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At least 793 records · Page 44
All sourcesNASA NTRSDOE OSTI
DOE OSTI2015

The temporal patterns of disease severity and prevalence in schistosomiasis

Schistosomiasis is one of the most widespread public health problems in the world. In this work, we introduce an eco-epidemiological model for its transmission and dynamics with the purpose of explaining both intra- and inter-annual fluctuations of disease severity and prevalence. The model takes the form of a system of nonlinear differential equations that incorporate biological complexity associated with schistosome's life cycle, including a prepatent period in snails (i.e., the time between initial infection and onset of infectiousness). Nonlinear analysis is used to explore the parametric conditions that produce different temporal patterns (stationary, endemic, periodic, and chaotic). For the time-invariant model, we identify a transcritical and a Hopf bifurcation in the space of the human and snail infection parameters. The first corresponds to the occurrence of an endemic equilibrium, while the latter marks the transition to interannual periodic oscillations. We then investigate a more realistic time-varying model in which fertility of the intermediate host population is assumed to seasonally vary. We show that seasonality can give rise to a cascade of period-doubling bifurcations leading to chaos for larger, though realistic, values of the amplitude of the seasonal variation of fertility.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
DOE OSTI2015

Microsecond-pulsed dielectric barrier discharge plasma stimulation of tissue macrophages for treatment of peripheral vascular disease

Angiogenesis is the formation of new blood vessels from pre-existing vessels and normally occurs during the process of inflammatory reactions, wound healing, tissue repair, and restoration of blood flow after injury or insult. Stimulation of angiogenesis is a promising and an important step in the treatment of peripheral artery disease. Reactive oxygen species have been shown to be involved in stimulation of this process. For this reason, we have developed and validated a non-equilibrium atmospheric temperature and pressure short-pulsed dielectric barrier discharge plasma system, which can non-destructively generate reactive oxygen species and other active species at the surface of the tissue being treated. We show that this plasma treatment stimulates the production of vascular endothelial growth factor, matrix metalloproteinase-9, and CXCL 1 that in turn induces angiogenesis in mouse aortic rings in vitro. This effect may be mediated by the direct effect of plasma generated reactive oxygen species on tissue.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Impact of Nd : YAG laser radiation (λ = 1.44 mm) on myocardial tissue in the treatment of coronary heart disease by transmyocardial laser revascularisation

We have studied the impact of Nd : YAG laser radiation with a wavelength of λ = 1.44 μm on the myocardial tissue for the formation of channels in the treatment of coronary heart disease by transmyocardial laser revascularisation (TMLR). The mechanism of perforation of the myocardial tissue by a laser pulse is presented and an experimental setup for TMLR is developed. In experiments on biological objects, the optimal parameters of radiation energy and duration necessary for the formation of channels of a given size in a single laser pulse are determined. The exposure regime ensures the adequate character of myocardial tissue destruction, assessed by such criteria as the perforation force, exposure energy, size of the coagulation zone, and level of carbonisation. (laser medicine)

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2025

Uncovering heterogeneous intercommunity disease transmission from neutral allele frequency time series

The COVID-19 pandemic has underscored the need for accurate epidemic forecasting to predict pathogen spread, evolution, and evaluate intervention strategies. Forecast reliability hinges on detailed knowledge of disease transmission across population segments, which may be inferred from contact surveys or mobility data. However, these indirect approaches make it difficult to estimate rare transmissions between socially or geographically distant communities. We show that the steep ramp-up of genome sequencing surveillance during the pandemic can be leveraged to directly identify transmission patterns between geographically defined communities. Our approach uses a hidden Markov model to infer the fraction of infections a community imports from others based on how rapidly allele frequencies in the focal community converge to those in the donor communities. Applying this method to SARS-CoV-2 sequencing data from England and the United States, we uncover networks of intercommunity transmission that reflect geographical relationships while exposing significant long-range interactions. The scaling of importation rate with distance is consistent across both countries, yet weaker than expected based on mobility data, highlighting limitations of indirect inference. We show that transmission patterns can change between waves of variants of concern and analyze how the inferred heterogeneity in intercommunity transmission impacts evolutionary forecasts. While applied here to geographically defined communities, our approach could be applied to those defined by other traits (e.g., age, socioeconomic status), provided time-series data can be stratified accordingly. Overall, our study highlights population genomic time series data as a crucial record of epidemiological interactions, which can be deciphered using tree-free inference methods.

