Linking the Human Gut Microbiome to Inflammatory Cytokine Production Capacity.

PubMed

Schirmer, Melanie; Smeekens, Sanne P; Vlamakis, Hera; Jaeger, Martin; Oosting, Marije; Franzosa, Eric A; Ter Horst, Rob; Jansen, Trees; Jacobs, Liesbeth; Bonder, Marc Jan; Kurilshikov, Alexander; Fu, Jingyuan; Joosten, Leo A B; Zhernakova, Alexandra; Huttenhower, Curtis; Wijmenga, Cisca; Netea, Mihai G; Xavier, Ramnik J

2016-11-03

Gut microbial dysbioses are linked to aberrant immune responses, which are often accompanied by abnormal production of inflammatory cytokines. As part of the Human Functional Genomics Project (HFGP), we investigate how differences in composition and function of gut microbial communities may contribute to inter-individual variation in cytokine responses to microbial stimulations in healthy humans. We observe microbiome-cytokine interaction patterns that are stimulus specific, cytokine specific, and cytokine and stimulus specific. Validation of two predicted host-microbial interactions reveal that TNFα and IFNγ production are associated with specific microbial metabolic pathways: palmitoleic acid metabolism and tryptophan degradation to tryptophol. Besides providing a resource of predicted microbially derived mediators that influence immune phenotypes in response to common microorganisms, these data can help to define principles for understanding disease susceptibility. The three HFGP studies presented in this issue lay the groundwork for further studies aimed at understanding the interplay between microbial, genetic, and environmental factors in the regulation of the immune response in humans. PAPERCLIP. Copyright © 2016 Elsevier Inc. All rights reserved.

Human Thermal Model Evaluation Using the JSC Human Thermal Database

NASA Technical Reports Server (NTRS)

Bue, Grant; Makinen, Janice; Cognata, Thomas

2012-01-01

Human thermal modeling has considerable long term utility to human space flight. Such models provide a tool to predict crew survivability in support of vehicle design and to evaluate crew response in untested space environments. It is to the benefit of any such model not only to collect relevant experimental data to correlate it against, but also to maintain an experimental standard or benchmark for future development in a readily and rapidly searchable and software accessible format. The Human thermal database project is intended to do just so; to collect relevant data from literature and experimentation and to store the data in a database structure for immediate and future use as a benchmark to judge human thermal models against, in identifying model strengths and weakness, to support model development and improve correlation, and to statistically quantify a model s predictive quality. The human thermal database developed at the Johnson Space Center (JSC) is intended to evaluate a set of widely used human thermal models. This set includes the Wissler human thermal model, a model that has been widely used to predict the human thermoregulatory response to a variety of cold and hot environments. These models are statistically compared to the current database, which contains experiments of human subjects primarily in air from a literature survey ranging between 1953 and 2004 and from a suited experiment recently performed by the authors, for a quantitative study of relative strength and predictive quality of the models.

Silent Expectations: Dynamic Causal Modeling of Cortical Prediction and Attention to Sounds That Weren't.

PubMed

Chennu, Srivas; Noreika, Valdas; Gueorguiev, David; Shtyrov, Yury; Bekinschtein, Tristan A; Henson, Richard

2016-08-10

There is increasing evidence that human perception is realized by a hierarchy of neural processes in which predictions sent backward from higher levels result in prediction errors that are fed forward from lower levels, to update the current model of the environment. Moreover, the precision of prediction errors is thought to be modulated by attention. Much of this evidence comes from paradigms in which a stimulus differs from that predicted by the recent history of other stimuli (generating a so-called "mismatch response"). There is less evidence from situations where a prediction is not fulfilled by any sensory input (an "omission" response). This situation arguably provides a more direct measure of "top-down" predictions in the absence of confounding "bottom-up" input. We applied Dynamic Causal Modeling of evoked electromagnetic responses recorded by EEG and MEG to an auditory paradigm in which we factorially crossed the presence versus absence of "bottom-up" stimuli with the presence versus absence of "top-down" attention. Model comparison revealed that both mismatch and omission responses were mediated by increased forward and backward connections, differing primarily in the driving input. In both responses, modeling results suggested that the presence of attention selectively modulated backward "prediction" connections. Our results provide new model-driven evidence of the pure top-down prediction signal posited in theories of hierarchical perception, and highlight the role of attentional precision in strengthening this prediction. Human auditory perception is thought to be realized by a network of neurons that maintain a model of and predict future stimuli. Much of the evidence for this comes from experiments where a stimulus unexpectedly differs from previous ones, which generates a well-known "mismatch response." But what happens when a stimulus is unexpectedly omitted altogether? By measuring the brain's electromagnetic activity, we show that it also generates an "omission response" that is contingent on the presence of attention. We model these responses computationally, revealing that mismatch and omission responses only differ in the location of inputs into the same underlying neuronal network. In both cases, we show that attention selectively strengthens the brain's prediction of the future. Copyright © 2016 Chennu et al.

Prediction of interindividual differences in hepatic functions and drug sensitivity by using human iPS-derived hepatocytes.

PubMed

Takayama, Kazuo; Morisaki, Yuta; Kuno, Shuichi; Nagamoto, Yasuhito; Harada, Kazuo; Furukawa, Norihisa; Ohtaka, Manami; Nishimura, Ken; Imagawa, Kazuo; Sakurai, Fuminori; Tachibana, Masashi; Sumazaki, Ryo; Noguchi, Emiko; Nakanishi, Mahito; Hirata, Kazumasa; Kawabata, Kenji; Mizuguchi, Hiroyuki

2014-11-25

Interindividual differences in hepatic metabolism, which are mainly due to genetic polymorphism in its gene, have a large influence on individual drug efficacy and adverse reaction. Hepatocyte-like cells (HLCs) differentiated from human induced pluripotent stem (iPS) cells have the potential to predict interindividual differences in drug metabolism capacity and drug response. However, it remains uncertain whether human iPSC-derived HLCs can reproduce the interindividual difference in hepatic metabolism and drug response. We found that cytochrome P450 (CYP) metabolism capacity and drug responsiveness of the primary human hepatocytes (PHH)-iPS-HLCs were highly correlated with those of PHHs, suggesting that the PHH-iPS-HLCs retained donor-specific CYP metabolism capacity and drug responsiveness. We also demonstrated that the interindividual differences, which are due to the diversity of individual SNPs in the CYP gene, could also be reproduced in PHH-iPS-HLCs. We succeeded in establishing, to our knowledge, the first PHH-iPS-HLC panel that reflects the interindividual differences of hepatic drug-metabolizing capacity and drug responsiveness.

Experimental investigation of biodynamic human body models subjected to whole-body vibration during a vehicle ride.

PubMed

Taskin, Yener; Hacioglu, Yuksel; Ortes, Faruk; Karabulut, Derya; Arslan, Yunus Ziya

2018-02-06

In this study, responses of biodynamic human body models to whole-body vibration during a vehicle ride were investigated. Accelerations were acquired from three different body parts, such as the head, upper torso and lower torso, of 10 seated passengers during a car ride while two different road conditions were considered. The same multipurpose vehicle was used during all experiments. Additionally, by two widely used biodynamic models in the literature, a set of simulations were run to obtain theoretical accelerations of the models and were compared with those obtained experimentally. To sustain a quantified comparison between experimental and theoretical approaches, the root mean square acceleration and acceleration spectral density were calculated. Time and frequency responses of the models demonstrated that neither of the models showed the best prediction performance of the human body behaviour in all cases, indicating that further models are required for better prediction of the human body responses.

Developing Predictive Approaches to Characterize Adaptive Responses of the Reproductive Endocrine Axis to Aromatase Inhibition: Computational Modeling

EPA Science Inventory

Exposure to endocrine disrupting chemicals can affect reproduction and development in both humans and wildlife. We developed a mechanistic mathematical model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict dose-response and time-course (DRTC)...

Predicting Adaptive Response to Fadrozole Exposure: Computational Model of the Fathead Minnow Hypothalamic-Pituitary-Gonadal Axis

EPA Science Inventory

Exposure to endocrine disrupting chemicals can affect reproduction and development in both humans and wildlife. We are developing a mechanistic mathematical model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict dose-response and time-course (...

Explaining neural signals in human visual cortex with an associative learning model.

PubMed

Jiang, Jiefeng; Schmajuk, Nestor; Egner, Tobias

2012-08-01

"Predictive coding" models posit a key role for associative learning in visual cognition, viewing perceptual inference as a process of matching (learned) top-down predictions (or expectations) against bottom-up sensory evidence. At the neural level, these models propose that each region along the visual processing hierarchy entails one set of processing units encoding predictions of bottom-up input, and another set computing mismatches (prediction error or surprise) between predictions and evidence. This contrasts with traditional views of visual neurons operating purely as bottom-up feature detectors. In support of the predictive coding hypothesis, a recent human neuroimaging study (Egner, Monti, & Summerfield, 2010) showed that neural population responses to expected and unexpected face and house stimuli in the "fusiform face area" (FFA) could be well-described as a summation of hypothetical face-expectation and -surprise signals, but not by feature detector responses. Here, we used computer simulations to test whether these imaging data could be formally explained within the broader framework of a mathematical neural network model of associative learning (Schmajuk, Gray, & Lam, 1996). Results show that FFA responses could be fit very closely by model variables coding for conditional predictions (and their violations) of stimuli that unconditionally activate the FFA. These data document that neural population signals in the ventral visual stream that deviate from classic feature detection responses can formally be explained by associative prediction and surprise signals.

Human Adaptation Genetic Response Suites: Toward New Interventions and Countermeasures for Spaceflight

NASA Technical Reports Server (NTRS)

Sundaresan, A.; Pellis, N. R.

2005-01-01

Genetic response suites in human lymphocytes in response to microgravity are important to identify and further study in order to augment human physiological adaptation to novel environments. Emerging technologies, such as DNA micro array profiling, have the potential to identify novel genes that are involved in mediating adaptation to these environments. These genes may prove to be therapeutically valuable as new targets for countermeasures, or as predictive biomarkers of response to these new environments. Human lymphocytes cultured in lg and microgravity analog culture were analyzed for their differential gene expression response. Different groups of genes related to the immune response, cardiovascular system and stress response were then analyzed. Analysis of cells from multiple donors reveals a small shared set that are likely to be essential to adaptation. These three groups focus on human adaptation to new environments. The shared set contains genes related to T cell activation, immune response and stress response to analog microgravity.

Review of Nearshore Morphologic Prediction

NASA Astrophysics Data System (ADS)

Plant, N. G.; Dalyander, S.; Long, J.

2014-12-01

The evolution of the world's erodible coastlines will determine the balance between the benefits and costs associated with human and ecological utilization of shores, beaches, dunes, barrier islands, wetlands, and estuaries. So, we would like to predict coastal evolution to guide management and planning of human and ecological response to coastal changes. After decades of research investment in data collection, theoretical and statistical analysis, and model development we have a number of empirical, statistical, and deterministic models that can predict the evolution of the shoreline, beaches, dunes, and wetlands over time scales of hours to decades, and even predict the evolution of geologic strata over the course of millennia. Comparisons of predictions to data have demonstrated that these models can have meaningful predictive skill. But these comparisons also highlight the deficiencies in fundamental understanding, formulations, or data that are responsible for prediction errors and uncertainty. Here, we review a subset of predictive models of the nearshore to illustrate tradeoffs in complexity, predictive skill, and sensitivity to input data and parameterization errors. We identify where future improvement in prediction skill will result from improved theoretical understanding, and data collection, and model-data assimilation.

Can responses to basic non-numerical visual features explain neural numerosity responses?

PubMed

Harvey, Ben M; Dumoulin, Serge O

2017-04-01

Humans and many animals can distinguish between stimuli that differ in numerosity, the number of objects in a set. Human and macaque parietal lobes contain neurons that respond to changes in stimulus numerosity. However, basic non-numerical visual features can affect neural responses to and perception of numerosity, and visual features often co-vary with numerosity. Therefore, it is debated whether numerosity or co-varying low-level visual features underlie neural and behavioral responses to numerosity. To test the hypothesis that non-numerical visual features underlie neural numerosity responses in a human parietal numerosity map, we analyze responses to a group of numerosity stimulus configurations that have the same numerosity progression but vary considerably in their non-numerical visual features. Using ultra-high-field (7T) fMRI, we measure responses to these stimulus configurations in an area of posterior parietal cortex whose responses are believed to reflect numerosity-selective activity. We describe an fMRI analysis method to distinguish between alternative models of neural response functions, following a population receptive field (pRF) modeling approach. For each stimulus configuration, we first quantify the relationships between numerosity and several non-numerical visual features that have been proposed to underlie performance in numerosity discrimination tasks. We then determine how well responses to these non-numerical visual features predict the observed fMRI responses, and compare this to the predictions of responses to numerosity. We demonstrate that a numerosity response model predicts observed responses more accurately than models of responses to simple non-numerical visual features. As such, neural responses in cognitive processing need not reflect simpler properties of early sensory inputs. Copyright © 2017 Elsevier Inc. All rights reserved.

The database of the PREDICTS (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems) project

Treesearch

Lawrence N. Hudson; Joseph Wunderle M.; And Others

2016-01-01

The PREDICTS project—Projecting Responses of Ecological Diversity In Changing Terrestrial Systems (www.predicts.org.uk)—has collated from published studies a large, reasonably representative database of comparable samples of biodiversity from multiple sites that differ in the nature or intensity of human impacts relating to land use. We have used this evidence base to...

Computational Modeling of Hypothalamic-Pituitary-Gonadal Axis to Predict Adaptive Responses in Female Fathead Minnows Exposed to an Aromatase Inhibitor

EPA Science Inventory

Exposure to endocrine disrupting chemicals can affect reproduction and development in both humans and wildlife. We are developing a mechanistic computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict dose response and time-course...

Evaluation of Human and Anthropomorphic Test Device Finite Element Models under Spaceflight Loading Conditions

NASA Technical Reports Server (NTRS)

Putnam, Jacob P.; Untaroiu, Costin; Somers. Jeffrey

2014-01-01

In an effort to develop occupant protection standards for future multipurpose crew vehicles, the National Aeronautics and Space Administration (NASA) has looked to evaluate the test device for human occupant restraint with the modification kit (THOR-K) anthropomorphic test device (ATD) in relevant impact test scenarios. With the allowance and support of the National Highway Traffic Safety Administration, NASA has performed a series of sled impact tests on the latest developed THOR-K ATD. These tests were performed to match test conditions from human volunteer data previously collected by the U.S. Air Force. The objective of this study was to evaluate the THOR-K finite element (FE) model and the Total HUman Model for Safety (THUMS) FE model with respect to the tests performed. These models were evaluated in spinal and frontal impacts against kinematic and kinetic data recorded in ATD and human testing. Methods: The FE simulations were developed based on recorded pretest ATD/human position and sled acceleration pulses measured during testing. Predicted responses by both human and ATD models were compared to test data recorded under the same impact conditions. The kinematic responses of the models were quantitatively evaluated using the ISO-metric curve rating system. In addition, ATD injury criteria and human stress/strain data were calculated to evaluate the risk of injury predicted by the ATD and human model, respectively. Results: Preliminary results show well-correlated response between both FE models and their physical counterparts. In addition, predicted ATD injury criteria and human model stress/strain values are shown to positively relate. Kinematic comparison between human and ATD models indicates promising biofidelic response, although a slightly stiffer response is observed within the ATD. Conclusion: As a compliment to ATD testing, numerical simulation provides efficient means to assess vehicle safety throughout the design process and further improve the design of physical ATDs. The assessment of the THOR-K and THUMS FE models in a spaceflight testing condition is an essential first step to implementing these models in the computational evaluation of spacecraft occupant safety. Promising results suggest future use of these models in the aerospace field.

Comparison of Biophysical Characteristics and Predicted Thermophysiological Responses of Three Prototype Body Armor Systems Versus Baseline U.S. Army Body Armor Systems

DTIC Science & Technology

2015-06-19

effective and scientifically valid method of making comparisons of clothing and equipment changes prior to conducting human research. predictive modeling...valid method of making comparisons of clothing and equipment changes prior to conducting human research. 2 INTRODUCTION Modern day...clothing and equipment changes prior to conducting human research. METHODS Ensembles Three different body armor (BA) plus clothing ensembles were

A Semi-Supervised Approach for Refining Transcriptional Signatures of Drug Response and Repositioning Predictions

PubMed Central

Iorio, Francesco; Shrestha, Roshan L.; Levin, Nicolas; Boilot, Viviane; Garnett, Mathew J.; Saez-Rodriguez, Julio; Draviam, Viji M.

2015-01-01

We present a novel strategy to identify drug-repositioning opportunities. The starting point of our method is the generation of a signature summarising the consensual transcriptional response of multiple human cell lines to a compound of interest (namely the seed compound). This signature can be derived from data in existing databases, such as the connectivity-map, and it is used at first instance to query a network interlinking all the connectivity-map compounds, based on the similarity of their transcriptional responses. This provides a drug neighbourhood, composed of compounds predicted to share some effects with the seed one. The original signature is then refined by systematically reducing its overlap with the transcriptional responses induced by drugs in this neighbourhood that are known to share a secondary effect with the seed compound. Finally, the drug network is queried again with the resulting refined signatures and the whole process is carried on for a number of iterations. Drugs in the final refined neighbourhood are then predicted to exert the principal mode of action of the seed compound. We illustrate our approach using paclitaxel (a microtubule stabilising agent) as seed compound. Our method predicts that glipizide and splitomicin perturb microtubule function in human cells: a result that could not be obtained through standard signature matching methods. In agreement, we find that glipizide and splitomicin reduce interphase microtubule growth rates and transiently increase the percentage of mitotic cells–consistent with our prediction. Finally, we validated the refined signatures of paclitaxel response by mining a large drug screening dataset, showing that human cancer cell lines whose basal transcriptional profile is anti-correlated to them are significantly more sensitive to paclitaxel and docetaxel. PMID:26452147

Reconciled rat and human metabolic networks for comparative toxicogenomics and biomarker predictions

PubMed Central

Blais, Edik M.; Rawls, Kristopher D.; Dougherty, Bonnie V.; Li, Zhuo I.; Kolling, Glynis L.; Ye, Ping; Wallqvist, Anders; Papin, Jason A.

2017-01-01

The laboratory rat has been used as a surrogate to study human biology for more than a century. Here we present the first genome-scale network reconstruction of Rattus norvegicus metabolism, iRno, and a significantly improved reconstruction of human metabolism, iHsa. These curated models comprehensively capture metabolic features known to distinguish rats from humans including vitamin C and bile acid synthesis pathways. After reconciling network differences between iRno and iHsa, we integrate toxicogenomics data from rat and human hepatocytes, to generate biomarker predictions in response to 76 drugs. We validate comparative predictions for xanthine derivatives with new experimental data and literature-based evidence delineating metabolite biomarkers unique to humans. Our results provide mechanistic insights into species-specific metabolism and facilitate the selection of biomarkers consistent with rat and human biology. These models can serve as powerful computational platforms for contextualizing experimental data and making functional predictions for clinical and basic science applications. PMID:28176778

Intra- and interspecies gene expression models for predicting drug response in canine osteosarcoma.

PubMed

Fowles, Jared S; Brown, Kristen C; Hess, Ann M; Duval, Dawn L; Gustafson, Daniel L

2016-02-19

Genomics-based predictors of drug response have the potential to improve outcomes associated with cancer therapy. Osteosarcoma (OS), the most common primary bone cancer in dogs, is commonly treated with adjuvant doxorubicin or carboplatin following amputation of the affected limb. We evaluated the use of gene-expression based models built in an intra- or interspecies manner to predict chemosensitivity and treatment outcome in canine OS. Models were built and evaluated using microarray gene expression and drug sensitivity data from human and canine cancer cell lines, and canine OS tumor datasets. The "COXEN" method was utilized to filter gene signatures between human and dog datasets based on strong co-expression patterns. Models were built using linear discriminant analysis via the misclassification penalized posterior algorithm. The best doxorubicin model involved genes identified in human lines that were co-expressed and trained on canine OS tumor data, which accurately predicted clinical outcome in 73 % of dogs (p = 0.0262, binomial). The best carboplatin model utilized canine lines for gene identification and model training, with canine OS tumor data for co-expression. Dogs whose treatment matched our predictions had significantly better clinical outcomes than those that didn't (p = 0.0006, Log Rank), and this predictor significantly associated with longer disease free intervals in a Cox multivariate analysis (hazard ratio = 0.3102, p = 0.0124). Our data show that intra- and interspecies gene expression models can successfully predict response in canine OS, which may improve outcome in dogs and serve as pre-clinical validation for similar methods in human cancer research.

Human adaptation genetic response suites: Toward new interventions and countermeasures for spaceflight

NASA Astrophysics Data System (ADS)

Sundaresan, A.; Pellis, N. R.

2005-08-01

Genetic response suites in human lymphocytes in response to microgravity are important to identify and further study in order to augment human physiological adaptation to novel environments. Emerging technologies, such as DNA micro array profiling, have the potential to identify novel genes that are involved in mediating adaptation to these environments. These genes may prove to be therapeutically valuable as new targets for countermeasures, or as predictive biomarkers of response to these new environments. Human lymphocytes cultured in 1g and microgravity analog culture were analyzed for their differential gene expression response. Different groups of genes related to the immune response, cardiovascular system and stress response were then analyzed. Analysis of cells from multiple donors reveals a small shared set that are likely to be essential to adaptation. These three groups focus on human adaptation to new environments. The shared set contains genes related to T cell activation, immune response and stress response to analog microgravity.

Human-centric predictive model of task difficulty for human-in-the-loop control tasks

PubMed Central

Majewicz Fey, Ann

2018-01-01

Quantitatively measuring the difficulty of a manipulation task in human-in-the-loop control systems is ill-defined. Currently, systems are typically evaluated through task-specific performance measures and post-experiment user surveys; however, these methods do not capture the real-time experience of human users. In this study, we propose to analyze and predict the difficulty of a bivariate pointing task, with a haptic device interface, using human-centric measurement data in terms of cognition, physical effort, and motion kinematics. Noninvasive sensors were used to record the multimodal response of human user for 14 subjects performing the task. A data-driven approach for predicting task difficulty was implemented based on several task-independent metrics. We compare four possible models for predicting task difficulty to evaluated the roles of the various types of metrics, including: (I) a movement time model, (II) a fusion model using both physiological and kinematic metrics, (III) a model only with kinematic metrics, and (IV) a model only with physiological metrics. The results show significant correlation between task difficulty and the user sensorimotor response. The fusion model, integrating user physiology and motion kinematics, provided the best estimate of task difficulty (R2 = 0.927), followed by a model using only kinematic metrics (R2 = 0.921). Both models were better predictors of task difficulty than the movement time model (R2 = 0.847), derived from Fitt’s law, a well studied difficulty model for human psychomotor control. PMID:29621301

Prediction of skin sensitization potency using machine learning approaches.

PubMed

Zang, Qingda; Paris, Michael; Lehmann, David M; Bell, Shannon; Kleinstreuer, Nicole; Allen, David; Matheson, Joanna; Jacobs, Abigail; Casey, Warren; Strickland, Judy

2017-07-01

The replacement of animal use in testing for regulatory classification of skin sensitizers is a priority for US federal agencies that use data from such testing. Machine learning models that classify substances as sensitizers or non-sensitizers without using animal data have been developed and evaluated. Because some regulatory agencies require that sensitizers be further classified into potency categories, we developed statistical models to predict skin sensitization potency for murine local lymph node assay (LLNA) and human outcomes. Input variables for our models included six physicochemical properties and data from three non-animal test methods: direct peptide reactivity assay; human cell line activation test; and KeratinoSens™ assay. Models were built to predict three potency categories using four machine learning approaches and were validated using external test sets and leave-one-out cross-validation. A one-tiered strategy modeled all three categories of response together while a two-tiered strategy modeled sensitizer/non-sensitizer responses and then classified the sensitizers as strong or weak sensitizers. The two-tiered model using the support vector machine with all assay and physicochemical data inputs provided the best performance, yielding accuracy of 88% for prediction of LLNA outcomes (120 substances) and 81% for prediction of human test outcomes (87 substances). The best one-tiered model predicted LLNA outcomes with 78% accuracy and human outcomes with 75% accuracy. By comparison, the LLNA predicts human potency categories with 69% accuracy (60 of 87 substances correctly categorized). These results suggest that computational models using non-animal methods may provide valuable information for assessing skin sensitization potency. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Analytic Guided-Search Model of Human Performance Accuracy in Target- Localization Search Tasks

NASA Technical Reports Server (NTRS)

Eckstein, Miguel P.; Beutter, Brent R.; Stone, Leland S.

2000-01-01

Current models of human visual search have extended the traditional serial/parallel search dichotomy. Two successful models for predicting human visual search are the Guided Search model and the Signal Detection Theory model. Although these models are inherently different, it has been difficult to compare them because the Guided Search model is designed to predict response time, while Signal Detection Theory models are designed to predict performance accuracy. Moreover, current implementations of the Guided Search model require the use of Monte-Carlo simulations, a method that makes fitting the model's performance quantitatively to human data more computationally time consuming. We have extended the Guided Search model to predict human accuracy in target-localization search tasks. We have also developed analytic expressions that simplify simulation of the model to the evaluation of a small set of equations using only three free parameters. This new implementation and extension of the Guided Search model will enable direct quantitative comparisons with human performance in target-localization search experiments and with the predictions of Signal Detection Theory and other search accuracy models.

Hybrid Human-Computing Distributed Sense-Making: Extending the SOA Paradigm for Dynamic Adjudication and Optimization of Human and Computer Roles

ERIC Educational Resources Information Center

Rimland, Jeffrey C.

2013-01-01

In many evolving systems, inputs can be derived from both human observations and physical sensors. Additionally, many computation and analysis tasks can be performed by either human beings or artificial intelligence (AI) applications. For example, weather prediction, emergency event response, assistive technology for various human sensory and…

An integrated physiology model to study regional lung damage effects and the physiologic response

PubMed Central

2014-01-01

Background This work expands upon a previously developed exercise dynamic physiology model (DPM) with the addition of an anatomic pulmonary system in order to quantify the impact of lung damage on oxygen transport and physical performance decrement. Methods A pulmonary model is derived with an anatomic structure based on morphometric measurements, accounting for heterogeneous ventilation and perfusion observed experimentally. The model is incorporated into an existing exercise physiology model; the combined system is validated using human exercise data. Pulmonary damage from blast, blunt trauma, and chemical injury is quantified in the model based on lung fluid infiltration (edema) which reduces oxygen delivery to the blood. The pulmonary damage component is derived and calibrated based on published animal experiments; scaling laws are used to predict the human response to lung injury in terms of physical performance decrement. Results The augmented dynamic physiology model (DPM) accurately predicted the human response to hypoxia, altitude, and exercise observed experimentally. The pulmonary damage parameters (shunt and diffusing capacity reduction) were fit to experimental animal data obtained in blast, blunt trauma, and chemical damage studies which link lung damage to lung weight change; the model is able to predict the reduced oxygen delivery in damage conditions. The model accurately estimates physical performance reduction with pulmonary damage. Conclusions We have developed a physiologically-based mathematical model to predict performance decrement endpoints in the presence of thoracic damage; simulations can be extended to estimate human performance and escape in extreme situations. PMID:25044032

Ecosystem processes and human influences regulate streamflow response to climate change at long-term ecological research sites

Treesearch

Julia A. Jones; Irena F. Creed; Kendra L. Hatcher; Robert J. Warren; Mary Beth Adams; Melinda H. Benson; Emery Boose; Warren A. Brown; John L. Campbell; Alan Covich; David W. Clow; Clifford N. Dahm; Kelly Elder; Chelcy R. Ford; Nancy B. Grimm; Donald L Henshaw; Kelli L. Larson; Evan S. Miles; Kathleen M. Miles; Stephen D. Sebestyen; Adam T. Spargo; Asa B. Stone; James M. Vose; Mark W. Williams

2012-01-01

Analyses of long-term records at 35 headwater basins in the United States and Canada indicate that climate change effects on streamflow are not as clear as might be expected, perhaps because of ecosystem processes and human influences. Evapotranspiration was higher than was predicted by temperature in water-surplus ecosystems and lower than was predicted in water-...

How ecology shapes exploitation: a framework to predict the behavioural response of human and animal foragers along exploration-exploitation trade-offs.

