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  • 1
    Language: English
    In: PloS one, 2017, Vol.12 (2), p.e0171240-e0171240
    Description: Inferring the structure of molecular networks from time series protein or gene expression data provides valuable information about the complex biological processes of the cell. Causal network structure inference has been approached using different methods in the past. Most causal network inference techniques, such as Dynamic Bayesian Networks and ordinary differential equations, are limited by their computational complexity and thus make large scale inference infeasible. This is specifically true if a Bayesian framework is applied in order to deal with the unavoidable uncertainty about the correct model. We devise a novel Bayesian network reverse engineering approach using ordinary differential equations with the ability to include non-linearity. Besides modeling arbitrary, possibly combinatorial and time dependent perturbations with unknown targets, one of our main contributions is the use of Expectation Propagation, an algorithm for approximate Bayesian inference over large scale network structures in short computation time. We further explore the possibility of integrating prior knowledge into network inference. We evaluate the proposed model on DREAM4 and DREAM8 data and find it competitive against several state-of-the-art existing network inference methods.
    Subject(s): Algorithms ; Bayes Theorem ; Bayesian analysis ; Bayesian statistical decision theory ; Biochemistry ; Bioinformatics ; Biological activity ; Biology and Life Sciences ; Biophysics ; Causal inference ; Combinatorial analysis ; Complexity ; Computer and Information Sciences ; Computer applications ; Computer Simulation ; Differential equations ; Gene expression ; Gene Regulatory Networks ; Generalized linear models ; Genes ; Knowledge management ; Laboratories ; Linearity ; Mathematical models ; Methods ; Molecular neurobiology ; Molecular structure ; Networks ; Nonlinearity ; Perturbation (Mathematics) ; Physical Sciences ; Propagation ; Proteins ; Research ; Research and Analysis Methods ; Research methodology ; Reverse engineering ; Signal Transduction ; Statistical inference ; Time series ; Usage
    ISSN: 1932-6203
    E-ISSN: 1932-6203
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 2
    Language: English
    In: The EPMA journal, 2020-08-10, Vol.11 (3), p.505-515
    Description: Over the last decade, a rapid rise in deaths due to liver disease has been observed especially amongst young people. Nowadays liver disease accounts for approximately 2 million deaths per year worldwide: 1 million due to complications of cirrhosis and 1 million due to viral hepatitis and hepatocellular carcinoma. Besides primary liver malignancies, almost all solid tumours are capable to spread metastases to the liver, in particular, gastrointestinal cancers, breast and genitourinary cancers, lung cancer, melanomas and sarcomas. A big portion of liver malignancies undergo palliative care. To this end, the paradigm of the palliative care in the liver cancer management is evolving from “just end of the life” care to careful evaluation of all aspects relevant for the survivorship. In the presented study, an evidence-based approach has been taken to target molecular pathways and subcellular components for modelling most optimal conditions with the longest survival rates for patients diagnosed with advanced liver malignancies who underwent palliative treatments. We developed an unsupervised machine learning (UML) approach to robustly identify patient subgroups based on estimated survival curves for each individual patient and each individual potential biomarker. UML using consensus hierarchical clustering of biomarker derived risk profiles resulted into 3 stable patient subgroups. There were no significant differences in age, gender, therapy, diagnosis or comorbidities across clusters. Survival times across clusters differed significantly. Furthermore, several of the biomarkers demonstrated highly significant pairwise differences between clusters after correction for multiple testing, namely, “comet assay” patterns of classes I, III, IV and expression rates of calgranulin A (S100), SOD2 and profilin—all measured ex vivo in circulating leucocytes. Considering worst, intermediate and best survival curves with regard to identified clusters and corresponding patterns of parameters measured, clear differences were found for “comet assay” and S100 expression patterns. In conclusion, multi-faceted cancer control within the palliative care of liver malignancies is crucial for improved disease outcomes including individualised patient profiling, predictive models and implementation of corresponding cost-effective risks mitigating measures detailed in the paper. The “proof-of-principle” model is presented.
