Multi-Scale Modeling of Antigen Presentation With Applications to Tuberculosis.

Antigen presentation is the process by which cells of the immune system display peptides from pathogens on their surface after binding the peptides to major histocompatibility complex (MHC) molecules. T helper cells recognize peptides from pathogens in this context then secrete cytokines that activate other cells, initiating an immune response. Antigen presentation is therefore a requisite for immunity to several pathogens including Mycobacterium tuberculosis (Mtb). To approach questions related to antigen presentation and disease, I represented antigen presentation at different scales using a series of mathematical and statistical models. At the molecular scale, I asked whether heterogeneity in peptide length affects binding to MHC class II, the class of MHC responsible for binding peptides from bacteria such as Mtb. By developing statistical models of peptide-MHC binding, I found that length has a nonlinear effect on binding affinity and that this information, or a more accurate representation of register shifting, could improve the accuracy of binding prediction. At the cellular scale, I asked why Mtb possesses multiple mechanisms to inhibit antigen presentation on the cell surface. My mathematical model shows that these mechanisms may be acting on different timescales and therefore complementary rather than merely redundant. Finally, at the multi-cellular level, I asked how polymorphisms in multiple genes related to antigen presentation might affect T cell response and susceptibility to infectious diseases such as tuberculosis. Using a multi-scale model representing both an antigen-presenting cell and T cell, I found that polymorphisms in two different genes may exert the same influence on the output, potentially canceling out their effects. Future work with these models may include evaluation of candidate peptide-based vaccines to ensure high-affinity binding, T cell response, and broad efficacy in diverse populations.Ph.D.BioinformaticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/57605/2/stchang_1.pd

Dynamical chiral symmetry breaking and a critical mass

On a bounded, measurable domain of non-negative current-quark mass, realistic models of QCD's gap equation can simultaneously admit two inequivalent dynamical chiral symmetry breaking (DCSB) solutions and a solution that is unambiguously connected with the realisation of chiral symmetry in the Wigner mode. The Wigner solution and one of the DCSB solutions are destabilised by a current-quark mass and both disappear when that mass exceeds a critical value. This critical value also bounds the domain on which the surviving DCSB solution possesses a chiral expansion. This value can therefore be viewed as an upper bound on the domain within which a perturbative expansion in the current-quark mass around the chiral limit is uniformly valid for physical quantities. For a pseudoscalar meson constituted of equal mass current-quarks, it corresponds to a mass m_{0^-}~0.45GeV. In our discussion we employ properties of the two DCSB solutions of the gap equation that enable a valid definition of in the presence of a nonzero current-mass. The behaviour of this condensate indicates that the essentially dynamical component of chiral symmetry breaking decreases with increasing current-quark mass.Comment: 9 pages, 7 figures. Minor wording change

A chemokine gene expression signature derived from meta-analysis predicts the pathogenicity of viral respiratory infections

<p>Abstract</p> <p>Background</p> <p>During respiratory viral infections host injury occurs due in part to inappropriate host responses. In this study we sought to uncover the host transcriptional responses underlying differences between high- and low-pathogenic infections.</p> <p>Results</p> <p>From a compendium of 12 studies that included responses to influenza A subtype H5N1, reconstructed 1918 influenza A virus, and SARS coronavirus, we used meta-analysis to derive multiple gene expression signatures. We compared these signatures by their capacity to segregate biological conditions by pathogenicity and predict pathogenicity in a test data set. The highest-performing signature was expressed as a continuum in low-, medium-, and high-pathogenicity samples, suggesting a direct, analog relationship between expression and pathogenicity. This signature comprised 57 genes including a subnetwork of chemokines, implicating dysregulated cell recruitment in injury.</p> <p>Conclusions</p> <p>Highly pathogenic viruses elicit expression of many of the same key genes as lower pathogenic viruses but to a higher degree. This increased degree of expression may result in the uncontrolled co-localization of inflammatory cell types and lead to irreversible host damage.</p

Decitabine impact on the endocytosis regulator RhoA, the folate carriers RFC1 and FOLR1, and the glucose transporter GLUT4 in human tumors.