PubMed

Monk, Christopher T; Barbier, Matthieu; Romanczuk, Pawel; Watson, James R; Alós, Josep; Nakayama, Shinnosuke; Rubenstein, Daniel I; Levin, Simon A; Arlinghaus, Robert

2018-06-01

Understanding how humans and other animals behave in response to changes in their environments is vital for predicting population dynamics and the trajectory of coupled social-ecological systems. Here, we present a novel framework for identifying emergent social behaviours in foragers (including humans engaged in fishing or hunting) in predator-prey contexts based on the exploration difficulty and exploitation potential of a renewable natural resource. A qualitative framework is introduced that predicts when foragers should behave territorially, search collectively, act independently or switch among these states. To validate it, we derived quantitative predictions from two models of different structure: a generic mathematical model, and a lattice-based evolutionary model emphasising exploitation and exclusion costs. These models independently identified that the exploration difficulty and exploitation potential of the natural resource controls the social behaviour of resource exploiters. Our theoretical predictions were finally compared to a diverse set of empirical cases focusing on fisheries and aquatic organisms across a range of taxa, substantiating the framework's predictions. Understanding social behaviour for given social-ecological characteristics has important implications, particularly for the design of governance structures and regulations to move exploited systems, such as fisheries, towards sustainability. Our framework provides concrete steps in this direction. © 2018 John Wiley & Sons Ltd/CNRS.

Can quantitative sensory testing predict responses to analgesic treatment?

PubMed

Grosen, K; Fischer, I W D; Olesen, A E; Drewes, A M

2013-10-01

The role of quantitative sensory testing (QST) in prediction of analgesic effect in humans is scarcely investigated. This updated review assesses the effectiveness in predicting analgesic effects in healthy volunteers, surgical patients and patients with chronic pain. A systematic review of English written, peer-reviewed articles was conducted using PubMed and Embase (1980-2013). Additional studies were identified by chain searching. Search terms included 'quantitative sensory testing', 'sensory testing' and 'analgesics'. Studies on the relationship between QST and response to analgesic treatment in human adults were included. Appraisal of the methodological quality of the included studies was based on evaluative criteria for prognostic studies. Fourteen studies (including 720 individuals) met the inclusion criteria. Significant correlations were observed between responses to analgesics and several QST parameters including (1) heat pain threshold in experimental human pain, (2) electrical and heat pain thresholds, pressure pain tolerance and suprathreshold heat pain in surgical patients, and (3) electrical and heat pain threshold and conditioned pain modulation in patients with chronic pain. Heterogeneity among studies was observed especially with regard to application of QST and type and use of analgesics. Although promising, the current evidence is not sufficiently robust to recommend the use of any specific QST parameter in predicting analgesic response. Future studies should focus on a range of different experimental pain modalities rather than a single static pain stimulation paradigm. © 2013 European Federation of International Association for the Study of Pain Chapters.

Application of response surface methodology to maximize the productivity of scalable automated human embryonic stem cell manufacture.

PubMed

Ratcliffe, Elizabeth; Hourd, Paul; Guijarro-Leach, Juan; Rayment, Erin; Williams, David J; Thomas, Robert J

2013-01-01

Commercial regenerative medicine will require large quantities of clinical-specification human cells. The cost and quality of manufacture is notoriously difficult to control due to highly complex processes with poorly defined tolerances. As a step to overcome this, we aimed to demonstrate the use of 'quality-by-design' tools to define the operating space for economic passage of a scalable human embryonic stem cell production method with minimal cell loss. Design of experiments response surface methodology was applied to generate empirical models to predict optimal operating conditions for a unit of manufacture of a previously developed automatable and scalable human embryonic stem cell production method. Two models were defined to predict cell yield and cell recovery rate postpassage, in terms of the predictor variables of media volume, cell seeding density, media exchange and length of passage. Predicted operating conditions for maximized productivity were successfully validated. Such 'quality-by-design' type approaches to process design and optimization will be essential to reduce the risk of product failure and patient harm, and to build regulatory confidence in cell therapy manufacturing processes.

Validating genetic markers of response to recombinant human growth hormone in children with growth hormone deficiency and Turner syndrome: the PREDICT validation study

PubMed Central

Stevens, Adam; Murray, Philip; Wojcik, Jerome; Raelson, John; Koledova, Ekaterina; Chatelain, Pierre

2016-01-01

Objective Single-nucleotide polymorphisms (SNPs) associated with the response to recombinant human growth hormone (r-hGH) have previously been identified in growth hormone deficiency (GHD) and Turner syndrome (TS) children in the PREDICT long-term follow-up (LTFU) study (Nbib699855). Here, we describe the PREDICT validation (VAL) study (Nbib1419249), which aimed to confirm these genetic associations. Design and methods Children with GHD (n = 293) or TS (n = 132) were recruited retrospectively from 29 sites in nine countries. All children had completed 1 year of r-hGH therapy. 48 SNPs previously identified as associated with first year growth response to r-hGH were genotyped. Regression analysis was used to assess the association between genotype and growth response using clinical/auxological variables as covariates. Further analysis was undertaken using random forest classification. Results The children were younger, and the growth response was higher in VAL study. Direct genotype analysis did not replicate what was found in the LTFU study. However, using exploratory regression models with covariates, a consistent relationship with growth response in both VAL and LTFU was shown for four genes – SOS1 and INPPL1 in GHD and ESR1 and PTPN1 in TS. The random forest analysis demonstrated that only clinical covariates were important in the prediction of growth response in mild GHD (>4 to <10 μg/L on GH stimulation test), however, in severe GHD (≤4 μg/L) several SNPs contributed (in IGF2, GRB10, FOS, IGFBP3 and GHRHR). Conclusions The PREDICT validation study supports, in an independent cohort, the association of four of 48 genetic markers with growth response to r-hGH treatment in both pre-pubertal GHD and TS children after controlling for clinical/auxological covariates. However, the contribution of these SNPs in a prediction model of first-year response is not sufficient for routine clinical use. PMID:27651465

Validating genetic markers of response to recombinant human growth hormone in children with growth hormone deficiency and Turner syndrome: the PREDICT validation study.

PubMed

Stevens, Adam; Murray, Philip; Wojcik, Jerome; Raelson, John; Koledova, Ekaterina; Chatelain, Pierre; Clayton, Peter

2016-12-01

Single-nucleotide polymorphisms (SNPs) associated with the response to recombinant human growth hormone (r-hGH) have previously been identified in growth hormone deficiency (GHD) and Turner syndrome (TS) children in the PREDICT long-term follow-up (LTFU) study (Nbib699855). Here, we describe the PREDICT validation (VAL) study (Nbib1419249), which aimed to confirm these genetic associations. Children with GHD (n = 293) or TS (n = 132) were recruited retrospectively from 29 sites in nine countries. All children had completed 1 year of r-hGH therapy. 48 SNPs previously identified as associated with first year growth response to r-hGH were genotyped. Regression analysis was used to assess the association between genotype and growth response using clinical/auxological variables as covariates. Further analysis was undertaken using random forest classification. The children were younger, and the growth response was higher in VAL study. Direct genotype analysis did not replicate what was found in the LTFU study. However, using exploratory regression models with covariates, a consistent relationship with growth response in both VAL and LTFU was shown for four genes - SOS1 and INPPL1 in GHD and ESR1 and PTPN1 in TS. The random forest analysis demonstrated that only clinical covariates were important in the prediction of growth response in mild GHD (>4 to <10 μg/L on GH stimulation test), however, in severe GHD (≤4 μg/L) several SNPs contributed (in IGF2, GRB10, FOS, IGFBP3 and GHRHR). The PREDICT validation study supports, in an independent cohort, the association of four of 48 genetic markers with growth response to r-hGH treatment in both pre-pubertal GHD and TS children after controlling for clinical/auxological covariates. However, the contribution of these SNPs in a prediction model of first-year response is not sufficient for routine clinical use. © 2016 European Society of Endocrinology.

An investigation of human body model morphing for the assessment of abdomen responses to impact against a population of test subjects.

PubMed

Beillas, Philippe; Berthet, Fabien

2017-05-29

Human body models have the potential to better describe the human anatomy and variability than dummies. However, data sets available to verify the human response to impact are typically limited in numbers, and they are not size or gender specific. The objective of this study was to investigate the use of model morphing methodologies within that context. In this study, a simple human model scaling methodology was developed to morph two detailed human models (Global Human Body Model Consortium models 50th male, M50, and 5th female, F05) to the dimensions of post mortem human surrogates (PMHS) used in published literature. The methodology was then successfully applied to 52 PMHS tested in 14 impact conditions loading the abdomen. The corresponding 104 simulations were compared to the responses of the PMHS and to the responses of the baseline models without scaling (28 simulations). The responses were analysed using the CORA method and peak values. The results suggest that model scaling leads to an improvement of the predicted force and deflection but has more marginal effects on the predicted abdominal compressions. M50 and F05 models scaled to the same PMHS were also found to have similar external responses, but large differences were found between the two sets of models for the strain energy densities in the liver and the spleen for mid-abdomen impact simulations. These differences, which were attributed to the anatomical differences in the abdomen of the baseline models, highlight the importance of the selection of the impact condition for simulation studies, especially if the organ location is not known in the test. While the methodology could be further improved, it shows the feasibility of using model scaling methodologies to compare human models of different sizes and to evaluate scaling approaches within the context of human model validation.

Development of Newborn and Infant Vaccines

PubMed Central

Sanchez-Schmitz, Guzman; Levy, Ofer

2014-01-01

Vaccines for early-life immunization are a crucial biomedical intervention to reduce global morbidity and mortality, yet their developmental path has been largely ad hoc, empiric, and inconsistent. Immune responses of human newborns and infants are distinct and cannot be predicted from those of human adults or animal models. Therefore, understanding and modeling age-specific human immune responses will be vital to the rational design and development of safe and effective vaccines for newborns and infants. PMID:21734174

A human life-stage physiologically based pharmacokinetic and pharmacodynamic model for chlorpyrifos: development and validation.

PubMed

Smith, Jordan Ned; Hinderliter, Paul M; Timchalk, Charles; Bartels, Michael J; Poet, Torka S

2014-08-01

Sensitivity to some chemicals in animals and humans are known to vary with age. Age-related changes in sensitivity to chlorpyrifos have been reported in animal models. A life-stage physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was developed to predict disposition of chlorpyrifos and its metabolites, chlorpyrifos-oxon (the ultimate toxicant) and 3,5,6-trichloro-2-pyridinol (TCPy), as well as B-esterase inhibition by chlorpyrifos-oxon in humans. In this model, previously measured age-dependent metabolism of chlorpyrifos and chlorpyrifos-oxon were integrated into age-related descriptions of human anatomy and physiology. The life-stage PBPK/PD model was calibrated and tested against controlled adult human exposure studies. Simulations suggest age-dependent pharmacokinetics and response may exist. At oral doses ⩾0.6mg/kg of chlorpyrifos (100- to 1000-fold higher than environmental exposure levels), 6months old children are predicted to have higher levels of chlorpyrifos-oxon in blood and higher levels of red blood cell cholinesterase inhibition compared to adults from equivalent doses. At lower doses more relevant to environmental exposures, simulations predict that adults will have slightly higher levels of chlorpyrifos-oxon in blood and greater cholinesterase inhibition. This model provides a computational framework for age-comparative simulations that can be utilized to predict chlorpyrifos disposition and biological response over various postnatal life stages. Copyright © 2013 Elsevier Inc. All rights reserved.

Human oocyte calcium analysis predicts the response to assisted oocyte activation in patients experiencing fertilization failure after ICSI.

PubMed

Ferrer-Buitrago, M; Dhaenens, L; Lu, Y; Bonte, D; Vanden Meerschaut, F; De Sutter, P; Leybaert, L; Heindryckx, B

2018-01-10

Can human oocyte calcium analysis predict fertilization success after assisted oocyte activation (AOA) in patients experiencing fertilization failure after ICSI? ICSI-AOA restores the fertilization rate only in patients displaying abnormal Ca2+ oscillations during human oocyte activation. Patients capable of activating mouse oocytes and who showed abnormal Ca2+ profiles after mouse oocyte Ca2+ analysis (M-OCA), have variable responses to ICSI-AOA. It remains unsettled whether human oocyte Ca2+ analysis (H-OCA) would yield an improved accuracy to predict fertilization success after ICSI-AOA. Sperm activation potential was first evaluated by MOAT. Subsequently, Ca2+ oscillatory patterns were determined with sperm from patients showing moderate to normal activation potential based on the capacity of human sperm to generate Ca2+ responses upon microinjection in mouse and human oocytes. Altogether, this study includes a total of 255 mouse and 122 human oocytes. M-OCA was performed with 16 different sperm samples before undergoing ICSI-AOA treatment. H-OCA was performed for 11 patients who finally underwent ICSI-AOA treatment. The diagnostic accuracy to predict fertilization success was calculated based on the response to ICSI-AOA. Patients experiencing low or total failed fertilization after conventional ICSI were included in the study. All participants showed moderate to high rates of activation after MOAT. Metaphase II (MII) oocytes from B6D2F1 mice were used for M-OCA. Control fertile sperm samples were used to obtain a reference Ca2+ oscillation profile elicited in human oocytes. Donated human oocytes, non-suitable for IVF treatments, were collected and vitrified at MII stage for further analysis by H-OCA. M-OCA and H-OCA predicted the response to ICSI-AOA in 8 out of 11 (73%) patients. Compared to M-OCA, H-OCA detected the presence of sperm activation deficiencies with greater sensitivity (75 vs 100%, respectively). ICSI-AOA never showed benefit to overcome fertilization failure in patients showing normal capacity to generate Ca2+ oscillations in H-OCA and was likely to be beneficial in cases displaying abnormal H-OCA Ca2+ oscillations patterns. The scarce availability of human oocytes donated for research purposes is a limiting factor to perform H-OCA. Ca2+ imaging requires specific equipment to monitor fluorescence changes over time. H-OCA is a sensitive test to diagnose gamete-linked fertilization failure. H-OCA allows treatment counseling for couples experiencing ICSI failures to either undergo ICSI-AOA or to participate in gamete donation programs. The present data provide an important template of the Ca2+ signature observed during human fertilization in cases with normal, low and failed fertilization after conventional ICSI. This work was supported by the Flemish fund for scientific research (FWO-Vlaanderen, G060615N). The authors have no conflict of interest to declare. © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Improving in vitro to in vivo extrapolation by incorporating toxicokinetic measurements: A case study of lindane-induced neurotoxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Croom, Edward L.; Shafer, Timothy J.; Evans, Marina V.

Approaches for extrapolating in vitro toxicity testing results for prediction of human in vivo outcomes are needed. The purpose of this case study was to employ in vitro toxicokinetics and PBPK modeling to perform in vitro to in vivo extrapolation (IVIVE) of lindane neurotoxicity. Lindane cell and media concentrations in vitro, together with in vitro concentration-response data for lindane effects on neuronal network firing rates, were compared to in vivo data and model simulations as an exercise in extrapolation for chemical-induced neurotoxicity in rodents and humans. Time- and concentration-dependent lindane dosimetry was determined in primary cultures of rat cortical neuronsmore » in vitro using “faux” (without electrodes) microelectrode arrays (MEAs). In vivo data were derived from literature values, and physiologically based pharmacokinetic (PBPK) modeling was used to extrapolate from rat to human. The previously determined EC{sub 50} for increased firing rates in primary cultures of cortical neurons was 0.6 μg/ml. Media and cell lindane concentrations at the EC{sub 50} were 0.4 μg/ml and 7.1 μg/ml, respectively, and cellular lindane accumulation was time- and concentration-dependent. Rat blood and brain lindane levels during seizures were 1.7–1.9 μg/ml and 5–11 μg/ml, respectively. Brain lindane levels associated with seizures in rats and those predicted for humans (average = 7 μg/ml) by PBPK modeling were very similar to in vitro concentrations detected in cortical cells at the EC{sub 50} dose. PBPK model predictions matched literature data and timing. These findings indicate that in vitro MEA results are predictive of in vivo responses to lindane and demonstrate a successful modeling approach for IVIVE of rat and human neurotoxicity. - Highlights: • In vitro to in vivo extrapolation for lindane neurotoxicity was performed. • Dosimetry of lindane in a micro-electrode array (MEA) test system was assessed. • Cell concentrations at the MEA EC{sub 50} equaled rat brain levels associated with seizure. • PBPK-predicted human brain levels at seizure also equaled EC{sub 50} cell concentrations. • In vitro MEA results are predictive of lindane in vivo dose–response in rats/humans.« less

EPA perspective - exposure and effects prediction and monitoring

EPA Science Inventory

Risk-based decisions for environmental chemicals often rely on estimates of human exposure and biological response. Biomarkers have proven a useful empirical tool for evaluating exposure and hazard predictions. In the United States, the Centers for Disease Control and Preventio...

An experimental design for quantification of cardiovascular responses to music stimuli in humans.

PubMed

Chang, S-H; Luo, C-H; Yeh, T-L

2004-01-01

There have been several researches on the relationship between music and human physiological or psychological responses. However, there are cardiovascular index factors that have not been explored quantitatively due to the qualitative nature of acoustic stimuli. This study proposes and demonstrates an experimental design for quantification of cardiovascular responses to music stimuli in humans. The system comprises two components: a unit for generating and monitoring quantitative acoustic stimuli and a portable autonomic nervous system (ANS) analysis unit for quantitative recording and analysis of the cardiovascular responses. The experimental results indicate that the proposed system can exactly achieve the goal of full control and measurement for the music stimuli, and also effectively support many quantitative indices of cardiovascular response in humans. In addition, the analysis results are discussed and predicted in the future clinical research.

Increased startle potentiation to unpredictable stressors in alcohol dependence: Possible stress neuroadaptation in humans

PubMed Central

Moberg, Christine A.; Bradford, Daniel E.; Kaye, Jesse T.; Curtin, John J.

2017-01-01

Stress plays a key role in addiction etiology and relapse. Rodent models posit that following repeated periods of alcohol and other drug intoxication, compensatory allostatic changes occur in the central nervous system (CNS) circuits involved in behavioral and emotional response to stressors. We examine a predicted manifestation of this neuroadaptation in recently abstinent alcohol dependent humans. Participants completed a translational laboratory task that uses startle potentiation to unpredictable (vs. predictable) stressors implicated in the putative CNS mechanisms that mediate this neuroadaptation. Alcohol dependent participants displayed significantly greater startle potentiation to unpredictable than predictable stressors relative to non-alcoholic controls. The size of this effect covaried with alcohol-related problems and degree of withdrawal syndrome. This supports the rodent model thesis of a sensitized stress response in abstinent alcoholics. However, this effect could also represent pre-morbid risk or mark more severe and/or comorbid psychopathology. Regardless, pharmacotherapy and psychological interventions may target unpredictable stressor response to reduce stress-induced relapse. PMID:28394145

Theory of Mind: A Neural Prediction Problem

PubMed Central

Koster-Hale, Jorie; Saxe, Rebecca

2014-01-01

Predictive coding posits that neural systems make forward-looking predictions about incoming information. Neural signals contain information not about the currently perceived stimulus, but about the difference between the observed and the predicted stimulus. We propose to extend the predictive coding framework from high-level sensory processing to the more abstract domain of theory of mind; that is, to inferences about others’ goals, thoughts, and personalities. We review evidence that, across brain regions, neural responses to depictions of human behavior, from biological motion to trait descriptions, exhibit a key signature of predictive coding: reduced activity to predictable stimuli. We discuss how future experiments could distinguish predictive coding from alternative explanations of this response profile. This framework may provide an important new window on the neural computations underlying theory of mind. PMID:24012000

Dissociable Learning Processes Underlie Human Pain Conditioning

PubMed Central

Zhang, Suyi; Mano, Hiroaki; Ganesh, Gowrishankar; Robbins, Trevor; Seymour, Ben

2016-01-01

Summary Pavlovian conditioning underlies many aspects of pain behavior, including fear and threat detection [1], escape and avoidance learning [2], and endogenous analgesia [3]. Although a central role for the amygdala is well established [4], both human and animal studies implicate other brain regions in learning, notably ventral striatum and cerebellum [5]. It remains unclear whether these regions make different contributions to a single aversive learning process or represent independent learning mechanisms that interact to generate the expression of pain-related behavior. We designed a human parallel aversive conditioning paradigm in which different Pavlovian visual cues probabilistically predicted thermal pain primarily to either the left or right arm and studied the acquisition of conditioned Pavlovian responses using combined physiological recordings and fMRI. Using computational modeling based on reinforcement learning theory, we found that conditioning involves two distinct types of learning process. First, a non-specific “preparatory” system learns aversive facial expressions and autonomic responses such as skin conductance. The associated learning signals—the learned associability and prediction error—were correlated with fMRI brain responses in amygdala-striatal regions, corresponding to the classic aversive (fear) learning circuit. Second, a specific lateralized system learns “consummatory” limb-withdrawal responses, detectable with electromyography of the arm to which pain is predicted. Its related learned associability was correlated with responses in ipsilateral cerebellar cortex, suggesting a novel computational role for the cerebellum in pain. In conclusion, our results show that the overall phenotype of conditioned pain behavior depends on two dissociable reinforcement learning circuits. PMID:26711494

Chimpanzee choice rates in competitive games match equilibrium game theory predictions.

PubMed

Martin, Christopher Flynn; Bhui, Rahul; Bossaerts, Peter; Matsuzawa, Tetsuro; Camerer, Colin

2014-06-05

The capacity for strategic thinking about the payoff-relevant actions of conspecifics is not well understood across species. We use game theory to make predictions about choices and temporal dynamics in three abstract competitive situations with chimpanzee participants. Frequencies of chimpanzee choices are extremely close to equilibrium (accurate-guessing) predictions, and shift as payoffs change, just as equilibrium theory predicts. The chimpanzee choices are also closer to the equilibrium prediction, and more responsive to past history and payoff changes, than two samples of human choices from experiments in which humans were also initially uninformed about opponent payoffs and could not communicate verbally. The results are consistent with a tentative interpretation of game theory as explaining evolved behavior, with the additional hypothesis that chimpanzees may retain or practice a specialized capacity to adjust strategy choice during competition to perform at least as well as, or better than, humans have.

KRAS Genomic Status Predicts the Sensitivity of Ovarian Cancer Cells to Decitabine | Office of Cancer Genomics

Cancer.gov

Decitabine, a cancer therapeutic that inhibits DNA methylation, produces variable antitumor response rates in patients with solid tumors that might be leveraged clinically with identification of a predictive biomarker. In this study, we profiled the response of human ovarian, melanoma, and breast cancer cells treated with decitabine, finding that RAS/MEK/ERK pathway activation and DNMT1 expression correlated with cytotoxic activity. Further, we showed that KRAS genomic status predicted decitabine sensitivity in low-grade and high-grade serous ovarian cancer cells.

Diversifying Selection Analysis Predicts Antigenic Evolution of 2009 Pandemic H1N1 Influenza A Virus in Humans.

PubMed

Lee, Alexandra J; Das, Suman R; Wang, Wei; Fitzgerald, Theresa; Pickett, Brett E; Aevermann, Brian D; Topham, David J; Falsey, Ann R; Scheuermann, Richard H

2015-05-01

Although a large number of immune epitopes have been identified in the influenza A virus (IAV) hemagglutinin (HA) protein using various experimental systems, it is unclear which are involved in protective immunity to natural infection in humans. We developed a data mining approach analyzing natural H1N1 human isolates to identify HA protein regions that may be targeted by the human immune system and can predict the evolution of IAV. We identified 16 amino acid sites experiencing diversifying selection during the evolution of prepandemic seasonal H1N1 strains and found that 11 sites were located in experimentally determined B-cell/antibody (Ab) epitopes, including three distinct neutralizing Caton epitopes: Sa, Sb, and Ca2 [A. J. Caton, G. G. Brownlee, J. W. Yewdell, and W. Gerhard, Cell 31:417-427, 1982, http://dx.doi.org/10.1016/0092-8674(82)90135-0]. We predicted that these diversified epitope regions would be the targets of mutation as the 2009 H1N1 pandemic (pH1N1) lineage evolves in response to the development of population-level protective immunity in humans. Using a chi-squared goodness-of-fit test, we identified 10 amino acid sites that significantly differed between the pH1N1 isolates and isolates from the recent 2012-2013 and 2013-2014 influenza seasons. Three of these sites were located in the same diversified B-cell/Ab epitope regions as identified in the analysis of prepandemic sequences, including Sa and Sb. As predicted, hemagglutination inhibition (HI) assays using human sera from subjects vaccinated with the initial pH1N1 isolate demonstrated reduced reactivity against 2013-2014 isolates. Taken together, these results suggest that diversifying selection analysis can identify key immune epitopes responsible for protective immunity to influenza virus in humans and thereby predict virus evolution. The WHO estimates that approximately 5 to 10% of adults and 20 to 30% of children in the world are infected by influenza virus each year. While an adaptive immune response helps eliminate the virus following acute infection, the virus rapidly evolves to evade the established protective memory immune response, thus allowing for the regular seasonal cycles of influenza virus infection. The analytical approach described here, which combines an analysis of diversifying selection with an integration of immune epitope data, has allowed us to identify antigenic regions that contribute to protective immunity and are therefore the key targets of immune evasion by the virus. This information can be used to determine when sequence variations in seasonal influenza virus strains have affected regions responsible for protective immunity in order to decide when new vaccine formulations are warranted. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Comparison of in vitro eye irritation potential by bovine corneal opacity and permeability (BCOP) assay to erythema scores in human eye sting test of surfactant-based formulations.

PubMed

Cater, Kathleen C; Harbell, John W

2008-01-01

The bovine corneal opacity and permeability (BCOP) assay can be used to predict relative eye irritation potential of surfactant-based personal care formulations relative to a corporate benchmark. The human eye sting test is typically used to evaluate product claims of no tears/no stinging for children's bath products. A preliminary investigation was conducted to test a hypothesis that the BCOP assay could be used as a prediction model for relative ranking of human eye irritation responses under conditions of a standard human eye sting test to surfactant-based formulations. BCOP assays and human eye sting tests were conducted on 4 commercial and 1 prototype body wash (BW) developed specifically for children or as mild bath products. In the human eye sting test, 10 mul of a 10% dosing solution is instilled into one eye of each panelist (n = 20), and the contralateral eye is dosed with sterile water as a control. Bulbar conjunctival erythema responses of each eye are graded at 30 seconds by an ophthalmologist. The BCOP assay permeability values (optical density at 490 nm [OD(490)]) for the 5 BWs ranged from 0.438 to 1.252 (i.e., least to most irritating). By comparison, the number of panelists exhibiting erythema responses (mild to moderately pink) ranged from 3 of 20 panelists for the least irritating BW to 10 of 20 panelists for the most irritating BW tested. The relative ranking of eye irritation potential of the 5 BWs in the BCOP assay compares favorably with the relative ranking of the BWs in the human eye sting test. Based on these findings, the permeability endpoint of the BCOP assay, as described for surfactant-based formulations, showed promise as a prediction model for relative ranking of conjunctival erythema responses in the human eye. Consequently, screening of prototype formulations in the BCOP assay would allow for formula optimization of mild bath products prior to investment in a human eye sting test.

Predictors of immune function in space flight

NASA Astrophysics Data System (ADS)

Shearer, William T.; Zhang, Shaojie; Reuben, James M.; Lee, Bang-Ning; Butel, Janet S.

2007-02-01

Of all of the environmental conditions of space flight that might have an adverse effect upon human immunity and the incidence of infection, space radiation stands out as the single-most important threat. As important as this would be on humans engaged in long and deep space flight, it obviously is not possible to plan Earth-bound radiation and infection studies in humans. Therefore, we propose to develop a murine model that could predict the adverse effects of space flight radiation and reactivation of latent virus infection for humans. Recent observations on the effects of gamma and latent virus infection demonstrate latent virus reactivation and loss of T cell mediated immune responses in a murine model. We conclude that using this small animal method of quantitating the amounts of radiation and latent virus infection and resulting alterations in immune responses, it may be possible to predict the degree of immunosuppression in interplanetary space travel for humans. Moreover, this model could be extended to include other space flight conditions, such as microgravity, sleep deprivation, and isolation, to obtain a more complete assessment of space flight risks for humans.

[Prediction of the molecular response to pertubations from single cell measurements].