    Subject(s): Biomarkers ; Biomedical and Life Sciences ; Biomedicine ; Cancer therapies ; general ; Liver cancer ; Liver diseases ; Machine learning ; Medicine/Public Health ; Palliative care ; Research
    ISSN: 1878-5077
    E-ISSN: 1878-5085
    Source: Springer Online Journals Complete
    Source: PubMed Central
    Source: Alma/SFX Local Collection
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  • 3
    Language: English
    In: Biology (Basel, Switzerland), 2021-07-28, Vol.10 (8), p.716
    Description: Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease. Accumulating evidence demonstrates that alpha-synuclein (α-Syn), an apparently predominant neuronal protein, is a major contributor to PD pathology. As α-Syn is also highly abundant in blood, particularly in red blood cells (RBCs) and platelets, this in turn raises the question on the function of presumably dysfunctional α-Syn in “peripheral” cells and its putative effect on the other enclosed constituents. Herein, we detected the internal variance in erythrocytes of PD patients by Raman spectroscopy, but no measurable amount of erythrocytic behavioural change (eryptosis) or any haemoglobin variation was noticed. An elevated level of plasmin-antiplasmin complexes (PAP) was observed in the plasma of PD patients, indicating activation of the fibrinolytic system, but platelet activation after thrombin stimulation was not altered. Sex-specific patterns were noticed for blood coagulation factor XIII and factor XII activity in PD patients. Additionally, the alterations in homocysteine levels which have often been observed in PD patients were found to be independent from L-DOPA usage and PAP levels. Furthermore, a selective gene expression analysis identified subsets of genes related to different blood-associated compartments (RBCs, platelets, coagulation-fibrinolysis) also involved in PD-related pathways.
    Subject(s): blood coagulation ; eryptosis ; haemoglobin ; homocysteine ; Parkinson’s disease ; plasmin-antiplasmin complexes
    ISSN: 2079-7737
    E-ISSN: 2079-7737
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
    Source: ProQuest Central
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  • 4
    Language: English
    In: Movement disorders, 2015-11-01, Vol.30 (13), p.1794
    Description: Byline: Ina Schmitt, Oliver Kaut, Hassan Khazneh, Laura deBoni, Ashar Ahmad, Daniela Berg, Christine Klein, Holger Frohlich, Ullrich Wullner Keywords: Parkinson's disease; [alpha]-synuclein; DNA methylation; blood; l-dopa Background Increasing gene dosages of [alpha]-synuclein induce familial Parkinson's disease (PD); thus, the hypothesis has been put forward that regulation of gene expression, in particular altered [alpha]-synuclein gene methylation, might be associated with sporadic PD and could be used as a biological marker. Methods We performed a thorough analysis of [alpha]-synuclein methylation in bisulfite-treated DNA from peripheral blood of 490 sporadic PD patients and 485 healthy controls and in addition analyzed the effect of levodopa (l-dopa) on [alpha]-synuclein methylation and expression in cultured mononuclear cells. Results [alpha]-Synuclein was hypomethylated in sporadic PD patients, correlated with sex, age, and a polymorphism in the analyzed sequence stretch (rs3756063). [alpha]-Synuclein methylation separated healthy individuals from sporadic PD with a specificity of 74% (male) and 78% (female), respectively. [alpha]-Synuclein methylation was increased in sporadic PD patients with higher l-dopa dosage, and l-dopa specifically induced methylation of [alpha]-synuclein intron 1 in cultured mononuclear cells. Conclusions [alpha]-Synuclein methylation levels depended on disease status, sex, age, and the genotype of rs3756063. The pharmacological action of l-dopa was not limited to the dopamine precursor function but included epigenetic off-target effects. The hypomethylation of [alpha]-synuclein in sporadic PD patients' blood already observed in previous studies was probably underestimated because of effect of l-dopa, which was not known previously. The analysis of [alpha]-synuclein methylation can help to identify nonparkinsonian individuals with reasonable specificity, which offers a valuable tool for researchers and clinicians. [c] 2015 International Parkinson and Movement Disorder Society Article Note: Funding agencies: This work was supported by the Deutsche Parkinson Vereinigung (dPV); the Hans Tauber Stiftung; the Internationale Parkinson Fonds; and the pure consortium, in particular J. Wiltfang, the German Research Council (DFG: WU 184/9-1) and the Deutsche Zentrum fur neurodegenerative Erkrankungen (DZNE). This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking [Aetionomy [grant number 115568]). Relevant conflicts of interest/financial disclosures: The analysis of the methylation pattern of the [alpha]-synuclein gene for diagnostic purposes is part of the European patent application EP 2668291 A1. Full financial disclosures and author roles may be found in the online version of this article. Supporting information: Additional Supporting Information may be found in the online version of this article Additional Supporting Information may be found in the online version of this article at the publisher's web-site. CAPTION(S): Supplementary Information
