Multi-scale Modeling and Sensitivity Analysis in Biological Systems

2021 ◽  
Author(s):  
◽  
An Do Dela

We develop a multi-method sensitivity framework, which incorporates two variance-based methods, namely Sobol's method, eFAST and Derivative-based global measures to identify which parameters are most influential to the model outputs. A new implementation version of eFAST, namely DeFAST, was developed to address some critical issues in an existing published algorithm. Sensitivity analysis is a powerful tool in the modeling process that can be leveraged in various ways including model reduction and model fitting to data. There are two novel models that have been developed in this work where sensitivity analysis was applied. A stochastic computational model was constructed to understand mechanistic division event in Caulobacter crecentus bacterium in order to investigate how precise measurements can be made at the micron scale in the face of stochastic fluctuations. In this context, sensitivity analysis is used to derive a minimal PDE model in a minimal intermittent-search framework that could capture key results of the computational model closely. In addition, a new single compartment mathematical model for type I diabetes was analyzed to understand which parameters are the main driver of the blood glucose dynamics with the intention to understand the curative potential of dendritic-cell-based vaccine therapies. In this case, the sensitivity analysis was used to rank parameters and reduce the parameter space so that we can calibrate the model with in-vivo data in the future. The novelty of this work is that we validate our sensitivity analysis approach on highly nonlinear and stochastic models. These complex models present significant challenges for the application of sensitivity analysis algorithms as compared to the simpler case-study models that are typically used for testing sensitivity analysis methods.

2019 ◽  
Vol 18 (1) ◽  
pp. 133-143 ◽  
Author(s):  
Arjun Jain ◽  
Vidhi Mehrotra ◽  
Ira Jha ◽  
Ashok Jain

2021 ◽  
Author(s):  
Ariel Galindo-Albarrán ◽  
Sarah Castan ◽  
Jérémy C. Santamaria ◽  
Olivier P. Joffre ◽  
Bart Haegeman ◽  
...  

Regulatory T lymphocytes expressing the forkhead/winged helix transcription factor Foxp3 (Treg) play a vital role in the protection of the organism from autoimmune disease and other immunopathologies. The antigen-specificity of Treg plays an important role in their <i>in vivo</i> activity. We therefore assessed the diversity of the T cell receptors for antigen (TCR) expressed by Treg newly developed in the thymus of autoimmune type I diabetes-prone NOD mice and compared it to the control mouse strain C57BL/6. Our results demonstrate that usage of the TCRa and TCRb variable (V) and joining (J) segments, length of the complementarity determining region (CDR) 3, and the diversity of the TCRa and TCRb chains are comparable between NOD and C57BL/6 mice. Genetic defects affecting the diversity of the TCR expressed by newly developed Treg therefore do not appear to be involved in the etiology of type I diabetes in the NOD mouse.


2008 ◽  
Vol 294 (5) ◽  
pp. H2204-H2211 ◽  
Author(s):  
Ian P. Luttrell ◽  
Mei Swee ◽  
Barry Starcher ◽  
William C. Parks ◽  
Kanchan Chitaley

The number of men with type II diabetes-associated erectile dysfunction (ED) continues to grow rapidly; however, the majority of basic science studies has examined mechanisms of ED in animal models of type I diabetes. In this study, we first establish an in vivo mouse model of type II diabetic ED using the leptin receptor mutated db/ db and wild-type control BKS mouse. Furthermore, we hypothesized that dual mechanistic impairments contribute to the impaired erectile function in the type II diabetic mouse, altered vasoreactivity, and venoocclusive disorder. In vivo erectile function was measured as intracavernosal pressure (ICP) normalized to mean arterial pressure (MAP) following electrical stimulation of the cavernosal nerve. Venoocclusion was assessed by the maintenance of elevated in vivo ICP following intracorporal saline infusion. Vasoreactivity of isolated cavernosum in response to contractile and dilatory stimulation was examined in vitro by myography. Collagen and elastin content were evaluated by quantification of hydroxyproline and desmosine, respectively, as well as by quantitative PCR and histological analysis of isolated cavernosum. Erectile function was significantly decreased in db/ db vs. BKS mice in a manner consistent with impairments in venoocclusive ability and decreased inflow. Heightened vasoconstriction and attenuated dilation in cavernosum of db/ db vs. BKS mice suggest an overall lowered relaxation ability and thus impaired filling of the cavernosal spaces. A decrease in desmosine and hydroxyproline as well as lowered mRNA levels for tropoelastin, fibrillin-1, and α1(I) collagen were detected. These vasoreactive and sinusoidal matrix alterations may alter tissue compliance dispensability, preventing the normal expansion necessary for erection.