PubMed

Remacle, Françoise; Levine, Raphael D

2014-12-01

The response of protein signalization networks to perturbations is analysed from single cell measurements. This experimental approach allows characterizing the fluctuations in protein expression levels from cell to cell. The analysis is based on an information theoretic approach grounded in thermodynamics leading to a quantitative version of Le Chatelier principle which allows to predict the molecular response. Two systems are investigated: human macrophages subjected to lipopolysaccharide challenge, analogous to the immune response against Gram-negative bacteria and the response of the proteins involved in the mTOR signalizing network of GBM cancer cells to changes in partial oxygen pressure. © 2014 médecine/sciences – Inserm.

Development, Testing, and Validation of a Model-Based Tool to Predict Operator Responses in Unexpected Workload Transitions

NASA Technical Reports Server (NTRS)

Sebok, Angelia; Wickens, Christopher; Sargent, Robert

2015-01-01

One human factors challenge is predicting operator performance in novel situations. Approaches such as drawing on relevant previous experience, and developing computational models to predict operator performance in complex situations, offer potential methods to address this challenge. A few concerns with modeling operator performance are that models need to realistic, and they need to be tested empirically and validated. In addition, many existing human performance modeling tools are complex and require that an analyst gain significant experience to be able to develop models for meaningful data collection. This paper describes an effort to address these challenges by developing an easy to use model-based tool, using models that were developed from a review of existing human performance literature and targeted experimental studies, and performing an empirical validation of key model predictions.

Driver Vision Based Perception-Response Time Prediction and Assistance Model on Mountain Highway Curve.

PubMed

Li, Yi; Chen, Yuren

2016-12-30

To make driving assistance system more humanized, this study focused on the prediction and assistance of drivers' perception-response time on mountain highway curves. Field tests were conducted to collect real-time driving data and driver vision information. A driver-vision lane model quantified curve elements in drivers' vision. A multinomial log-linear model was established to predict perception-response time with traffic/road environment information, driver-vision lane model, and mechanical status (last second). A corresponding assistance model showed a positive impact on drivers' perception-response times on mountain highway curves. Model results revealed that the driver-vision lane model and visual elements did have important influence on drivers' perception-response time. Compared with roadside passive road safety infrastructure, proper visual geometry design, timely visual guidance, and visual information integrality of a curve are significant factors for drivers' perception-response time.

Expanded Prediction Equations of Human Sweat Loss and Water Needs

DTIC Science & Technology

2009-01-01

Evaluation of the limits to accurate sweat loss prediction during prolonged exercise. Eur J Appl Physiol 101: 215–224, 2007. 4. Chinevere TD ...113–117, 2001. 17. Miller RG. Simultaneous Statistical Interference (2nd ed.). New York: Springer, 1981. 18. Mitchell JW, Nadel ER, Stolwijk JAJ ...modeling of physiological responses and human performance in the heat. Comput Biol Med 16: 319–329, 1986. 20. Saltin B, Gagge AP, Stolwijk JAJ . Body

A competitive binding model predicts the response of mammalian olfactory receptors to mixtures

NASA Astrophysics Data System (ADS)

Singh, Vijay; Murphy, Nicolle; Mainland, Joel; Balasubramanian, Vijay

Most natural odors are complex mixtures of many odorants, but due to the large number of possible mixtures only a small fraction can be studied experimentally. To get a realistic understanding of the olfactory system we need methods to predict responses to complex mixtures from single odorant responses. Focusing on mammalian olfactory receptors (ORs in mouse and human), we propose a simple biophysical model for odor-receptor interactions where only one odor molecule can bind to a receptor at a time. The resulting competition for occupancy of the receptor accounts for the experimentally observed nonlinear mixture responses. We first fit a dose-response relationship to individual odor responses and then use those parameters in a competitive binding model to predict mixture responses. With no additional parameters, the model predicts responses of 15 (of 18 tested) receptors to within 10 - 30 % of the observed values, for mixtures with 2, 3 and 12 odorants chosen from a panel of 30. Extensions of our basic model with odorant interactions lead to additional nonlinearities observed in mixture response like suppression, cooperativity, and overshadowing. Our model provides a systematic framework for characterizing and parameterizing such mixing nonlinearities from mixture response data.

A Bayesian network approach to predicting nest presence of thefederally-threatened piping plover (Charadrius melodus) using barrier island features

USGS Publications Warehouse

Gieder, Katherina D.; Karpanty, Sarah M.; Fraser, James D.; Catlin, Daniel H.; Gutierrez, Benjamin T.; Plant, Nathaniel G.; Turecek, Aaron M.; Thieler, E. Robert

2014-01-01

Sea-level rise and human development pose significant threats to shorebirds, particularly for species that utilize barrier island habitat. The piping plover (Charadrius melodus) is a federally-listed shorebird that nests on barrier islands and rapidly responds to changes in its physical environment, making it an excellent species with which to model how shorebird species may respond to habitat change related to sea-level rise and human development. The uncertainty and complexity in predicting sea-level rise, the responses of barrier island habitats to sea-level rise, and the responses of species to sea-level rise and human development necessitate a modelling approach that can link species to the physical habitat features that will be altered by changes in sea level and human development. We used a Bayesian network framework to develop a model that links piping plover nest presence to the physical features of their nesting habitat on a barrier island that is impacted by sea-level rise and human development, using three years of data (1999, 2002, and 2008) from Assateague Island National Seashore in Maryland. Our model performance results showed that we were able to successfully predict nest presence given a wide range of physical conditions within the model’s dataset. We found that model predictions were more successful when the range of physical conditions included in model development was varied rather than when those physical conditions were narrow. We also found that all model predictions had fewer false negatives (nests predicted to be absent when they were actually present in the dataset) than false positives (nests predicted to be present when they were actually absent in the dataset), indicating that our model correctly predicted nest presence better than nest absence. These results indicated that our approach of using a Bayesian network to link specific physical features to nest presence will be useful for modelling impacts of sea-level rise- or human-related habitat change on barrier islands. We recommend that potential users of this method utilize multiple years of data that represent a wide range of physical conditions in model development, because the model performed less well when constructed using a narrow range of physical conditions. Further, given that there will always be some uncertainty in predictions of future physical habitat conditions related to sea-level rise and/or human development, predictive models will perform best when developed using multiple, varied years of data input.

Isolation predicts compositional change after discrete disturbances in a global meta-study

USDA-ARS?s Scientific Manuscript database

Globally, anthropogenic disturbances are occurring at unprecedented rates and over extensive spatial and temporal scales. Human activities also affect natural disturbances, prompting shifts in their timing and intensities. Thus, there is an urgent need to understand and predict the response of ecosy...

Predicting Adaptive Response to Fadrozole Exposure:Computational Model of the Fathead MinnowsHypothalamic-Pituitary-Gonadal Axis

EPA Science Inventory

Exposure to endocrine disrupting chemicals can affect reproduction and development in both humans and wildlife. We are developing a mechanistic mathematical model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict doseresponse and time-course (...

Predicting Career Advancement with Structural Equation Modelling

ERIC Educational Resources Information Center

Heimler, Ronald; Rosenberg, Stuart; Morote, Elsa-Sofia

2012-01-01

Purpose: The purpose of this paper is to use the authors' prior findings concerning basic employability skills in order to determine which skills best predict career advancement potential. Design/methodology/approach: Utilizing survey responses of human resource managers, the employability skills showing the largest relationships to career…

Validation of Shoulder Response of Human Body Finite-Element Model (GHBMC) Under Whole Body Lateral Impact Condition.

PubMed

Park, Gwansik; Kim, Taewung; Panzer, Matthew B; Crandall, Jeff R

2016-08-01

In previous shoulder impact studies, the 50th-percentile male GHBMC human body finite-element model was shown to have good biofidelity regarding impact force, but under-predicted shoulder deflection by 80% compared to those observed in the experiment. The goal of this study was to validate the response of the GHBMC M50 model by focusing on three-dimensional shoulder kinematics under a whole-body lateral impact condition. Five modifications, focused on material properties and modeling techniques, were introduced into the model and a supplementary sensitivity analysis was done to determine the influence of each modification to the biomechanical response of the body. The modified model predicted substantially improved shoulder response and peak shoulder deflection within 10% of the observed experimental data, and showed good correlation in the scapula kinematics on sagittal and transverse planes. The improvement in the biofidelity of the shoulder region was mainly due to the modifications of material properties of muscle, the acromioclavicular joint, and the attachment region between the pectoralis major and ribs. Predictions of rib fracture and chest deflection were also improved because of these modifications.

Mechanisms of Dietary Response in Mice and Primates: A Role for EGR1 in Regulating the Reaction to Human-Specific Nutritional Content

PubMed Central

Weng, Kai; Hu, Haiyang; Xu, Augix Guohua; Khaitovich, Philipp; Somel, Mehmet

2012-01-01

Background Humans have a widely different diet from other primate species, and are dependent on its high nutritional content. The molecular mechanisms responsible for adaptation to the human diet are currently unknown. Here, we addressed this question by investigating whether the gene expression response observed in mice fed human and chimpanzee diets involves the same regulatory mechanisms as expression differences between humans and chimpanzees. Results Using mouse and primate transcriptomic data, we identified the transcription factor EGR1 (early growth response 1) as a putative regulator of diet-related differential gene expression between human and chimpanzee livers. Specifically, we predict that EGR1 regulates the response to the high caloric content of human diets. However, we also show that close to 90% of the dietary response to the primate diet found in mice, is not observed in primates. This might be explained by changes in tissue-specific gene expression between taxa. Conclusion Our results suggest that the gene expression response to the nutritionally rich human diet is partially mediated by the transcription factor EGR1. While this EGR1-driven response is conserved between mice and primates, the bulk of the mouse response to human and chimpanzee dietary differences is not observed in primates. This result highlights the rapid evolution of diet-related expression regulation and underscores potential limitations of mouse models in dietary studies. PMID:22937124

Automating Content Analysis of Open-Ended Responses: Wordscores and Affective Intonation

PubMed Central

Baek, Young Min; Cappella, Joseph N.; Bindman, Alyssa

2014-01-01

This study presents automated methods for predicting valence and quantifying valenced thoughts of a text. First, it examines whether Wordscores, developed by Laver, Benoit, and Garry (2003), can be adapted to reliably predict the valence of open-ended responses in a survey about bioethical issues in genetics research, and then tests a complementary and novel technique for coding the number of valenced thoughts in open-ended responses, termed Affective Intonation. Results show that Wordscores successfully predicts the valence of brief and grammatically imperfect open-ended responses, and Affective Intonation achieves comparable performance to human coders when estimating number of valenced thoughts. Both Wordscores and Affective Intonation have promise as reliable, effective, and efficient methods when researchers content-analyze large amounts of textual data systematically. PMID:25558294

Simple Learned Weighted Sums of Inferior Temporal Neuronal Firing Rates Accurately Predict Human Core Object Recognition Performance

PubMed Central

Hong, Ha; Solomon, Ethan A.; DiCarlo, James J.

2015-01-01

To go beyond qualitative models of the biological substrate of object recognition, we ask: can a single ventral stream neuronal linking hypothesis quantitatively account for core object recognition performance over a broad range of tasks? We measured human performance in 64 object recognition tests using thousands of challenging images that explore shape similarity and identity preserving object variation. We then used multielectrode arrays to measure neuronal population responses to those same images in visual areas V4 and inferior temporal (IT) cortex of monkeys and simulated V1 population responses. We tested leading candidate linking hypotheses and control hypotheses, each postulating how ventral stream neuronal responses underlie object recognition behavior. Specifically, for each hypothesis, we computed the predicted performance on the 64 tests and compared it with the measured pattern of human performance. All tested hypotheses based on low- and mid-level visually evoked activity (pixels, V1, and V4) were very poor predictors of the human behavioral pattern. However, simple learned weighted sums of distributed average IT firing rates exactly predicted the behavioral pattern. More elaborate linking hypotheses relying on IT trial-by-trial correlational structure, finer IT temporal codes, or ones that strictly respect the known spatial substructures of IT (“face patches”) did not improve predictive power. Although these results do not reject those more elaborate hypotheses, they suggest a simple, sufficient quantitative model: each object recognition task is learned from the spatially distributed mean firing rates (100 ms) of ∼60,000 IT neurons and is executed as a simple weighted sum of those firing rates. SIGNIFICANCE STATEMENT We sought to go beyond qualitative models of visual object recognition and determine whether a single neuronal linking hypothesis can quantitatively account for core object recognition behavior. To achieve this, we designed a database of images for evaluating object recognition performance. We used multielectrode arrays to characterize hundreds of neurons in the visual ventral stream of nonhuman primates and measured the object recognition performance of >100 human observers. Remarkably, we found that simple learned weighted sums of firing rates of neurons in monkey inferior temporal (IT) cortex accurately predicted human performance. Although previous work led us to expect that IT would outperform V4, we were surprised by the quantitative precision with which simple IT-based linking hypotheses accounted for human behavior. PMID:26424887

Determination of Human Hepatic CYP2C8 and CYP1A2 Age-Dependent Expression to Support Human Health Risk Assessment for Early Ages

EPA Science Inventory

Predicting age-specific metabolism is important for evaluating age-related drug and chemical sensitivity. Multiple cytochrome P450s and carboxylesterase enzymes are responsible for human pyrethroid metabolism. Complete ontogeny data for each enzyme are needed to support in vitro ...

The structure of distractor-response bindings: Conditions for configural and elemental integration.

PubMed

Moeller, Birte; Frings, Christian; Pfister, Roland

2016-04-01

Human action control is influenced by bindings between perceived stimuli and responses carried out in their presence. Notably, responses given to a target stimulus can also be integrated with additional response-irrelevant distractor stimuli that accompany the target (distractor-response binding). Subsequently reencountering such a distractor then retrieves the associated response. Although a large body of evidence supports the existence of this effect, the specific structure of distractor-response bindings is still unclear. Here, we test the predictions derived from 2 possible assumptions about the structure of bindings between distractors and responses. According to a configural approach, the entire distractor object is integrated with a response, and only upon repetition of the entire distractor object the associated response would be retrieved. According to an elemental approach, one would predict integration of individual distractor features with the response and retrieval due to the repetition of an individual distractor feature. Four experiments indicate that both, configural and elemental bindings exist and specify boundary conditions for each type of binding. These findings provide detailed insights into the architecture of bindings between response-irrelevant stimuli and actions and thus allow for specifying how distractor stimuli influence human behavior. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Adaptive Response in Female Modeling of the Hypothalamic-pituitary-gonadal Axis

EPA Science Inventory

Exposure to endocrine disrupting chemicals can affect reproduction and development in both humans and wildlife. We are developing a mechanistic computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict dose-response and time-course ...

Rational Design of Mouse Models for Cancer Research.

PubMed

Landgraf, Marietta; McGovern, Jacqui A; Friedl, Peter; Hutmacher, Dietmar W

2018-03-01

The laboratory mouse is widely considered as a valid and affordable model organism to study human disease. Attempts to improve the relevance of murine models for the investigation of human pathologies led to the development of various genetically engineered, xenograft and humanized mouse models. Nevertheless, most preclinical studies in mice suffer from insufficient predictive value when compared with cancer biology and therapy response of human patients. We propose an innovative strategy to improve the predictive power of preclinical cancer models. Combining (i) genomic, tissue engineering and regenerative medicine approaches for rational design of mouse models with (ii) rapid prototyping and computational benchmarking against human clinical data will enable fast and nonbiased validation of newly generated models. Copyright © 2017 Elsevier Ltd. All rights reserved.

In vitro cytotoxicity testing of 30 reference chemicals to predict acute human and animal toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barile, F.A.; Arjun, S.; Borges, L.

1991-03-11

This study was conducted in cooperation with the Scandinavian Society of Cell Toxicology, as part of the Multicenter Evaluation for In Vitro Cytotoxicity (MEIC), and was designed to develop an in vitro model for predicting acute human and animal toxicity. The technique relies on the ability of cultured transformed rat lung epithelial cells (L2) to incorporate radiolabled amino acids into newly synthesized proteins in the absence or presence of increasing doses of the test chemical, during a 24-hr incubation. IC50 values were extrapolated from the dose-response curves after linear regression analysis. Human toxic blood concentrations estimated from rodent LD50 valuesmore » suggest that our experimental IC50's are in close correlation with the former. Validation of the data by the MEIC committee shows that our IC50 values predicted human lethal dosage as efficient as rodent LD50's. It is anticipated that this and related procedures may supplement or replace currently used animal protocols for predicting human toxicity.« less

Dissociable Learning Processes Underlie Human Pain Conditioning.

PubMed

Zhang, Suyi; Mano, Hiroaki; Ganesh, Gowrishankar; Robbins, Trevor; Seymour, Ben

2016-01-11

Pavlovian conditioning underlies many aspects of pain behavior, including fear and threat detection [1], escape and avoidance learning [2], and endogenous analgesia [3]. Although a central role for the amygdala is well established [4], both human and animal studies implicate other brain regions in learning, notably ventral striatum and cerebellum [5]. It remains unclear whether these regions make different contributions to a single aversive learning process or represent independent learning mechanisms that interact to generate the expression of pain-related behavior. We designed a human parallel aversive conditioning paradigm in which different Pavlovian visual cues probabilistically predicted thermal pain primarily to either the left or right arm and studied the acquisition of conditioned Pavlovian responses using combined physiological recordings and fMRI. Using computational modeling based on reinforcement learning theory, we found that conditioning involves two distinct types of learning process. First, a non-specific "preparatory" system learns aversive facial expressions and autonomic responses such as skin conductance. The associated learning signals-the learned associability and prediction error-were correlated with fMRI brain responses in amygdala-striatal regions, corresponding to the classic aversive (fear) learning circuit. Second, a specific lateralized system learns "consummatory" limb-withdrawal responses, detectable with electromyography of the arm to which pain is predicted. Its related learned associability was correlated with responses in ipsilateral cerebellar cortex, suggesting a novel computational role for the cerebellum in pain. In conclusion, our results show that the overall phenotype of conditioned pain behavior depends on two dissociable reinforcement learning circuits. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Novelty response and 50 kHz ultrasonic vocalizations: Differential prediction of locomotor and affective response to amphetamine in Sprague-Dawley rats.

PubMed

Garcia, Erik J; Cain, Mary E

2016-02-01

Novelty and sensation seeking (NSS) predisposes humans and rats to experiment with psychostimulants. In animal models, different tests of NSS predict different phases of drug dependence. Ultrasonic vocalizations (USVs) are evoked by psychomotor stimulants and measure the affective/motivation response to stimuli, yet the role NSS has on USVs in response to amphetamine is not determined. The aim of the present study was to determine if individual differences in NSS and USVs can predict locomotor and USV response to amphetamine (0.0, 0.3, and 1.0 mg/kg) after acute and chronic exposure. Thirty male rats were tested for their response to novelty (IEN), choice to engage in novelty (NPP), and heterospecific play (H-USV). Rats were administered non-contingent amphetamine or saline for seven exposures, and USVs and locomotor activity were measured. After a 14-day rest, rats were administered a challenge dose of amphetamine. Regression analyses indicated that amphetamine dose-dependently increased locomotor activity and the NPP test negatively predicted treatment-induced locomotor activity. The H-USV test predicted treatment-induced frequency-modulated (FM) USVs, but the strength of prediction depended on IEN response. Results provide evidence that locomotor activity and FM USVs induced by amphetamine represent different behavioral responses. The prediction of amphetamine-induced FM USVs by the H-USV screen was changed by the novelty response, indicating that the affective value of amphetamine-measured by FM USVs-depends on novelty response. This provides evidence that higher novelty responders may develop a tolerance faster and may escalate intake faster.

Reconstituted human corneal epithelium: a new alternative to the Draize eye test for the assessment of the eye irritation potential of chemicals and cosmetic products.

PubMed

Doucet, O; Lanvin, M; Thillou, C; Linossier, C; Pupat, C; Merlin, B; Zastrow, L

2006-06-01

The aim of this study was to evaluate the interest of a new three-dimensional epithelial model cultivated from human corneal cells to replace animal testing in the assessment of eye tolerance. To this end, 65 formulated cosmetic products and 36 chemicals were tested by means of this in vitro model using a simplified toxicokinetic approach. The chemicals were selected from the ECETOC data bank and the EC/HO International validation study list. Very satisfactory results were obtained in terms of concordance with the Draize test data for the formulated cosmetic products. Moreover, the response of the corneal model appeared predictive of human ocular response clinically observed by ophthalmologists. The in vitro scores for the chemicals tested strongly correlated with their respective scores in vivo. For all the compounds tested, the response of the corneal model to irritants was similar regardless of their chemical structure, suggesting a good robustness of the prediction model proposed. We concluded that this new three-dimensional epithelial model, developed from human corneal cells, could be promising for the prediction of eye irritation induced by chemicals and complex formulated products, and that these two types of materials should be tested using a similar protocol. A simple shortening of the exposure period was required for the chemicals assumed to be more aggressively irritant to the epithelial tissues than the cosmetic formulae.

Natural antibody responses to the capsid protein in sera of Dengue infected patients from Sri Lanka.

PubMed

Nadugala, Mahesha N; Jeewandara, Chandima; Malavige, Gathsaurie N; Premaratne, Prasad H; Goonasekara, Charitha L

2017-01-01

This study aims to characterize the antigenicity of the Capsid (C) protein and the human antibody responses to C protein from the four dengue virus (DENV) serotypes. Parker hydrophilicity prediction, Emini surface accessibility prediction and Karplus & Schulz flexibility predictions were used to bioinformatically characterize antigenicity. The human antibody response to C protein was assessed by ELISA using immune sera and an array of overlapping DENV2 C peptides. DENV2 C protein peptides P1 (located on C protein at 2-18 a.a), P11 (79-95 a.a) and P12 (86-101 a.a) were recognized by most individuals exposed to infections with only one of the 4 DENV serotypes as well as people exposed to infections with two serotypes. These conserved peptide epitopes are located on the amino (1-40 a.a) and carboxy (70-100 a.a) terminal regions of C protein, which were predicted to be antigenic using different bioinformatic tools. DENV2 C peptide P6 (39-56 a.a) was recognized by all individuals exposed to DENV2 infections, some individuals exposed to DENV4 infections and none of the individuals exposed to DENV1 or 3 infections. Thus, unlike C peptides P1, P11 and P12, which contain epitopes, recognized by DENV serotype cross-reactive antibodies, DENV2 peptide P6 contains an epitope that is preferentially recognized by antibodies in people exposed to this serotype compared to other serotypes. We discuss our results in the context of the known structure of C protein and recent work on the human B-cell response to DENV infection.

New developments and concepts related to biomarker application to vaccines

PubMed Central

Ahmed, S. Sohail; Black, Steve; Ulmer, Jeffrey

2012-01-01

Summary This minireview will provide a perspective on new developments and concepts related to biomarker applications for vaccines. In the context of preventive vaccines, biomarkers have the potential to predict adverse events in select subjects due to differences in genetic make‐up/underlying medical conditions or to predict effectiveness (good versus poor response). When expanding them to therapeutic vaccines, their utility in identification of patients most likely to respond favourably (or avoid potentially negative effects of treatment) becomes self‐explanatory. Despite the progress made so far on dissection of various pathways of biological significance in humans, there is still plenty to unravel about the mysteries related to the quantitative and qualitative aspects of the human host response. This review will provide a focused overview of new concepts and developments in the field of vaccine biomarkers including (i) vaccine‐dependent signatures predicting subject response and safety, (ii) predicting therapeutic vaccine efficacy in chronic diseases, (iii) exploring the genetic make‐up of the host that may modulate subject‐specific adverse events or affect the quality of immune responses, and (iv) the topic of volunteer stratification as a result of biomarker screening (e.g. for therapeutic vaccines but also potentially for preventive vaccines) or as a reflection of an effort to compare select groups (e.g. vaccinated subjects versus patients recovering from infection) to enable the discovery of clinically relevant biomarkers for preventive vaccines. PMID:21895991

Turing Trade: A Hybrid of a Turing Test and a Prediction Market

NASA Astrophysics Data System (ADS)

Farfel, Joseph; Conitzer, Vincent

We present Turing Trade, a web-based game that is a hybrid of a Turing test and a prediction market. In this game, there is a mystery conversation partner, the “target,” who is trying to appear human, but may in reality be either a human or a bot. There are multiple judges (or “bettors”), who interrogate the target in order to assess whether it is a human or a bot. Throughout the interrogation, each bettor bets on the nature of the target by buying or selling human (or bot) securities, which pay out if the target is a human (bot). The resulting market price represents the bettors’ aggregate belief that the target is a human. This game offers multiple advantages over standard variants of the Turing test. Most significantly, our game gathers much more fine-grained data, since we obtain not only the judges’ final assessment of the target’s humanity, but rather the entire progression of their aggregate belief over time. This gives us the precise moments in conversations where the target’s response caused a significant shift in the aggregate belief, indicating that the response was decidedly human or unhuman. An additional benefit is that (we believe) the game is more enjoyable to participants than a standard Turing test. This is important because otherwise, we will fail to collect significant amounts of data. In this paper, we describe in detail how Turing Trade works, exhibit some example logs, and analyze how well Turing Trade functions as a prediction market by studying the calibration and sharpness of its forecasts (from real user data).

Developing Hydrogeological Site Characterization Strategies based on Human Health Risk

NASA Astrophysics Data System (ADS)

de Barros, F.; Rubin, Y.; Maxwell, R. M.

2013-12-01

In order to provide better sustainable groundwater quality management and minimize the impact of contamination in humans, improved understanding and quantification of the interaction between hydrogeological models, geological site information and human health are needed. Considering the joint influence of these components in the overall human health risk assessment and the corresponding sources of uncertainty aid decision makers to better allocate resources in data acquisition campaigns. This is important to (1) achieve remediation goals in a cost-effective manner, (2) protect human health and (3) keep water supplies clean in order to keep with quality standards. Such task is challenging since a full characterization of the subsurface is unfeasible due to financial and technological constraints. In addition, human exposure and physiological response to contamination are subject to uncertainty and variability. Normally, sampling strategies are developed with the goal of reducing uncertainty, but less often they are developed in the context of their impacts on the overall system uncertainty. Therefore, quantifying the impact from each of these components (hydrogeological, behavioral and physiological) in final human health risk prediction can provide guidance for decision makers to best allocate resources towards minimal prediction uncertainty. In this presentation, a multi-component human health risk-based framework is presented which allows decision makers to set priorities through an information entropy-based visualization tool. Results highlight the role of characteristic length-scales characterizing flow and transport in determining data needs within an integrated hydrogeological-health framework. Conditions where uncertainty reduction in human health risk predictions may benefit from better understanding of the health component, as opposed to a more detailed hydrogeological characterization, are also discussed. Finally, results illustrate how different dose-response models can impact the probability of human health risk exceeding a regulatory threshold.

Can the PHS model (ISO7933) predict reasonable thermophysiological responses while wearing protective clothing in hot environments?

PubMed

Wang, Faming; Kuklane, Kalev; Gao, Chuansi; Holmér, Ingvar

2011-02-01

In this paper, the prediction accuracy of the PHS (predicted heat strain) model on human physiological responses while wearing protective clothing ensembles was examined. Six human subjects (aged 29 ± 3 years) underwent three experimental trials in three different protective garments (clothing thermal insulation I(cl) ranges from 0.63 to 2.01 clo) in two hot environments (40 °C, relative humidities: 30% and 45%). The observed and predicted mean skin temperature, core body temperature and sweat rate were presented and statistically compared. A significant difference was found in the metabolic rate between FIRE (firefighting clothing) and HV (high visibility clothing) or MIL (military clothing) (p < 0.001). Also, the development of heart rate demonstrated the significant effects of the exposure time and clothing ensembles. In addition, the predicted evaporation rate during HV, MIL and FIRE was much lower than the experimental values. Hence, the current PHS model is not applicable for protective clothing with intrinsic thermal insulations above 1.0 clo. The results showed that the PHS model generated unreliable predictions on body core temperature when human subjects wore thick protective clothing such as firefighting clothing (I(cl) > 1.0 clo). The predicted mean skin temperatures in three clothing ensembles HV, MIL and FIRE were also outside the expected limits. Thus, there is a need for further extension for the clothing insulation validation range of the PHS model. It is recommended that the PHS model should be amended and validated by individual algorithms, physical or physiological parameters, and further subject studies.

Human discomfort response to noise combined with vertical vibration

NASA Technical Reports Server (NTRS)

Leatherwood, J. D.