    Subject(s): Analysis ; DNA ; Dopa ; Epigenetic inheritance ; Gene expression ; Genetic research ; Methylation ; Phenols ; Sulfites
    ISSN: 0885-3185
    E-ISSN: 1531-8257
    Source: Hellenic Academic Libraries Link
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  • 5
    Language: English
    In: Frontiers in oncology, 2018, Vol.8, p.205-205
    Description: Colorectal cancer (CRC) is the third most common type of cancer and leading cause of death worldwide. Major risk factors involved in the development of CRC are increased dietary sources, genetics, and increasing age. Purpose of the study was to find the role of different variables in the progression of CRC. 50 blood samples from CRC patients and 20 samples from control were collected. Serum was separated from the blood by centrifugation. This serum was assessed for several antioxidants like superoxide dismutase (SOD), glutathione, glutathione peroxidase, glutathione reductase, catalase, vitamin A, C, and E, and pro-oxidants such as malondialdehyde, advanced oxidation protein products (AOPPs), and AGEs according to their respective protocols. Matrix metalloproteinase-7 (MMP-7) and isoprostanes were assessed by ELISA kits. Lower levels of GSH (4.86 ± 0.78 vs 9.65 ± 1.13 μg/dl), SOD (0.08 ± 0.012 vs 0.46 ± 0.017 μg/dl), CAT (2.45 ± 0.03 vs 4.22 ± 0.19 μmol/mol of protein), and GRx (5.16 ± 0.06 vs 7.23 ± 0.36 μmol/ml) in the diseased group were recorded as compared with control. Higher levels of GPx (6.64 ± 0.19 mmol/dl) were observed in the subjects in comparison with control group (1.58 ± 0.30 mmol/dl). Highly significant decreased levels of vitamin A (0.81 ± 0.07 vs 2.37 ± 0.15 mg/ml), vitamin E (15.42 ± 1.26 vs 25.96 ± 2.19 mg/ml), and vitamin C (47.67 ± 7.69 vs 80.37 ± 10.21 mg/ml) were observed in the patients in contrast to control group. The reversal of antioxidants in later stages of CRC may be due to compensatory mechanisms in cancerous cells. The levels of MDA (nmol/ml) were also assessed, which shows significantly increased level in CRC patients as compared with control groups (3.67 ± 0.19 vs 1.31 ± 0.27). The levels of protein oxidation products [AGEs (2.74 ± 0.16 vs 0.84 ± 0.05 IU) and AOPPs (1.32 ± 0.02 vs 0.82 ± 0.07 ng/ml)] were significantly increased in subjects as compared with control. The levels of MMP-7 (64.75 ± 3.03 vs 50.61 ± 4.09 ng/ml) and isoprostanes (0.71 ± 0.03 vs 0.16 ± 0.02 ng/ml) were also analyzed. This shows that the levels of isoprostanes increased due to high lipid peroxidation mediate higher levels of MMP-7, which promotes development of CRC. Following study suggested that elevated oxidative and inflammatory status along with lipid peroxidation and matrix metalloproteinases are the chief contributors in the progression of CRC.
    Subject(s): Care and treatment ; Colorectal cancer ; Development and progression ; Genetic aspects ; Health aspects ; Isoprostanes ; lipid peroxidation ; liver metastasis ; matrix metalloproteinase-7 ; Oncology ; Proteases
    ISSN: 2234-943X
    E-ISSN: 2234-943X
    Source: PubMed Central
    Source: Alma/SFX Local Collection
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 6
    Language: English
    In: Bioinformatics (Oxford, England), 2017-11-15, Vol.33 (22), p.3558-3566
    Description: Discovery of clinically relevant disease sub-types is of prime importance in personalized medicine. Disease sub-type identification has in the past often been explored in an unsupervised machine learning paradigm which involves clustering of patients based on available-omics data, such as gene expression. A follow-up analysis involves determining the clinical relevance of the molecular sub-types such as that reflected by comparing their disease progressions. The above methodology, however, fails to guarantee the separability of the sub-types based on their subtype-specific survival curves. We propose a new algorithm, Survival-based Bayesian Clustering (SBC) which simultaneously clusters heterogeneous-omics and clinical end point data (time to event) in order to discover clinically relevant disease subtypes. For this purpose we formulate a novel Hierarchical Bayesian Graphical Model which combines a Dirichlet Process Gaussian Mixture Model with an Accelerated Failure Time model. In this way we make sure that patients are grouped in the same cluster only when they show similar characteristics with respect to molecular features across data types (e.g. gene expression, mi-RNA) as well as survival times. We extensively test our model in simulation studies and apply it to cancer patient data from the Breast Cancer dataset and The Cancer Genome Atlas repository. Notably, our method is not only able to find clinically relevant sub-groups, but is also able to predict cluster membership and survival on test data in a better way than other competing methods. Our R-code can be accessed as https://github.com/ashar799/SBC. ashar@bit.uni-bonn.de. Supplementary data are available at Bioinformatics online.