BackgroundIn 31 solid tumor patients treated with the demethylating agent decitabine, we performed tumor biopsies before and after the first cycle of decitabine and used immunohistochemistry (IHC) to assess whether decitabine increased expression of various membrane transporters. Resistance to chemotherapy may arise due to promoter methylation/downregulation of expression of transporters required for drug uptake, and decitabine can reverse resistance in vitro. The endocytosis regulator RhoA, the folate carriers FOLR1 and RFC1, and the glucose transporter GLUT4 were assessed.ResultsPre-decitabine RhoA was higher in patients who had received their last therapy &gt;3&nbsp;months previously than in patients with more recent prior therapy (P = 0.02), and varied inversely with global DNA methylation as assessed by LINE1 methylation (r = -0.58, P = 0.006). Tumor RhoA scores increased with decitabine (P = 0.03), and RFC1 also increased in patients with pre-decitabine scores ≤150 (P = 0.004). Change in LINE1 methylation with decitabine did not correlate significantly with change in IHC scores for any transporter assessed. We also assessed methylation of the RFC1 gene (alias SLC19A1). SLC19A1 methylation correlated with tumor LINE1 methylation (r = 0.45, P = 0.02). There was a small (statistically insignificant) decrease in SLC19A1 methylation with decitabine, and there was a trend towards change in SLC19A1 methylation with decitabine correlating with change in LINE1 methylation (r = 0.47, P &lt;0.15). While SLC19A1 methylation did not correlate with RFC1 scores, there was a trend towards an inverse correlation between change in SLC19A1 methylation and change in RFC1 expression (r = -0.45, P = 0.19).ConclusionsIn conclusion, after decitabine administration, there was increased expression of some (but not other) transporters that may play a role in chemotherapy uptake. Larger patient numbers will be needed to define the extent to which this increased expression is associated with changes in DNA methylation

Statistics of Coulomb blockade peak spacings for a partially open dot

We show that randomness of the electron wave functions in a quantum dot contributes to the fluctuations of the positions of the conductance peaks. This contribution grows with the conductance of the junctions connecting the dot to the leads. It becomes comparable with the fluctuations coming from the randomness of the single particle spectrum in the dot while the Coulomb blockade peaks are still well-defined. In addition, the fluctuations of the peak spacings are correlated with the fluctuations of the conductance peak heights.Comment: 13 pages, 1 figur

Small contribution of gold mines to the ongoing tuberculosis epidemic in South Africa: a modeling-based study.

BACKGROUND: Gold mines represent a potential hotspot for Mycobacterium tuberculosis (Mtb) transmission and may be exacerbating the tuberculosis (TB) epidemic in South Africa. However, the presence of multiple factors complicates estimation of the mining contribution to the TB burden in South Africa. METHODS: We developed two models of TB in South Africa, a static risk model and an individual-based model that accounts for longer-term trends. Both models account for four populations - mine workers, peri-mining residents, labor-sending residents, and other residents of South Africa - including the size and prevalence of latent TB infection, active TB, and HIV of each population and mixing between populations. We calibrated to mine- and country-level data and used the static model to estimate force of infection (FOI) and new infections attributable to local residents in each community compared to other residents. Using the individual-based model, we simulated a counterfactual scenario to estimate the fraction of overall TB incidence in South Africa attributable to recent transmission in mines. RESULTS: We estimated that the majority of FOI in each community is attributable to local residents: 93.9% (95% confidence interval 92.4-95.1%), 91.5% (91.4-91.5%), and 94.7% (94.7-94.7%) in gold mining, peri-mining, and labor-sending communities, respectively. Assuming a higher rate of Mtb transmission in mines, 4.1% (2.6-5.8%), 5.0% (4.5-5.5%), and 9.0% (8.8-9.1%) of new infections in South Africa are attributable to gold mine workers, peri-mining residents, and labor-sending residents, respectively. Therefore, mine workers with TB disease, who constitute ~ 2.5% of the prevalent TB cases in South Africa, contribute 1.62 (1.04-2.30) times as many new infections as TB cases in South Africa on average. By modeling TB on a longer time scale, we estimate 63.0% (58.5-67.7%) of incident TB disease in gold mining communities to be attributable to recent transmission, of which 92.5% (92.1-92.9%) is attributable to local transmission. CONCLUSIONS: Gold mine workers are estimated to contribute a disproportionately large number of Mtb infections in South Africa on a per-capita basis. However, mine workers contribute only a small fraction of overall Mtb infections in South Africa. Our results suggest that curtailing transmission in mines may have limited impact at the country level, despite potentially significant impact at the mining level