1979-01-01

An experimental investigation was conducted (1) to determine the effects of combined environmental noise and vertical vibration upon human subjective discomfort response, (2) to develop a model for the prediction of passenger discomfort response to the combined environment, and (3) to develop a set of noise-vibration curves for use as criteria in ride quality design. Subjects were exposed to parametric combinations of noise and vibrations through the use of a realistic laboratory simulator. Results indicated that accurate prediction of passenger ride comfort requires knowledge of both the level and frequency content of the noise and vibration components of a ride environment as well as knowledge of the interactive effects of combined noise and vibration. A design tool in the form of an empirical model of passenger discomfort response to combined noise and vertical vibration was developed and illustrated by several computational examples. Finally, a set of noise-vibration criteria curves were generated to illustrate the fundamental design trade-off possible between passenger discomfort and the noise-vibration levels that produce the discomfort.

Bayesian Mapping Reveals That Attention Boosts Neural Responses to Predicted and Unpredicted Stimuli.

PubMed

Garrido, Marta I; Rowe, Elise G; Halász, Veronika; Mattingley, Jason B

2018-05-01

Predictive coding posits that the human brain continually monitors the environment for regularities and detects inconsistencies. It is unclear, however, what effect attention has on expectation processes, as there have been relatively few studies and the results of these have yielded contradictory findings. Here, we employed Bayesian model comparison to adjudicate between 2 alternative computational models. The "Opposition" model states that attention boosts neural responses equally to predicted and unpredicted stimuli, whereas the "Interaction" model assumes that attentional boosting of neural signals depends on the level of predictability. We designed a novel, audiospatial attention task that orthogonally manipulated attention and prediction by playing oddball sequences in either the attended or unattended ear. We observed sensory prediction error responses, with electroencephalography, across all attentional manipulations. Crucially, posterior probability maps revealed that, overall, the Opposition model better explained scalp and source data, suggesting that attention boosts responses to predicted and unpredicted stimuli equally. Furthermore, Dynamic Causal Modeling showed that these Opposition effects were expressed in plastic changes within the mismatch negativity network. Our findings provide empirical evidence for a computational model of the opposing interplay of attention and expectation in the brain.

Cell host response to infection with novel human coronavirus EMC predicts potential antivirals and important differences with SARS coronavirus.

PubMed

Josset, Laurence; Menachery, Vineet D; Gralinski, Lisa E; Agnihothram, Sudhakar; Sova, Pavel; Carter, Victoria S; Yount, Boyd L; Graham, Rachel L; Baric, Ralph S; Katze, Michael G

2013-04-30

A novel human coronavirus (HCoV-EMC) was recently identified in the Middle East as the causative agent of a severe acute respiratory syndrome (SARS) resembling the illness caused by SARS coronavirus (SARS-CoV). Although derived from the CoV family, the two viruses are genetically distinct and do not use the same receptor. Here, we investigated whether HCoV-EMC and SARS-CoV induce similar or distinct host responses after infection of a human lung epithelial cell line. HCoV-EMC was able to replicate as efficiently as SARS-CoV in Calu-3 cells and similarly induced minimal transcriptomic changes before 12 h postinfection. Later in infection, HCoV-EMC induced a massive dysregulation of the host transcriptome, to a much greater extent than SARS-CoV. Both viruses induced a similar activation of pattern recognition receptors and the interleukin 17 (IL-17) pathway, but HCoV-EMC specifically down-regulated the expression of several genes within the antigen presentation pathway, including both type I and II major histocompatibility complex (MHC) genes. This could have an important impact on the ability of the host to mount an adaptive host response. A unique set of 207 genes was dysregulated early and permanently throughout infection with HCoV-EMC, and was used in a computational screen to predict potential antiviral compounds, including kinase inhibitors and glucocorticoids. Overall, HCoV-EMC and SARS-CoV elicit distinct host gene expression responses, which might impact in vivo pathogenesis and could orient therapeutic strategies against that emergent virus. Identification of a novel coronavirus causing fatal respiratory infection in humans raises concerns about a possible widespread outbreak of severe respiratory infection similar to the one caused by SARS-CoV. Using a human lung epithelial cell line and global transcriptomic profiling, we identified differences in the host response between HCoV-EMC and SARS-CoV. This enables rapid assessment of viral properties and the ability to anticipate possible differences in human clinical responses to HCoV-EMC and SARS-CoV. We used this information to predict potential effective drugs against HCoV-EMC, a method that could be more generally used to identify candidate therapeutics in future disease outbreaks. These data will help to generate hypotheses and make rapid advancements in characterizing this new virus.

Reward rate optimization in two-alternative decision making: empirical tests of theoretical predictions.

PubMed

Simen, Patrick; Contreras, David; Buck, Cara; Hu, Peter; Holmes, Philip; Cohen, Jonathan D

2009-12-01

The drift-diffusion model (DDM) implements an optimal decision procedure for stationary, 2-alternative forced-choice tasks. The height of a decision threshold applied to accumulating information on each trial determines a speed-accuracy tradeoff (SAT) for the DDM, thereby accounting for a ubiquitous feature of human performance in speeded response tasks. However, little is known about how participants settle on particular tradeoffs. One possibility is that they select SATs that maximize a subjective rate of reward earned for performance. For the DDM, there exist unique, reward-rate-maximizing values for its threshold and starting point parameters in free-response tasks that reward correct responses (R. Bogacz, E. Brown, J. Moehlis, P. Holmes, & J. D. Cohen, 2006). These optimal values vary as a function of response-stimulus interval, prior stimulus probability, and relative reward magnitude for correct responses. We tested the resulting quantitative predictions regarding response time, accuracy, and response bias under these task manipulations and found that grouped data conformed well to the predictions of an optimally parameterized DDM.

Sex Differences in Orienting to Pictures with and without Humans: Evidence from the Cardiac Evoked Response (ECR) and the Cortical Long Latency Parietal Positivity (LPP)

PubMed Central

Althaus, Monika; Groen, Yvonne; van der Schaft, Lutske; Minderaa, Ruud B.; Tucha, Oliver; Mulder, Lambertus J. M.; Wijers, Albertus A.

2014-01-01

Objective This study investigated the effect of social relevance in affective pictures on two orienting responses, i.e. the evoked cardiac response (ECR), and a long latency cortical evoked potential (LPP) and whether this effect would differ between males and females. Assuming that orienting to affective social information is fundamental to experiencing affective empathy, associations between self-report measures of empathy and the two orienting responses were investigated. Method ECRs were obtained from 34 female and 30 male students, and LPPs from 25 female and 27 male students viewing 414 pictures from the International Affective Picture System. Pictures portrayed pleasant, unpleasant and neutral scenes with and without humans. Results Both the ECR and LPP showed the largest response to pictures with humans in unpleasant situations. For both measures, the responses to pictures with humans correlated with self-report measures of empathy. While we found a greater male than female responsiveness to the pictures without humans in the ECR, a greater female than male responsiveness was observed in the LPP response to pictures with humans. Conclusion and Significance The sensitivity of these orienting responses to social relevance and their differential contribution to the prediction of individual differences underline the validity of their combined use in clinical studies investigating individuals with social disabilities. PMID:25330003

Relationship between BOLD amplitude and pattern classification of orientation-selective activity in the human visual cortex.

PubMed

Tong, Frank; Harrison, Stephenie A; Dewey, John A; Kamitani, Yukiyasu

2012-11-15

Orientation-selective responses can be decoded from fMRI activity patterns in the human visual cortex, using multivariate pattern analysis (MVPA). To what extent do these feature-selective activity patterns depend on the strength and quality of the sensory input, and might the reliability of these activity patterns be predicted by the gross amplitude of the stimulus-driven BOLD response? Observers viewed oriented gratings that varied in luminance contrast (4, 20 or 100%) or spatial frequency (0.25, 1.0 or 4.0 cpd). As predicted, activity patterns in early visual areas led to better discrimination of orientations presented at high than low contrast, with greater effects of contrast found in area V1 than in V3. A second experiment revealed generally better decoding of orientations at low or moderate as compared to high spatial frequencies. Interestingly however, V1 exhibited a relative advantage at discriminating high spatial frequency orientations, consistent with the finer scale of representation in the primary visual cortex. In both experiments, the reliability of these orientation-selective activity patterns was well predicted by the average BOLD amplitude in each region of interest, as indicated by correlation analyses, as well as decoding applied to a simple model of voxel responses to simulated orientation columns. Moreover, individual differences in decoding accuracy could be predicted by the signal-to-noise ratio of an individual's BOLD response. Our results indicate that decoding accuracy can be well predicted by incorporating the amplitude of the BOLD response into simple simulation models of cortical selectivity; such models could prove useful in future applications of fMRI pattern classification. Copyright © 2012 Elsevier Inc. All rights reserved.

Relationship between BOLD amplitude and pattern classification of orientation-selective activity in the human visual cortex

PubMed Central

Tong, Frank; Harrison, Stephenie A.; Dewey, John A.; Kamitani, Yukiyasu

2012-01-01

Orientation-selective responses can be decoded from fMRI activity patterns in the human visual cortex, using multivariate pattern analysis (MVPA). To what extent do these feature-selective activity patterns depend on the strength and quality of the sensory input, and might the reliability of these activity patterns be predicted by the gross amplitude of the stimulus-driven BOLD response? Observers viewed oriented gratings that varied in luminance contrast (4, 20 or 100%) or spatial frequency (0.25, 1.0 or 4.0 cpd). As predicted, activity patterns in early visual areas led to better discrimination of orientations presented at high than low contrast, with greater effects of contrast found in area V1 than in V3. A second experiment revealed generally better decoding of orientations at low or moderate as compared to high spatial frequencies. Interestingly however, V1 exhibited a relative advantage at discriminating high spatial frequency orientations, consistent with the finer scale of representation in the primary visual cortex. In both experiments, the reliability of these orientation-selective activity patterns was well predicted by the average BOLD amplitude in each region of interest, as indicated by correlation analyses, as well as decoding applied to a simple model of voxel responses to simulated orientation columns. Moreover, individual differences in decoding accuracy could be predicted by the signal-to-noise ratio of an individual's BOLD response. Our results indicate that decoding accuracy can be well predicted by incorporating the amplitude of the BOLD response into simple simulation models of cortical selectivity; such models could prove useful in future applications of fMRI pattern classification. PMID:22917989

Correlation of Wissler Human Thermal Model Blood Flow and Shiver Algorithms

NASA Technical Reports Server (NTRS)

Bue, Grant; Makinen, Janice; Cognata, Thomas

2010-01-01

The Wissler Human Thermal Model (WHTM) is a thermal math model of the human body that has been widely used to predict the human thermoregulatory response to a variety of cold and hot environments. The model has been shown to predict core temperature and skin temperatures higher and lower, respectively, than in tests of subjects in crew escape suit working in a controlled hot environments. Conversely the model predicts core temperature and skin temperatures lower and higher, respectively, than in tests of lightly clad subjects immersed in cold water conditions. The blood flow algorithms of the model has been investigated to allow for more and less flow, respectively, for the cold and hot case. These changes in the model have yielded better correlation of skin and core temperatures in the cold and hot cases. The algorithm for onset of shiver did not need to be modified to achieve good agreement in cold immersion simulations

Social cycling and conditional responses in the Rock-Paper-Scissors game

PubMed Central

Wang, Zhijian; Xu, Bin; Zhou, Hai-Jun

2014-01-01

How humans make decisions in non-cooperative strategic interactions is a big question. For the fundamental Rock-Paper-Scissors (RPS) model game system, classic Nash equilibrium (NE) theory predicts that players randomize completely their action choices to avoid being exploited, while evolutionary game theory of bounded rationality in general predicts persistent cyclic motions, especially in finite populations. However as empirical studies have been relatively sparse, it is still a controversial issue as to which theoretical framework is more appropriate to describe decision-making of human subjects. Here we observe population-level persistent cyclic motions in a laboratory experiment of the discrete-time iterated RPS game under the traditional random pairwise-matching protocol. This collective behavior contradicts with the NE theory but is quantitatively explained, without any adjustable parameter, by a microscopic model of win-lose-tie conditional response. Theoretical calculations suggest that if all players adopt the same optimized conditional response strategy, their accumulated payoff will be much higher than the reference value of the NE mixed strategy. Our work demonstrates the feasibility of understanding human competition behaviors from the angle of non-equilibrium statistical physics. PMID:25060115

Proceedings, 1995 meeting of the Northern Global Change Program; 1995 March 14-16; Pittsburgh, PA. : Introduction/Environmental Change

Treesearch

John Hom; Richard Birdsey; Kelly O' Brian; eds.

1996-01-01

Contains articles presented at the 1995 Northern Global Change Program meeting on the following topics: monitoring and predicting regional environmental change, responses of northern tree species to regional stress, responses of ecosystem processes to regional stress, forest and landscape responses to regional stress and management activities, human-forest interactions...

Conceptual beliefs about human values and their implications: human nature beliefs predict value importance, value trade-offs, and responses to value-laden rhetoric.

PubMed

Bain, Paul G; Kashima, Yoshihisa; Haslam, Nick

2006-08-01

Beliefs that may underlie the importance of human values were investigated in 4 studies, drawing on research that distinguishes natural-kind (natural), nominal-kind (conventional), and artifact (functional) beliefs. Values were best characterized by artifact and nominal-kind beliefs, as well as a natural-kind belief specific to the social domain, "human nature" (Studies 1 and 2). The extent to which values were considered central to human nature was associated with value importance in both Australia and Japan (Study 2), and experimentally manipulating human nature beliefs influenced value importance (Study 3). Beyond their association with importance, human nature beliefs predicted participants' reactions to value trade-offs (Study 1) and to value-laden rhetorical statements (Study 4). Human nature beliefs therefore play a central role in the psychology of values.

Systematic Proteomic Approach to Characterize the Impacts of ...

EPA Pesticide Factsheets

Chemical interactions have posed a big challenge in toxicity characterization and human health risk assessment of environmental mixtures. To characterize the impacts of chemical interactions on protein and cytotoxicity responses to environmental mixtures, we established a systems biology approach integrating proteomics, bioinformatics, statistics, and computational toxicology to measure expression or phosphorylation levels of 21 critical toxicity pathway regulators and 445 downstream proteins in human BEAS-28 cells treated with 4 concentrations of nickel, 2 concentrations each of cadmium and chromium, as well as 12 defined binary and 8 defined ternary mixtures of these metals in vitro. Multivariate statistical analysis and mathematical modeling of the metal-mediated proteomic response patterns showed a high correlation between changes in protein expression or phosphorylation and cellular toxic responses to both individual metals and metal mixtures. Of the identified correlated proteins, only a small set of proteins including HIF-1a is likely to be responsible for selective cytotoxic responses to different metals and metals mixtures. Furthermore, support vector machine learning was utilized to computationally predict protein responses to uncharacterized metal mixtures using experimentally generated protein response profiles corresponding to known metal mixtures. This study provides a novel proteomic approach for characterization and prediction of toxicities of

Evaluation of a Novel Renewable Hepatic Cell Model for Prediction of Clinical CYP3A4 Induction Using a Correlation-Based Relative Induction Score Approach.

PubMed

Zuo, Rongjun; Li, Feng; Parikh, Sweta; Cao, Li; Cooper, Kirsten L; Hong, Yulong; Liu, Jin; Faris, Ronald A; Li, Daochuan; Wang, Hongbing

2017-02-01

Metabolism enzyme induction-mediated drug-drug interactions need to be carefully characterized in vitro for drug candidates to predict in vivo safety risk and therapeutic efficiency. Currently, both the Food and Drug Administration and European Medicines Agency recommend using primary human hepatocytes as the gold standard in vitro test system for studying the induction potential of candidate drugs on cytochrome P450 (CYP), CYP3A4, CYP1A2, and CYP2B6. However, primary human hepatocytes are known to bear inherent limitations such as limited supply and large lot-to-lot variations, which result in an experimental burden to qualify new lots. To overcome these shortcomings, a renewable source of human hepatocytes (i.e., Corning HepatoCells) was developed from primary human hepatocytes and was evaluated for in vitro CYP3A4 induction using methods well established by the pharmaceutical industry. HepatoCells have shown mature hepatocyte-like morphology and demonstrated primary hepatocyte-like response to prototypical inducers of all three CYP enzymes with excellent consistency. Importantly, HepatoCells retain a phenobarbital-responsive nuclear translocation of human constitutive androstane receptor from the cytoplasm, characteristic to primary hepatocytes. To validate HepatoCells as a useful tool to predict potential clinical relevant CYP3A4 induction, we tested three different lots of HepatoCells with a group of clinical strong, moderate/weak CYP3A4 inducers, and noninducers. A relative induction score calibration curve-based approach was used for prediction. HepatoCells showed accurate prediction comparable to primary human hepatocytes. Together, these results demonstrate that Corning HepatoCells is a reliable in vitro model for drug-drug interaction studies during the early phase of drug testing. Copyright © 2017 by The Author(s).

Human brain detects short-time nonlinear predictability in the temporal fine structure of deterministic chaotic sounds

NASA Astrophysics Data System (ADS)

Itoh, Kosuke; Nakada, Tsutomu

2013-04-01

Deterministic nonlinear dynamical processes are ubiquitous in nature. Chaotic sounds generated by such processes may appear irregular and random in waveform, but these sounds are mathematically distinguished from random stochastic sounds in that they contain deterministic short-time predictability in their temporal fine structures. We show that the human brain distinguishes deterministic chaotic sounds from spectrally matched stochastic sounds in neural processing and perception. Deterministic chaotic sounds, even without being attended to, elicited greater cerebral cortical responses than the surrogate control sounds after about 150 ms in latency after sound onset. Listeners also clearly discriminated these sounds in perception. The results support the hypothesis that the human auditory system is sensitive to the subtle short-time predictability embedded in the temporal fine structure of sounds.

Mortality of atomic bomb survivors predicted from laboratory animals

NASA Technical Reports Server (NTRS)

Carnes, Bruce A.; Grahn, Douglas; Hoel, David

2003-01-01

Exposure, pathology and mortality data for mice, dogs and humans were examined to determine whether accurate interspecies predictions of radiation-induced mortality could be achieved. The analyses revealed that (1) days of life lost per unit dose can be estimated for a species even without information on radiation effects in that species, and (2) accurate predictions of age-specific radiation-induced mortality in beagles and the atomic bomb survivors can be obtained from a dose-response model for comparably exposed mice. These findings illustrate the value of comparative mortality analyses and the relevance of animal data to the study of human health effects.

Predicting Survey Responses: How and Why Semantics Shape Survey Statistics on Organizational Behaviour

PubMed Central

Arnulf, Jan Ketil; Larsen, Kai Rune; Martinsen, Øyvind Lund; Bong, Chih How

2014-01-01

Some disciplines in the social sciences rely heavily on collecting survey responses to detect empirical relationships among variables. We explored whether these relationships were a priori predictable from the semantic properties of the survey items, using language processing algorithms which are now available as new research methods. Language processing algorithms were used to calculate the semantic similarity among all items in state-of-the-art surveys from Organisational Behaviour research. These surveys covered areas such as transformational leadership, work motivation and work outcomes. This information was used to explain and predict the response patterns from real subjects. Semantic algorithms explained 60–86% of the variance in the response patterns and allowed remarkably precise prediction of survey responses from humans, except in a personality test. Even the relationships between independent and their purported dependent variables were accurately predicted. This raises concern about the empirical nature of data collected through some surveys if results are already given a priori through the way subjects are being asked. Survey response patterns seem heavily determined by semantics. Language algorithms may suggest these prior to administering a survey. This study suggests that semantic algorithms are becoming new tools for the social sciences, opening perspectives on survey responses that prevalent psychometric theory cannot explain. PMID:25184672

Predicting survey responses: how and why semantics shape survey statistics on organizational behaviour.

PubMed

Arnulf, Jan Ketil; Larsen, Kai Rune; Martinsen, Øyvind Lund; Bong, Chih How

2014-01-01

Some disciplines in the social sciences rely heavily on collecting survey responses to detect empirical relationships among variables. We explored whether these relationships were a priori predictable from the semantic properties of the survey items, using language processing algorithms which are now available as new research methods. Language processing algorithms were used to calculate the semantic similarity among all items in state-of-the-art surveys from Organisational Behaviour research. These surveys covered areas such as transformational leadership, work motivation and work outcomes. This information was used to explain and predict the response patterns from real subjects. Semantic algorithms explained 60-86% of the variance in the response patterns and allowed remarkably precise prediction of survey responses from humans, except in a personality test. Even the relationships between independent and their purported dependent variables were accurately predicted. This raises concern about the empirical nature of data collected through some surveys if results are already given a priori through the way subjects are being asked. Survey response patterns seem heavily determined by semantics. Language algorithms may suggest these prior to administering a survey. This study suggests that semantic algorithms are becoming new tools for the social sciences, opening perspectives on survey responses that prevalent psychometric theory cannot explain.

Predicting Metapopulation Responses to Conservation in Human-Dominated Landscapes

Treesearch

Zachary S. Ladin; Vincent D' Amico; Jan M. Baetens; Roland R. Roth; W. Gregory Shriver

2016-01-01

Loss of habitat to urbanization is a primary cause of population declines as human-dominated landscapes expand at increasing rates. Understanding how the relative effects of different conservation strategies is important to slow population declines for species in urban landscapes. We studied the wood thrush Hylocichla mustelina, a declining forest-...

The Long-Term Effects of Youth Unemployment

ERIC Educational Resources Information Center

Mroz, Thomas A.; Savage, Timothy H.

2006-01-01

Using NLSY data, we examine the long-term effects of youth unemployment on later labor market outcomes. Involuntary unemployment may yield suboptimal investments in human capital in the short run. A theoretical model of dynamic human capital investment predicts a rational "catch-up" response. Using semiparametric techniques to control for the…

Host responses to mycobacterial infections: Spotlight on biomarker discovery to predict vaccine

USDA-ARS?s Scientific Manuscript database

The global spread of tuberculosis (TB) in animals and humans result in enormous economic. social and public health burdens. TB vaccine development in both humans and animals has produced a growing portfolio of candidates with potential applicability across species. However, the lack of understandin...

Adaptive allocation of decisionmaking responsibility between human and computer in multitask situations

NASA Technical Reports Server (NTRS)

Chu, Y.-Y.; Rouse, W. B.

1979-01-01

As human and computer come to have overlapping decisionmaking abilities, a dynamic or adaptive allocation of responsibilities may be the best mode of human-computer interaction. It is suggested that the computer serve as a backup decisionmaker, accepting responsibility when human workload becomes excessive and relinquishing responsibility when workload becomes acceptable. A queueing theory formulation of multitask decisionmaking is used and a threshold policy for turning the computer on/off is proposed. This policy minimizes event-waiting cost subject to human workload constraints. An experiment was conducted with a balanced design of several subject runs within a computer-aided multitask flight management situation with different task demand levels. It was found that computer aiding enhanced subsystem performance as well as subjective ratings. The queueing model appears to be an adequate representation of the multitask decisionmaking situation, and to be capable of predicting system performance in terms of average waiting time and server occupancy. Server occupancy was further found to correlate highly with the subjective effort ratings.

Comparison of human and rhesus macaque T-cell responses elicited by boosting with NYVAC encoding human immunodeficiency virus type 1 clade C immunogens.

PubMed

Mooij, Petra; Balla-Jhagjhoorsingh, Sunita S; Beenhakker, Niels; van Haaften, Patricia; Baak, Ilona; Nieuwenhuis, Ivonne G; Heidari, Shirin; Wolf, Hans; Frachette, Marie-Joelle; Bieler, Kurt; Sheppard, Neil; Harari, Alexandre; Bart, Pierre-Alexandre; Liljeström, Peter; Wagner, Ralf; Pantaleo, Giuseppe; Heeney, Jonathan L

2009-06-01

Rhesus macaques (Macaca mulatta) have played a valuable role in the development of human immunodeficiency virus (HIV) vaccine candidates prior to human clinical trials. However, changes and/or improvements in immunogen quality in the good manufacturing practice (GMP) process or changes in adjuvants, schedule, route, dose, or readouts have compromised the direct comparison of T-cell responses between species. Here we report a comparative study in which T-cell responses from humans and macaques to HIV type 1 antigens (Gag, Pol, Nef, and Env) were induced by the same vaccine batches prepared under GMP and administered according to the same schedules in the absence and presence of priming. Priming with DNA (humans and macaques) or alphavirus (macaques) and boosting with NYVAC induced robust and broad antigen-specific responses, with highly similar Env-specific gamma interferon (IFN-gamma) enzyme-linked immunospot assay responses in rhesus monkeys and human volunteers. Persistent cytokine responses of antigen-specific CD4(+) and CD8(+) T cells of the central memory as well as the effector memory phenotype, capable of simultaneously eliciting multiple cytokines (IFN-gamma, interleukin 2, and tumor necrosis factor alpha), were induced. Responses were highly similar in humans and primates, confirming earlier data indicating that priming is essential for inducing robust NYVAC-boosted IFN-gamma T-cell responses. While significant similarities were observed in Env-specific responses in both species, differences were also observed with respect to responses to other HIV antigens. Future studies with other vaccines using identical lots, immunization schedules, and readouts will establish a broader data set of species similarities and differences with which increased confidence in predicting human responses may be achieved.

Comparison of Human and Rhesus Macaque T-Cell Responses Elicited by Boosting with NYVAC Encoding Human Immunodeficiency Virus Type 1 Clade C Immunogens▿

PubMed Central

Mooij, Petra; Balla-Jhagjhoorsingh, Sunita S.; Beenhakker, Niels; van Haaften, Patricia; Baak, Ilona; Nieuwenhuis, Ivonne G.; Heidari, Shirin; Wolf, Hans; Frachette, Marie-Joelle; Bieler, Kurt; Sheppard, Neil; Harari, Alexandre; Bart, Pierre-Alexandre; Liljeström, Peter; Wagner, Ralf; Pantaleo, Giuseppe; Heeney, Jonathan L.

2009-01-01

Rhesus macaques (Macaca mulatta) have played a valuable role in the development of human immunodeficiency virus (HIV) vaccine candidates prior to human clinical trials. However, changes and/or improvements in immunogen quality in the good manufacturing practice (GMP) process or changes in adjuvants, schedule, route, dose, or readouts have compromised the direct comparison of T-cell responses between species. Here we report a comparative study in which T-cell responses from humans and macaques to HIV type 1 antigens (Gag, Pol, Nef, and Env) were induced by the same vaccine batches prepared under GMP and administered according to the same schedules in the absence and presence of priming. Priming with DNA (humans and macaques) or alphavirus (macaques) and boosting with NYVAC induced robust and broad antigen-specific responses, with highly similar Env-specific gamma interferon (IFN-γ) enzyme-linked immunospot assay responses in rhesus monkeys and human volunteers. Persistent cytokine responses of antigen-specific CD4+ and CD8+ T cells of the central memory as well as the effector memory phenotype, capable of simultaneously eliciting multiple cytokines (IFN-γ, interleukin 2, and tumor necrosis factor alpha), were induced. Responses were highly similar in humans and primates, confirming earlier data indicating that priming is essential for inducing robust NYVAC-boosted IFN-γ T-cell responses. While significant similarities were observed in Env-specific responses in both species, differences were also observed with respect to responses to other HIV antigens. Future studies with other vaccines using identical lots, immunization schedules, and readouts will establish a broader data set of species similarities and differences with which increased confidence in predicting human responses may be achieved. PMID:19321612

A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors.