    Subject(s): Algorithms ; Bayes Theorem ; Breast Neoplasms - classification ; Breast Neoplasms - diagnosis ; Breast Neoplasms - genetics ; Cluster Analysis ; Female ; Gene Expression Profiling ; Humans ; Models, Biological ; Precision Medicine - methods ; Survival Analysis
    ISSN: 1367-4803
    E-ISSN: 1367-4811
    E-ISSN: 1460-2059
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: Alma/SFX Local Collection
    Source: Oxford Journals 2016 Current and Archive A-Z Collection
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  • 7
    Language: English
    In: Jurnal alam bina, 2015-05-06, Vol.2 (2)
    Description: Architectural philosophy can be defined as a set of ideas, theories or concepts that governed the work of architecture with architects incessantly seek to create new concepts or thoughts in defining architecture. It is completely debatable to postulate that architectural excellence has indebted itself to architectural philosophy, but evidently, many eminent architects across the history and geography upheld philosophy as their main design apparatus. Contrastingly, there are problems recognized as in the bracket of architecture and philosophy where architects in Malaysia are treated as patrons’ and decision makers’ architectural ‘prostitute’. On the other hand, there is a lack of publications and documentation done that encompasses Malaysia architectural scene. The main concern of this research is to review how local architects develop their philosophy since there are really no studies made by past scholars that systematically scrutinize, compile and document in depth the philosophy of Malaysian contemporary architects and the mechanism involved in developing architectural philosophy. With this in mind, Architect Razin Mahmood, an award-winning Johor Bahru-based architect has been selected as main case study, with interview and documentation as main research tactics. By extrapolating the variables found in eminent architect’s philosophical development as a theoretical starting point, local architect is interviewed accordingly. Subsequently, the data gained is analyzed and reviewed as a model of architect philosophical development. At the end of this paper, we learned that architect develops philosophies progressively, with a typified matrix of personality and is inspired by their surroundings.
    ISSN: 1511-1369
    E-ISSN: 2289-8948
    Source: Alma/SFX Local Collection
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  • 8
    Language: English
    In: Movement disorders, 2015-11, Vol.30 (13), p.1794-1801
    Description: Background Increasing gene dosages of α‐synuclein induce familial Parkinson's disease (PD); thus, the hypothesis has been put forward that regulation of gene expression, in particular altered α‐synuclein gene methylation, might be associated with sporadic PD and could be used as a biological marker. Methods We performed a thorough analysis of α‐synuclein methylation in bisulfite‐treated DNA from peripheral blood of 490 sporadic PD patients and 485 healthy controls and in addition analyzed the effect of levodopa (l‐dopa) on α‐synuclein methylation and expression in cultured mononuclear cells. Results α‐Synuclein was hypomethylated in sporadic PD patients, correlated with sex, age, and a polymorphism in the analyzed sequence stretch (rs3756063). α‐Synuclein methylation separated healthy individuals from sporadic PD with a specificity of 74% (male) and 78% (female), respectively. α‐Synuclein methylation was increased in sporadic PD patients with higher l‐dopa dosage, and l‐dopa specifically induced methylation of α‐synuclein intron 1 in cultured mononuclear cells. Conclusions α‐Synuclein methylation levels depended on disease status, sex, age, and the genotype of rs3756063. The pharmacological action of l‐dopa was not limited to the dopamine precursor function but included epigenetic off‐target effects. The hypomethylation of α‐synuclein in sporadic PD patients' blood already observed in previous studies was probably underestimated because of effect of l‐dopa, which was not known previously. The analysis of α‐synuclein methylation can help to identify nonparkinsonian individuals with reasonable specificity, which offers a valuable tool for researchers and clinicians. © 2015 International Parkinson and Movement Disorder Society