Okada, Takashi [Department of Physics; University ↗
DOE OSTI2023

Characterization of Humoral Responses to Nipah Virus Infection in the Syrian Hamster Model of Disease

Abstract Nipah virus (NiV) is a highly pathogenic paramyxovirus. The Syrian hamster model recapitulates key features of human NiV disease and is a critical tool for evaluating antivirals and vaccines. Here we describe longitudinal humoral immune responses in NiV-infected Syrian hamsters. Samples were obtained 1–28 days after infection and analyzed by ELISA, neutralization, and Fc-mediated effector function assays. NiV infection elicited robust antibody responses against the nucleoprotein and attachment glycoprotein. Levels of neutralizing antibodies were modest and only detectable in surviving animals. Fc-mediated effector functions were mostly observed in nucleoprotein-targeting antibodies. Antibody levels and activities positively correlated with challenge dose.

Immunology↗
DOE OSTI2013

Trapping volumetric measurement by multidetector CT in chronic obstructive pulmonary disease: Effect of CT threshold

Purpose: The purpose of this study was to evaluate the effect of various computed tomography (CT) thresholds on trapping volumetric measurements by multidetector CT in chronic obstructive pulmonary disease (COPD).Methods: Twenty-three COPD patients were scanned with a 64-slice CT scanner in both the inspiratory and expiratory phase. CT thresholds of −950 Hu in inspiration and −950 to −890 Hu in expiration were used, after which trapping volumetric measurements were made using computer software. Trapping volume percentage (Vtrap%) under the different CT thresholds in the expiratory phase and below −950 Hu in the inspiratory phase was compared and correlated with lung function.Results: Mean Vtrap% was similar under −930 Hu in the expiratory phase and below −950 Hu in the inspiratory phase, being 13.18 ± 9.66 and 13.95 ± 6.72 (both lungs), respectively; this difference was not significant (P= 0.240). Vtrap% under −950 Hu in the inspiratory phase and below the −950 to −890 Hu threshold in the expiratory phase was moderately negatively correlated with the ratio of forced expiratory volume in one second to forced vital capacity and the measured value of forced expiratory volume in one second as a percentage of the predicted value.Conclusions: Trapping volumetric measurement with multidetector CT is a promising method for the quantification of COPD. It is important to know the effect of various CT thresholds on trapping volumetric measurements.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2014

Poster — Thur Eve — 03: Application of the non-negative matrix factorization technique to [{sup 11}C]-DTBZ dynamic PET data for the early detection of Parkinson's disease

In this work, a class of non-negative matrix factorization (NMF) technique known as alternating non-negative least squares, combined with the projected gradient method, is used to analyze twenty-five [{sup 11}C]-DTBZ dynamic PET/CT brain data. For each subject, a two-factor model is assumed and two factors representing the striatum (factor 1) and the non-striatum (factor 2) tissues are extracted using the proposed NMF technique and commercially available factor analysis software “Pixies”. The extracted factor 1 and 2 curves represent the binding site of the radiotracer and describe the uptake and clearance of the radiotracer by soft tissues in the brain, respectively. The proposed NMF technique uses prior information about the dynamic data to obtain sample time-activity curves representing the striatum and the non-striatum tissues. These curves are then used for “warm” starting the optimization. Factor solutions from the two methods are compared graphically and quantitatively. In healthy subjects, radiotracer uptake by factors 1 and 2 are approximately 35–40% and 60–65%, respectively. The solutions are also used to develop a factor-based metric for the detection of early, untreated Parkinson's disease. The metric stratifies healthy subjects from suspected Parkinson's patients (based on the graphical method). The analysis shows that both techniques produce comparable results with similar computational time. The “semi-automatic” approach used by the NMF technique allows clinicians to manually set a starting condition for “warm” starting the optimization in order to facilitate control and efficient interaction with the data.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Selecting registration schemes in case of interstitial lung disease follow-up in CT

