149 research outputs found
Evaluating the mobility and environmental effects of light-rail transit developments using a multi-state supernetwork approach
Mass light-rail transit (LRT) has been promoted as an effective solution toward sustainable transportation in urban areas. This paper presents a micro-simulation framework combining the multi-state supernetwork (MSN) approach and a mobility-related emission module to evaluate the mobility and environmental effects of LRT developments. The evaluation framework considers individualsā mode choice of LRT and particularly the trip chaining with their private vehicles to conduct daily activity programs. As complementary policies to LRT developments, parking pricing and park & ride (P + R) developments are also integrated. The output of daily travel patterns from the MSN approach can be used congruently to calculate the air pollutant emissions. The framework is applied to the extended Metropolitan area of Eindhoven (the Netherlands), where new LRT developments and additional parking policies are considered to improve accessibility and reduce environmental effects. The micro-simulation concerns a synthetic population of approximately 110,000 individuals and seven LRT scenarios. The simulation results show a decrease in overall vehicle kilometers traveled and travel time, an increase in public transport use, a decrease in total air pollutant emissions, and an increase in activities in areas around public transport stops and P + R locations. It appears that the inclusion of parking measures in the simulations strengthens the effects, confirming the effectiveness of policy combinations
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An integrative functional genomics framework for effective identification of novel regulatory variants in genomeāphenome studies
Background: Genomeāphenome studies have identified thousands of variants that are statistically associated with disease or traits; however, their functional roles are largely unclear. A comprehensive investigation of regulatory mechanisms and the gene regulatory networks between phenome-wide association study (PheWAS) and genome-wide association study (GWAS) is needed to identify novel regulatory variants contributing to risk for human diseases. Methods: In this study, we developed an integrative functional genomics framework that maps 215,107 significant single nucleotide polymorphism (SNP) traits generated from the PheWAS Catalog and 28,870 genome-wide significant SNP traits collected from the GWAS Catalog into a global human genome regulatory map via incorporating various functional annotation data, including transcription factor (TF)-based motifs, promoters, enhancers, and expression quantitative trait loci (eQTLs) generated from four major functional genomics databases: FANTOM5, ENCODE, NIH Roadmap, and Genotype-Tissue Expression (GTEx). In addition, we performed a tissue-specific regulatory circuit analysis through the integration of the identified regulatory variants and tissue-specific gene expression profiles in 7051 samples across 32 tissues from GTEx. Results: We found that the disease-associated loci in both the PheWAS and GWAS Catalogs were significantly enriched with functional SNPs. The integration of functional annotations significantly improved the power of detecting novel associations in PheWAS, through which we found a number of functional associations with strong regulatory evidence in the PheWAS Catalog. Finally, we constructed tissue-specific regulatory circuits for several complex traits: mental diseases, autoimmune diseases, and cancer, via exploring tissue-specific TF-promoter/enhancer-target gene interaction networks. We uncovered several promising tissue-specific regulatory TFs or genes for Alzheimerās disease (e.g. ZIC1 and STX1B) and asthma (e.g. CSF3 and IL1RL1). Conclusions: This study offers powerful tools for exploring the functional consequences of variants generated from genomeāphenome association studies in terms of their mechanisms on affecting multiple complex diseases and traits. Electronic supplementary material The online version of this article (10.1186/s13073-018-0513-x) contains supplementary material, which is available to authorized users
A network-based approach to uncover microRNA-mediated disease comorbidities and potential pathobiological implications.
Disease-disease relationships (e.g., disease comorbidities) play crucial roles in pathobiological manifestations of diseases and personalized approaches to managing those conditions. In this study, we develop a network-based methodology, termed meta-path-based Disease Network (mpDisNet) capturing algorithm, to infer disease-disease relationships by assembling four biological networks: disease-miRNA, miRNA-gene, disease-gene, and the human protein-protein interactome. mpDisNet is a meta-path-based random walk to reconstruct the heterogeneous neighbors of a given node. mpDisNet uses a heterogeneous skip-gram model to solve the network representation of the nodes. We find that mpDisNet reveals high performance in inferring clinically reported disease-disease relationships, outperforming that of traditional gene/miRNA-overlap approaches. In addition, mpDisNet identifies network-based comorbidities for pulmonary diseases driven by underlying miRNA-mediated pathobiological pathways (i.e., hsa-let-7a- or hsa-let-7b-mediated airway epithelial apoptosis and pro-inflammatory cytokine pathways) as derived from the human interactome network analysis. The mpDisNet offers a powerful tool for network-based identification of disease-disease relationships with miRNA-mediated pathobiological pathways
The Concurrent Initiation of Medications Is Associated with Discontinuation of Buprenorphine Treatment for Opioid Use Disorder
Introduction Retention in buprenorphine treatment for opioid use disorder (OUD) yields better opioid abstinence and reduces all-cause mortality for patients with OUD. Despite significant efforts have been made to expand the availability and use of buprenorphine in the United States, its retention rates remain on a low level. The current study examines discontinuation of buprenorphine with respect to concurrent initiation of other medications using real-world evidence.