    Subject(s): Age Factors ; Aged ; alpha-Synuclein - genetics ; alpha-Synuclein - metabolism ; blood ; Cells, Cultured ; CpG Islands - drug effects ; CpG Islands - genetics ; DNA methylation ; DNA Methylation - drug effects ; Dopamine Agents - pharmacology ; Dopamine Agents - therapeutic use ; Female ; Gene Expression Regulation - drug effects ; Gene Expression Regulation - genetics ; Genotype ; Humans ; l-dopa ; Levodopa - pharmacology ; Levodopa - therapeutic use ; Lymphocytes - drug effects ; Male ; Middle Aged ; Parkinson Disease - drug therapy ; Parkinson Disease - genetics ; Parkinson Disease - pathology ; Parkinson's disease ; Polymorphism, Single Nucleotide ; Regression Analysis ; ROC Curve ; Sex Factors ; α-synuclein
    ISSN: 0885-3185
    E-ISSN: 1531-8257
    Source: Hellenic Academic Libraries Link
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  • 9
    Language: English
    In: IEEE systems journal, 2021-09-02, p.1-13
    Description: Audit trails are critical components in enterprise business applications, typically used for storing, tracking, and auditing data. Entities in the audit trail applications have weak trust boundaries, which expose them to various security risks and attacks. To harden the security and develop secure by design applications, blockchain technology has been recently introduced in the audit trails. Blockchains take a consensus-driven clean slate approach to equip audit trails with secure and transparent data processing, without a trusted intermediary. On a downside, blockchains significantly increase the space-time complexity of the audit trails, leading to high storage costs and low transaction throughput. In this article, we introduce BlockTrail, a novel blockchain architecture that fragments the legacy blockchain systems into layers of codependent hierarchies, thereby reducing the space-time complexity and increasing the throughput. BlockTrail is prototyped on the "practical Byzantine fault tolerance" protocol with a custom-built blockchain. Experiments with BlockTrail show that compared to the conventional schemes, BlockTrail is secure and efficient, with low storage footprint.
    Subject(s): Audit logs ; audit trails ; Bitcoin ; blockchain ; Blockchains ; Buildings ; Databases ; distributed systems ; e-government performance ; Servers ; Throughput ; Urban areas
    ISSN: 1932-8184
    E-ISSN: 1937-9234
    Source: IEEE Electronic Library (IEL)
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  • 10
    Language: English
    In: Stroke (1970), 2018-01-22, Vol.49 (Suppl_1)
    Description: Background: Non-vitamin K oral anticoagulants (NOACs) are guideline-endorsed therapies for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). Information on NOAC comparative effectiveness and safety is limited. Purpose: To compare stroke and major bleeding risks in matched NVAF patients initiating treatment of dabigatran versus rivaroxaban and apixaban, using the US Department of Defense Military Health System (MHS). Methods: Primary analysis included two standard dose cohorts derived from newly initiated adult MHS patients with NVAF based on the date of clinical approval as follows: 1) dabigatran (150 mg) or rivaroxaban (20 mg) (July 2011-June 2016) and 2) dabigatran (150 mg) or apixaban (5mg) (January 2013-June 2016). To reduce potential channeling bias, propensity score matching (PSM 1:1) was used to account for differences in baseline characteristics. Cox proportional hazard regression was utilized to estimate hazard ratios for primary outcomes of stroke and major bleeding. Results: Prior to PSM, there were 12,763 dabigatran and 17,177 rivaroxaban users in cohort 1 and 4,802 dabigatran and 12,594 apixaban users in cohort 2. There were limited dabigatran users available for matching with apixaban. However, PSM resulted in 2 well balanced cohorts. At least 70% of patients were at least 65 years old in both cohorts. Baseline characteristics, follow-up duration, effectiveness and safety outcomes for the PSM cohorts are displayed in the Table. Conclusions: In PSM NVAF patients newly initiated on standard doses of NOACs, dabigatran users demonstrated a statistically significant lower risk of major bleeding compared to rivaroxaban users and no difference compared to apixaban users. Neither cohort demonstrated a significant difference in stroke risk. This large-scale, U.S. practice-based comparison may help inform medical decision making in the absence of head-to-head clinical trials of available NOACs.
    ISSN: 0039-2499
    E-ISSN: 1524-4628
    Source: Hellenic Academic Libraries Link
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: Alma/SFX Local Collection
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