Purpose: Primary goal of this study is to select optimal registration schemes in the framework of interstitial lung disease (ILD) follow-up analysis in CT. Methods: A set of 128 multiresolution schemes composed of multiresolution nonrigid and combinations of rigid and nonrigid registration schemes are evaluated, utilizing ten artificially warped ILD follow-up volumes, originating from ten clinical volumetric CT scans of ILD affected patients, to select candidate optimal schemes. Specifically, all combinations of four transformation models (three rigid: rigid, similarity, affine and one nonrigid: third order B-spline), four cost functions (sum-of-square distances, normalized correlation coefficient, mutual information, and normalized mutual information), four gradient descent optimizers (standard, regular step, adaptive stochastic, and finite difference), and two types of pyramids (recursive and Gaussian-smoothing) were considered. The selection process involves two stages. The first stage involves identification of schemes with deformation field singularities, according to the determinant of the Jacobian matrix. In the second stage, evaluation methodology is based on distance between corresponding landmark points in both normal lung parenchyma (NLP) and ILD affected regions. Statistical analysis was performed in order to select near optimal registration schemes per evaluation metric. Performance of the candidate registration schemes was verified on a case sample of ten clinical follow-up CT scans to obtain the selected registration schemes. Results: By considering near optimal schemes common to all ranking lists, 16 out of 128 registration schemes were initially selected. These schemes obtained submillimeter registration accuracies in terms of average distance errors 0.18 ± 0.01 mm for NLP and 0.20 ± 0.01 mm for ILD, in case of artificially generated follow-up data. Registration accuracy in terms of average distance error in clinical follow-up data was in the range of 1.985–2.156 mm and 1.966–2.234 mm, for NLP and ILD affected regions, respectively, excluding schemes with statistically significant lower performance (Wilcoxon signed-ranks test, p < 0.05), resulting in 13 finally selected registration schemes. Conclusions: Selected registration schemes in case of ILD CT follow-up analysis indicate the significance of adaptive stochastic gradient descent optimizer, as well as the importance of combined rigid and nonrigid schemes providing high accuracy and time efficiency. The selected optimal deformable registration schemes are equivalent in terms of their accuracy and thus compatible in terms of their clinical outcome.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Three-dimensional quadratic modeling and quantitative evaluation of the diaphragm on a volumetric CT scan in patients with chronic obstructive pulmonary disease

Purpose: In patients with chronic obstructive pulmonary disease (COPD), diaphragm function may deteriorate due to reduced muscle fiber length. Quantitative analysis of the morphology of the diaphragm is therefore important. In the authors current study, they propose a diaphragm segmentation method for COPD patients that uses volumetric chest computed tomography (CT) data, and they provide a quantitative analysis of the diaphragmatic dimensions. Methods: Volumetric CT data were obtained from 30 COPD patients and 10 normal control patients using a 16-row multidetector CT scanner (Siemens Sensation 16) with 0.75-mm collimation. Diaphragm segmentation using 3D ray projections on the lower surface of the lungs was performed to identify the draft diaphragmatic lung surface, which was modeled using quadratic 3D surface fitting and robust regression in order to minimize the effects of segmentation error and parameterize diaphragm morphology. This result was visually evaluated by an expert thoracic radiologist. To take into consideration the shape features of the diaphragm, several quantification parameters—including the shape index on the apex (SIA) (which was computed using gradient set to 0), principal curvatures on the apex on the fitted diaphragm surface (CA), the height between the apex and the base plane (H), the diaphragm lengths along the x-, y-, and z-axes (XL, YL, ZL), quadratic-fitted diaphragm lengths on the z-axis (FZL), average curvature (C), and surface area (SA)—were measured using in-house software and compared with the pulmonary function test (PFT) results. Results: The overall accuracy of the combined segmentation method was 97.22% ± 4.44% while the visual accuracy of the models for the segmented diaphragms was 95.28% ± 2.52% (mean ± SD). The quantitative parameters, including SIA, CA, H, XL, YL, ZL, FZL, C, and SA were 0.85 ± 0.05 (mm{sup −1}), 0.01 ± 0.00 (mm{sup −1}), 17.93 ± 10.78 (mm), 129.80 ± 11.66 (mm), 163.19 ± 13.45 (mm), 71.27 ± 17.52 (mm), 61.59 ± 16.98 (mm), 0.01 ± 0.00 (mm{sup −1}), and 34 380.75 ± 6680.06 (mm{sup 2}), respectively. Several parameters were correlated with the PFT parameters. Conclusions: The authors propose an automatic method for quantitatively evaluating the morphological parameters of the diaphragm on volumetric chest CT in COPD patients. By measuring not only the conventional length and surface area but also the shape features of the diaphragm using quadratic 3D surface modeling, the proposed method is especially useful for quantifying diaphragm characteristics. Their method may be useful for assessing morphological diaphragmatic changes in COPD patients.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