Author(s):  
Ryo Ikegami ◽  
Hiroaki Eshima ◽  
Toshiaki Nakajima ◽  
Shigeru Toyoda ◽  
David C. Poole ◽  
...  

Heat stress, via its effects on muscle intracellular Ca2+ concentrations ([Ca2+]i), has been invoked as a putative therapeutic countermeasure to Type 1 diabetes-induced muscle atrophy. Using in vivo muscle preparation we tested the hypothesis that impaired muscle Ca2+ homeostasis in type I diabetic rats is due to attenuated heat stress tolerance mediated via TRPV1. Male Wistar rats were assigned to 1 of 4 groups: 1.control 30oC (CONT 30oC), 2.CONT 40oC, 3.diabetes 30oC (DIA 30oC), 4.DIA 40oC. 40oC was selected because it just exceeds the TRPV1 activation threshold. Spinotrapezius muscles were exteriorized in vivo and loaded with the fluorescent Ca2+ probe Fura-2AM. [Ca2+]i was estimated over 20min using fluorescence microscopy in quiescent muscle held at the required temperature using calibrated heat source applied to the ventral muscle surface. Western blotting was performed to determine the protein expression levels of TRPV1 in spinotrapezius muscle. After 20min of heat stress, the CONT 40oC condition induced a 12.3% [Ca2+]i elevation that was absent from the DIA 40oC or other conditions. Thus, no significant differences were found among DIA 40oC, DIA 30oC and CONT 30oC. TRPV1 protein expression was decreased by 42.0% in DIA compared with CONT (P<0.05) and, unlike CONT, heat stress did not increase TRPV1 phosphorylation. In conclusion, diabetes suppresses TRPV1 protein expression and function and inhibits the elevated myocyte [Ca2+]i evoked normally by heat stress. These results suggest that capsaicin or other therapeutic strategies to increase Ca2+ accumulation via TRPV1 might be more effective than hyperthermic therapy for Type I diabetic patients.


1994 ◽  
Vol 131 (4) ◽  
pp. 431-437 ◽  
Author(s):  
Alberto Signore ◽  
Marco Chianelli ◽  
Elisabetta Ferretti ◽  
Anna Toscano ◽  
Keith E Britton ◽  
...  

Signore A, Chianelli M, Ferretti E, Toscano A, Britton KE, Andreani D, Gale EAM, Pozzilli P. New approach for in vivo detection of insulitis in type I diabetes: activated lymphocyte targeting with 123I-labelled interleukin 2. Eur J Endocrinol 1994;131:431–7. ISSN 0804–4643 Insulitis is considered the histopathological hallmark of type I (insulin-dependent) diabetes. In the nonobese diabetic (NOD) mouse, diabetes has never been observed in the absence of insulitis. The in vivo detection of insulitis could be of relevance for early prediction of diabetes. As approximately 15% of islet-infiltrating lymphocytes express interleukin 2 receptors, we have labelled recombinant interleukin 2 with 123I and used this radiopharmaceutical to detect insulitis by gamma camera imaging. We studied 71 prediabetic NOD and 27 normal Balb/c mice. Labelled α-lactalbumin was used as the control protein. In the first set of experiments we studied the tissue distribution of radiolabelled interleukin 2 in isolated organs from animals sacrificed at different time points. Higher radioactivity was detected in the pancreas of NOD mice injected with labelled interleukin 2, as compared to NOD mice receiving labelled α-lactalbumin (p < 0.003 at 20 min; p< 0.001 at 40 min; p< 0.0001 at 60 min) or Balb/c mice injected with labelled interleukin 2 (p< 0.05 at 40 min; p< 0.001 at 60 min). In another set of experiments, gamma camera images have been acquired after injection of 123I-labelled interleukin 2. Radioactivity in the pancreatic region of prediabetic NOD and Balb/c mice showed similar kinetics to those observed by single organ counting, with higher accumulation in the pancreatic region of NOD mice (p < 0.04 after 22–45 min in NOD mice vs Balb/c mice). Finally, a positive correlation was found between the radioactivity in the pancreas and the extent of lymphocytic infiltration (p < 0.01 for pancreas radioactivity counted in vitro and p< 0.004 for pancreas radioactivity counted in vivo by gamma camera). This study demonstrates that 123I-labelled interleukin 2 administered iv accumulates specifically in the inflamed pancreas of diabetes-prone NOD mice, suggesting its potential application in human insulin-dependent diabetes mellitus. A Signore, Servizio Speciale di Medicina Nucleare, II Clinica Medica, Policlinico Umberto I, 00161 Roma, Italy


2008 ◽  
Vol 198 (3) ◽  
pp. 581-589 ◽  
Author(s):  
Jon G Mabley ◽  
Pal Pacher ◽  
Kanneganti G K Murthy ◽  
William Williams ◽  
Garry J Southan ◽  
...  

