PI3K/AKT/mTOR pathway, providing new therapeutic targets.

Cell migration↗

PubMed2025

Deciphering microbial and metabolic influences in gastrointestinal diseases-unveiling their roles in gastric cancer, colorectal cancer, and inflammatory bowel disease.

INTRODUCTION: Gastrointestinal disorders (GIDs) affect nearly 40% of the global population, with gut microbiome-metabolome interactions playing a crucial role in gastric cancer (GC), colorectal cancer (CRC), and inflammatory bowel disease (IBD). This study aims to investigate how microbial and metabolic alterations contribute to disease development and assess whether biomarkers identified in one disease could potentially be used to predict another, highlighting cross-disease applicability. METHODS: Microbiome and metabolome datasets from Erawijantari et al. (GC: n = 42, Healthy: n = 54), Franzosa et al. (IBD: n = 164, Healthy: n = 56), and Yachida et al. (CRC: n = 150, Healthy: n = 127) were subjected to three machine learning algorithms, eXtreme gradient boosting (XGBoost), Random Forest, and Least Absolute Shrinkage and Selection Operator (LASSO). Feature selection identified microbial and metabolite biomarkers unique to each disease and shared across conditions. A microbial community (MICOM) model simulated gut microbial growth and metabolite fluxes, revealing metabolic differences between healthy and diseased states. Finally, network analysis uncovered metabolite clusters associated with disease traits. RESULTS: Combined machine learning models demonstrated strong predictive performance, with Random Forest achieving the highest Area Under the Curve(AUC) scores for GC(0.94[0.83-1.00]), CRC (0.75[0.62-0.86]), and IBD (0.93[0.86-0.98]). These models were then employed for cross-disease analysis, revealing that models trained on GC data successfully predicted IBD biomarkers, while CRC models predicted GC biomarkers with optimal performance scores. CONCLUSION: These findings emphasize the potential of microbial and metabolic profiling in cross-disease characterization particularly for GIDs, advancing biomarker discovery for improved diagnostics and targeted therapies.

Humans↗

PubMed2026

Non-syndromic premature ovarian insufficiency associated with monoallelic LIG4 mutation via haploinsufficiency.

BACKGROUND: Premature ovarian insufficiency (POI) is a heterogeneous reproductive disorder, with genetic factors, particularly defects in DNA damage response pathways, increasingly implicated in its pathogenesis. DNA ligase IV (LIG4) is a key enzyme in the non-homologous end joining (NHEJ) pathway responsible for repairing DNA double-strand breaks (DSBs). However, its role in non-syndromic POI remains unclear. This study aimed to investigate the potential contribution of LIG4 variants to non-syndromic POI. RESULTS: Whole-exome sequencing identified a heterozygous frameshift variant in LIG4 (c.1271_1275del) in a three-generation Han Chinese family with non-syndromic POI, which co-segregated with affected individuals. AlphaFold-based structural modeling predicted truncation of the C-terminal XRCC4 interaction region. Functional experiments demonstrated that the mutant LIG4 protein showed reduced stability and was predominantly mislocalized to the cytoplasm of cells. In ovarian KGN cells, LIG4 depletion reduced cell viability, induced stress-associated cellular senescence, and impaired DNA damage repair capacity. In LIG4 knockout 293T cells, co-transfection of wild-type and mutant constructs revealed dose-dependent functional impairment, resulting in increased apoptosis under basal conditions and after phleomycin induced DNA damage, together with delayed repair of DSBs. Reanalysis of public single-cell RNA sequencing data further showed stage specific upregulation of LIG4 during oocyte maturation. Co-expression network analysis revealed enrichment in the Fanconi anemia pathway, phosphatidylinositol 3-kinase signaling pathway, and glycan metabolism. CONCLUSIONS: Our findings suggest that monoallelic LIG4 mutations may represent a potential genetic etiology for non-syndromic POI with sex-limited penetrance. While further validation in more physiologically relevant models is warranted, our data indicate that LIG4 haploinsufficiency may impair DSB repair and disrupt molecular pathways crucial for oocyte maturation and survival, highlighting a potential role of the NHEJ pathway in maintaining human ovarian function.

Humans↗

PubMed2006

Impact of estrogen receptor beta on gene networks regulated by estrogen receptor alpha in breast cancer cells.

Two subtypes of the estrogen receptor (ER), ERalpha and ERbeta, mediate the actions of estrogens, and although 70% of human breast cancers express ERbeta along with ERalpha, little is known about the possible comodulatory effects of these two ERs. To investigate this, we have used adenoviral gene delivery to produce human breast cancer (MCF-7) cells expressing different levels of ERbeta, along with their endogenous ERalpha, and have examined the effects of ERbeta and receptor occupancy, using ER subtype selective ligands, on genome-wide gene expression by microarray and pathway network analysis. ERbeta had diverse effects on gene expression, enhancing or counteracting ERalpha regulation for distinct subsets of estrogen target genes. Strikingly, ERbeta in the absence of estradiol (E2), elicited the stimulation or suppression of many genes that were normally only regulated by ERalpha with E2. In addition, ERbeta plus E2 elicited the expression of a unique group of genes that were not regulated by ERalpha plus E2 alone. The expression of genes in many functional categories were modulated by ERbeta, with the greatest numbers associated with transcription factors and signal transduction pathways. Regulation of multiple components in the TGFbeta and semaphorin pathways, and of genes controlling cell cycle progression and apoptosis, may contribute to the suppression of cell proliferation observed with ERbeta. Our observations suggest that the relative levels of ERbeta and ERalpha in breast cancers are likely to impact cell proliferation and the activities of diverse signaling pathways and their response to ER ligands and endocrine therapies.