PubMed

Loboda, Andrey; Nebozhyn, Michael; Klinghoffer, Rich; Frazier, Jason; Chastain, Michael; Arthur, William; Roberts, Brian; Zhang, Theresa; Chenard, Melissa; Haines, Brian; Andersen, Jannik; Nagashima, Kumiko; Paweletz, Cloud; Lynch, Bethany; Feldman, Igor; Dai, Hongyue; Huang, Pearl; Watters, James

2010-06-30

Hyperactivation of the Ras signaling pathway is a driver of many cancers, and RAS pathway activation can predict response to targeted therapies. Therefore, optimal methods for measuring Ras pathway activation are critical. The main focus of our work was to develop a gene expression signature that is predictive of RAS pathway dependence. We used the coherent expression of RAS pathway-related genes across multiple datasets to derive a RAS pathway gene expression signature and generate RAS pathway activation scores in pre-clinical cancer models and human tumors. We then related this signature to KRAS mutation status and drug response data in pre-clinical and clinical datasets. The RAS signature score is predictive of KRAS mutation status in lung tumors and cell lines with high (> 90%) sensitivity but relatively low (50%) specificity due to samples that have apparent RAS pathway activation in the absence of a KRAS mutation. In lung and breast cancer cell line panels, the RAS pathway signature score correlates with pMEK and pERK expression, and predicts resistance to AKT inhibition and sensitivity to MEK inhibition within both KRAS mutant and KRAS wild-type groups. The RAS pathway signature is upregulated in breast cancer cell lines that have acquired resistance to AKT inhibition, and is downregulated by inhibition of MEK. In lung cancer cell lines knockdown of KRAS using siRNA demonstrates that the RAS pathway signature is a better measure of dependence on RAS compared to KRAS mutation status. In human tumors, the RAS pathway signature is elevated in ER negative breast tumors and lung adenocarcinomas, and predicts resistance to cetuximab in metastatic colorectal cancer. These data demonstrate that the RAS pathway signature is superior to KRAS mutation status for the prediction of dependence on RAS signaling, can predict response to PI3K and RAS pathway inhibitors, and is likely to have the most clinical utility in lung and breast tumors.

Blinded Prospective Evaluation of Computer-Based Mechanistic Schizophrenia Disease Model for Predicting Drug Response

PubMed Central

Geerts, Hugo; Spiros, Athan; Roberts, Patrick; Twyman, Roy; Alphs, Larry; Grace, Anthony A.

2012-01-01

The tremendous advances in understanding the neurobiological circuits involved in schizophrenia have not translated into more effective treatments. An alternative strategy is to use a recently published ‘Quantitative Systems Pharmacology’ computer-based mechanistic disease model of cortical/subcortical and striatal circuits based upon preclinical physiology, human pathology and pharmacology. The physiology of 27 relevant dopamine, serotonin, acetylcholine, norepinephrine, gamma-aminobutyric acid (GABA) and glutamate-mediated targets is calibrated using retrospective clinical data on 24 different antipsychotics. The model was challenged to predict quantitatively the clinical outcome in a blinded fashion of two experimental antipsychotic drugs; JNJ37822681, a highly selective low-affinity dopamine D2 antagonist and ocaperidone, a very high affinity dopamine D2 antagonist, using only pharmacology and human positron emission tomography (PET) imaging data. The model correctly predicted the lower performance of JNJ37822681 on the positive and negative syndrome scale (PANSS) total score and the higher extra-pyramidal symptom (EPS) liability compared to olanzapine and the relative performance of ocaperidone against olanzapine, but did not predict the absolute PANSS total score outcome and EPS liability for ocaperidone, possibly due to placebo responses and EPS assessment methods. Because of its virtual nature, this modeling approach can support central nervous system research and development by accounting for unique human drug properties, such as human metabolites, exposure, genotypes and off-target effects and can be a helpful tool for drug discovery and development. PMID:23251349

Curved Saccade Trajectories Reveal Conflicting Predictions in Associative Learning

ERIC Educational Resources Information Center

Koenig, Stephan; Lachnit, Harald

2011-01-01

We report how the trajectories of saccadic eye movements are affected by memory interference acquired during associative learning. Human participants learned to perform saccadic choice responses based on the presentation of arbitrary central cues A, B, AC, BC, AX, BY, X, and Y that were trained to predict the appearance of a peripheral target…

Predicting Semantic Changes in Abstraction in Tutor Responses to Students

ERIC Educational Resources Information Center

Lipschultz, Michael; Litman, Diane; Katz, Sandra; Albacete, Patricia; Jordan, Pamela

2014-01-01

Post-problem reflective tutorial dialogues between human tutors and students are examined to predict when the tutor changed the level of abstraction from the student's preceding turn (i.e., used more general terms or more specific terms); such changes correlate with learning. Prior work examined lexical changes in abstraction. In this work, we…

Role of KEAP1/NRF2 and TP53 mutations in lung squamous cell carcinoma development and radiotherapy response prediction

PubMed Central

Jeong, Youngtae; Hoang, Ngoc T.; Lovejoy, Alexander; Stehr, Henning; Newman, Aaron M.; Gentles, Andrew J.; Kong, William; Truong, Diana; Martin, Shanique; Chaudhuri, Aadel; Heiser, Diane; Zhou, Li; Say, Carmen; Carter, Justin N.; Hiniker, Susan M.; Loo, Billy W.; West, Robert B.; Beachy, Philip; Alizadeh, Ash A.; Diehn, Maximilian

2016-01-01

Lung squamous cell carcinomas (LSCC) pathogenesis remains incompletely understood and biomarkers predicting treatment response remain lacking. Here we describe novel murine LSCC models driven by loss of Trp53 and Keap1, both of which are frequently mutated in human LSCCs. Homozygous inactivation of Keap1 or Trp53 promoted airway basal stem cell (ABSC) self-renewal, suggesting that mutations in these genes lead to expansion of mutant stem cell clones. Deletion of Trp53 and Keap1 in ABSCs, but not more differentiated tracheal cells, produced tumors recapitulating histological and molecular features of human LSCCs, indicating that they represent the likely cell of origin in this model. Deletion of Keap1 promoted tumor aggressiveness, metastasis, and resistance to oxidative stress and radiotherapy (RT). KEAP1/NRF2 mutation status predicted risk of local recurrence after RT in non-small lung cancer (NSCLC) patients and could be non-invasively identified in circulating tumor DNA. Thus, KEAP1/NRF2 mutations could serve as predictive biomarkers for personalization of therapeutic strategies for NSCLCs. PMID:27663899

Learning-dependent plasticity in human auditory cortex during appetitive operant conditioning.

PubMed

Puschmann, Sebastian; Brechmann, André; Thiel, Christiane M

2013-11-01

Animal experiments provide evidence that learning to associate an auditory stimulus with a reward causes representational changes in auditory cortex. However, most studies did not investigate the temporal formation of learning-dependent plasticity during the task but rather compared auditory cortex receptive fields before and after conditioning. We here present a functional magnetic resonance imaging study on learning-related plasticity in the human auditory cortex during operant appetitive conditioning. Participants had to learn to associate a specific category of frequency-modulated tones with a reward. Only participants who learned this association developed learning-dependent plasticity in left auditory cortex over the course of the experiment. No differential responses to reward predicting and nonreward predicting tones were found in auditory cortex in nonlearners. In addition, learners showed similar learning-induced differential responses to reward-predicting and nonreward-predicting tones in the ventral tegmental area and the nucleus accumbens, two core regions of the dopaminergic neurotransmitter system. This may indicate a dopaminergic influence on the formation of learning-dependent plasticity in auditory cortex, as it has been suggested by previous animal studies. Copyright © 2012 Wiley Periodicals, Inc.

Integrating a human thermoregulatory model with a clothing model to predict core and skin temperatures.

PubMed

Yang, Jie; Weng, Wenguo; Wang, Faming; Song, Guowen

2017-05-01

This paper aims to integrate a human thermoregulatory model with a clothing model to predict core and skin temperatures. The human thermoregulatory model, consisting of an active system and a passive system, was used to determine the thermoregulation and heat exchanges within the body. The clothing model simulated heat and moisture transfer from the human skin to the environment through the microenvironment and fabric. In this clothing model, the air gap between skin and clothing, as well as clothing properties such as thickness, thermal conductivity, density, porosity, and tortuosity were taken into consideration. The simulated core and mean skin temperatures were compared to the published experimental results of subject tests at three levels of ambient temperatures of 20 °C, 30 °C, and 40 °C. Although lower signal-to-noise-ratio was observed, the developed model demonstrated positive performance at predicting core temperatures with a maximum difference between the simulations and measurements of no more than 0.43 °C. Generally, the current model predicted the mean skin temperatures with reasonable accuracy. It could be applied to predict human physiological responses and assess thermal comfort and heat stress. Copyright © 2017 Elsevier Ltd. All rights reserved.

Computational identification of gene–social environment interaction at the human IL6 locus

PubMed Central

Cole, Steven W.; Arevalo, Jesusa M. G.; Takahashi, Rie; Sloan, Erica K.; Lutgendorf, Susan K.; Sood, Anil K.; Sheridan, John F.; Seeman, Teresa E.

2010-01-01

To identify genetic factors that interact with social environments to impact human health, we used a bioinformatic strategy that couples expression array–based detection of environmentally responsive transcription factors with in silico discovery of regulatory polymorphisms to predict genetic loci that modulate transcriptional responses to stressful environments. Tests of one predicted interaction locus in the human IL6 promoter (SNP rs1800795) verified that it modulates transcriptional response to β-adrenergic activation of the GATA1 transcription factor in vitro. In vivo validation studies confirmed links between adverse social conditions and increased transcription of GATA1 target genes in primary neural, immune, and cancer cells. Epidemiologic analyses verified the health significance of those molecular interactions by documenting increased 10-year mortality risk associated with late-life depressive symptoms that occurred solely for homozygous carriers of the GATA1-sensitive G allele of rs1800795. Gating of depression-related mortality risk by IL6 genotype pertained only to inflammation-related causes of death and was associated with increased chronic inflammation as indexed by plasma C-reactive protein. Computational modeling of molecular interactions, in vitro biochemical analyses, in vivo animal modeling, and human molecular epidemiologic analyses thus converge in identifying β-adrenergic activation of GATA1 as a molecular pathway by which social adversity can alter human health risk selectively depending on individual genetic status at the IL6 locus. PMID:20176930

Computational Model of the Hypothalamic-pituitary-gonadal Axis to Predict Biochemical Adaptive Response to Endocrine Disrupting Fungicide Prochloraz

EPA Science Inventory

There is increasing evidence that exposure to endocrine disrupting chemicals can induce adverse effects on reproduction and development in both humans and wildlife. Recent studies report adaptive changes within exposed organisms in response to endocrine disrupting chemicals, and ...

DEVELOPMENT AND EVALUATION OF NOVEL DOSE-RESPONSE MODELS FOR USE IN MICROBIAL RISK ASSESSMENT

EPA Science Inventory

This document contains a description of dose-response modeling methods designed to provide a robust approach under uncertainty for predicting human population risk from exposure to pathogens in drinking water.

The purpose of this document is to describe a body of literatu...

Adaptive Response in Female Fathead Minnows Exposed to an Aromatase Inhibitor: Computational Modeling of the Hypothalamic-Pituitary-Gonadal Axis

EPA Science Inventory

Exposure to endocrine disrupting chemicals can affect reproduction and development in both humans and wildlife. We are developing a mechanistic computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict dose-response and time-course ...

Effects of noise upon human information processing

NASA Technical Reports Server (NTRS)

Cohen, H. H.; Conrad, D. W.; Obrien, J. F.; Pearson, R. G.

1974-01-01

Studies of noise effects upon human information processing are described which investigated whether or not effects of noise upon performance are dependent upon specific characteristics of noise stimulation and their interaction with task conditions. The difficulty of predicting noise effects was emphasized. Arousal theory was considered to have explanatory value in interpreting the findings of all the studies. Performance under noise was found to involve a psychophysiological cost, measured by vasoconstriction response, with the degree of response cost being related to scores on a noise annoyance sensitivity scale. Noise sensitive subjects showed a greater autonomic response under noise stimulation.

Characterizing the Associative Content of Brain Structures Involved in Habitual and Goal-Directed Actions in Humans: A Multivariate fMRI Study

PubMed Central

Liljeholm, Mimi; Zika, Ondrej; O'Doherty, John P.

2015-01-01

While there is accumulating evidence for the existence of distinct neural systems supporting goal-directed and habitual action selection in the mammalian brain, much less is known about the nature of the information being processed in these different brain regions. Associative learning theory predicts that brain systems involved in habitual control, such as the dorsolateral striatum, should contain stimulus and response information only, but not outcome information, while regions involved in goal-directed action, such as ventromedial and dorsolateral prefrontal cortex and dorsomedial striatum, should be involved in processing information about outcomes as well as stimuli and responses. To test this prediction, human participants underwent fMRI while engaging in a binary choice task designed to enable the separate identification of these different representations with a multivariate classification analysis approach. Consistent with our predictions, the dorsolateral striatum contained information about responses but not outcomes at the time of an initial stimulus, while the regions implicated in goal-directed action selection contained information about both responses and outcomes. These findings suggest that differential contributions of these regions to habitual and goal-directed behavioral control may depend in part on basic differences in the type of information that these regions have access to at the time of decision making. PMID:25740507

Optical metabolic imaging measures early drug response in an allograft murine breast cancer model (Conference Presentation)

NASA Astrophysics Data System (ADS)

Sharick, Joe T.; Cook, Rebecca S.; Skala, Melissa C.

2017-02-01

Previous work has shown that cellular-level Optical Metabolic Imaging (OMI) of organoids derived from human breast cancer cell-line xenografts accurately and rapidly predicts in vivo response to therapy. To validate OMI as a predictive measure of treatment response in an immune-competent model, we used the polyomavirus middle-T (PyVmT) transgenic mouse breast cancer model. The PyVmT model includes intra-tumoral heterogeneity and a complex tumor microenvironment that can influence treatment responses. Three-dimensional organoids generated from primary PyVmT tumor tissue were treated with a chemotherapy (paclitaxel) and a PI3K inhibitor (XL147), each alone or in combination. Cellular subpopulations of response were measured using the OMI Index, a composite endpoint of metabolic response comprised of the optical redox ratio (ratio of the fluorescence intensities of metabolic co-enzymes NAD(P)H to FAD) as well as the fluorescence lifetimes of NAD(P)H and FAD. Combination treatment significantly decreased the OMI Index of PyVmT tumor organoids (p<0.0001) and in vivo tumors (p<0.0001) versus controls. Subpopulation analyses revealed a homogeneous response to combined therapy in both cultured organoids and in vivo tumors, while single agent treatment with XL147 alone or paclitaxel alone elicited heterogeneous responses in organoids. Tumor volume decreased with combination treatment through treatment day 30. These results indicate that OMI of organoids generated from PyVmT tumors can accurately reflect drug response in heterogeneous allografts with both innate and adaptive immunity. Thus, this method is promising for use in humans to predict long-term treatment responses accurately and rapidly, and could aid in clinical treatment planning.

A genomic biomarker signature can predict skin sensitizers using a cell-based in vitro alternative to animal tests

PubMed Central

2011-01-01

Background Allergic contact dermatitis is an inflammatory skin disease that affects a significant proportion of the population. This disease is caused by an adverse immune response towards chemical haptens, and leads to a substantial economic burden for society. Current test of sensitizing chemicals rely on animal experimentation. New legislations on the registration and use of chemicals within pharmaceutical and cosmetic industries have stimulated significant research efforts to develop alternative, human cell-based assays for the prediction of sensitization. The aim is to replace animal experiments with in vitro tests displaying a higher predictive power. Results We have developed a novel cell-based assay for the prediction of sensitizing chemicals. By analyzing the transcriptome of the human cell line MUTZ-3 after 24 h stimulation, using 20 different sensitizing chemicals, 20 non-sensitizing chemicals and vehicle controls, we have identified a biomarker signature of 200 genes with potent discriminatory ability. Using a Support Vector Machine for supervised classification, the prediction performance of the assay revealed an area under the ROC curve of 0.98. In addition, categorizing the chemicals according to the LLNA assay, this gene signature could also predict sensitizing potency. The identified markers are involved in biological pathways with immunological relevant functions, which can shed light on the process of human sensitization. Conclusions A gene signature predicting sensitization, using a human cell line in vitro, has been identified. This simple and robust cell-based assay has the potential to completely replace or drastically reduce the utilization of test systems based on experimental animals. Being based on human biology, the assay is proposed to be more accurate for predicting sensitization in humans, than the traditional animal-based tests. PMID:21824406

Evolution and behavioural responses to human-induced rapid environmental change

PubMed Central

Sih, Andrew; Ferrari, Maud C O; Harris, David J

2011-01-01

Almost all organisms live in environments that have been altered, to some degree, by human activities. Because behaviour mediates interactions between an individual and its environment, the ability of organisms to behave appropriately under these new conditions is crucial for determining their immediate success or failure in these modified environments. While hundreds of species are suffering dramatically from these environmental changes, others, such as urbanized and pest species, are doing better than ever. Our goal is to provide insights into explaining such variation. We first summarize the responses of some species to novel situations, including novel risks and resources, habitat loss/fragmentation, pollutants and climate change. Using a sensory ecology approach, we present a mechanistic framework for predicting variation in behavioural responses to environmental change, drawing from models of decision-making processes and an understanding of the selective background against which they evolved. Where immediate behavioural responses are inadequate, learning or evolutionary adaptation may prove useful, although these mechanisms are also constrained by evolutionary history. Although predicting the responses of species to environmental change is difficult, we highlight the need for a better understanding of the role of evolutionary history in shaping individuals’ responses to their environment and provide suggestion for future work. PMID:25567979

Evolution and behavioural responses to human-induced rapid environmental change.

PubMed

Sih, Andrew; Ferrari, Maud C O; Harris, David J

2011-03-01

Almost all organisms live in environments that have been altered, to some degree, by human activities. Because behaviour mediates interactions between an individual and its environment, the ability of organisms to behave appropriately under these new conditions is crucial for determining their immediate success or failure in these modified environments. While hundreds of species are suffering dramatically from these environmental changes, others, such as urbanized and pest species, are doing better than ever. Our goal is to provide insights into explaining such variation. We first summarize the responses of some species to novel situations, including novel risks and resources, habitat loss/fragmentation, pollutants and climate change. Using a sensory ecology approach, we present a mechanistic framework for predicting variation in behavioural responses to environmental change, drawing from models of decision-making processes and an understanding of the selective background against which they evolved. Where immediate behavioural responses are inadequate, learning or evolutionary adaptation may prove useful, although these mechanisms are also constrained by evolutionary history. Although predicting the responses of species to environmental change is difficult, we highlight the need for a better understanding of the role of evolutionary history in shaping individuals' responses to their environment and provide suggestion for future work.

Molecular Evolution of the Tissue-nonspecific Alkaline Phosphatase Allows Prediction and Validation of Missense Mutations Responsible for Hypophosphatasia*

PubMed Central

Silvent, Jérémie; Gasse, Barbara; Mornet, Etienne; Sire, Jean-Yves

2014-01-01

ALPL encodes the tissue nonspecific alkaline phosphatase (TNSALP), which removes phosphate groups from various substrates. Its function is essential for bone and tooth mineralization. In humans, ALPL mutations lead to hypophosphatasia, a genetic disorder characterized by defective bone and/or tooth mineralization. To date, 275 ALPL mutations have been reported to cause hypophosphatasia, of which 204 were simple missense mutations. Molecular evolutionary analysis has proved to be an efficient method to highlight residues important for the protein function and to predict or validate sensitive positions for genetic disease. Here we analyzed 58 mammalian TNSALP to identify amino acids unchanged, or only substituted by residues sharing similar properties, through 220 millions years of mammalian evolution. We found 469 sensitive positions of the 524 residues of human TNSALP, which indicates a highly constrained protein. Any substitution occurring at one of these positions is predicted to lead to hypophosphatasia. We tested the 204 missense mutations resulting in hypophosphatasia against our predictive chart, and validated 99% of them. Most sensitive positions were located in functionally important regions of TNSALP (active site, homodimeric interface, crown domain, calcium site, …). However, some important positions are located in regions, the structure and/or biological function of which are still unknown. Our chart of sensitive positions in human TNSALP (i) enables to validate or invalidate at low cost any ALPL mutation, which would be suspected to be responsible for hypophosphatasia, by contrast with time consuming and expensive functional tests, and (ii) displays higher predictive power than in silico models of prediction. PMID:25023282

Rhesus macaque and mouse models for down-selecting circumsporozoite protein based malaria vaccines differ significantly in immunogenicity and functional outcomes.

PubMed

Phares, Timothy W; May, Anthony D; Genito, Christopher J; Hoyt, Nathan A; Khan, Farhat A; Porter, Michael D; DeBot, Margot; Waters, Norman C; Saudan, Philippe; Dutta, Sheetij

2017-03-13

Non-human primates, such as the rhesus macaques, are the preferred model for down-selecting human malaria vaccine formulations, but the rhesus model is expensive and does not allow for direct efficacy testing of human malaria vaccines. Transgenic rodent parasites expressing genes of human Plasmodium are now routinely used for efficacy studies of human malaria vaccines. Mice have however rarely predicted success in human malaria trials and there is scepticism whether mouse studies alone are sufficient to move a vaccine candidate into the clinic. A comparison of immunogenicity, fine-specificity and functional activity of two Alum-adjuvanted Plasmodium falciparum circumsporozoite protein (CSP)-based vaccines was conducted in mouse and rhesus models. One vaccine was a soluble recombinant protein (CSP) and the other was the same CSP covalently conjugated to the Qβ phage particle (Qβ-CSP). Mice showed different kinetics of antibody responses and different sensitivity to the NANP-repeat and N-terminal epitopes as compared to rhesus. While mice failed to discern differences between the protective efficacy of CSP versus Qβ-CSP vaccine following direct challenge with transgenic Plasmodium berghei parasites, rhesus serum from the Qβ-CSP-vaccinated animals induced higher in vivo sporozoite neutralization activity. Despite some immunologic parallels between models, these data demonstrate that differences between the immune responses induced in the two models risk conflicting decisions regarding potential vaccine utility in humans. In combination with historical observations, the data presented here suggest that although murine models may be useful for some purposes, non-human primate models may be more likely to predict the human response to investigational vaccines.

Deep Visual Attention Prediction

NASA Astrophysics Data System (ADS)

Wang, Wenguan; Shen, Jianbing

2018-05-01

In this work, we aim to predict human eye fixation with view-free scenes based on an end-to-end deep learning architecture. Although Convolutional Neural Networks (CNNs) have made substantial improvement on human attention prediction, it is still needed to improve CNN based attention models by efficiently leveraging multi-scale features. Our visual attention network is proposed to capture hierarchical saliency information from deep, coarse layers with global saliency information to shallow, fine layers with local saliency response. Our model is based on a skip-layer network structure, which predicts human attention from multiple convolutional layers with various reception fields. Final saliency prediction is achieved via the cooperation of those global and local predictions. Our model is learned in a deep supervision manner, where supervision is directly fed into multi-level layers, instead of previous approaches of providing supervision only at the output layer and propagating this supervision back to earlier layers. Our model thus incorporates multi-level saliency predictions within a single network, which significantly decreases the redundancy of previous approaches of learning multiple network streams with different input scales. Extensive experimental analysis on various challenging benchmark datasets demonstrate our method yields state-of-the-art performance with competitive inference time.

A predictive model of human performance.

NASA Technical Reports Server (NTRS)

Walters, R. F.; Carlson, L. D.

1971-01-01

An attempt is made to develop a model describing the overall responses of humans to exercise and environmental stresses for prediction of exhaustion vs an individual's physical characteristics. The principal components of the model are a steady state description of circulation and a dynamic description of thermal regulation. The circulatory portion of the system accepts changes in work load and oxygen pressure, while the thermal portion is influenced by external factors of ambient temperature, humidity and air movement, affecting skin blood flow. The operation of the model is discussed and its structural details are given.

Computational Model of Steroidogenesis in Human H295R Cells to Predict Biochemical Response to Endocrine Active Chemicals: Model Development for Metyrapone

EPA Science Inventory

BACKGROUND: An in vitro steroidogenesis assay using the human adrenocortical carcinoma cells H295R is being evaluated as a possible toxicity screening approach to detect and assess the impact of endocrine active chemicals (EAC) capable of altering steroid biosynthesis. Interpreta...

Human myosin VIIA responsible for the Usher 1B syndrome: a predicted membrane-associated motor protein expressed in developing sensory epithelia.

PubMed

Weil, D; Levy, G; Sahly, I; Levi-Acobas, F; Blanchard, S; El-Amraoui, A; Crozet, F; Philippe, H; Abitbol, M; Petit, C

1996-04-16

The gene encoding human myosin VIIA is responsible for Usher syndrome type III (USH1B), a disease which associates profound congenital sensorineural deafness, vestibular dysfunction, and retinitis pigmentosa. The reconstituted cDNA sequence presented here predicts a 2215 amino acid protein with a typical unconventional myosin structure. This protein is expected to dimerize into a two-headed molecule. The C terminus of its tail shares homology with the membrane-binding domain of the band 4.1 protein superfamily. The gene consists of 48 coding exons. It encodes several alternatively spliced forms. In situ hybridization analysis in human embryos demonstrates that the myosin VIIA gene is expressed in the pigment epithelium and the photoreceptor cells of the retina, thus indicating that both cell types may be involved in the USH1B retinal degenerative process. In addition, the gene is expressed in the human embryonic cochlear and vestibular neuroepithelia. We suggest that deafness and vestibular dysfunction in USH1B patients result from a defect in the morphogenesis of the inner ear sensory cell stereocilia.

Pep19 drives epitope spreading in periodontitis and periodontitis-associated autoimmune diseases.

PubMed

Kwon, E-Y; Cha, G S; Jeong, E; Lee, J-Y; Kim, S-J; Surh, C D; Choi, J

2016-06-01

Epitope spreading is one of valid mechanisms operating in immunopathological processes of infection-induced autoimmune diseases. We hypothesized that the peptide 19 from Porphyromonas gingivalis heat shock protein (HSP) 60 (Pep19) may be the dominant epitope from which epitope-specific immune response to subdominant epitopes may diversify sequentially into autoimmune responses directed at human neoepitopes in P. gingivalis-induced periodontitis and autoimmune diseases. However, the exact feature and mechanism on how Pep19 may drive epitope spreading into human autoantigens in chronic periodontitis or P. gingivalis-induced experimental periodontitis has not been clarified. The present study was performed with the following specific aims: (i) to delineate retrospectively the features of epitope spreading by human cross-sectional analysis; (ii) to demonstrate prospectively the epitope spreading into new antigenic determinants in an ordered, predictable and sequential manner in experimental periodontitis; and (iii) to clarify the mechanism on how immunization with Pep19 may mobilize helper T cells or elicit B-cell responses to human autoantigens and neoantigen. The study was devised for two independent investigations - a cross-sectional analysis on clinical subjects and a prospective analysis on experimental periodontitis - each being subdivided further into two additional independent observations. Cross-sectional dot immunoblot pattern against a panel of peptides of P. gingivalis HSP60 and human HSP60 was performed among age-dependent healthy subjects and between healthy subjects, patients with chronic periodontitis and patients with autoimmune disease, to identify epitope spreading. A peptide-specific T-cell line was established for phenotype analysis and for proliferation assay to an array of identical peptides. An identical prospective analysis was performed in P. gingivalis-induced experimental periodontitis or in Pep19-immunized mice. Cross-reactivity of anti-Pep19 monoclonal antibody was also investigated. A dominant immune response exclusively to Pep19 prevailed in healthy human subjects (before the age of 40) and mice that persisted in chronic periodontitis and autoimmune diseases without being replaced further by subsequent subdominant epitopes. A sequential epitope spreading provoked by Pep19 to subdominant autoantigen peptide 19 from human HSP60 (Hu19) in most healthy human subjects and mice, and to autoantigen peptide 9 from human HSP60 (Hu9) and neoantigen oxidized low-density lipoprotein (ox-LDL) in P. gingivalis-induced chronic periodontitis and autoimmune diseases could be demonstrated in a reproducible and predictable manner. T-cell proliferative activity to multiple autoantigens Hu19, Hu9 and ox-LDL, and cross-reactivity of anti-Pep19 monoclonal antibody to these epitopes may be proposed as cellular and molecular mechanisms responsible for the phenomenon. Moreover, the predictive value of Pep19 for Hu9 increased remarkably in the disease group when compared with that of the healthy group. Taken together, epitope spreading to Hu19, Hu9 and ox-LDL provoked by Pep19 could be proposed as a solid phenomenon observed in P. gingivalis-induced chronic periodontitis and infection-induced autoimmune diseases in a reproducible and predictable manner. T-cell proliferative activity to these peptides and cross-reactivity of anti-Pep19 antibodies to multiple human autoantigens could be proposed as cellular and molecular mechanisms responsible for this phenomenon. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Simple Learned Weighted Sums of Inferior Temporal Neuronal Firing Rates Accurately Predict Human Core Object Recognition Performance.