Endogenous purines including inosine have been shown to exert immunomodulatory and anti-inflammatory effects in a variety of disease models. The dosage of inosine required for protection is very high because of the rapid metabolism of inosine in vivo. The aim of this study was to determine whether a metabolic-resistant purine analogue, INO-2002, exerts anti-inflammatory effects in two animal models of type I diabetes. Type I diabetes was induced chemically with streptozotocin or genetically using the non-obese diabetic (NOD) female mouse model. Mice were treated with INO-2002 or inosine as required at 30, 100, or 200 mg/kg per day, while blood glucose and diabetes incidence were monitored. The effect of INO-2002 on the pancreatic cytokine profile was also determined. INO-2002 reduced both the hyperglycaemia and incidence of diabetes in both streptozotocin-induced and spontaneous diabetes in NOD mice. INO-2002 proved to be more effective in protecting against diabetes than the naturally occurring purine, inosine, when administered at the same dose. INO-2002 treatment decreased pancreatic levels of interleukin (IL)-12 and tumour necrosis factor-α, while increasing levels of IL-4 and IL-10. INO-2002 also reduced pancreatic levels of the chemokine MIP-1α. The inosine analogue, INO-2002, was protected more effectively than the naturally occurring purine, inosine, against development of diabetes in two separate animal models. INO-2002 exerts protective effects by changing the pancreatic cytokine expression from a destructive Th1 to a protective Th2 profile. The use of analogues of inosine such as INO-2002 should be considered as a potential preventative therapy in individuals susceptible to developing type I diabetes.


2011 ◽  
Vol 53 (3) ◽  
pp. 348-357 ◽  
Author(s):  
Jan Freark de Boer ◽  
Wijtske Annema ◽  
Marijke Schreurs ◽  
Jelske N. van der Veen ◽  
Markus van der Giet ◽  
...  

1985 ◽  
Vol 61 (2) ◽  
pp. 247-251 ◽  
Author(s):  
A. PERNET ◽  
E. R. TRIMBLE ◽  
F. KUNTSCHEN ◽  
J.-Ph. ASSAL ◽  
C. HAHN ◽  
...  

2019 ◽  
Author(s):  
Nsrein Ali ◽  
Hamid Reza Rezvani ◽  
Diana Motei ◽  
Sufyan Suleman ◽  
Walid Mahfouf ◽  
...  

AbstractCoping with diabetes requires frequent and even today mostly invasive blood glucose-based monitoring. Partly due to this invasive nature and the associated reduced skin wound healing and increased risk of infection, non-invasive glucose monitoring technologies would represent considerable progress. Edited keratinocytes may enable such a function.To address this hypothesis, we conducted a proteomic screen in the skin by making use of the experimental in vivo mouse model of type I diabetes alongside controls. We identified Trisk 95 as the only protein whose expression is induced in response to high blood glucose. A luciferase reporter assay demonstrated that induction of Trisk 95 expression occurs not only at the protein level but also transcriptionally. This induction was associated with a marked elevation in the Fluo-4 signal, suggesting a role for intracellular calcium changes in the signalling cascade. Strikingly, these changes lead concurrently to fragmentation of the mitochondria. As judged from the knockout findings, both the calcium flux and the mitochondrial phenotype were dependent on Trisk 95 function, since the phenotypes in question were abolished.The data demonstrate that the skin represents an organ that reacts robustly and thus mirrors changes in systemic blood glucose levels. The findings are also consistent with a channelling model of Trisk 95 that serves as an insulin-independent but glucose-responsive biomarker taking part in releasing calcium from the cellular stores in the skin. The skin cells may thus provide a novel mean for glucose monitoring when analysing changes in labelled Trisk 95 and calcium. By that, this study is the first proof of the concept of our registered patent (No. PCT FI2016/050917), which proposes the use of cells as biosensors for developing personalized health-monitoring devices.


2008 ◽  
Vol 87 (2) ◽  
pp. 178-185 ◽  
Author(s):  
Eveline Angstetra ◽  
Kate L Graham ◽  
Sarah Emmett ◽  
Nadine L Dudek ◽  
Rima Darwiche ◽  
...  

Sign in / Sign up

Export Citation Format

Share Document