Emerging studies suggest a role for tau in regulating the biology of RNA binding proteins (RBPs). We now show that reducing the RBP T-cell intracellular antigen 1 (TIA1) in vivo protects against ...neurodegeneration and prolongs survival in transgenic P301S Tau mice. Biochemical fractionation shows co-enrichment and co-localization of tau oligomers and RBPs in transgenic P301S Tau mice. Reducing TIA1 decreased the number and size of granules co-localizing with stress granule markers. Decreasing TIA1 also inhibited the accumulation of tau oligomers at the expense of increasing neurofibrillary tangles. Despite the increase in neurofibrillary tangles, TIA1 reduction increased neuronal survival and rescued behavioral deficits and lifespan. These data provide in vivo evidence that TIA1 plays a key role in mediating toxicity and further suggest that RBPs direct the pathway of tau aggregation and the resulting neurodegeneration. We propose a model in which dysfunction of the translational stress response leads to tau-mediated pathology.
Current understandings of individual disease etiology and therapeutics are limited despite great need. To fill the gap, we propose a novel computational pipeline that collects potent disease gene ...cooperative pathways to envision individualized disease etiology and therapies. Our algorithm constructs individualized disease modules de novo, which enables us to elucidate the importance of mutated genes in specific patients and to understand the synthetic penetrance of these genes across patients. We reveal that importance of the notorious cancer drivers
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fluctuate widely across breast cancers and peak in tumors with distinct numbers of mutations and that rarely mutated genes such as
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have high disease module importance in specific individuals. Furthermore, individualized module disruption enables us to devise customized singular and combinatorial target therapies that were highly varied across patients, showing the need for precision therapeutics pipelines. As the first analysis of de novo individualized disease modules, we illustrate the power of individualized disease modules for precision medicine by providing deep novel insights on the activity of diseased genes in individuals.
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Neuroblastoma (NB) is the most common extracranial solid tumor in children. Although only a few recurrent somatic mutations have been identified, chromosomal abnormalities, including ...the loss of heterozygosity (LOH) at the chromosome 1p and gains of chromosome 17q, are often seen in the high-risk cases. The biological basis and evolutionary forces that drive such genetic abnormalities remain enigmatic. Here, we conceptualize the Gene Utility Model (GUM) that seeks to identify genes driving biological signaling via their collective gene utilities and apply it to understand the impact of those differentially utilized genes on constraining the evolution of NB karyotypes. By employing a computational process-guided flow algorithm to model gene utility in protein–protein networks that built based on transcriptomic data, we conducted several pairwise comparative analyses to uncover genes with differential utilities in stage 4 NBs with distinct classification. We then constructed a utility karyotype by mapping these differentially utilized genes to their respective chromosomal loci. Intriguingly, hotspots of the utility karyotype, to certain extent, can consistently recapitulate the major chromosomal abnormalities of NBs and also provides clues to yet identified predisposition sites. Hence, our study not only provides a new look, from a gene utility perspective, into the known chromosomal abnormalities detected by integrative genomic sequencing efforts, but also offers new insights into the etiology of NB and provides a framework to facilitate the identification of novel therapeutic targets for this devastating childhood cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mercury is a prominent environmental contaminant that causes detrimental effects to human health. Although the liver has been known to be a main target organ, there is limited information on in vivo ...molecular mechanism of mercury-induced toxicity in the liver. By using transcriptome analysis, phenotypic anchoring and validation of targeted gene expression in zebrafish, mercury-induced hepatotoxicity was investigated and a number of perturbed cellular processes were identified and compared with those captured in the in vitro human cell line studies.
Hepato-transcriptome analysis of mercury-exposed zebrafish revealed that the earliest deregulated genes were associated with electron transport chain, mitochondrial fatty acid beta-oxidation, nuclear receptor signaling and apoptotic pathway, followed by complement system and proteasome pathway, and thereafter DNA damage, hypoxia, Wnt signaling, fatty acid synthesis, gluconeogenesis, cell cycle and motility. Comparative meta-analysis of microarray data between zebrafish liver and human HepG2 cells exposed to mercury identified some common toxicological effects of mercury-induced hepatotoxicity in both models. Histological analyses of liver from mercury-exposed fish revealed morphological changes of liver parenchyma, decreased nucleated cell count, increased lipid vesicles, glycogen and apoptotic bodies, thus providing phenotypic evidence for anchoring of the transcriptome analysis. Validation of targeted gene expression confirmed deregulated gene-pathways from enrichment analysis. Some of these genes responding to low concentrations of mercury may serve as toxicogenomic-based markers for detection and health risk assessment of environmental mercury contaminations.