Methods Case-crossover study was conducted to examine discontinuation of buprenorphine using a large-scale longitudinal health dataset including 148,306 commercially-insured individuals initiated on medications for opioid use disorder (MOUD). Odds ratios and Bonferroni adjusted p-values were calculated for medications and therapeutic classes of medications.
Results Clonidine was associated with increased discontinuation risk of buprenorphine both using the buprenorphine dataset alone (OR = 1.583 and adjusted p-value = 1.22 Ć 10ā6) and using naltrexone as a comparison drug (OR = 2.706 and adjusted p-value = 4.11 Ć 10ā5). Opioid medications (oxycodone, morphine and fentanyl) and methocarbamol were associated with increased discontinuation risk of buprenorphine using the buprenorphine dataset alone (adjusted p-value < 0.05), but not significant using naltrexone as a comparison drug. 6 drug therapeutic classes were associated with increased discontinuation risk of buprenorphine both using the buprenorphine dataset alone and using naltrexone as a comparison drug (adjusted p-value < 0.05).
Conclusion Concurrent initiation of medications is associated with increased discontinuation risk of buprenorphine. Opioid medications are prescribed among patients on MOUD and associated with increased discontinuation risk of buprenorphine. Analgesics is associated with increased discontinuation risk of buprenorphine for patients without previous exposure of pain medications
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My personal mutanome: a computational genomic medicine platform for searching network perturbing alleles linking genotype to phenotype
Massive genome sequencing data have inspired new challenges in personalized treatments and facilitated oncological drug discovery. We present a comprehensive database, My Personal Mutanome (MPM), for accelerating the development of precision cancer medicine protocols. MPM contains 490,245 mutations from over 10,800 tumor exomes across 33 cancer types in The Cancer Genome Atlas mapped to 94,563 structure-resolved/predicted protein-protein interactionĀ interfaces (āedgeticā) and 311,022 functional sites (ānodeticā), including ligand-protein binding sites and 8 types of protein posttranslational modifications. In total, 8884 survival results and 1,271,132 drug responses are obtained for these mapped interactions. MPM is available at
https://mutanome.lerner.ccf.org
Artificial Intelligence Framework Identifies Candidate Targets for Drug Repurposing in Alzheimerās Disease
Background: Genome-wide association studies (GWAS) have identified numerous susceptibility loci for Alzheimerās disease (AD). However, utilizing GWAS and multi-omics data to identify high-confidence AD risk genes (ARGs) and druggable targets that can guide development of new therapeutics for patients suffering from AD has heretofore not been successful. Methods: To address this critical problem in the field, we have developed a network-based artificial intelligence framework that is capable of integrating multi-omics data along with human proteināprotein interactome networks to accurately infer accurate drug targets impacted by GWAS-identified variants to identify new therapeutics. When applied to AD, this approach integrates GWAS findings, multi-omics data from brain samples of AD patients and AD transgenic animal models, drug-target networks, and the human proteināprotein interactome, along with large-scale patient database validation and in vitro mechanistic observations in human microglia cells. Results: Through this approach, we identified 103 ARGs validated by various levels of pathobiological evidence in AD. Via network-based prediction and population-based validation, we then showed that three drugs (pioglitazone, febuxostat, and atenolol) are significantly associated with decreased risk of AD compared with matched control populations. Pioglitazone usage is significantly associated with decreased risk of AD (hazard ratio (HR) = 0.916, 95% confidence interval [CI] 0.861ā0.974, P = 0.005) in a retrospective case-control validation. Pioglitazone is a peroxisome proliferator-activated receptor (PPAR) agonist used to treat type 2 diabetes, and propensity score matching cohort studies confirmed its association with reduced risk of AD in comparison to glipizide (HR = 0.921, 95% CI 0.862ā0.984, P = 0.0159), an insulin secretagogue that is also used to treat type 2 diabetes. In vitro experiments showed that pioglitazone downregulated glycogen synthase kinase 3 beta (GSK3Ī²) and cyclin-dependent kinase (CDK5) in human microglia cells, supporting a possible mechanism-of-action for its beneficial effect in AD. Conclusions: In summary, we present an integrated, network-based artificial intelligence methodology to rapidly translate GWAS findings and multi-omics data to genotype-informed therapeutic discovery in AD
Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK
No effective targeted therapies exist for cancers with somatic KRAS mutations. Here we develop a synthetic lethal chemical screen in isogenic KRAS-mutant and wild-type cells to identify clinical drug pairs. Our results show that dual inhibition of polo-like kinase 1 and RhoA/Rho kinase (ROCK) leads to the synergistic effects in KRAS-mutant cancers. Microarray analysis reveals that this combinatory inhibition significantly increases transcription and activity of cyclin-dependent kinase inhibitor p21(WAF1/CIP1), leading to specific G2/M phase blockade in KRAS-mutant cells. Overexpression of p21(WAF1/CIP1), either by cDNA transfection or clinical drugs, preferentially impairs the growth of KRAS-mutant cells, suggesting a druggable synthetic lethal interaction between KRAS and p21(WAF1/CIP1). Co-administration of BI-2536 and fasudil either in the LSL-KRAS(G12D) mouse model or in a patient tumour explant mouse model of KRAS-mutant lung cancer suppresses tumour growth and significantly prolongs mouse survival, suggesting a strong synergy in vivo and a potential avenue for therapeutic treatment of KRAS-mutant cancers
Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment
Background
Dementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive and therapeutic interventions.
Methods
In this study, we conducted a network-based, multimodal omics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9-based genetic assay results and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimerās disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2.
Results
We found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors (BSG and FURIN) and antiviral defense genes (LY6E, IFITM2, IFITM3, and IFNAR1) was elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Overall, individuals with the AD risk allele APOE E4/E4 displayed reduced expression of antiviral defense genes compared to APOE E3/E3 individuals.
Conclusion
Our results suggest significant mechanistic overlap between AD and COVID-19, centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions, although causal relationship and mechanistic pathways between COVID-19 and AD need future investigations
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Identification of Parkinsons disease PACE subtypes and repurposing treatments through integrative analyses of multimodal data.
Parkinsons disease (PD) is a serious neurodegenerative disorder marked by significant clinical and progression heterogeneity. This study aimed at addressing heterogeneity of PD through integrative analysis of various data modalities. We analyzed clinical progression data (ā„5 years) of individuals with de novo PD using machine learning and deep learning, to characterize individuals phenotypic progression trajectories for PD subtyping. We discovered three pace subtypes of PD exhibiting distinct progression patterns: the Inching Pace subtype (PD-I) with mild baseline severity and mild progression speed; the Moderate Pace subtype (PD-M) with mild baseline severity but advancing at a moderate progression rate; and the Rapid Pace subtype (PD-R) with the most rapid symptom progression rate. We found cerebrospinal fluid P-tau/Ī±-synuclein ratio and atrophy in certain brain regions as potential markers of these subtypes. Analyses of genetic and transcriptomic profiles with network-based approaches identified molecular modules associated with each subtype. For instance, the PD-R-specific module suggested STAT3, FYN, BECN1, APOA1, NEDD4, and GATA2 as potential driver genes of PD-R. It also suggested neuroinflammation, oxidative stress, metabolism, PI3K/AKT, and angiogenesis pathways as potential drivers for rapid PD progression (i.e., PD-R). Moreover, we identified repurposable drug candidates by targeting these subtype-specific molecular modules using network-based approach and cell line drug-gene signature data. We further estimated their treatment effects using two large-scale real-world patient databases; the real-world evidence we gained highlighted the potential of metformin in ameliorating PD progression. In conclusion, this work helps better understand clinical and pathophysiological complexity of PD progression and accelerate precision medicine
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