Tuneable resolution as a systems biology approach for multi-scale, multi-compartment computational models

The use of multi-scale mathematical and computational models to study complex biological processes is becoming increasingly productive. Multi-scale models span a range of spatial and/or temporal scales and can encompass multi-compartment (e.g., multi-organ) models. Modeling advances are enabling virtual experiments to explore and answer questions that are problematic to address in the wet-lab. Wet-lab experimental technologies now allow scientists to observe, measure, record, and analyze experiments focusing on different system aspects at a variety of biological scales. We need the technical ability to mirror that same flexibility in virtual experiments using multi-scale models. Here we present a new approach, tuneable resolution, which can begin providing that flexibility. Tuneable resolution involves fine- or coarse-graining existing multi-scale models at the user's discretion, allowing adjustment of the level of resolution specific to a question, an experiment, or a scale of interest. Tuneable resolution expands options for revising and validating mechanistic multi-scale models, can extend the longevity of multi-scale models, and may increase computational efficiency. The tuneable resolution approach can be applied to many model types, including differential equation, agent-based, and hybrid models. We demonstrate our tuneable resolution ideas with examples relevant to infectious disease modeling, illustrating key principles at work. WIREs Syst Biol Med 2014, 6:225–245. doi:10.1002/wsbm.1270 How to cite this article: WIREs Syst Biol Med 2014, 6:289–309. doi:10.1002/wsbm.127

Daidzein Prevents the Increase in CD4+CD28null T Cells and B Lymphopoesis in Ovariectomized Mice: A Key Mechanism for Anti-Osteoclastogenic Effect

Estrogen deficiency leads to an upregulation of TNF-α producing T cells and B-lymphopoesis which augments osteoclastogenesis. Estrogen deficiency also increases the population of premature senescent CD4+CD28null T cells which secrete a higher amount of TNF-α thus leading to enhanced osteoclastogenesis. Isoflavonoids like daidzein and genistein are found mostly in soybeans, legumes, and peas. These share structural similarity with 17β-stradiol (E2) and have osteoprotective role. This study explores the effect of daidzein (Daid) on the proliferation of TNF-α producing T cells, premature senescent T cells and B cell lymphopoesis under estrogen deficient conditions. For this study adult Balb/c mice were treated with Daid at 10 mg/kg body weight dose by oral gavage daily post ovariectomy (Ovx). After six weeks animals were autopsied and bone marrow and spleen cells were collected for FACS analysis. Blood serum was collected for ELISA. It was observed that Ovx mice treated with Daid for six weeks show reduction in Ovx induced expansion of CD4+ T cells in bone marrow and spleen when analysed by flow cytometry. Estrogen deficiency led to increased prevalence of TNF-α secreting CD4+CD28null T cells, however, treatment with Daid increased the percentage of CD4+CD28+ T cells. Co-culture of CD4+CD28null T cells and bone marrow resulted in enhanced osteoclastogenesis as evident by increased tartarate resistant acid phosphatase (TRAP) expression, an osteoclast marker. However, treatment with Daid resulted in reduced osteoclastogenesis in CD4+CD28null T cells and bone marrow cell co-culture. Daid also regulated B lymphopoesis and decreased mRNA levels of RANKL in B220+ cells. Taken together, we propose that one of the mechanisms by which Daid prevents bone loss is by reversing the detrimental immune changes as a result of estrogen deficiency

Regulatory T Cells Suppress T Cell Activation at the Pathologic Site of Human Visceral Leishmaniasis

Suppression of T cell response is thought to be involved in the pathogenesis of visceral leishmaniasis (VL). Regulatory T cell (Treg) mediated immune-suppression is reported in animal models of Leishmania infection. However, their precise role among human patients still requires pathologic validation. The present study is aimed at understanding the frequency dynamics and function of Treg cells in the blood and bone marrow (BM) of VL patients. The study included 42 parasitologically confirmed patients, 17 healthy contact and 9 normal bone marrow specimens (NBM). We show i) the selective accumulation of Treg cells at one of the disease inflicted site(s), the BM, ii) their in vitro expansion in response to LD antigen and iii) persistence after successful chemotherapy. Results indicate that the Treg cells isolated from BM produces IL-10 and may inhibit T cell activation in IL-10 dependent manner. Moreover, we observed significantly higher levels of IL-10 among drug unresponsive patients, suggesting their critical role in suppression of immunity among VL patients. Our results suggest that IL-10 plays an important role in suppression of host immunity in human VL and possibly determines the efficacy of chemotherapy