TH-AB-207A-11: Anatomical and Functional Assessment of Coronary Artery Disease Using Low-Dose Whole-Organ Dynamic Computed Tomography

Purpose: To evaluate the accuracy of a low-dose, first-pass-analysis (FPA) dynamic computed tomography angiography and perfusion (CTAP) technique, for whole-organ anatomical and functional assessment of coronary artery disease (CAD). Methods: An angioplasty balloon was advanced into the left anterior descending (LAD) coronary artery of five swine (35–45 kg) to induce several levels of stenosis at maximal hyperemia (intracoronary adenosine, 240 µg/min). Reference fluorescence microspheres and intravenous contrast (370 mg/mL iodine, 25 mL, 7 mL/s) were injected centrally and dynamic imaging was performed using a 320-slice CT scanner at 100 kVp and 200 mA. Twenty volume scans were acquired per stenosis level to capture complete aortic and myocardial enhancement curves, but only two volume scans were used for whole-organ dynamic FPA CTAP measurement. All CTAP measurements in the LAD were compared to the reference microsphere perfusion measurements using linear regression, concordance correlation, and Bland-Altman analysis. Results: The result of dynamic FPA CTAP measurement in the LAD was in good agreement with the reference microsphere perfusion measurement (P-CTAP = 1.01 P-MICRO + 0.16, R{sup 2} = 0.95). The root mean square error (RMSE) and difference (RMSD) of measurement were 0.51 mL/min/g and 0.47 mL/min/g, respectively. Bland-Altman analysis demonstrated negligible systematic measurement bias. Additionally, the concordance correlation coefficient (CCC) was found to be ρ = 0.97, indicating excellent agreement between dynamic FPA CTAP measurement and the reference microsphere perfusion measurement. Lastly, the effective dose of the proposed technique using the “simulated” two-volume scan CTAP acquisition protocol was 2.6 mSv; much lower than the ∼10 mSv effective dose of current dynamic CTP techniques alone. Conclusion: The results indicate the potential for significant improvements in CAD assessment through low-dose, quantitative dynamic FPA CTAP. Such improvements are afforded through whole-organ CT scanning technology, and have the potential to improve patient outcomes and lead to healthier patient lives. Conflict of Interest (only if applicable): Grant funding from Toshiba America Medical Systems.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Association Between Prevalence of Peripheral Artery Disease and Radiation Exposure in the Atomic Bomb Survivors

Past reports suggested that total-body irradiation at 0.5 to 1.0 Gy could be responsible for atherosclerosis. Peripheral artery disease (PAD) is a manifestation of systematic atherosclerosis. Whether the consequences of a low-to-moderate dose of radiation include increased risk of PAD remains to be determined. The purpose of this study was to examine the association between radiation exposure and prevalence of PAD among Japanese atomic bomb survivors. Radiation exposure from the atomic bombing was assessed in 3476 participants (41.1% men, mean age 74.8 years with SD 6.4 years) with a cross-sectional survey in 2010 to 2014. Left- and right-side ankle-brachial indexes and upstroke time (UT) were obtained using oscillometric VP-2000. PAD was defined as an ankle-brachial index of 1.0 or less or a prior history related to revascularization. UT was considered a sensitive marker of early-stage PAD. Association between radiation exposure and PAD or UT was assessed using multivariable regression analyses with adjustment for potential confounding factors. Of 3476 participants, 79 (2.3%) were identified as having prevalent PAD. Multivariate logistic regression analysis indicated that radiation dose was unrelated to PAD prevalence (odds ratio, 0.83; 95% confidence interval [0.57-1.21]). UT appeared to increase with radiation dose, but the increase was not statistically significant (1.09 ms/Gy; 95% confidence interval [-0.17 to 2.36]). We found no clear association of radiation dose with PAD, but it remains to be determined whether UT is associated with radiation dose.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Results from the centers for disease control and prevention’s predict the 2013–2014 Influenza Season Challenge

