scholarly journals A personalised approach for identifying disease-relevant pathways in heterogeneous diseases

2019 ◽  
Author(s):  
Juhi Somani ◽  
Siddharth Ramchandran ◽  
Harri Lähdesmäki
Keyword(s):  
Time Course ◽  
Time Windows ◽  
Disease Process ◽  
Complex Diseases ◽  
Control Pair ◽  
Clinical Onset ◽  
Heterogeneous Datasets ◽  
Gene Level ◽  
Time Course Data

AbstractNumerous time-course gene expression datasets have been curated for studying the biological dynamics that drive disease progression; and nearly as many methods have been proposed to analyse them. However, barely any method exists that can appropriately model time-course data and at the same time account for heterogeneity that entails many complex diseases. Most methods manage to fulfil either one of those qualities, but not both. The lack of appropriate methods hinders our capability of understanding the disease process and pursuing preventive or curative treatments. Here, we present a method that models time-course data in a personalised manner, i.e. for each case-control pair individually, using Gaussian processes in order to identify differentially expressed genes (DEGs); and combines the lists of DEGs on a pathway-level using a permutation-based empirical hypothesis testing in order to overcome gene-level variability and inconsistencies prevalent to heterogeneous datasets from complex diseases. Our method can be applied to study the time-course dynamics as well as specific time-windows of heterogeneous diseases. We apply our personalised approach on two longitudinal type 1 diabetes (T1D) datasets to determine perturbations that take place during early prognosis of the disease as well as in time-windows before seroconversion and clinical onset of T1D. By comparing to non-personalised methods, we demonstrate that our approach is biologically motivated and can reveal more insights into progression of heterogeneous diseases. With its robust capabilities of identifying immunologically interesting and disease-relevant pathways, our approach could be useful for predicting certain events in the progression of heterogeneous diseases and even biomarker identification.AvailabilityThe implemented code of our personalised approach will be available online upon publication.

scholarly journals Model-based inference from multiple dose, time course data reveals Wolbachia effects on infection profiles of type 1 dengue virus in Aedes aegypti

2018 ◽  
Vol 12 (3) ◽  
pp. e0006339 ◽  
Author(s):  
Caetano Souto-Maior ◽  
Gabriel Sylvestre ◽  
Fernando Braga Stehling Dias ◽  
M. Gabriela M. Gomes ◽  
Rafael Maciel-de-Freitas
Keyword(s):  
Aedes Aegypti ◽  
Dengue Virus ◽  
Multiple Dose ◽  
Time Course ◽  
Dose Time ◽  
Model Based ◽  
Time Course Data

scholarly journals Cardiac Manifestations in a Group of Romanian Patients with Gaucher Disease Type 1 (a Monocentric Study)

Diagnostics ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 989
Author(s):  
Cecilia Lazea ◽  
Simona Bucerzan ◽  
Camelia Al-Khzouz ◽  
Anca Zimmermann ◽  
Ștefan Cristian Vesa ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Cardiac Involvement ◽  
Disease Type ◽  
Clinical Onset ◽  
Lysosomal Disorders ◽  
Electrocardiographic Changes ◽  
Gaucher Disease Type 1 ◽  
And Function ◽  
Cardiac Manifestations

Gaucher disease (GD), one of the most common lysosomal disorders, is characterised by clinical heterogeneity. Cardiac involvement is rare and refers to pulmonary hypertension (PH), valvular abnormalities and myocardial infiltrative damage. The aim of this study was to evaluate cardiac involvement in a group of Romanian GD patients. Phenotypic and genotypic characterisation was carried out in 69 patients with GD type 1. Annual echocardiography and electrocardiography were performed to assess pulmonary pressure, morphology and function of the valves and electrocardiographic changes. Nine patients (13%) exhibited baseline echocardiographic signs suggesting PH. Mitral regurgitation was present in 33 patients (48%) and aortic regurgitation in 11 patients (16%). One patient presented aortic stenosis. Significant valvular dysfunction was diagnosed in 10% of patients. PH was associated with greater age (p < 0.001), longer time since splenectomy (p = 0.045) and longer time between clinical onset and the start of enzyme replacing therapy (p < 0.001). Electrocardiographic changes were present in five patients (7%).