PubMed

Majaj, Najib J; Hong, Ha; Solomon, Ethan A; DiCarlo, James J

2015-09-30

To go beyond qualitative models of the biological substrate of object recognition, we ask: can a single ventral stream neuronal linking hypothesis quantitatively account for core object recognition performance over a broad range of tasks? We measured human performance in 64 object recognition tests using thousands of challenging images that explore shape similarity and identity preserving object variation. We then used multielectrode arrays to measure neuronal population responses to those same images in visual areas V4 and inferior temporal (IT) cortex of monkeys and simulated V1 population responses. We tested leading candidate linking hypotheses and control hypotheses, each postulating how ventral stream neuronal responses underlie object recognition behavior. Specifically, for each hypothesis, we computed the predicted performance on the 64 tests and compared it with the measured pattern of human performance. All tested hypotheses based on low- and mid-level visually evoked activity (pixels, V1, and V4) were very poor predictors of the human behavioral pattern. However, simple learned weighted sums of distributed average IT firing rates exactly predicted the behavioral pattern. More elaborate linking hypotheses relying on IT trial-by-trial correlational structure, finer IT temporal codes, or ones that strictly respect the known spatial substructures of IT ("face patches") did not improve predictive power. Although these results do not reject those more elaborate hypotheses, they suggest a simple, sufficient quantitative model: each object recognition task is learned from the spatially distributed mean firing rates (100 ms) of ∼60,000 IT neurons and is executed as a simple weighted sum of those firing rates. Significance statement: We sought to go beyond qualitative models of visual object recognition and determine whether a single neuronal linking hypothesis can quantitatively account for core object recognition behavior. To achieve this, we designed a database of images for evaluating object recognition performance. We used multielectrode arrays to characterize hundreds of neurons in the visual ventral stream of nonhuman primates and measured the object recognition performance of >100 human observers. Remarkably, we found that simple learned weighted sums of firing rates of neurons in monkey inferior temporal (IT) cortex accurately predicted human performance. Although previous work led us to expect that IT would outperform V4, we were surprised by the quantitative precision with which simple IT-based linking hypotheses accounted for human behavior. Copyright © 2015 the authors 0270-6474/15/3513402-17$15.00/0.

Synthesising empirical results to improve predictions of post-wildfire runoff and erosion response

USGS Publications Warehouse

Shakesby, Richard A.; Moody, John A.; Martin, Deborah A.; Robichaud, Peter R.

2016-01-01

Advances in research into wildfire impacts on runoff and erosion have demonstrated increasing complexity of controlling factors and responses, which, combined with changing fire frequency, present challenges for modellers. We convened a conference attended by experts and practitioners in post-wildfire impacts, meteorology and related research, including modelling, to focus on priority research issues. The aim was to improve our understanding of controls and responses and the predictive capabilities of models. This conference led to the eight selected papers in this special issue. They address aspects of the distinctiveness in the controls and responses among wildfire regions, spatiotemporal rainfall variability, infiltration, runoff connectivity, debris flow formation and modelling applications. Here we summarise key findings from these papers and evaluate their contribution to improving understanding and prediction of post-wildfire runoff and erosion under changes in climate, human intervention and population pressure on wildfire-prone areas.

Social group dynamics predict stress variability among children in a New Zealand classroom.

PubMed

Spray, Julie; Floyd, Bruce; Littleton, Judith; Trnka, Susanna; Mattison, Siobhan

2018-03-27

Previous research proposes stress as a mechanism for linking social environments and biological bodies. In particular, non-human primate studies investigate relationships between cortisol as a measure of stress response and social hierarchies. Because human social structures often include hierarchies of dominance and social status, humans may exhibit similar patterns. Studies of non-human primates, however, have not reached consistent conclusions with respect to relationships between social position and levels of cortisol. While human studies report associations between cortisol and various aspects of social environments, studies that consider social status as a predictor of stress response also report mixed results. Others have argued that perceptions of social status may have different implications for stress response depending upon social context. We propose here that characteristics of children's social networks may be a better predictor of central tendencies and variability of stress response than their perceptions of social status. This is evaluated among 24 children from 9.4 to 11.3 years of age in one upper middle-class New Zealand primary school classroom, assessed through observation within the classroom, self-reports during semi-structured interviews and 221 serial saliva samples provided daily over 10 consecutive school days. A synthetic assessment of the children's networks and peer-relationships was developed prior to saliva-cortisol analysis. We found that greater stability of peer-relationships within groups significantly predicts lower within-group variation in mid-morning cortisol over the two-week period, but not overall within-group differences in mean cortisol. Copyright © 2018 Elsevier GmbH. All rights reserved.

Brucella melitensis T Cell Epitope Recognition in Humans with Brucellosis in Peru

PubMed Central

Cannella, Anthony P.; Arlehamn, Cecilia S. Lindestam; Sidney, John; Patra, Kailash P.; Torres, Katherine; Tsolis, Renee M.; Liang, Li; Felgner, Philip L.; Saito, Mayuko; Gotuzzo, Eduardo; Gilman, Robert H.; Sette, Alessandro

2014-01-01

Brucella melitensis, one of the causative agents of human brucellosis, causes acute, chronic, and relapsing infection. While T cell immunity in brucellosis has been extensively studied in mice, no recognized human T cell epitopes that might provide new approaches to classifying and prognosticating B. melitensis infection have ever been delineated. Twenty-seven pools of 500 major histocompatibility complex class II (MHC-II) restricted peptides were created by computational prediction of promiscuous MHC-II CD4+ T cell derived from the top 50 proteins recognized by IgG in human sera on a genome level B. melitensis protein microarray. Gamma interferon (IFN-γ) and interleukin-5 (IL-5) enzyme-linked immunospot (ELISPOT) analyses were used to quantify and compare Th1 and Th2 responses of leukapheresis-obtained peripheral blood mononuclear cells from Peruvian subjects cured after acute infection (n = 9) and from patients who relapsed (n = 5). Four peptide epitopes derived from 3 B. melitensis proteins (BMEI 1330, a DegP/HtrA protease; BMEII 0029, type IV secretion system component VirB5; and BMEII 0691, a predicted periplasmic binding protein of a peptide transport system) were found repeatedly to produce significant IFN-γ ELISPOT responses in both acute-infection and relapsing patients; none of the peptides distinguished the patient groups. IL-5 responses against the panel of peptides were insignificant. These experiments are the first to systematically identify B. melitensis MHC-II-restricted CD4+ T cell epitopes recognized by the human immune response, with the potential for new approaches to brucellosis diagnostics and understanding the immunopathogenesis related to this intracellular pathogen. PMID:24126518

Using the brain's fight-or-flight response for predicting mental illness on the human space flight program

NASA Astrophysics Data System (ADS)

Losik, L.

A predictive medicine program allows disease and illness including mental illness to be predicted using tools created to identify the presence of accelerated aging (a.k.a. disease) in electrical and mechanical equipment. When illness and disease can be predicted, actions can be taken so that the illness and disease can be prevented and eliminated. A predictive medicine program uses the same tools and practices from a prognostic and health management program to process biological and engineering diagnostic data provided in analog telemetry during prelaunch readiness and space exploration missions. The biological and engineering diagnostic data necessary to predict illness and disease is collected from the pre-launch spaceflight readiness activities and during space flight for the ground crew to perform a prognostic analysis on the results from a diagnostic analysis. The diagnostic, biological data provided in telemetry is converted to prognostic (predictive) data using the predictive algorithms. Predictive algorithms demodulate telemetry behavior. They illustrate the presence of accelerated aging/disease in normal appearing systems that function normally. Mental illness can predicted using biological diagnostic measurements provided in CCSDS telemetry from a spacecraft such as the ISS or from a manned spacecraft in deep space. The measurements used to predict mental illness include biological and engineering data from an astronaut's circadian and ultranian rhythms. This data originates deep in the brain that is also damaged from the long-term exposure to cortisol and adrenaline anytime the body's fight or flight response is activated. This paper defines the brain's FOFR; the diagnostic, biological and engineering measurements needed to predict mental illness, identifies the predictive algorithms necessary to process the behavior in CCSDS analog telemetry to predict and thus prevent mental illness from occurring on human spaceflight missions.

Species-specific responses of Late Quaternary megafauna to climate and humans

PubMed Central

Lorenzen, Eline D.; Nogués-Bravo, David; Orlando, Ludovic; Weinstock, Jaco; Binladen, Jonas; Marske, Katharine A.; Ugan, Andrew; Borregaard, Michael K.; Gilbert, M. Thomas P.; Nielsen, Rasmus; Ho, Simon Y. W.; Goebel, Ted; Graf, Kelly E.; Byers, David; Stenderup, Jesper T.; Rasmussen, Morten; Campos, Paula F.; Leonard, Jennifer A.; Koepfli, Klaus-Peter; Froese, Duane; Zazula, Grant; Stafford, Thomas W.; Aaris-Sørensen, Kim; Batra, Persaram; Haywood, Alan M.; Singarayer, Joy S.; Valdes, Paul J.; Boeskorov, Gennady; Burns, James A.; Davydov, Sergey P.; Haile, James; Jenkins, Dennis L.; Kosintsev, Pavel; Kuznetsova, Tatyana; Lai, Xulong; Martin, Larry D.; McDonald, H. Gregory; Mol, Dick; Meldgaard, Morten; Munch, Kasper; Stephan, Elisabeth; Sablin, Mikhail; Sommer, Robert S.; Sipko, Taras; Scott, Eric; Suchard, Marc A.; Tikhonov, Alexei; Willerslev, Rane; Wayne, Robert K.; Cooper, Alan; Hofreiter, Michael; Sher, Andrei; Shapiro, Beth; Rahbek, Carsten; Willerslev, Eske

2014-01-01

Despite decades of research, the roles of climate and humans in driving the dramatic extinctions of large-bodied mammals during the Late Quaternary remain contentious. We use ancient DNA, species distribution models and the human fossil record to elucidate how climate and humans shaped the demographic history of woolly rhinoceros, woolly mammoth, wild horse, reindeer, bison and musk ox. We show that climate has been a major driver of population change over the past 50,000 years. However, each species responds differently to the effects of climatic shifts, habitat redistribution and human encroachment. Although climate change alone can explain the extinction of some species, such as Eurasian musk ox and woolly rhinoceros, a combination of climatic and anthropogenic effects appears to be responsible for the extinction of others, including Eurasian steppe bison and wild horse. We find no genetic signature or any distinctive range dynamics distinguishing extinct from surviving species, underscoring the challenges associated with predicting future responses of extant mammals to climate and human-mediated habitat change. PMID:22048313

Hormones and Endocrine-Disrupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses

PubMed Central

Colborn, Theo; Hayes, Tyrone B.; Heindel, Jerrold J.; Jacobs, David R.; Lee, Duk-Hee; Shioda, Toshi; Soto, Ana M.; vom Saal, Frederick S.; Welshons, Wade V.; Zoeller, R. Thomas

2012-01-01

For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from the cell culture, animal, and epidemiology literature. We illustrate that nonmonotonic responses and low-dose effects are remarkably common in studies of natural hormones and EDCs. Whether low doses of EDCs influence certain human disorders is no longer conjecture, because epidemiological studies show that environmental exposures to EDCs are associated with human diseases and disabilities. We conclude that when nonmonotonic dose-response curves occur, the effects of low doses cannot be predicted by the effects observed at high doses. Thus, fundamental changes in chemical testing and safety determination are needed to protect human health. PMID:22419778

The use of ex vivo human skin tissue for genotoxicity testing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Reus, Astrid A.; Usta, Mustafa; Krul, Cyrille A.M., E-mail: cyrille.krul@tno.nl

2012-06-01

As a result of the chemical legislation concerning the registration, evaluation, authorization and restriction of chemicals (REACH), and the Seventh Amendment to the Cosmetics Directive, which prohibits animal testing in Europe for cosmetics, alternative methods for safety evaluation of chemicals are urgently needed. Current in vitro genotoxicity assays are not sufficiently predictive for the in vivo situation, resulting in an unacceptably high number of misleading positives. For many chemicals and ingredients of personal care products the skin is the first site of contact, but there are no in vitro genotoxicity assays available in the skin for additional evaluation of positivemore » or equivocal responses observed in regulatory in vitro genotoxicity assays. In the present study ex vivo human skin tissue obtained from surgery was used for genotoxicity evaluation of chemicals by using the comet assay. Fresh ex vivo human skin tissue was cultured in an air–liquid interface and topically exposed to 20 chemicals, including true positive, misleading positive and true negative genotoxins. Based on the results obtained in the present study, the sensitivity, specificity and accuracy of the ex vivo skin comet assay to predict in vivo genotoxicity were 89%, 90% and 89%, respectively. Donor and experimental variability were mainly reflected in the magnitude of the response and not the difference between the presence and absence of a genotoxic response. The present study indicates that human skin obtained from surgery is a promising and robust model for safety evaluation of chemicals that are in direct contact with the skin. -- Highlights: ► We use human skin obtained from surgery for genotoxicity evaluation of chemicals. ► We use the comet assay as parameter for genotoxicity in ex vivo human skin. ► Sensitivity, specificity and accuracy to predict in vivo genotoxins are determined. ► Sensitivity, specificity and accuracy are 89%, 90% and 90%, respectively. ► The method is suitable for evaluation of chemicals that are in contact with skin.« less

Systematic Reviews of Animal Models: Methodology versus Epistemology

PubMed Central

Greek, Ray; Menache, Andre

2013-01-01

Systematic reviews are currently favored methods of evaluating research in order to reach conclusions regarding medical practice. The need for such reviews is necessitated by the fact that no research is perfect and experts are prone to bias. By combining many studies that fulfill specific criteria, one hopes that the strengths can be multiplied and thus reliable conclusions attained. Potential flaws in this process include the assumptions that underlie the research under examination. If the assumptions, or axioms, upon which the research studies are based, are untenable either scientifically or logically, then the results must be highly suspect regardless of the otherwise high quality of the studies or the systematic reviews. We outline recent criticisms of animal-based research, namely that animal models are failing to predict human responses. It is this failure that is purportedly being corrected via systematic reviews. We then examine the assumption that animal models can predict human outcomes to perturbations such as disease or drugs, even under the best of circumstances. We examine the use of animal models in light of empirical evidence comparing human outcomes to those from animal models, complexity theory, and evolutionary biology. We conclude that even if legitimate criticisms of animal models were addressed, through standardization of protocols and systematic reviews, the animal model would still fail as a predictive modality for human response to drugs and disease. Therefore, systematic reviews and meta-analyses of animal-based research are poor tools for attempting to reach conclusions regarding human interventions. PMID:23372426

Review on modeling heat transfer and thermoregulatory responses in human body.

PubMed

Fu, Ming; Weng, Wenguo; Chen, Weiwang; Luo, Na

2016-12-01

Several mathematical models of human thermoregulation have been developed, contributing to a deep understanding of thermal responses in different thermal conditions and applications. In these models, the human body is represented by two interacting systems of thermoregulation: the controlling active system and the controlled passive system. This paper reviews the recent research of human thermoregulation models. The accuracy and scope of the thermal models are improved, for the consideration of individual differences, integration to clothing models, exposure to cold and hot conditions, and the changes of physiological responses for the elders. The experimental validated methods for human subjects and manikin are compared. The coupled method is provided for the manikin, controlled by the thermal model as an active system. Computational Fluid Dynamics (CFD) is also used along with the manikin or/and the thermal model, to evaluate the thermal responses of human body in various applications, such as evaluation of thermal comfort to increase the energy efficiency, prediction of tolerance limits and thermal acceptability exposed to hostile environments, indoor air quality assessment in the car and aerospace industry, and design protective equipment to improve function of the human activities. Copyright © 2016 Elsevier Ltd. All rights reserved.

Forecasting extreme temperature health hazards in Europe

NASA Astrophysics Data System (ADS)

Di Napoli, Claudia; Pappenberger, Florian; Cloke, Hannah L.

2017-04-01

Extreme hot temperatures, such as those experienced during a heat wave, represent a dangerous meteorological hazard to human health. Heat disorders such as sunstroke are harmful to people of all ages and responsible for excess mortality in the affected areas. In 2003 more than 50,000 people died in western and southern Europe because of a severe and sustained episode of summer heat [1]. Furthermore, according to the Intergovernmental Panel on Climate Change heat waves are expected to get more frequent in the future thus posing an increasing threat to human lives. Developing appropriate tools for extreme hot temperatures prediction is therefore mandatory to increase public preparedness and mitigate heat-induced impacts. A recent study has shown that forecasts of the Universal Thermal Climate Index (UTCI) provide a valid overview of extreme temperature health hazards on a global scale [2]. UTCI is a parameter related to the temperature of the human body and its regulatory responses to the surrounding atmospheric environment. UTCI is calculated using an advanced thermo-physiological model that includes the human heat budget, physiology and clothing. To forecast UTCI the model uses meteorological inputs, such as 2m air temperature, 2m water vapour pressure and wind velocity at body height derived from 10m wind speed, from NWP models. Here we examine the potential of UTCI as an extreme hot temperature prediction tool for the European area. UTCI forecasts calculated using above-mentioned parameters from ECMWF models are presented. The skill in predicting UTCI for medium lead times is also analysed and discussed for implementation to international health-hazard warning systems. This research is supported by the ANYWHERE project (EnhANcing emergencY management and response to extreme WeatHER and climate Events) which is funded by the European Commission's HORIZON2020 programme. [1] Koppe C. et al., Heat waves: risks and responses. World Health Organization. Health and Global Environmental Change, Series No. 2, Copenhagen, Denmark, 2004. [2] Pappenberger F. et al., Global forecasting of thermal health hazards: the skill of probabilistic predictions of the Universal Thermal Climate Index (UTCI), International Journal of Biometeorology 59(3): 311-323, 2015.

Variation in the human ribs geometrical properties and mechanical response based on X-ray computed tomography images resolution.

PubMed

Perz, Rafał; Toczyski, Jacek; Subit, Damien

2015-01-01

Computational models of the human body are commonly used for injury prediction in automobile safety research. To create these models, the geometry of the human body is typically obtained from segmentation of medical images such as computed tomography (CT) images that have a resolution between 0.2 and 1mm/pixel. While the accuracy of the geometrical and structural information obtained from these images depend greatly on their resolution, the effect of image resolution on the estimation of the ribs geometrical properties has yet to be established. To do so, each of the thirty-four sections of ribs obtained from a Post Mortem Human Surrogate (PMHS) was imaged using three different CT modalities: standard clinical CT (clinCT), high resolution clinical CT (HRclinCT), and microCT. The images were processed to estimate the rib cross-section geometry and mechanical properties, and the results were compared to those obtained from the microCT images by computing the 'deviation factor', a metric that quantifies the relative difference between results obtained from clinCT and HRclinCT to those obtained from microCT. Overall, clinCT images gave a deviation greater than 100%, and were therefore deemed inadequate for the purpose of this study. HRclinCT overestimated the rib cross-sectional area by 7.6%, the moments of inertia by about 50%, and the cortical shell area by 40.2%, while underestimating the trabecular area by 14.7%. Next, a parametric analysis was performed to quantify how the variations in the estimate of the geometrical properties affected the rib predicted mechanical response under antero-posterior loading. A variation of up to 45% for the predicted peak force and up to 50% for the predicted stiffness was observed. These results provide a quantitative estimate of the sensitivity of the response of the FE model to the resolution of the images used to generate it. They also suggest that a correction factor could be derived from the comparison between microCT and HRclinCT images to improve the response of the model developed based on HRclinCT images. Copyright © 2014 Elsevier Ltd. All rights reserved.

Impact Response Comparison Between Parametric Human Models and Postmortem Human Subjects with a Wide Range of Obesity Levels.

PubMed

Zhang, Kai; Cao, Libo; Wang, Yulong; Hwang, Eunjoo; Reed, Matthew P; Forman, Jason; Hu, Jingwen

2017-10-01

Field data analyses have shown that obesity significantly increases the occupant injury risks in motor vehicle crashes, but the injury assessment tools for people with obesity are largely lacking. The objectives of this study were to use a mesh morphing method to rapidly generate parametric finite element models with a wide range of obesity levels and to evaluate their biofidelity against impact tests using postmortem human subjects (PMHS). Frontal crash tests using three PMHS seated in a vehicle rear seat compartment with body mass index (BMI) from 24 to 40 kg/m 2 were selected. To develop the human models matching the PMHS geometry, statistical models of external body shape, rib cage, pelvis, and femur were applied to predict the target geometry using age, sex, stature, and BMI. A mesh morphing method based on radial basis functions was used to rapidly morph a baseline human model into the target geometry. The model-predicted body excursions and injury measures were compared to the PMHS tests. Comparisons of occupant kinematics and injury measures between the tests and simulations showed reasonable correlations across the wide range of BMI levels. The parametric human models have the capability to account for the obesity effects on the occupant impact responses and injury risks. © 2017 The Obesity Society.

Advanced systems biology methods in drug discovery and translational biomedicine.

PubMed

Zou, Jun; Zheng, Ming-Wu; Li, Gen; Su, Zhi-Guang

2013-01-01

Systems biology is in an exponential development stage in recent years and has been widely utilized in biomedicine to better understand the molecular basis of human disease and the mechanism of drug action. Here, we discuss the fundamental concept of systems biology and its two computational methods that have been commonly used, that is, network analysis and dynamical modeling. The applications of systems biology in elucidating human disease are highlighted, consisting of human disease networks, treatment response prediction, investigation of disease mechanisms, and disease-associated gene prediction. In addition, important advances in drug discovery, to which systems biology makes significant contributions, are discussed, including drug-target networks, prediction of drug-target interactions, investigation of drug adverse effects, drug repositioning, and drug combination prediction. The systems biology methods and applications covered in this review provide a framework for addressing disease mechanism and approaching drug discovery, which will facilitate the translation of research findings into clinical benefits such as novel biomarkers and promising therapies.

Hunted Woolly Monkeys (Lagothrix poeppigii) Show Threat-Sensitive Responses to Human Presence

PubMed Central

Papworth, Sarah; Milner-Gulland, E. J.; Slocombe, Katie

2013-01-01

Responding only to individuals of a predator species which display threatening behaviour allows prey species to minimise energy expenditure and other costs of predator avoidance, such as disruption of feeding. The threat sensitivity hypothesis predicts such behaviour in prey species. If hunted animals are unable to distinguish dangerous humans from non-dangerous humans, human hunting is likely to have a greater effect on prey populations as all human encounters should lead to predator avoidance, increasing stress and creating opportunity costs for exploited populations. We test the threat sensitivity hypothesis in wild Poeppigi's woolly monkeys (Lagothrix poeppigii) in Yasuní National Park, Ecuador, by presenting human models engaging in one of three behaviours “hunting”, “gathering” or “researching”. These experiments were conducted at two sites with differing hunting pressures. Visibility, movement and vocalisations were recorded and results from two sites showed that groups changed their behaviours after being exposed to humans, and did so in different ways depending on the behaviour of the human model. Results at the site with higher hunting pressure were consistent with predictions based on the threat sensitivity hypothesis. Although results at the site with lower hunting pressure were not consistent with the results at the site with higher hunting pressure, groups at this site also showed differential responses to different human behaviours. These results provide evidence of threat-sensitive predator avoidance in hunted primates, which may allow them to conserve both time and energy when encountering humans which pose no threat. PMID:23614003

Sulfation of minoxidil by multiple human cytosolic sulfotransferases.

PubMed

Anderson, R J; Kudlacek, P E; Clemens, D L

1998-02-20

Minoxidil is an antihypertensive agent and hair growth promoter that is metabolized by sulfation to the active compound, minoxidil sulfate. Thermostable phenol sulfotransferase (TS PST or P-PST) was initially thought to catalyze the reaction, and the enzyme was designated minoxidil sulfotransferase (MNX-ST). Information about human ST activities toward minoxidil would be useful in developing the capacity to predict individual responses to minoxidil based on tissue levels of STs. Therefore, human STs were studied from platelet homogenates, partially purified platelets, scalp skin high speed supernatants and COS-1 cell cDNA expressed preparations using a radiochemical enzymatic assay with minoxidil as the substrate. Studies showed the presence of TS PST, TL (thermolabile) PST and MNX-ST activities in human scalp skin. Biochemical properties and correlation studies suggested that in addition to TS PST, the TL PST activity, another ST activity or both were involved in the reaction. Partially purified human platelet TL PST tested with minoxidil and dopamine showed identical thermal stabilities and similar responses to the inhibitors 2,6-dichloro-4-nitrophenol (DCNP) and NaCl. To characterize the activity of TL PST toward minoxidil, several biochemical properties of the enzyme expressed from a human liver cDNA clone were investigated. When assayed with minoxidil and dopamine, thermal stabilities of the expressed enzyme were identical and IC50 values for the inhibitors DCNP and NaCl were similar. It was also demonstrated that cDNA encoded human liver dehydroepiandrosterone sulfotransferase and estrogen sulfotransferase contributed to the sulfation of minoxidil. The results confirm that at least four human STs contribute to minoxidil sulfation. MNX-ST activity represents a combination of ST activities. The data indicate that multiple ST activities should be taken into account in attempts to predict the regulation of minoxidil sulfation and individual responses to minoxidil.

The Effects of Prediction on the Perception for Own-Race and Other-Race Faces

PubMed Central

Ran, Guangming; Zhang, Qi; Chen, Xu; Pan, Yangu

2014-01-01

Human beings do not passively perceive important social features about others such as race and age in social interactions. Instead, it is proposed that humans might continuously generate predictions about these social features based on prior similar experiences. Pre-awareness of racial information conveyed by others' faces enables individuals to act in “culturally appropriate” ways, which is useful for interpersonal relations in different ethnicity groups. However, little is known about the effects of prediction on the perception for own-race and other-race faces. Here, we addressed this issue using high temporal resolution event-related potential techniques. In total, data from 24 participants (13 women and 11 men) were analyzed. It was found that the N170 amplitudes elicited by other-race faces, but not own-race faces, were significantly smaller in the predictable condition compared to the unpredictable condition, reflecting a switch to holistic processing of other-race faces when those faces were predictable. In this respect, top-down prediction about face race might contribute to the elimination of the other-race effect (one face recognition impairment). Furthermore, smaller P300 amplitudes were observed for the predictable than for unpredictable conditions, which suggested that the prediction of race reduced the neural responses of human brains. PMID:25422892

Compositional stability of boreal understorey vegetation after overstorey harvesting across a riparian ecotone

Treesearch

Rebecca L. MacDonald; Han Y.H. Chen; Samuel F. Bartels; Brian J. Palik; Ellie E. Prepas; Frank Gilliam

2015-01-01

Questions: Understanding factors that contribute to the stability of an ecosystem following harvesting is central to predicting responses of boreal ecosystems to increasing human disturbances.While the response of understorey vegetation to harvesting is well understood for upland sites, little is known about compositional stability of riparian understorey vegetation....

Gradual Growth versus Shape Invariance in Perceptual Decision Making

ERIC Educational Resources Information Center

Rouder, Jeffrey N.; Yue, Yu; Speckman, Paul L.; Pratte, Michael S.; Province, Jordan M.

2010-01-01

A dominant theme in modeling human perceptual judgments is that sensory neural activity is summed or integrated until a critical bound is reached. Such models predict that, in general, the shape of response time distributions change across conditions, although in practice, this shape change may be subtle. An alternative view is that response time…

Experimental studies for determining human discomfort response to vertical sinusoidal vibration

NASA Technical Reports Server (NTRS)

Dempsey, T. K.; Leatherwood, J. D.

1975-01-01

A study was conducted to investigate several problems related to methodology and design of experiments to obtain human comfort response to vertical sinusoidal vibration. Specifically, the studies were directed to the determination of (1) the adequacy of frequency averaging of vibration data to obtain discomfort predictors, (2) the effect of practice on subject ratings, (3) the effect of the demographic factors of age, sex, and weight, and (4) the relative importance of seat and floor vibrations in the determination of measurement and criteria specification location. Results indicate that accurate prediction of discomfort requires knowledge of both the acceleration level and frequency content of the vibration stimuli. More importantly, the prediction of discomfort was shown to be equally good based upon either floor accelerations or seat accelerations. Furthermore, it was demonstrated that the discomfort levels in different seats resulting from similar vibratory imputs were equal. Therefore, it was recommended that criteria specifications and acceleration measurements be made at the floor location. The results also indicated that practice did not systematically influence discomfort responses nor did the demographic factors of age, weight, and sex contribute to the discomfort response variation.

Diminished neural responses predict enhanced intrinsic motivation and sensitivity to external incentive.