Background: Early insights into the timing of the start, peak, and intensity of the influenza season could be useful in planning influenza prevention and control activities. To encourage development and innovation in influenza forecasting, the Centers for Disease Control and Prevention (CDC) organized a challenge to predict the 2013–14 Unites States influenza season. Methods: Challenge contestants were asked to forecast the start, peak, and intensity of the 2013–2014 influenza season at the national level and at any or all Health and Human Services (HHS) region level(s). The challenge ran from December 1, 2013–March 27, 2014; contestants were required to submit 9 biweekly forecasts at the national level to be eligible. The selection of the winner was based on expert evaluation of the methodology used to make the prediction and the accuracy of the prediction as judged against the U.S. Outpatient Influenza-like Illness Surveillance Network (ILINet). Results: Nine teams submitted 13 forecasts for all required milestones. The first forecast was due on December 2, 2013; 3/13 forecasts received correctly predicted the start of the influenza season within one week, 1/13 predicted the peak within 1 week, 3/13 predicted the peak ILINet percentage within 1 %, and 4/13 predicted the season duration within 1 week. For the prediction due on December 19, 2013, the number of forecasts that correctly forecasted the peak week increased to 2/13, the peak percentage to 6/13, and the duration of the season to 6/13. As the season progressed, the forecasts became more stable and were closer to the season milestones. Conclusion: Forecasting has become technically feasible, but further efforts are needed to improve forecast accuracy so that policy makers can reliably use these predictions. CDC and challenge contestants plan to build upon the methods developed during this contest to improve the accuracy of influenza forecasts.

Infectious Diseases↗
DOE OSTI2023

NREM sleep as a novel protective cognitive reserve factor in the face of Alzheimer's disease pathology

Alzheimer’s disease (AD) pathology impairs cognitive function. Yet some individuals with high amounts of AD pathology suffer marked memory impairment, while others with the same degree of pathology burden show little impairment. Why is this? One proposed explanation is cognitive reserve i.e., factors that confer resilience against, or compensation for the effects of AD pathology. Deep NREM slow wave sleep (SWS) is recognized to enhance functions of learning and memory in healthy older adults. However, that the quality of NREM SWS (NREM slow wave activity, SWA) represents a novel cognitive reserve factor in older adults with AD pathology, thereby providing compensation against memory dysfunction otherwise caused by high AD pathology burden, remains unknown. Here, we tested this hypothesis in cognitively normal older adults (N = 62) by combining 11 C-PiB (Pittsburgh compound B) positron emission tomography (PET) scanning for the quantification of β-amyloid (Aβ) with sleep electroencephalography (EEG) recordings to quantify NREM SWA and a hippocampal-dependent face-name learning task. We demonstrated that NREM SWA significantly moderates the effect of Aβ status on memory function. Specifically, NREM SWA selectively supported superior memory function in individuals suffering high Aβ burden, i.e., those most in need of cognitive reserve (B = 2.694, p = 0.019). In contrast, those without significant Aβ pathological burden, and thus without the same need for cognitive reserve, did not similarly benefit from the presence of NREM SWA (B = -0.115, p = 0.876). This interaction between NREM SWA and Aβ status predicting memory function was significant after correcting for age, sex, Body Mass Index, gray matter atrophy, and previously identified cognitive reserve factors, such as education and physical activity (p = 0.042). These findings indicate that NREM SWA is a novel cognitive reserve factor providing resilience against the memory impairment otherwise caused by high AD pathology burden. Furthermore, this cognitive reserve function of NREM SWA remained significant when accounting both for covariates, and factors previously linked to resilience, suggesting that sleep might be an independent cognitive reserve resource. Beyond such mechanistic insights are potential therapeutic implications. Unlike many other cognitive reserve factors (e.g., years of education, prior job complexity), sleep is a modifiable factor. As such, it represents an intervention possibility that may aid the preservation of cognitive function in the face of AD pathology, both present moment and longitudinally.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Investigating the clinico-anatomical dissociation in the behavioral variant of Alzheimer disease