scholarly journals Bayesian approach for predicting responses to therapy from high-dimensional time-course gene expression profiles

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Arika Fukushima ◽  
Masahiro Sugimoto ◽  
Satoru Hiwa ◽  
Tomoyuki Hiroyasu
Keyword(s):  
Gene Expression ◽  
Time Course ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Response To Therapy ◽  
Hcv Infection ◽  
Entire Treatment Period ◽  
Time Points ◽  
Time Course Data ◽  
Conventional Methods

Abstract Background Historical and updated information provided by time-course data collected during an entire treatment period proves to be more useful than information provided by single-point data. Accurate predictions made using time-course data on multiple biomarkers that indicate a patient’s response to therapy contribute positively to the decision-making process associated with designing effective treatment programs for various diseases. Therefore, the development of prediction methods incorporating time-course data on multiple markers is necessary. Results We proposed new methods that may be used for prediction and gene selection via time-course gene expression profiles. Our prediction method consolidated multiple probabilities calculated using gene expression profiles collected over a series of time points to predict therapy response. Using two data sets collected from patients with hepatitis C virus (HCV) infection and multiple sclerosis (MS), we performed numerical experiments that predicted response to therapy and evaluated their accuracies. Our methods were more accurate than conventional methods and successfully selected genes, the functions of which were associated with the pathology of HCV infection and MS. Conclusions The proposed method accurately predicted response to therapy using data at multiple time points. It showed higher accuracies at early time points compared to those of conventional methods. Furthermore, this method successfully selected genes that were directly associated with diseases.

Enhanced reactivation and enhanced mutagenesis of herpes simplex virus in normal human and xeroderma pigmentosum cells

1984 ◽  
Vol 4 (11) ◽  
pp. 2341-2346
Author(s):  
P J Abrahams ◽  
B A Huitema ◽  
A J van der EB
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Xeroderma Pigmentosum ◽  
Time Course ◽  
Normal Human ◽  
Uv Dose ◽  
Simplex Virus

Enhanced reactivation (ER) and enhanced mutagenesis (EM) of herpes simplex virus type 1 were studied simultaneously in UV-irradiated stationary cultures of diploid normal human and xeroderma pigmentosum (XP) fibroblasts. Mutagenesis was assayed with unirradiated herpes simplex virus type 1 as a probe in a forward mutation assay (resistance to iododeoxycytidine). Dose-response studies showed that ER increased with the UV dose given to the virus. Optimal reactivation levels were obtained when normal cells and XP variant cells were exposed to a UV dose of 8 J . m-2 and the virus was irradiated with 150 J . m-2. Repair-deficient XP cells of complementation groups A, C, and D showed optimal reactivation levels with a UV dose to the cells of 1.0 J . m-2 and a UV dose to the virus of 40 J . m-2. The time course of appearance of ER and EM was also studied, both in the normal and XP cells. In all cell types except the XP variant cells, EM followed similar kinetics of appearance as did ER. Maximal activities occurred when infection was delayed 1 or 2 days after cell treatment. In XP variant cells, however, maximal expression of the EM function was significantly delayed with respect to ER. The results indicate that ER and EM are transiently expressed in normal and repair-deficient XP cells. Although both phenomena may be triggered by the same cellular event, ER and EM appear to be separate processes that occur independently of each other.

scholarly journals Generalized Correlation Coefficient for Non-Parametric Analysis of Microarray Time-Course Data

2017 ◽  
Vol 14 (2) ◽  
Author(s):  
Qihua Tan ◽  
Mads Thomassen ◽  
Mark Burton ◽  
Kristian Fredløv Mose ◽  
Klaus Ejner Andersen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Correlation Coefficient ◽  
Parametric Analysis ◽  
Time Course ◽  
Expression Patterns ◽  
Gene Expression Patterns ◽  
Microarray Time Course ◽  
Time Course Data ◽  
Generalized Correlation ◽  
Non Parametric

AbstractModeling complex time-course patterns is a challenging issue in microarray study due to complex gene expression patterns in response to the time-course experiment. We introduce the generalized correlation coefficient and propose a combinatory approach for detecting, testing and clustering the heterogeneous time-course gene expression patterns. Application of the method identified nonlinear time-course patterns in high agreement with parametric analysis. We conclude that the non-parametric nature in the generalized correlation analysis could be an useful and efficient tool for analyzing microarray time-course data and for exploring the complex relationships in the omics data for studying their association with disease and health.