Central IKKβ inhibition prevents air pollution mediated peripheral inflammation and exaggeration of type II diabetes

Abstract Background Prior experimental and epidemiologic data support a link between exposure to fine ambient particulate matter (<2.5 μm in aerodynamic diameter, PM2.5) and development of insulin resistance/Type II diabetes mellitus (Type II DM). We investigated the role of hypothalamic inflammation in PM2.5-mediated diabetes development. Methods KKay mice, a genetically susceptible model of Type II DM, were assigned to either concentrated PM2.5 or filtered air (FA) for 4–8 weeks via a versatile aerosol concentrator and exposure system, or administered intra-cerebroventricular with either IKKβ inhibitor (IMD-0354) or TNFα antibody (infliximab) for 4–5 weeks simultaneously with PM2.5 exposure. Glucose tolerance, insulin sensitivity, oxygen consumption and heat production were evaluated. At euthanasia, blood, spleen, visceral adipose tissue and hypothalamus were collected to measure inflammatory cells using flow cytometry. Standard immunohistochemical methods and quantitative PCR were used to assess targets of interest. Results PM2.5 exposure led to hyperglycemia and insulin resistance, which was accompanied by increased hypothalamic IL-6, TNFα, and IKKβ mRNA expression and microglial/astrocyte reactivity. Targeting the NFκB pathway with intra-cerebroventricular administration of an IKKβ inhibitor [IMD-0354, n = 8 for each group)], but not TNFα blockade with infliximab [(n = 6 for each group], improved glucose tolerance, insulin sensitivity, rectified energy homeostasis (O2 consumption, CO2 production, respiratory exchange ratio and heat generation) and reduced peripheral inflammation in response to PM2.5. Conclusions Central inhibition of IKKβ prevents PM2.5 mediated peripheral inflammation and exaggeration of type II diabetes. These results provide novel insights into how air pollution may mediate susceptibility to insulin resistance and Type II DM.http://deepblue.lib.umich.edu/bitstream/2027.42/109486/1/12989_2014_Article_53.pd

Methods of model reduction for large-scale biological systems: a survey of current methods and trends

Complex models of biochemical reaction systems have become increasingly common in the systems biology literature. The complexity of such models can present a number of obstacles for their practical use, often making problems difficult to intuit or computationally intractable. Methods of model reduction can be employed to alleviate the issue of complexity by seeking to eliminate those portions of a reaction network that have little or no effect upon the outcomes of interest, hence yielding simplified systems that retain an accurate predictive capacity. This review paper seeks to provide a brief overview of a range of such methods and their application in the context of biochemical reaction network models. To achieve this, we provide a brief mathematical account of the main methods including timescale exploitation approaches, reduction via sensitivity analysis, optimisation methods, lumping, and singular value decomposition-based approaches. Methods are reviewed in the context of large-scale systems biology type models, and future areas of research are briefly discussed

Investigations of optoelectronic properties in DMS SnO2 nanoparticles

M–H curve of SnO2 nanoparticles calcinated at 400°C and 600°C. [Display omitted] •The room temperature ferromagnetism has been observed in SnO2 nanoparticles.•The band gap shows a blue shift with increasing calcinations temperature.•The particle size and shape changes after calcination at different temperatures. The structural, optical and magnetic properties of SnO2 nanoparticles synthesized by co-precipitation technique at different calcination temperatures have been investigated. The calcination affects the luminescence and morphological properties of SnO2 nanoparticles. The defects and vacancies formed during synthesis processes which are responsible for photoluminescence and magnetic properties in SnO2 nanoparticles. The band gap shows a blue shift with increasing calcination temperature but shows a red shift compared to bulk SnO2. The calcination temperature affects the particle shape and size of the synthesized samples. The room temperature ferromagnetism has been observed which indicates SnO2 behave like a dilute magnetic semiconductor material (DMS). The photoluminescence (PL) emission spectra show the blue and green emissions at different calcination temperatures