PubMed

Marsden, Karen E; Ma, Wei Ji; Deci, Edward L; Ryan, Richard M; Chiu, Pearl H

2015-06-01

The duration and quality of human performance depend on both intrinsic motivation and external incentives. However, little is known about the neuroscientific basis of this interplay between internal and external motivators. Here, we used functional magnetic resonance imaging to examine the neural substrates of intrinsic motivation, operationalized as the free-choice time spent on a task when this was not required, and tested the neural and behavioral effects of external reward on intrinsic motivation. We found that increased duration of free-choice time was predicted by generally diminished neural responses in regions associated with cognitive and affective regulation. By comparison, the possibility of additional reward improved task accuracy, and specifically increased neural and behavioral responses following errors. Those individuals with the smallest neural responses associated with intrinsic motivation exhibited the greatest error-related neural enhancement under the external contingency of possible reward. Together, these data suggest that human performance is guided by a "tonic" and "phasic" relationship between the neural substrates of intrinsic motivation (tonic) and the impact of external incentives (phasic).

Dynamic transcriptional signatures and network responses for clinical symptoms in influenza-infected human subjects using systems biology approaches.

PubMed

Linel, Patrice; Wu, Shuang; Deng, Nan; Wu, Hulin

2014-10-01

Recent studies demonstrate that human blood transcriptional signatures may be used to support diagnosis and clinical decisions for acute respiratory viral infections such as influenza. In this article, we propose to use a newly developed systems biology approach for time course gene expression data to identify significant dynamically response genes and dynamic gene network responses to viral infection. We illustrate the methodological pipeline by reanalyzing the time course gene expression data from a study with healthy human subjects challenged by live influenza virus. We observed clear differences in the number of significant dynamic response genes (DRGs) between the symptomatic and asymptomatic subjects and also identified DRG signatures for symptomatic subjects with influenza infection. The 505 common DRGs shared by the symptomatic subjects have high consistency with the signature genes for predicting viral infection identified in previous works. The temporal response patterns and network response features were carefully analyzed and investigated.

Comparison of experimental models for predicting laser-tissue interaction from 3.8-micron lasers

NASA Astrophysics Data System (ADS)

Williams, Piper C. M.; Winston, Golda C. H.; Randolph, Don Q.; Neal, Thomas A.; Eurell, Thomas E.; Johnson, Thomas E.

2004-07-01

The purpose of this study was to evaluate the laser-tissue interactions of engineered human skin and in-vivo pig skin following exposure to a single 3.8 micron laser light pulse. The goal of the study was to determine if these tissues shared common histologic features following laser exposure that might prove useful in developing in-vitro and in-vivo experimental models to predict the bioeffects of human laser exposure. The minimum exposure required to produce gross morphologic changes following a four microsecond, pulsed skin exposure for both models was determined. Histology was used to compare the cellular responses of the experimental models following laser exposure. Eighteen engineered skin equivalents (in-vitro model), were exposed to 3.8 micron laser light and the tissue responses compared to equivalent exposures made on five Yorkshire pigs (in-vivo model). Representative biopsies of pig skin were taken for histologic evaluation from various body locations immediately, one hour, and 24 hours following exposure. The pattern of epithelial changes seen following in-vitro laser exposure of the engineered human skin and in-vivo exposure of pig skin indicated a common histologic response for this particular combination of laser parameters.

The prediction of human skin responses by using the combined in vitro fluorescein leakage/Alamar Blue (resazurin) assay.

PubMed

Clothier, Richard; Starzec, Gemma; Pradel, Lionel; Baxter, Victoria; Jones, Melanie; Cox, Helen; Noble, Linda

2002-01-01

A range of cosmetics formulations with human patch-test data were supplied in a coded form, for the examination of the use of a combined in vitro permeability barrier assay and cell viability assay to generate, and then test, a prediction model for assessing potential human skin patch-test results. The target cells employed were of the Madin Darby canine kidney cell line, which establish tight junctions and adherens junctions able to restrict the permeability of sodium fluorescein across the barrier of the confluent cell layer. The prediction model for interpretation of the in vitro assay results included initial effects and the recovery profile over 72 hours. A set of the hand-wash, surfactant-based formulations were tested to generate the prediction model, and then six others were evaluated. The model system was then also evaluated with powder laundry detergents and hand moisturisers: their effects were predicted by the in vitro test system. The model was under-predictive for two of the ten hand-wash products. It was over-predictive for the moisturisers, (two out of six) and eight out of ten laundry powders. However, the in vivo human patch test data were variable, and 19 of the 26 predictions were correct or within 0.5 on the 0-4.0 scale used for the in vivo scores, i.e. within the same variable range reported for the repeat-test hand-wash in vivo data.

Attention is necessary for subliminal instrumental conditioning.

PubMed

Mastropasqua, Tommaso; Turatto, Massimo

2015-08-10

The capacity of humans and other animals to provide appropriate responses to stimuli anticipating motivationally significant events is exemplified by instrumental conditioning. Interestingly, in humans instrumental conditioning can occur also for subliminal outcome-predicting stimuli. However, it remains unclear whether attention is necessary for subliminal instrumental conditioning to take place. In two experiments, human participants had to learn to collect rewards (monetary gains) while avoiding punishments (monetary losses), on the basis of subliminal outcome-predicting cues. We found that instrumental conditioning can proceed subconsciously only if spatial attention is aligned with the subliminal cue. Conversely, if spatial attention is briefly diverted from the subliminal cue, then instrumental conditioning is blocked. In humans, attention but not awareness is therefore mandatory for instrumental conditioning, thus revealing a dissociation between awareness and attention in the control of motivated behavior.

How we learn to make decisions: rapid propagation of reinforcement learning prediction errors in humans.

PubMed

Krigolson, Olav E; Hassall, Cameron D; Handy, Todd C

2014-03-01

Our ability to make decisions is predicated upon our knowledge of the outcomes of the actions available to us. Reinforcement learning theory posits that actions followed by a reward or punishment acquire value through the computation of prediction errors-discrepancies between the predicted and the actual reward. A multitude of neuroimaging studies have demonstrated that rewards and punishments evoke neural responses that appear to reflect reinforcement learning prediction errors [e.g., Krigolson, O. E., Pierce, L. J., Holroyd, C. B., & Tanaka, J. W. Learning to become an expert: Reinforcement learning and the acquisition of perceptual expertise. Journal of Cognitive Neuroscience, 21, 1833-1840, 2009; Bayer, H. M., & Glimcher, P. W. Midbrain dopamine neurons encode a quantitative reward prediction error signal. Neuron, 47, 129-141, 2005; O'Doherty, J. P. Reward representations and reward-related learning in the human brain: Insights from neuroimaging. Current Opinion in Neurobiology, 14, 769-776, 2004; Holroyd, C. B., & Coles, M. G. H. The neural basis of human error processing: Reinforcement learning, dopamine, and the error-related negativity. Psychological Review, 109, 679-709, 2002]. Here, we used the brain ERP technique to demonstrate that not only do rewards elicit a neural response akin to a prediction error but also that this signal rapidly diminished and propagated to the time of choice presentation with learning. Specifically, in a simple, learnable gambling task, we show that novel rewards elicited a feedback error-related negativity that rapidly decreased in amplitude with learning. Furthermore, we demonstrate the existence of a reward positivity at choice presentation, a previously unreported ERP component that has a similar timing and topography as the feedback error-related negativity that increased in amplitude with learning. The pattern of results we observed mirrored the output of a computational model that we implemented to compute reward prediction errors and the changes in amplitude of these prediction errors at the time of choice presentation and reward delivery. Our results provide further support that the computations that underlie human learning and decision-making follow reinforcement learning principles.

On Why Targets Evoke P3 Components in Prediction Tasks: Drawing an Analogy between Prediction and Matching Tasks

PubMed Central

Verleger, Rolf; Cäsar, Stephanie; Siller, Bastian; Śmigasiewicz, Kamila

2017-01-01

P3 is the most conspicuous component in recordings of stimulus-evoked EEG potentials from the human scalp, occurring whenever some task has to be performed with the stimuli. The process underlying P3 has been assumed to be the updating of expectancies. More recently, P3 has been related to decision processing and to activation of established stimulus-response associations (S/R-link hypothesis). However, so far this latter approach has not provided a conception about how to explain the occurrence of P3 with predicted stimuli, although P3 was originally discovered in a prediction task. The present article proposes such a conception. We assume that the internal responses right or wrong both become associatively linked to each predicted target and that one of these two response alternatives gets activated as a function of match or mismatch of the target to the preceding prediction. This seems similar to comparison tasks where responses depend on the matching of the target stimulus with a preceding first stimulus (S1). Based on this idea, this study compared the effects of frequencies of first events (predictions or S1) on target-evoked P3s in prediction and comparison tasks. Indeed, frequencies not only of targets but also of first events had similar effects across tasks on target-evoked P3s. These results support the notion that P3 evoked by predicted stimuli reflects activation of appropriate internal “match” or “mismatch” responses, which is compatible with S/R-link hypothesis. PMID:29066965

Scaling approach in predicting the seatbelt loading and kinematics of vulnerable occupants: How far can we go?

PubMed

Nie, Bingbing; Forman, Jason L; Joodaki, Hamed; Wu, Taotao; Kent, Richard W

2016-09-01

Occupants with extreme body size and shape, such as the small female or the obese, were reported to sustain high risk of injury in motor vehicle crashes (MVCs). Dimensional scaling approaches are widely used in injury biomechanics research based on the assumption of geometrical similarity. However, its application scope has not been quantified ever since. The objective of this study is to demonstrate the valid range of scaling approaches in predicting the impact response of the occupants with focus on the vulnerable populations. The present analysis was based on a data set consisting of 60 previously reported frontal crash tests in the same sled buck representing a typical mid-size passenger car. The tests included two categories of human surrogates: 9 postmortem human surrogates (PMHS) of different anthropometries (stature range: 147-189 cm; weight range: 27-151 kg) and 5 anthropomorphic test devices (ATDs). The impact response was considered including the restraint loads and the kinematics of multiple body segments. For each category of the human surrogates, a mid-size occupant was selected as a baseline and the impact response was scaled specifically to another subject based on either the body mass (body shape) or stature (the overall body size). To identify the valid range of the scaling approach, the scaled response was compared to the experimental results using assessment scores on the peak value, peak timing (the time when the peak value occurred), and the overall curve shape ranging from 0 (extremely poor) to 1 (perfect match). Scores of 0.7 to 0.8 and 0.8 to 1.0 indicate fair and acceptable prediction. For both ATDs and PMHS, the scaling factor derived from body mass proved an overall good predictor of the peak timing for the shoulder belt (0.868, 0.829) and the lap belt (0.858, 0.774) and for the peak value of the lap belt force (0.796, 0.869). Scaled kinematics based on body stature provided fair or acceptable prediction on the overall head/shoulder kinematics (0.741, 0.822 for the head; 0.817, 0.728 for the shoulder) regardless of the anthropometry. The scaling approach exhibited poor prediction capability on the curve shape for the restraint force (0.494 and 0.546 for the shoulder belt; 0.585 and 0.530 for the lap belt). It also cannot well predict the excursion of the pelvis and the knee. The results revealed that for the peak lap belt force and the forward motion of the head and shoulder, the underlying linear relationship with body size and shape is valid over a wide anthropometric range. The chaotic nature of the dynamic response cannot be fully recovered by the assumption of the whole-body geometrical similarity, especially for the curve shape. The valid range of the scaling approach established in this study can be reasonably referenced in predicting the impact response of a given specific population with expected deviation. Application of this knowledge also includes proposing strategies for restraint configuration and providing reference for ATD and/or human body model (HBM) development for vulnerable occupants.

An Accuracy--Response Time Capacity Assessment Function that Measures Performance against Standard Parallel Predictions

ERIC Educational Resources Information Center

Townsend, James T.; Altieri, Nicholas

2012-01-01

Measures of human efficiency under increases in mental workload or attentional limitations are vital in studying human perception, cognition, and action. Assays of efficiency as workload changes have typically been confined to either reaction times (RTs) or accuracy alone. Within the realm of RTs, a nonparametric measure called the "workload…

Man's nature: innate determinants of response to natural environments

Treesearch

B. L. Driver; Peter Greene

1977-01-01

Man's sensory mechanisms evolved by natural selection in natural settings and humans survived as a species not so much by the "club in the hand" but by the "plan in the head." That plan or ability enabled man to remember, interpret, and predict environmental events. Humans have an innate capacity (but not necessarily a developed ability) to...

An exploration of human territoriality in forest recreation

Treesearch

Harry C. Zinn; Laurlyn K. Harmon; Brijesh Thapa; Deborah L. Kerstetter; Alan R. Graefe

2002-01-01

Previous studies in human territoriality have focused largely on behavior in urban settings. It is only recently that researchers are examining this construct in the context of forest settings. This study was designed to assess the territorial responses of visitors to Bald Eagle State Forest in central Pennsylvania and explore the structure and predictive validity of a...

Predictive Movements and Human Reinforcement Learning of Sequential Action

ERIC Educational Resources Information Center

de Kleijn, Roy; Kachergis, George; Hommel, Bernhard

2018-01-01

Sequential action makes up the bulk of human daily activity, and yet much remains unknown about how people learn such actions. In one motor learning paradigm, the serial reaction time (SRT) task, people are taught a consistent sequence of button presses by cueing them with the next target response. However, the SRT task only records keypress…

Contributions of visual and embodied expertise to body perception.

PubMed

Reed, Catherine L; Nyberg, Andrew A; Grubb, Jefferson D

2012-01-01

Recent research has demonstrated that our perception of the human body differs from that of inanimate objects. This study investigated whether the visual perception of the human body differs from that of other animate bodies and, if so, whether that difference could be attributed to visual experience and/or embodied experience. To dissociate differential effects of these two types of expertise, inversion effects (recognition of inverted stimuli is slower and less accurate than recognition of upright stimuli) were compared for two types of bodies in postures that varied in typicality: humans in human postures (human-typical), humans in dog postures (human-atypical), dogs in dog postures (dog-typical), and dogs in human postures (dog-atypical). Inversion disrupts global configural processing. Relative changes in the size and presence of inversion effects reflect changes in visual processing. Both visual and embodiment expertise predict larger inversion effects for human over dog postures because we see humans more and we have experience producing human postures. However, our design that crosses body type and typicality leads to distinct predictions for visual and embodied experience. Visual expertise predicts an interaction between typicality and orientation: greater inversion effects should be found for typical over atypical postures regardless of body type. Alternatively, embodiment expertise predicts a body, typicality, and orientation interaction: larger inversion effects should be found for all human postures but only for atypical dog postures because humans can map their bodily experience onto these postures. Accuracy data supported embodiment expertise with the three-way interaction. However, response-time data supported contributions of visual expertise with larger inversion effects for typical over atypical postures. Thus, both types of expertise affect the visual perception of bodies.

Inter-species prediction of protein phosphorylation in the sbv IMPROVER species translation challenge

PubMed Central

Biehl, Michael; Sadowski, Peter; Bhanot, Gyan; Bilal, Erhan; Dayarian, Adel; Meyer, Pablo; Norel, Raquel; Rhrissorrakrai, Kahn; Zeller, Michael D.; Hormoz, Sahand

2015-01-01

Motivation: Animal models are widely used in biomedical research for reasons ranging from practical to ethical. An important issue is whether rodent models are predictive of human biology. This has been addressed recently in the framework of a series of challenges designed by the systems biology verification for Industrial Methodology for Process Verification in Research (sbv IMPROVER) initiative. In particular, one of the sub-challenges was devoted to the prediction of protein phosphorylation responses in human bronchial epithelial cells, exposed to a number of different chemical stimuli, given the responses in rat bronchial epithelial cells. Participating teams were asked to make inter-species predictions on the basis of available training examples, comprising transcriptomics and phosphoproteomics data. Results: Here, the two best performing teams present their data-driven approaches and computational methods. In addition, post hoc analyses of the datasets and challenge results were performed by the participants and challenge organizers. The challenge outcome indicates that successful prediction of protein phosphorylation status in human based on rat phosphorylation levels is feasible. However, within the limitations of the computational tools used, the inclusion of gene expression data does not improve the prediction quality. The post hoc analysis of time-specific measurements sheds light on the signaling pathways in both species. Availability and implementation: A detailed description of the dataset, challenge design and outcome is available at www.sbvimprover.com. The code used by team IGB is provided under http://github.com/uci-igb/improver2013. Implementations of the algorithms applied by team AMG are available at http://bhanot.biomaps.rutgers.edu/wiki/AMG-sc2-code.zip. Contact: meikelbiehl@gmail.com PMID:24994890

Biological Networks for Predicting Chemical Hepatocarcinogenicity Using Gene Expression Data from Treated Mice and Relevance across Human and Rat Species

PubMed Central

Thomas, Reuben; Thomas, Russell S.; Auerbach, Scott S.; Portier, Christopher J.

2013-01-01

Background Several groups have employed genomic data from subchronic chemical toxicity studies in rodents (90 days) to derive gene-centric predictors of chronic toxicity and carcinogenicity. Genes are annotated to belong to biological processes or molecular pathways that are mechanistically well understood and are described in public databases. Objectives To develop a molecular pathway-based prediction model of long term hepatocarcinogenicity using 90-day gene expression data and to evaluate the performance of this model with respect to both intra-species, dose-dependent and cross-species predictions. Methods Genome-wide hepatic mRNA expression was retrospectively measured in B6C3F1 mice following subchronic exposure to twenty-six (26) chemicals (10 were positive, 2 equivocal and 14 negative for liver tumors) previously studied by the US National Toxicology Program. Using these data, a pathway-based predictor model for long-term liver cancer risk was derived using random forests. The prediction model was independently validated on test sets associated with liver cancer risk obtained from mice, rats and humans. Results Using 5-fold cross validation, the developed prediction model had reasonable predictive performance with the area under receiver-operator curve (AUC) equal to 0.66. The developed prediction model was then used to extrapolate the results to data associated with rat and human liver cancer. The extrapolated model worked well for both extrapolated species (AUC value of 0.74 for rats and 0.91 for humans). The prediction models implied a balanced interplay between all pathway responses leading to carcinogenicity predictions. Conclusions Pathway-based prediction models estimated from sub-chronic data hold promise for predicting long-term carcinogenicity and also for its ability to extrapolate results across multiple species. PMID:23737943

Biological networks for predicting chemical hepatocarcinogenicity using gene expression data from treated mice and relevance across human and rat species.

PubMed

Thomas, Reuben; Thomas, Russell S; Auerbach, Scott S; Portier, Christopher J

2013-01-01

Several groups have employed genomic data from subchronic chemical toxicity studies in rodents (90 days) to derive gene-centric predictors of chronic toxicity and carcinogenicity. Genes are annotated to belong to biological processes or molecular pathways that are mechanistically well understood and are described in public databases. To develop a molecular pathway-based prediction model of long term hepatocarcinogenicity using 90-day gene expression data and to evaluate the performance of this model with respect to both intra-species, dose-dependent and cross-species predictions. Genome-wide hepatic mRNA expression was retrospectively measured in B6C3F1 mice following subchronic exposure to twenty-six (26) chemicals (10 were positive, 2 equivocal and 14 negative for liver tumors) previously studied by the US National Toxicology Program. Using these data, a pathway-based predictor model for long-term liver cancer risk was derived using random forests. The prediction model was independently validated on test sets associated with liver cancer risk obtained from mice, rats and humans. Using 5-fold cross validation, the developed prediction model had reasonable predictive performance with the area under receiver-operator curve (AUC) equal to 0.66. The developed prediction model was then used to extrapolate the results to data associated with rat and human liver cancer. The extrapolated model worked well for both extrapolated species (AUC value of 0.74 for rats and 0.91 for humans). The prediction models implied a balanced interplay between all pathway responses leading to carcinogenicity predictions. Pathway-based prediction models estimated from sub-chronic data hold promise for predicting long-term carcinogenicity and also for its ability to extrapolate results across multiple species.

Predictability, Force and (Anti-)Resonance in Complex Object Control.

PubMed

Maurice, Pauline; Hogan, Neville; Sternad, Dagmar

2018-04-18

Manipulation of complex objects as in tool use is ubiquitous and has given humans an evolutionary advantage. This study examined the strategies humans choose when manipulating an object with underactuated internal dynamics, such as a cup of coffee. The object's dynamics renders the temporal evolution complex, possibly even chaotic, and difficult to predict. A cart-and-pendulum model, loosely mimicking coffee sloshing in a cup, was implemented in a virtual environment with a haptic interface. Participants rhythmically manipulated the virtual cup containing a rolling ball; they could choose the oscillation frequency, while the amplitude was prescribed. Three hypotheses were tested: 1) humans decrease interaction forces between hand and object; 2) humans increase the predictability of the object dynamics; 3) humans exploit the resonances of the coupled object-hand system. Analysis revealed that humans chose either a high-frequency strategy with anti-phase cup-and-ball movements or a low-frequency strategy with in-phase cup-and-ball movements. Counter Hypothesis 1, they did not decrease interaction force; instead, they increased the predictability of the interaction dynamics, quantified by mutual information, supporting Hypothesis 2. To address Hypothesis 3, frequency analysis of the coupled hand-object system revealed two resonance frequencies separated by an anti-resonance frequency. The low-frequency strategy exploited one resonance, while the high-frequency strategy afforded more choice, consistent with the frequency response of the coupled system; both strategies avoided the anti-resonance. Hence, humans did not prioritize interaction force, but rather strategies that rendered interactions predictable. These findings highlight that physical interactions with complex objects pose control challenges not present in unconstrained movements.

Predictive coding accelerates word recognition and learning in the early stages of language development.

PubMed

Ylinen, Sari; Bosseler, Alexis; Junttila, Katja; Huotilainen, Minna

2017-11-01

The ability to predict future events in the environment and learn from them is a fundamental component of adaptive behavior across species. Here we propose that inferring predictions facilitates speech processing and word learning in the early stages of language development. Twelve- and 24-month olds' electrophysiological brain responses to heard syllables are faster and more robust when the preceding word context predicts the ending of a familiar word. For unfamiliar, novel word forms, however, word-expectancy violation generates a prediction error response, the strength of which significantly correlates with children's vocabulary scores at 12 months. These results suggest that predictive coding may accelerate word recognition and support early learning of novel words, including not only the learning of heard word forms but also their mapping to meanings. Prediction error may mediate learning via attention, since infants' attention allocation to the entire learning situation in natural environments could account for the link between prediction error and the understanding of word meanings. On the whole, the present results on predictive coding support the view that principles of brain function reported across domains in humans and non-human animals apply to language and its development in the infant brain. A video abstract of this article can be viewed at: http://hy.fi/unitube/video/e1cbb495-41d8-462e-8660-0864a1abd02c. [Correction added on 27 January 2017, after first online publication: The video abstract link was added.]. © 2016 John Wiley & Sons Ltd.

Characterizing the associative content of brain structures involved in habitual and goal-directed actions in humans: a multivariate FMRI study.

PubMed

McNamee, Daniel; Liljeholm, Mimi; Zika, Ondrej; O'Doherty, John P

2015-03-04

While there is accumulating evidence for the existence of distinct neural systems supporting goal-directed and habitual action selection in the mammalian brain, much less is known about the nature of the information being processed in these different brain regions. Associative learning theory predicts that brain systems involved in habitual control, such as the dorsolateral striatum, should contain stimulus and response information only, but not outcome information, while regions involved in goal-directed action, such as ventromedial and dorsolateral prefrontal cortex and dorsomedial striatum, should be involved in processing information about outcomes as well as stimuli and responses. To test this prediction, human participants underwent fMRI while engaging in a binary choice task designed to enable the separate identification of these different representations with a multivariate classification analysis approach. Consistent with our predictions, the dorsolateral striatum contained information about responses but not outcomes at the time of an initial stimulus, while the regions implicated in goal-directed action selection contained information about both responses and outcomes. These findings suggest that differential contributions of these regions to habitual and goal-directed behavioral control may depend in part on basic differences in the type of information that these regions have access to at the time of decision making. Copyright © 2015 the authors 0270-6474/15/353764-08$15.00/0.

Predicting variation in subject thermal response during transcranial magnetic resonance guided focused ultrasound surgery: Comparison in seventeen subject datasets.

PubMed

Vyas, Urvi; Ghanouni, Pejman; Halpern, Casey H; Elias, Jeff; Pauly, Kim Butts

2016-09-01

In transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) treatments, the acoustic and spatial heterogeneity of the skull cause reflection, absorption, and scattering of the acoustic beams. These effects depend on skull-specific parameters and can lead to patient-specific thermal responses to the same transducer power. In this work, the authors develop a simulation tool to help predict these different experimental responses using 3D heterogeneous tissue models based on the subject CT images. The authors then validate and compare the predicted skull efficiencies to an experimental metric based on the subject thermal responses during tcMRgFUS treatments in a dataset of seventeen human subjects. Seventeen human head CT scans were used to create tissue acoustic models, simulating the effects of reflection, absorption, and scattering of the acoustic beam as it propagates through a heterogeneous skull. The hybrid angular spectrum technique was used to model the acoustic beam propagation of the InSightec ExAblate 4000 head transducer for each subject, yielding maps of the specific absorption rate (SAR). The simulation assumed the transducer was geometrically focused to the thalamus of each subject, and the focal SAR at the target was used as a measure of the simulated skull efficiency. Experimental skull efficiency for each subject was calculated using the thermal temperature maps from the tcMRgFUS treatments. Axial temperature images (with no artifacts) were reconstructed with a single baseline, corrected using a referenceless algorithm. The experimental skull efficiency was calculated by dividing the reconstructed temperature rise 8.8 s after sonication by the applied acoustic power. The simulated skull efficiency using individual-specific heterogeneous models predicts well (R(2) = 0.84) the experimental energy efficiency. This paper presents a simulation model to predict the variation in thermal responses measured in clinical ctMRGFYS treatments while being computationally feasible.

Predicting variation in subject thermal response during transcranial magnetic resonance guided focused ultrasound surgery: Comparison in seventeen subject datasets

PubMed Central

Vyas, Urvi; Ghanouni, Pejman; Halpern, Casey H.; Elias, Jeff; Pauly, Kim Butts

2016-01-01

Purpose: In transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) treatments, the acoustic and spatial heterogeneity of the skull cause reflection, absorption, and scattering of the acoustic beams. These effects depend on skull-specific parameters and can lead to patient-specific thermal responses to the same transducer power. In this work, the authors develop a simulation tool to help predict these different experimental responses using 3D heterogeneous tissue models based on the subject CT images. The authors then validate and compare the predicted skull efficiencies to an experimental metric based on the subject thermal responses during tcMRgFUS treatments in a dataset of seventeen human subjects. Methods: Seventeen human head CT scans were used to create tissue acoustic models, simulating the effects of reflection, absorption, and scattering of the acoustic beam as it propagates through a heterogeneous skull. The hybrid angular spectrum technique was used to model the acoustic beam propagation of the InSightec ExAblate 4000 head transducer for each subject, yielding maps of the specific absorption rate (SAR). The simulation assumed the transducer was geometrically focused to the thalamus of each subject, and the focal SAR at the target was used as a measure of the simulated skull efficiency. Experimental skull efficiency for each subject was calculated using the thermal temperature maps from the tcMRgFUS treatments. Axial temperature images (with no artifacts) were reconstructed with a single baseline, corrected using a referenceless algorithm. The experimental skull efficiency was calculated by dividing the reconstructed temperature rise 8.8 s after sonication by the applied acoustic power. Results: The simulated skull efficiency using individual-specific heterogeneous models predicts well (R2 = 0.84) the experimental energy efficiency. Conclusions: This paper presents a simulation model to predict the variation in thermal responses measured in clinical ctMRGFYS treatments while being computationally feasible. PMID:27587047

Human Papillomavirus DNA Methylation Predicts Response to Treatment Using Cidofovir and Imiquimod in Vulval Intraepithelial Neoplasia 3.