We previously found temporoparietal-predominant atrophy patterns in the behavioral variant of Alzheimer’s disease (bvAD), with relative sparing of frontal regions. Here, we aimed to understand the clinico-anatomical dissociation in bvAD based on alternative neuroimaging markers. We retrospectively included 150 participants, including 29 bvAD, 28 “typical” amnestic-predominant AD (tAD), 28 behavioral variant of frontotemporal dementia (bvFTD), and 65 cognitively normal participants. Patients with bvAD were compared with other diagnostic groups on glucose metabolism and metabolic connectivity measured by [ 18 F]FDG-PET, and on subcortical gray matter and white matter hyperintensity (WMH) volumes measured by MRI. A receiver-operating-characteristic-analysis was performed to determine the neuroimaging measures with highest diagnostic accuracy. bvAD and tAD showed predominant temporoparietal hypometabolism compared to controls, and did not differ in direct contrasts. However, overlaying statistical maps from contrasts between patients and controls revealed broader frontoinsular hypometabolism in bvAD than tAD, partially overlapping with bvFTD. bvAD showed greater anterior default mode network (DMN) involvement than tAD, mimicking bvFTD, and reduced connectivity of the posterior cingulate cortex with prefrontal regions. Analyses of WMH and subcortical volume showed closer resemblance of bvAD to tAD than to bvFTD, and larger amygdalar volumes in bvAD than tAD respectively. The top-3 discriminators for bvAD vs. bvFTD were FDG posterior-DMN-ratios (bvAD bvFTD, area under the curve [AUC] range 0.85–0.91, all p < 0.001). The top-3 for bvAD vs. tAD were amygdalar volume (bvAD>tAD), MRI anterior-DMN-ratios (bvAD<tAD), FDG anterior-DMN-ratios (bvAD<tAD, AUC range 0.71–0.84, all p < 0.05). Subtle frontoinsular hypometabolism and anterior DMN involvement may underlie the prominent behavioral phenotype in bvAD.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Optimizing Patient-Specific Medication Regimen Policies Using Wearable Sensors in Parkinson’s Disease

Effective treatment of Parkinson’s disease (PD) is a continual challenge for healthcare providers, and providers can benefit from leveraging emerging technologies to supplement traditional clinic care. We develop a data-driven reinforcement learning (RL) framework to optimize PD medication regimens through wearable sensors. We leverage a data set of n = 26 PD patients who wore wrist-mounted movement trackers for two separate six-day periods. Using these data, we first build and validate a simulation model of how individual patients’ movement symptoms respond to medication administration. We then pair this simulation model with an on-policy RL algorithm that recommends optimal medication types, timing, and dosages during the day while incorporating human-in-the-loop considerations on medication administration. The results show that the RL-prescribed medication regimens outperform physicians’ medication regimens, despite physicians having access to the same data as the RL agent. To validate our results, we assess our wearable-based RL medication regimens using n = 399 PD patients from the Parkinson’s Progression Markers Initiative data set. We show that the wearable-based RL medication regimens would lead to significant symptom improvement for these patients, even more so than training RL policies directly from this data set. In doing so, we show that RL models from even small data sets of wearable data can offer novel, generalizable clinical insights and medication strategies, which may outperform those derived from larger data sets without wearable data.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Early Events in the Pathogenesis of Foot-and-Mouth Disease in Pigs; Identification of Oropharyngeal Tonsils as Sites of Primary and Sustained Viral Replication