Induction of a fast-oxidative phenotype by chronic muscle stimulation: histochemical and metabolic studies

1996 ◽  
Vol 270 (1) ◽  
pp. C313-C320 ◽  
Author(s):  
C. N. Mayne ◽  
H. Sutherland ◽  
J. C. Jarvis ◽  
S. J. Gilroy ◽  
A. J. Craven ◽  
...  
Keyword(s):  
Time Course ◽  
Citrate Synthase ◽  
Fiber Type ◽  
Adult Rabbit ◽  
Myosin Isoforms ◽  
Two Phase ◽  
Coa Transferase ◽  
Oxidative Phenotype ◽  
Aggregate Amount

Chronic electrical stimulation of skeletal muscle at 10 Hz induces fast-to-slow fiber type transformation. Does a lower aggregate amount of activity lead to a less complete transformation, or does it produce the same transformation over a longer time course? We examined this question by subjecting adult rabbit tibialis anterior and extensor digitorum longus muscles to continuous stimulation at 2.5 Hz for 2-12 wk. Most of the fibers acquired the histochemical and immunocytochemical characteristics of type 2A, not type 1, fibers. There was a corresponding rise in oxidative activity, but this was accompanied by a marked decline in anaerobic glycolysis. The activities of hexokinase and 3-oxoacid CoA-transferase stopped increasing after 2 wk, glutamate oxaloacetate transaminase after 4 wk, and beta-hydroxyacyl-CoA dehydrogenase after 6 wk of stimulation. Succinate dehydrogenase, citrate synthase, lactate dehydrogenase, and creatine phosphokinase continued to change up to 12 wk of stimulation. Changes in enzyme activity were not as rapid or as marked as those observed for stimulation at 10 Hz, and none showed the typical two-phase response of oxidative enzyme activities to stimulation at 10 Hz. The latter may therefore be dependent on induction of type 1 myosin isoforms.

scholarly journals The post-translational processing of chromogranin A in the pancreatic islet: involvement of the eukaryote subtilisin PC2

1994 ◽  
Vol 298 (3) ◽  
pp. 521-528 ◽  
Author(s):  
S D Arden ◽  
N G Rutherford ◽  
P C Guest ◽  
W J Curry ◽  
E M Bailyes ◽  
...  
Keyword(s):  
Secretory Granule ◽  
Pancreatic Islet ◽  
Pancreatic Beta Cells ◽  
Chromogranin A ◽  
Time Course ◽  
Deae Cellulose ◽  
Neuroendocrine Cells ◽  
Time Period ◽  
Sds Page