What explains the uneven take-up of ISO 14001 at the global level?: a panel-data analysis

Since its release in the mid-1990s, close to 37 000 facilities have been certified to ISO 14001, the international voluntary standard for environmental management systems. Yet, despite claims that the standard can be readily adapted to very different corporate and geographic settings, its take-up has been highly geographically variable. This paper contributes to a growing body of work concerned with explaining the uneven diffusion of ISO 14001 at the global level. Drawing from the existing theoretical and empirical literature we develop a series of hypotheses about how various economic, market, and regulatory factors influence the national count of ISO 14001 certifications. These hypotheses are then tested using econometric estimation techniques with data for a panel of 142 developed and developing countries. We find that per capita ISO 14001 counts are positively correlated with income per capita, stock of foreign direct investment, exports of goods and services to Europe and Japan, and pressure from civil society. Conversely, productivity and levels of state intervention are negatively correlated. The paper finishes by offering a number of recommendations to policymakers concerned with accelerating the diffusion of voluntary environmental standards

Eosinophil and T Cell Markers Predict Functional Decline in COPD Patients

BACKGROUND. The major marker utilized to monitor COPD patients is forced expiratory volume in one second (FEV1). However, asingle measurement of FEV1 cannot reliably predict subsequent decline. Recent studies indicate that T lymphocytes and eosinophils are important determinants of disease stability in COPD. We therefore measured cytokine levels in the lung lavage fluid and plasma of COPD patients in order to determine if the levels of T cell or eosinophil related cytokines were predictive of the future course of the disease. METHODS. Baseline lung lavage and plasma samples were collected from COPD subjects with moderately severe airway obstruction and emphysematous changes on chest CT. The study participants were former smokers who had not had a disease exacerbation within the past six months or used steroids within the past two months. Those subjects who demonstrated stable disease over the following six months (ΔFEV1 % predicted = 4.7 ± 7.2; N = 34) were retrospectively compared with study participants who experienced a rapid decline in lung function (ΔFEV1 % predicted = -16.0 ± 6.0; N = 16) during the same time period and with normal controls (N = 11). Plasma and lung lavage cytokines were measured from clinical samples using the Luminex multiplex kit which enabled the simultaneous measurement of several T cell and eosinophil related cytokines. RESULTS AND DISCUSSION. Stable COPD participants had significantly higher plasma IL-2 levels compared to participants with rapidly progressive COPD (p = 0.04). In contrast, plasma eotaxin-1 levels were significantly lower in stable COPD subjects compared to normal controls (p < 0.03). In addition, lung lavage eotaxin-1 levels were significantly higher in rapidly progressive COPD participants compared to both normal controls (p < 0.02) and stable COPD participants (p < 0.05). CONCLUSION. These findings indicate that IL-2 and eotaxin-1 levels may be important markers of disease stability in advanced emphysema patients. Prospective studies will need to confirm whether measuring IL-2 or eotaxin-1 can identify patients at risk for rapid disease progression.National Heart, Lung, and Blood Institute (NO1-HR-96140, NO1-HR-96141-001, NO1-HR-96144, NO1-HR-96143; NO1-HR-96145; NO1-HR-96142, R01HL086936-03); The Flight Attendant Medical Research Institute; the Jo-Ann F. LeBuhn Center for Chest Diseas