Adenoviridae↗

PubMed2025

Sparse multitask group Lasso for genome-wide association studies.

A critical hurdle in Genome-Wide Association Studies (GWAS) involves population stratification, wherein differences in allele frequencies among subpopulations within samples are influenced by distinct ancestry. This stratification implies that risk variants may be distinct across populations with different allele frequencies. This study introduces Sparse Multitask Group Lasso (SMuGLasso) to tackle this challenge. SMuGLasso is based on MuGLasso, which formulates this problem using a multitask group lasso framework in which tasks are subpopulations, and groups are population-specific Linkage-Disequilibrium (LD)-groups of strongly correlated Single Nucleotide Polymorphisms (SNPs). The novelty in SMuGLasso is the incorporation of an additional [Formula: see text]-norm regularization for the selection of population-specific genetic variants. As MuGLasso, SMuGLasso uses a stability selection procedure to improve robustness and gap-safe screening rules for computational efficiency. We evaluate MuGLasso and SMuGLasso on simulated data sets as well as on a case-control breast cancer data set and a quantitative GWAS in Arabidopsis thaliana. We show that SMuGLasso is well suited to addressing linkage disequilibrium and population stratification in GWAS data, and show the superiority of SMuGLasso over MuGLasso in identifying population-specific SNPs. On real data, we confirm the relevance of the identified loci through pathway and network analysis, and observe that the findings of SMuGLasso are more consistent with the literature than those of MuGLasso. All in all, SMuGLasso is a promising tool for analyzing GWAS data and furthering our understanding of population-specific biological mechanisms.

Genome-Wide Association Study↗

PubMed2024

Use of extracellular vesicle microRNA profiles in patients with acute myeloid leukemia for the identification of novel biomarkers.

OBJECTIVES: This study aimed to establish clinically significant microRNA (miRNA) sets using extracellular vesicles (EVs) from bone marrow (BM) aspirates of patients with acute myelogenous leukemia (AML), and to identify the genes that interact with these EV-derived miRNAs in AML. MATERIALS AND METHODS: BM aspirates were collected from 32 patients with AML at the time of AML diagnosis. EVs were isolated using size-exclusion chromatography. A total of 965 EV-derived miRNAs were identified in all the samples. RESULTS: We analyzed the expression levels of these EV-derived miRNAs of the favorable (n = 10) and non-favorable (n = 22) risk groups; we identified 32 differentially expressed EV-derived miRNAs in the non-favorable risk group. The correlation of these miRNAs with risk stratification and patient survival was analyzed using the information of patients with AML from The Cancer Genome Atlas (TCGA) database. Of the miRNAs with downregulated expression in the non-favorable risk group, hsa-miR-181b and hsa-miR-143 were correlated with non-favorable risk and short overall survival. Regarding the miRNAs with upregulated expression in the non-favorable risk group, hsa-miR-188 and hsa-miR-501 were correlated with non-favorable risk and could predict poor survival. Through EV-derived miRNAs-mRNA network analysis using TCGA database, we identified 21 mRNAs that could be potential poor prognosis biomarkers. CONCLUSIONS: Overall, our findings revealed that EV-derived miRNAs can serve as biomarkers for risk stratification and prognosis in AML. In addition, these EV-derived miRNA-based bioinformatic analyses could help efficiently identify mRNAs with biomarker potential, similar to the previous cell-based approach.

Humans↗

PubMed2026

Mechanisms by which carbamoylated high-density lipoprotein (C-HDL) promotes calcific aortic valve disease and exploration of potential targeted therapies.

Calcific aortic valve disease (CAVD) is a progressive fibrocalcific illness for which no effective pharmaceutical treatment exists. This study investigated whether carbamoylated high-density lipoprotein (C-HDL), a defective type of HDL that can develop during inflammation, contributes to CAVD progression and the involved molecular pathways. Male ApoE-/- mice were divided into three groups: CAVD model, cyanate-treated, and inhibitor, and analyzed after 12 weeks. C57BL/6 mice on a regular diet served as blank controls. Serum paraoxonase-1 (PON1), aortic valve calcification, cluster of differentiation 31 (CD31), phosphorylated nuclear factor kappa B p65 (p-p65), NOTCH receptor 1 (NOTCH1), and runt-related transcription factor 2 (RUNX2) were evaluated. In parallel, using RNA sequencing (RNA-seq), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, protein-protein interaction (PPI) network analysis, and quantitative real-time polymerase chain reaction. Cyanate treatment reduced serum PON1 levels, increased von Kossa-positive calcium deposition, and raised CD31, p-p65, NOTCH1, and RUNX2 levels compared with the model group, but Gly partially corrected these effects. Transcriptomic research identified 270 C-HDL-associated differentially expressed genes (DEGs) enriched in pathways associated with inflammatory signaling and NF-κB activity. Five potential hub genes (BIRC6, PIK3R1, ATM, IFIH1, and DDX58) were discovered and verified using qRT-PCR. These data show that C-HDL may accelerate CAVD by disrupting valve endothelial homeostasis and stimulating inflammatory signaling, and they identify potential molecular targets for future functional validation.

bioinformatics↗