The post-translational processing of chromogranin A (CGA) and the nature of the enzyme(s) involved were investigated in rat pancreatic islet and insulinoma tissue. Pulse-chase radiolabelling experiments using sequence-specific antisera showed that the 98 kDa (determined by SDS/PAGE) precursor was processed to an N-terminal 21 kDa peptide, a C-terminal 14 kDa peptide and a 45 kDa centrally located peptide with a rapid time course (t1/2 approx. 30 min) after an initial delay of 30-60 min. The 45 kDa peptide was, in turn, converted partially into a 5 kDa peptide with pancreastatin immunoreactivity and a 3 kDa peptide with WE-14 immunoreactivity over a longer time period. Incubation of bovine CGA with rat insulinoma secretory-granule lysate produced peptides of 18, 16 and 40 kDa via intermediates of 65 and 55 kDa. N-terminal sequence analysis indicated that cleavage occurred at the conserved paired basic sites Lys114-Arg115 and Lys330-Arg331, suggesting that cleavage of the equivalent sites (Lys129-Arg130 and Lys357-Arg358) in the rat molecule produced the initial post-translational products observed in intact pancreatic beta-cells. The enzyme activity responsible for the cleavage of bovine CGA co-chromatographed on DEAE-cellulose with the type-2 proinsulin endopeptidase and with PC2 immunoreactivity. The type-1 enzyme (PC1/3) appeared inactive towards CGA. The requirement for Ca2+ ions and an acidic pH for conversion was consistent with the involvement of a member of the eukaryote subtilisin family, and the composition of the released peptides in pulse-chase and secretion studies suggested that conversion occurred in the secretory-granule compartment. The overall catalytic rate as well as the relative susceptibilities of the Lys114-Arg115 and Lys330-Arg331 sites to cleavage were affected by pH, suggesting that the ionic environment of the processing compartment may play a role in the differential processing of CGA which is evident in various neuroendocrine cells.

scholarly journals A Protective Role for Interleukin-1 Signaling during Mouse Adenovirus Type 1-Induced Encephalitis

2016 ◽  
Vol 91 (4) ◽  
Author(s):  
Luiza A. Castro-Jorge ◽  
Carla D. Pretto ◽  
Asa B. Smith ◽  
Oded Foreman ◽  
Kelly E. Carnahan ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Time Course ◽  
Interleukin 1 ◽  
Adenovirus Type ◽  
Mouse Strains ◽  
Complex Nature ◽  
Type I ◽  
Viral Loads ◽  
The Brain

ABSTRACT Interleukin-1β (IL-1β), an inflammatory cytokine and IL-1 receptor ligand, has diverse activities in the brain. We examined whether IL-1 signaling contributes to the encephalitis observed in mouse adenovirus type 1 (MAV-1) infection, using mice lacking the IL-1 receptor (Il1r1 −/− mice). Il1r1 −/− mice demonstrated reduced survival, greater disruption of the blood-brain barrier (BBB), higher brain viral loads, and higher brain inflammatory cytokine and chemokine levels than control C57BL/6J mice. We also examined infections of mice defective in IL-1β production (Pycard −/− mice) and mice defective in trafficking of Toll-like receptors to the endosome (Unc93b1 −/− mice). Pycard −/− and Unc93b1 −/− mice showed lower survival (similar to Il1r1 −/− mice) than control mice but, unlike Il1r1 −/− mice, did not have increased brain viral loads or BBB disruption. Based on the brain cytokine levels, MAV-1-infected Unc93b1 −/− mice had a very different inflammatory profile from infected Il1r1 −/− and Pycard −/− mice. Histological examination demonstrated pathological findings consistent with encephalitis in control and knockout mice; however, intranuclear viral inclusions were seen only in Il1r1 −/− mice. A time course of infection of control and Il1r1 −/− mice evaluating the kinetics of viral replication and cytokine production revealed differences between the mouse strains primarily at 7 to 8 days after infection, when mice began succumbing to MAV-1 infection. In the absence of IL-1 signaling, we noted an increase in the transcription of type I interferon (IFN)-stimulated genes. Together, these results indicate that IL-1 signaling is important during MAV-1 infection and suggest that, in its absence, increased IFN-β signaling may result in increased neuroinflammation. IMPORTANCE The investigation of encephalitis pathogenesis produced by different viruses is needed to characterize virus and host-specific factors that contribute to disease. MAV-1 produces viral encephalitis in its natural host, providing a good model for studying factors involved in encephalitis development. We investigated the role of IL-1 signaling during MAV-1-induced encephalitis. Unexpectedly, the lack of IL-1 signaling increased the mortality and inflammation in mice infected with MAV-1. Also, there was an increase in the transcription of type I IFN-stimulated genes that correlated with the observed increased mortality and inflammation. The findings highlight the complex nature of encephalitis and suggests that IL-1 has a protective effect for the development of MAV-1-induced encephalitis.

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