Mercury-induced hepatotoxicity was triggered by oxidative stresses, intrinsic apoptotic pathway, deregulation of nuclear receptor and kinase activities including Gsk3 that deregulates Wnt signaling pathway, gluconeogenesis, and adipogenesis, leading to mitochondrial dysfunction, endocrine disruption and metabolic disorders. This study provides important mechanistic insights into mercury-induced liver toxicity in a whole-animal physiology context, which will help in understanding the syndromes caused by mercury poisoning. The molecular conservation of mercury-induced hepatotoxicity between zebrafish and human cell line reveals the feasibility of using zebrafish to model molecular toxicity in human for toxicant risk assessments.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The ability or inability of a drug to penetrate into the brain is a key consideration in drug design. Drugs for treating central nervous system (CNS) disorders need to be able to penetrate the ...blood−brain barrier (BBB). BBB nonpenetration is desirable for non-CNS-targeting drugs to minimize potential CNS-related side effects. Computational methods have been employed for the prediction of BBB-penetrating (BBB+) and -nonpenetrating (BBB−) agents at impressive accuracies of 75∼92% and 60∼80%, respectively. However, the majority of these studies give a substantially lower BBB− accuracy, and thus overall accuracy, than the BBB+ accuracy. This work examined whether proper selection of molecular descriptors can improve both the BBB− and the overall accuracies of statistical learning methods. The methods tested include logistic regression, linear discriminate analysis, k nearest neighbor, C4.5 decision tree, probabilistic neural network, and support vector machine. Molecular descriptors were selected by using a feature selection method, recursive feature elimination (RFE). Results by using 415 BBB+ and BBB− agents show that RFE substantially improves both the BBB− and the overall accuracy for all of the methods studied. This suggests that statistical learning methods combined with proper feature selection is potentially useful for facilitating a more balanced and improved prediction of BBB+ and BBB− agents.
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IJS, KILJ, NUK, PNG, UL, UM
Inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) is associated with various diseases. We evaluated the diagnostic and prognostic significance of serum ITIH4 levels in healthy controls and ...patients with chronic hepatitis B (CHB), hepatitis B virus (HBV)-related liver cirrhosis, and HBV-related hepatocellular carcinoma (HCC).
The study enrolled 300 individuals (50 healthy controls, 50 with CHB, 100 with HBV-associated cirrhosis, and 100 with HBV-associated HCC). Serum ITIH4 levels were determined by western blot analysis and expressed in densitometry units (DU).
ITIH4 levels were higher in CHB (mean: 252.96 DU) and liver cirrhosis (mean: 206.43 DU) patients than in healthy controls (mean: 75.92 DU) and HCC patients (mean: 92.86 DU) (P<0.001). The area under the receiver operating characteristic curve was 0.71 for the diagnosis of HCC in patients with HBV-related liver disease. Multivariate Cox regression analysis showed that large tumor size (≥5cm) was independently associated with overall survival (hazard ratio 5.894, 95% confidence interval 1.373–25.300, P=0.017). A Kaplan–Meier survival analysis showed significantly worse survival among HCC patients with both low ITIH4 (<80 DU) and a large tumor size compared to that among other HCC patients (P<0.001), and among patients with high AFP (>200ng/mL) and low ITIH4 compared to that among other HCC patients (P=0.041).
Serum ITIH4 levels are reduced in HCC patients compared to that in CHB and cirrhosis patients, and low serum ITIH4 levels are associated with shorter survival in HBV-associated HCC patients.
•Inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) is associated with HCC development.•Serum ITIH4 levels are reduced in HCC compared to that in CHB and cirrhosis.•Low serum ITIH4 levels are associated with shorter survival in HCC patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Medicinal plants have been explored therapeutically in traditional medicines and are a valuable source for drug discovery. Insufficient knowledge about the molecular mechanism of these medicinal ...plants limits the scope of their application and hinders the effort to design new drugs using the therapeutic principles of herbal medicines. This problem can be partially alleviated if efficient methods for rapid identification of protein targets of herbal ingredients can be introduced. Efforts have been directed at developing efficient computer methods for facilitating target identification. Various methods being explored or under investigation are reviewed here. So far, one computer method, INVDOCK, has been specifically used for automated drug target identification. Its usefulness in the identification of therapeutic targets of medicinal herbal ingredients as well as synthetic chemicals is reviewed. The majority of INVDOCK identified therapeutic targets of several well-known medicinal herbal ingredients have been found to be confirmed or implicated by experiments, which suggests the potential of in silico methods in facilitating the study of molecular mechanism of medicinal plants.
Motivation: Small GTPase RhoA regulates cell-cycle progression via several mechanisms. Apart from its actions via ROCK, RhoA has recently been found to activate a scaffold protein MEKK1 known to ...promote ERK activation. We examined whether RhoA can substantially affect ERK activity via this MEKK1-mediated crosstalk between RhoA and EGFR-ERK pathway. By extending the published EGFR-ERK simulation models represented by ordinary differential equations, we developed a simulation model that includes this crosstalk, which was validated with a number of experimental findings and published simulation results. Results: Our simulation suggested that, via this crosstalk, RhoA elevation substantially prolonged duration of ERK activation at both normal and reduced Ras levels. Our model suggests ERK may be activated in the absence of Ras. When Ras is overexpressed, RhoA elevation significantly prolongs duration of ERK activation but reduces the amount of active ERK partly due to competitive binding between ERK and RhoA to MEKK1. Our results indicated possible roles of RhoA in affecting ERK activities via MEKK1-mediated crosstalk, which seems to be supported by indications from several experimental studies that may also implicate the collective regulation of cell fate and progression of cancer and other diseases. Contact: phacyz@nus.edu.sg Supplementary information: Supplementary data are available at Bioinformatics online.
Deregulations of EGFR endocytosis in EGFR-ERK signaling are known to cause cancers and developmental disorders. Mutations that impaired c-Cbl–EGFR association delay EGFR endocytosis and produce ...higher mitogenic signals in lung cancer. ROCK, an effector of small GTPase RhoA was shown to negatively regulate EGFR endocytosis via endophilin A1. A mathematical model was developed to study how RhoA and ROCK regulate EGFR endocytosis. Our study suggested that over-expressing RhoA as well as ROCK prolonged ERK activation partly by reducing EGFR endocytosis. Overall, our study hypothesized an alternative role of RhoA in tumorigenesis in addition to its regulation of cytoskeleton and cell motility.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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