A time-course study was performed to elucidate the early events of foot-and-mouth disease virus (FMDV) infection in pigs subsequent to simulated natural, intra-oropharyngeal, inoculation. The earliest detectable event was primary infection in the lingual and paraepiglottic tonsils at 6 hours post inoculation (hpi) characterized by regional localization of viral RNA, viral antigen, and infectious virus. At this time FMDV antigen was localized in cytokeratin-positive epithelial cells and CD172a-expressing leukocytes of the crypt epithelium of the paraepiglottic tonsils. De novo replication of FMDV was first detected in oropharyngeal swab samples at 12 hpi and viremia occurred at 18–24 hpi, approximately 24 hours prior to the appearance of vesicular lesions. From 12 through 78 hpi, microscopic detection of FMDV was consistently localized to cytokeratin-positive cells within morphologically characteristic segments of oropharyngeal tonsil crypt epithelium. During this period, leukocyte populations expressing CD172a, SLA-DQ class II and/or CD8 were found in close proximity to infected epithelial cells, but with little or no co-localization with viral proteins. Similarly, M-cells expressing cytokeratin-18 did not colocalize with FMDV proteins. Intra-epithelial micro-vesicles composed of acantholytic epithelial cells expressing large amounts of structural and non-structural FMDV proteins were present within crypts of the tonsil of the soft palate during peak clinical infection. These findings inculpate the paraepiglottic tonsils as the primary site of FMDV infection in pigs exposed via the gastrointestinal tract. Furthermore, the continuing replication of FMDV in the oropharyngeal tonsils during viremia and peak clinical infection with no concurrent amplification of virus occurring in the lower respiratory tract indicates that these sites are the major source of shedding of FMDV from pigs.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2015

Persistent Foot-and-Mouth Disease Virus Infection in the Nasopharynx of Cattle; Tissue-Specific Distribution and Local Cytokine Expression

Tissues obtained post-mortem from cattle persistently infected with foot-and-mouth disease virus (FMDV) were analyzed to characterize the tissue-specific localization of FMDV and partial transcriptome profiles for selected immunoregulatory cytokines. Analysis of 28 distinct anatomic sites from 21 steers infected with FMDV serotype A, O or SAT2, had the highest prevalence of overall viral detection in the dorsal nasopharynx (80.95%) and dorsal soft palate (71.43%). FMDV was less frequently detected in laryngeal mucosal tissues, oropharyngeal mucosal sites, and lymph nodes draining the pharynx. Immunomicroscopy indicated that within persistently infected mucosal tissues, FMDV antigens were rarely detectable within few epithelial cells in regions of mucosa-associated lymphoid tissue (MALT). Transcriptome analysis of persistently infected pharyngeal tissues by qRT-PCR for 14 cytokine genes indicated a general trend of decreased mRNA levels compared to uninfected control animals. Although, statistically significant differences were not observed, greatest suppression of relative expression (RE) was identified for IP-10 (RE = 0.198), IFN-β (RE = 0.269), IL-12 (RE = 0.275), and IL-2 (RE = 0.312). Increased relative expression was detected for IL-6 (RE = 2.065). Overall, this data demonstrates that during the FMDV carrier state in cattle, viral persistence is associated with epithelial cells of the nasopharynx in the upper respiratory tract and decreased levels of mRNA for several immunoregulatory cytokines in the infected tissues.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2015

Analyzing and modeling the kinetics of amyloid beta pores associated with Alzheimer’s disease pathology

Amyloid beta (Aβ) oligomers associated with Alzheimer’s disease (AD) form Ca 2+ -permeable plasma membrane pores, leading to a disruption of the otherwise well-controlled intracellular calcium (Ca 2+ ) homeostasis. The resultant up-regulation of intracellular Ca 2+ concentration has detrimental implications for memory formation and cell survival. The gating kinetics and Ca 2+ permeability of Aβ pores are not well understood. We have used computational modeling in conjunction with the ability of optical patch-clamping for massively parallel imaging of Ca 2+ flux through thousands of pores in the cell membrane of Xenopus oocytes to elucidate the kinetic properties of Aβ pores. The fluorescence time-series data from individual pores were idealized and used to develop data-driven Markov chain models for the kinetics of the Aβ pore at different stages of its evolution. Our study provides the first demonstration of developing Markov chain models for ion channel gating that are driven by optical-patch clamp data with the advantage of experiments being performed under close to physiological conditions. As a result, we demonstrate the up-regulation of gating of various Ca 2+ release channels due to Aβ pores and show that the extent and spatial range of such up-regulation increases as Aβ pores with low open probability and Ca 2+ permeability transition into those with high open probability and Ca 2+ permeability.

59 BASIC BIOLOGICAL SCIENCES↗