PubMed

Jones, Sadie E F; Hibbitts, Samantha; Hurt, Christopher N; Bryant, Dean; Fiander, Alison N; Powell, Ned; Tristram, Amanda J

2017-09-15

Purpose: Response rates to treatment of vulval intraepithelial neoplasia (VIN) with imiquimod and cidofovir are approximately 57% and 61%, respectively. Treatment is associated with significant side effects and, if ineffective, risk of malignant progression. Treatment response is not predicted by clinical factors. Identification of a biomarker that could predict response is an attractive prospect. This work investigated HPV DNA methylation as a potential predictive biomarker in this setting. Experimental Design: DNA from 167 cases of VIN 3 from the RT3 VIN clinical trial was assessed. HPV-positive cases were identified using Greiner PapilloCheck and HPV 16 type-specific PCR. HPV DNA methylation status was assessed in three viral regions: E2, L1/L2, and the promoter, using pyrosequencing. Results: Methylation of the HPV E2 region was associated with response to treatment. For cidofovir ( n = 30), median E2 methylation was significantly higher in patients who responded ( P ≤ 0.0001); E2 methylation >4% predicted response with 88.2% sensitivity and 84.6% specificity. For imiquimod ( n = 33), median E2 methylation was lower in patients who responded to treatment ( P = 0.03; not significant after Bonferroni correction); E2 methylation <4% predicted response with 70.6% sensitivity and 62.5% specificity. Conclusions: These data indicate that cidofovir and imiquimod may be effective in two biologically defined groups. HPV E2 DNA methylation demonstrated potential as a predictive biomarker for the treatment of VIN with cidofovir and may warrant investigation in a biomarker-guided clinical trial. Clin Cancer Res; 23(18); 5460-8. ©2017 AACR . ©2017 American Association for Cancer Research.

A Multiple Agent Model of Human Performance in Automated Air Traffic Control and Flight Management Operations

NASA Technical Reports Server (NTRS)

Corker, Kevin; Pisanich, Gregory; Condon, Gregory W. (Technical Monitor)

1995-01-01

A predictive model of human operator performance (flight crew and air traffic control (ATC)) has been developed and applied in order to evaluate the impact of automation developments in flight management and air traffic control. The model is used to predict the performance of a two person flight crew and the ATC operators generating and responding to clearances aided by the Center TRACON Automation System (CTAS). The purpose of the modeling is to support evaluation and design of automated aids for flight management and airspace management and to predict required changes in procedure both air and ground in response to advancing automation in both domains. Additional information is contained in the original extended abstract.

T-cell dependent immunogenicity of protein therapeutics: Preclinical assessment and mitigation.

PubMed

Jawa, Vibha; Cousens, Leslie P; Awwad, Michel; Wakshull, Eric; Kropshofer, Harald; De Groot, Anne S

2013-12-01

Protein therapeutics hold a prominent and rapidly expanding place among medicinal products. Purified blood products, recombinant cytokines, growth factors, enzyme replacement factors, monoclonal antibodies, fusion proteins, and chimeric fusion proteins are all examples of therapeutic proteins that have been developed in the past few decades and approved for use in the treatment of human disease. Despite early belief that the fully human nature of these proteins would represent a significant advantage, adverse effects associated with immune responses to some biologic therapies have become a topic of some concern. As a result, drug developers are devising strategies to assess immune responses to protein therapeutics during both the preclinical and the clinical phases of development. While there are many factors that contribute to protein immunogenicity, T cell- (thymus-) dependent (Td) responses appear to play a critical role in the development of antibody responses to biologic therapeutics. A range of methodologies to predict and measure Td immune responses to protein drugs has been developed. This review will focus on the Td contribution to immunogenicity, summarizing current approaches for the prediction and measurement of T cell-dependent immune responses to protein biologics, discussing the advantages and limitations of these technologies, and suggesting a practical approach for assessing and mitigating Td immunogenicity. © 2013. Published by Elsevier Inc. All rights reserved.

Modeling rate sensitivity of exercise transient responses to limb motion.

PubMed

Yamashiro, Stanley M; Kato, Takahide

2014-10-01

Transient responses of ventilation (V̇e) to limb motion can exhibit predictive characteristics. In response to a change in limb motion, a rapid change in V̇e is commonly observed with characteristics different than during a change in workload. This rapid change has been attributed to a feed-forward or adaptive response. Rate sensitivity was explored as a specific hypothesis to explain predictive V̇e responses to limb motion. A simple model assuming an additive feed-forward summation of V̇e proportional to the rate of change of limb motion was studied. This model was able to successfully account for the adaptive phase correction observed during human sinusoidal changes in limb motion. Adaptation of rate sensitivity might also explain the reduction of the fast component of V̇e responses previously reported following sudden exercise termination. Adaptation of the fast component of V̇e response could occur by reduction of rate sensitivity. Rate sensitivity of limb motion was predicted by the model to reduce the phase delay between limb motion and V̇e response without changing the steady-state response to exercise load. In this way, V̇e can respond more quickly to an exercise change without interfering with overall feedback control. The asymmetry between responses to an incremental and decremental ramp change in exercise can also be accounted for by the proposed model. Rate sensitivity leads to predicted behavior, which resembles responses observed in exercise tied to expiratory reserve volume. Copyright © 2014 the American Physiological Society.

A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors

PubMed Central

2010-01-01

Background Hyperactivation of the Ras signaling pathway is a driver of many cancers, and RAS pathway activation can predict response to targeted therapies. Therefore, optimal methods for measuring Ras pathway activation are critical. The main focus of our work was to develop a gene expression signature that is predictive of RAS pathway dependence. Methods We used the coherent expression of RAS pathway-related genes across multiple datasets to derive a RAS pathway gene expression signature and generate RAS pathway activation scores in pre-clinical cancer models and human tumors. We then related this signature to KRAS mutation status and drug response data in pre-clinical and clinical datasets. Results The RAS signature score is predictive of KRAS mutation status in lung tumors and cell lines with high (> 90%) sensitivity but relatively low (50%) specificity due to samples that have apparent RAS pathway activation in the absence of a KRAS mutation. In lung and breast cancer cell line panels, the RAS pathway signature score correlates with pMEK and pERK expression, and predicts resistance to AKT inhibition and sensitivity to MEK inhibition within both KRAS mutant and KRAS wild-type groups. The RAS pathway signature is upregulated in breast cancer cell lines that have acquired resistance to AKT inhibition, and is downregulated by inhibition of MEK. In lung cancer cell lines knockdown of KRAS using siRNA demonstrates that the RAS pathway signature is a better measure of dependence on RAS compared to KRAS mutation status. In human tumors, the RAS pathway signature is elevated in ER negative breast tumors and lung adenocarcinomas, and predicts resistance to cetuximab in metastatic colorectal cancer. Conclusions These data demonstrate that the RAS pathway signature is superior to KRAS mutation status for the prediction of dependence on RAS signaling, can predict response to PI3K and RAS pathway inhibitors, and is likely to have the most clinical utility in lung and breast tumors. PMID:20591134

N-terminal propeptide of type III procollagen as a biomarker of anabolic response to recombinant human GH and testosterone

USDA-ARS?s Scientific Manuscript database

Context: Biomarkers that predict musculoskeletal response to anabolic therapies should expedite drug development. During collagen synthesis in soft lean tissue, N-terminal propeptide of type III procollagen (P3NP) is released into circulation. We investigated P3NP as a biomarker of lean body mass (L...

US Geological Survey begins seismic ground response experiments in Washington State

USGS Publications Warehouse

Tarr, A.C.; King, K.W.

1988-01-01

This article briefly describes the experimental monitoring of minor seismic features caused by distant nuclear explosions, mining blasts and rhythmic human pushing against wooden homes. Some means of response prediction are outlined in Washington State and some effects of seismic amplification by weak clayey sediments are described. The results of several experiments are described. -A.Scarth

Management applications of discontinuity theory

EPA Science Inventory

1.Human impacts on the environment are multifaceted and can occur across distinct spatiotemporal scales. Ecological responses to environmental change are therefore difficult to predict, and entail large degrees of uncertainty. Such uncertainty requires robust tools for management...

Mental Health Functioning in the Human Rights Field: Findings from an International Internet-Based Survey.

PubMed

Joscelyne, Amy; Knuckey, Sarah; Satterthwaite, Margaret L; Bryant, Richard A; Li, Meng; Qian, Meng; Brown, Adam D

2015-01-01

Human rights advocates play a critical role in promoting respect for human rights world-wide, and engage in a broad range of strategies, including documentation of rights violations, monitoring, press work and report-writing, advocacy, and litigation. However, little is known about the impact of human rights work on the mental health of human rights advocates. This study examined the mental health profile of human rights advocates and risk factors associated with their psychological functioning. 346 individuals currently or previously working in the field of human rights completed an internet-based survey regarding trauma exposure, depression, posttraumatic stress disorder (PTSD), resilience and occupational burnout. PTSD was measured with the Posttraumatic Stress Disorder Checklist-Civilian Version (PCL-C) and depression was measured with the Patient History Questionnaire-9 (PHQ-9). These findings revealed that among human rights advocates that completed the survey, 19.4% met criteria for PTSD, 18.8% met criteria for subthreshold PTSD, and 14.7% met criteria for depression. Multiple linear regressions revealed that after controlling for symptoms of depression, PTSD symptom severity was predicted by human rights-related trauma exposure, perfectionism and negative self-appraisals about human rights work. In addition, after controlling for symptoms of PTSD, depressive symptoms were predicted by perfectionism and lower levels of self-efficacy. Survey responses also suggested high levels of resilience: 43% of responders reported minimal symptoms of PTSD. Although survey responses suggest that many human rights workers are resilient, they also suggest that human rights work is associated with elevated rates of PTSD and depression. The field of human rights would benefit from further empirical research, as well as additional education and training programs in the workplace about enhancing resilience in the context of human rights work.

Mental Health Functioning in the Human Rights Field: Findings from an International Internet-Based Survey

PubMed Central

Joscelyne, Amy; Knuckey, Sarah; Satterthwaite, Margaret L.; Bryant, Richard A.; Li, Meng; Qian, Meng; Brown, Adam D.

2015-01-01

Human rights advocates play a critical role in promoting respect for human rights world-wide, and engage in a broad range of strategies, including documentation of rights violations, monitoring, press work and report-writing, advocacy, and litigation. However, little is known about the impact of human rights work on the mental health of human rights advocates. This study examined the mental health profile of human rights advocates and risk factors associated with their psychological functioning. 346 individuals currently or previously working in the field of human rights completed an internet-based survey regarding trauma exposure, depression, posttraumatic stress disorder (PTSD), resilience and occupational burnout. PTSD was measured with the Posttraumatic Stress Disorder Checklist-Civilian Version (PCL-C) and depression was measured with the Patient History Questionnaire-9 (PHQ-9). These findings revealed that among human rights advocates that completed the survey, 19.4% met criteria for PTSD, 18.8% met criteria for subthreshold PTSD, and 14.7% met criteria for depression. Multiple linear regressions revealed that after controlling for symptoms of depression, PTSD symptom severity was predicted by human rights-related trauma exposure, perfectionism and negative self-appraisals about human rights work. In addition, after controlling for symptoms of PTSD, depressive symptoms were predicted by perfectionism and lower levels of self-efficacy. Survey responses also suggested high levels of resilience: 43% of responders reported minimal symptoms of PTSD. Although survey responses suggest that many human rights workers are resilient, they also suggest that human rights work is associated with elevated rates of PTSD and depression. The field of human rights would benefit from further empirical research, as well as additional education and training programs in the workplace about enhancing resilience in the context of human rights work. PMID:26700305

A neuronal model of predictive coding accounting for the mismatch negativity.

PubMed

Wacongne, Catherine; Changeux, Jean-Pierre; Dehaene, Stanislas

2012-03-14

The mismatch negativity (MMN) is thought to index the activation of specialized neural networks for active prediction and deviance detection. However, a detailed neuronal model of the neurobiological mechanisms underlying the MMN is still lacking, and its computational foundations remain debated. We propose here a detailed neuronal model of auditory cortex, based on predictive coding, that accounts for the critical features of MMN. The model is entirely composed of spiking excitatory and inhibitory neurons interconnected in a layered cortical architecture with distinct input, predictive, and prediction error units. A spike-timing dependent learning rule, relying upon NMDA receptor synaptic transmission, allows the network to adjust its internal predictions and use a memory of the recent past inputs to anticipate on future stimuli based on transition statistics. We demonstrate that this simple architecture can account for the major empirical properties of the MMN. These include a frequency-dependent response to rare deviants, a response to unexpected repeats in alternating sequences (ABABAA…), a lack of consideration of the global sequence context, a response to sound omission, and a sensitivity of the MMN to NMDA receptor antagonists. Novel predictions are presented, and a new magnetoencephalography experiment in healthy human subjects is presented that validates our key hypothesis: the MMN results from active cortical prediction rather than passive synaptic habituation.

Medial orbitofrontal cortex codes relative rather than absolute value of financial rewards in humans.

PubMed

Elliott, R; Agnew, Z; Deakin, J F W

2008-05-01

Functional imaging studies in recent years have confirmed the involvement of orbitofrontal cortex (OFC) in human reward processing and have suggested that OFC responses are context-dependent. A seminal electrophysiological experiment in primates taught animals to associate abstract visual stimuli with differently valuable food rewards. Subsequently, pairs of these learned abstract stimuli were presented and firing of OFC neurons to the medium-value stimulus was measured. OFC firing was shown to depend on the relative value context. In this study, we developed a human analogue of this paradigm and scanned subjects using functional magnetic resonance imaging. The analysis compared neuronal responses to two superficially identical events, which differed only in terms of the preceding context. Medial OFC response to the same perceptual stimulus was greater when the stimulus predicted the more valuable of two rewards than when it predicted the less valuable. Additional responses were observed in other components of reward circuitry, the amygdala and ventral striatum. The central finding is consistent with the primate results and suggests that OFC neurons code relative rather than absolute reward value. Amygdala and striatal involvement in coding reward value is also consistent with recent functional imaging data. By using a simpler and less confounded paradigm than many functional imaging studies, we are able to demonstrate that relative financial reward value per se is coded in distinct subregions of an extended reward and decision-making network.

The viscoelastic standard nonlinear solid model: predicting the response of the lumbar intervertebral disk to low-frequency vibrations.

PubMed

Groth, Kevin M; Granata, Kevin P

2008-06-01

Due to the mathematical complexity of current musculoskeletal spine models, there is a need for computationally efficient models of the intervertebral disk (IVD). The aim of this study is to develop a mathematical model that will adequately describe the motion of the IVD under axial cyclic loading as well as maintain computational efficiency for use in future musculoskeletal spine models. Several studies have successfully modeled the creep characteristics of the IVD using the three-parameter viscoelastic standard linear solid (SLS) model. However, when the SLS model is subjected to cyclic loading, it underestimates the load relaxation, the cyclic modulus, and the hysteresis of the human lumbar IVD. A viscoelastic standard nonlinear solid (SNS) model was used to predict the response of the human lumbar IVD subjected to low-frequency vibration. Nonlinear behavior of the SNS model was simulated by a strain-dependent elastic modulus on the SLS model. Parameters of the SNS model were estimated from experimental load deformation and stress-relaxation curves obtained from the literature. The SNS model was able to predict the cyclic modulus of the IVD at frequencies of 0.01 Hz, 0.1 Hz, and 1 Hz. Furthermore, the SNS model was able to quantitatively predict the load relaxation at a frequency of 0.01 Hz. However, model performance was unsatisfactory when predicting load relaxation and hysteresis at higher frequencies (0.1 Hz and 1 Hz). The SLS model of the lumbar IVD may require strain-dependent elastic and viscous behavior to represent the dynamic response to compressive strain.

Simulating Physiological Response with a Passive Sensor Manikin and an Adaptive Thermal Manikin to Predict Thermal Sensation and Comfort

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rugh, John P; Chaney, Larry; Hepokoski, Mark

2015-04-14

Reliable assessment of occupant thermal comfort can be difficult to obtain within automotive environments, especially under transient and asymmetric heating and cooling scenarios. Evaluation of HVAC system performance in terms of comfort commonly requires human subject testing, which may involve multiple repetitions, as well as multiple test subjects. Instrumentation (typically comprised of an array of temperature sensors) is usually only sparsely applied across the human body, significantly reducing the spatial resolution of available test data. Further, since comfort is highly subjective in nature, a single test protocol can yield a wide variation in results which can only be overcome bymore » increasing the number of test replications and subjects. In light of these difficulties, various types of manikins are finding use in automotive testing scenarios. These manikins can act as human surrogates from which local skin and core temperatures can be obtained, which are necessary for accurately predicting local and whole body thermal sensation and comfort using a physiology-based comfort model (e.g., the Berkeley Comfort Model). This paper evaluates two different types of manikins, i) an adaptive sweating thermal manikin, which is coupled with a human thermoregulation model, running in real-time, to obtain realistic skin temperatures; and, ii) a passive sensor manikin, which is used to measure boundary conditions as they would act on a human, from which skin and core temperatures can be predicted using a thermophysiological model. The simulated physiological responses and comfort obtained from both of these manikin-model coupling schemes are compared to those of a human subject within a vehicle cabin compartment transient heat-up scenario.« less

3D tumor microtissues as an in vitro testing platform for microenvironmentally-triggered drug delivery systems.

PubMed

Brancato, Virginia; Gioiella, Filomena; Profeta, Martina; Imparato, Giorgia; Guarnieri, Daniela; Urciuolo, Francesco; Melone, Pietro; Netti, Paolo A

2017-07-15

Therapeutic approaches based on nanomedicine have garnered great attention in cancer research. In vitro biological models that better mimic in vivo conditions are crucial tools to more accurately predict their therapeutic efficacy in vivo. In this work, a new 3D breast cancer microtissue has been developed to recapitulate the complexity of the tumor microenvironment and to test its efficacy as screening platform for drug delivery systems. The proposed 3D cancer model presents human breast adenocarcinoma cells and cancer-associated fibroblasts embedded in their own ECM, thus showing several features of an in vivo tumor, such as overexpression of metallo-proteinases (MMPs). After demonstrating at molecular and protein level the MMP2 overexpression in such tumor microtissues, we used them to test a recently validated formulation of endogenous MMP2-responsive nanoparticles (NP). The presence of the MMP2-sensitive linker allows doxorubicin release from NP only upon specific enzymatic cleavage of the peptide. The same NP without the MMP-sensitive linker and healthy breast microtissues were also produced to demonstrate NP specificity and selectivity. Cell viability after NP treatment confirmed that controlled drug delivery is achieved only in 3D tumor microtissues suggesting that the validation of therapeutic strategies in such 3D tumor model could predict human response. A major issue of modern cancer research is the development of accurate and predictive experimental models of human tumors consistent with tumor microenvironment and applicable as screening platforms for novel therapeutic strategies. In this work, we developed and validated a new 3D microtissue model of human breast tumor as a testing platform of anti-cancer drug delivery systems. To this aim, biodegradable nanoparticles responsive to physiological changes specifically occurring in tumor microenvironment were used. Our findings clearly demonstrate that the breast tumor microtissue well recapitulates in vivo physiological features of tumor tissue and elicits a specific response to microenvironmentally-responsive nanoparticles compared to healthy tissue. We believe this study is of particular interest for cancer research and paves the way to exploit tumor microtissues for several testing purposes. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Attention is necessary for subliminal instrumental conditioning

PubMed Central

Mastropasqua, Tommaso; Turatto, Massimo

2015-01-01

The capacity of humans and other animals to provide appropriate responses to stimuli anticipating motivationally significant events is exemplified by instrumental conditioning. Interestingly, in humans instrumental conditioning can occur also for subliminal outcome-predicting stimuli. However, it remains unclear whether attention is necessary for subliminal instrumental conditioning to take place. In two experiments, human participants had to learn to collect rewards (monetary gains) while avoiding punishments (monetary losses), on the basis of subliminal outcome-predicting cues. We found that instrumental conditioning can proceed subconsciously only if spatial attention is aligned with the subliminal cue. Conversely, if spatial attention is briefly diverted from the subliminal cue, then instrumental conditioning is blocked. In humans, attention but not awareness is therefore mandatory for instrumental conditioning, thus revealing a dissociation between awareness and attention in the control of motivated behavior. PMID:26257144

Interpreting the human phase response curve to multiple bright-light exposures.

PubMed

Strogatz, S H

1990-01-01

Czeisler and his colleagues have recently reported that bright light can induce strong (Type O) resetting of the human circadian pacemaker. This surprising result shows that the human clock is more responsive to light than has been previously thought. The interpretation of their results is subtle, however, because of an unconventional aspect of their experimental protocol: They measured the phase shift after three cycles of the bright-light stimulus, rather than after the usual single pulse. A natural question is whether the apparent Type O response could reflect the summation of three weaker Type 1 responses to each of the daily light pulses. In this paper I show mathematically that repeated Type 1 resetting cannot account for the observed Type O response. This finding corroborates the strong resetting reported by Czeisler et al., and supports their claim that bright light induces strong resetting by crushing the amplitude of the circadian pacemaker. Furthermore, the results indicate that back-to-back light pulses can have a cooperative effect different from that obtained by simple iteration of a phase response curve (PRC). In this sense the resetting response of humans is similar to that of Drosophila, Kalanchoe, and Culex, and is more complex than that predicted by conventional PRC theory. To describe the way in which light resets the human circadian pacemaker, one needs a theory that includes amplitude resetting, as pioneered by Winfree and developed for humans by Kronauer.

Behavioural responses to human-induced environmental change.

PubMed

Tuomainen, Ulla; Candolin, Ulrika

2011-08-01

The initial response of individuals to human-induced environmental change is often behavioural. This can improve the performance of individuals under sudden, large-scale perturbations and maintain viable populations. The response can also give additional time for genetic changes to arise and, hence, facilitate adaptation to new conditions. On the other hand, maladaptive responses, which reduce individual fitness, may occur when individuals encounter conditions that the population has not experienced during its evolutionary history, which can decrease population viability. A growing number of studies find human disturbances to induce behavioural responses, both directly and by altering factors that influence fitness. Common causes of behavioural responses are changes in the transmission of information, the concentration of endocrine disrupters, the availability of resources, the possibility of dispersal, and the abundance of interacting species. Frequent responses are alterations in habitat choice, movements, foraging, social behaviour and reproductive behaviour. Behavioural responses depend on the genetically determined reaction norm of the individuals, which evolves over generations. Populations first respond with individual behavioural plasticity, whereafter changes may arise through innovations and the social transmission of behavioural patterns within and across generations, and, finally, by evolution of the behavioural response over generations. Only a restricted number of species show behavioural adaptations that make them thrive in severely disturbed environments. Hence, rapid human-induced disturbances often decrease the diversity of native species, while facilitating the spread of invasive species with highly plastic behaviours. Consequently, behavioural responses to human-induced environmental change can have profound effects on the distribution, adaptation, speciation and extinction of populations and, hence, on biodiversity. A better understanding of the mechanisms of behavioural responses and their causes and consequences could improve our ability to predict the effects of human-induced environmental change on individual species and on biodiversity. © 2010 The Authors. Biological Reviews © 2010 Cambridge Philosophical Society.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, Jordan N.; Hinderliter, Paul M.; Timchalk, Charles

Sensitivity to chemicals in animals and humans are known to vary with age. Age-related changes in sensitivity to chlorpyrifos have been reported in animal models. A life-stage physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was developed to computationally predict disposition of CPF and its metabolites, chlorpyrifos-oxon (the ultimate toxicant) and 3,5,6-trichloro-2-pyridinol (TCPy), as well as B-esterase inhibition by chlorpyrifos-oxon in humans. In this model, age-dependent body weight was calculated from a generalized Gompertz function, and compartments (liver, brain, fat, blood, diaphragm, rapid, and slow) were scaled based on body weight from polynomial functions on a fractional body weight basis. Bloodmore » flows among compartments were calculated as a constant flow per compartment volume. The life-stage PBPK/PD model was calibrated and tested against controlled adult human exposure studies. Model simulations suggest age-dependent pharmacokinetics and response may exist. At oral doses ≥ 0.55 mg/kg of chlorpyrifos (significantly higher than environmental exposure levels), 6 mo old children are predicted to have higher levels of chlorpyrifos-oxon in blood and higher levels of red blood cell cholinesterase inhibition compared to adults from equivalent oral doses of chlorpyrifos. At lower doses that are more relevant to environmental exposures, the model predicts that adults will have slightly higher levels of chlorpyrifos-oxon in blood and greater cholinesterase inhibition. This model provides a computational framework for age-comparative simulations that can be utilized to predict CPF disposition and biological response over various postnatal life-stages.« less

Biodistribution and predictive value of 18F-fluorocyclophosphamide in mice bearing human breast cancer xenografts.

PubMed

Kesner, Amanda L; Hsueh, Wei-Ann; Htet, Nwe Linn; Pio, Betty S; Czernin, Johannes; Pegram, Mark D; Phelps, Michael E; Silverman, Daniel H S

2007-12-01

In mice bearing human breast cancer xenografts, we examined the biodistribution of (18)F-fluorocyclophosphamide ((18)F-F-CP) to evaluate its potential as a noninvasive prognostic tool for predicting the resistance of tumors to cyclophosphamide therapy. (18)F-F-CP was synthesized as we recently described, and PET data were acquired after administration of (18)F-F-CP in mice bearing human breast cancer xenografts (MCF-7 cells). Tracer biodistribution in reconstructed images was quantified by region-of-interest analysis. Distribution was also assessed by harvesting dissected organs, tumors, and blood, determining (18)F content in each tissue with a gamma-well counter. The mice were subsequently treated with cyclophosphamide, and tumor size was monitored for at least 3 wk after chemotherapy administration. The distribution of harvested activity correlated strongly with distribution observed in PET images. Target organs were related to routes of metabolism and excretion. (18)F-F-CP uptake was highest in kidneys, lowest in brain, and intermediate in tumors, as determined by both image-based and tissue-based measurements. (18)F-F-CP uptake was not inhibited by coadministration of an approximately x700 concentration of unlabeled cyclophosphamide. PET measures of (18)F-F-CP uptake in tumor predicted the magnitude of the response to subsequent administration of cyclophosphamide. Noninvasive assessment of (18)F-F-CP uptake using PET may potentially be helpful for predicting the response of breast tumors to cyclophosphamide before therapy begins.

A conceptual connectivity framework for understanding geomorphic change in human-impacted fluvial systems

NASA Astrophysics Data System (ADS)

Poeppl, Ronald E.; Keesstra, Saskia D.; Maroulis, Jerry

2017-01-01

Human-induced landscape change is difficult to predict due to the complexity inherent in both geomorphic and social systems as well as due to the coupling relationships between them. To better understand system complexity and system response to changing inputs, "connectivity thinking" has become an important recent paradigm within various disciplines including ecology, hydrology and geomorphology. With the presented conceptual connectivity framework on geomorphic change in human-impacted fluvial systems a cautionary note is flagged regarding the need (i) to include and to systematically conceptualise the role of different types of human agency in altering connectivity relationships in geomorphic systems and (ii) to integrate notions of human-environment interactions to connectivity concepts in geomorphology to better explain causes and trajectories of landscape change. Geomorphic response of fluvial systems to human disturbance is shown to be determined by system-specific boundary conditions (incl. system history, related legacy effects and lag times), vegetation dynamics and human-induced functional relationships (i.e. feedback mechanisms) between the different spatial dimensions of connectivity. It is further demonstrated how changes in social systems can trigger a process-response feedback loop between social and geomorphic systems that further governs the trajectory of landscape change in coupled human-geomorphic systems.

Culture Representation in Human Reliability Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

David Gertman; Julie Marble; Steven Novack

Understanding human-system response is critical to being able to plan and predict mission success in the modern battlespace. Commonly, human reliability analysis has been used to predict failures of human performance in complex, critical systems. However, most human reliability methods fail to take culture into account. This paper takes an easily understood state of the art human reliability analysis method and extends that method to account for the influence of culture, including acceptance of new technology, upon performance. The cultural parameters used to modify the human reliability analysis were determined from two standard industry approaches to cultural assessment: Hofstede’s (1991)more » cultural factors and Davis’ (1989) technology acceptance model (TAM). The result is called the Culture Adjustment Method (CAM). An example is presented that (1) reviews human reliability assessment with and without cultural attributes for a Supervisory Control and Data Acquisition (SCADA) system attack, (2) demonstrates how country specific information can be used to increase the realism of HRA modeling, and (3) discusses the differences in human error probability estimates arising from cultural differences.« less

AAA gunnermodel based on observer theory. [predicting a gunner's tracking response

NASA Technical Reports Server (NTRS)

Kou, R. S.; Glass, B. C.; Day, C. N.; Vikmanis, M. M.

1978-01-01

The Luenberger observer theory is used to develop a predictive model of a gunner's tracking response in antiaircraft artillery systems. This model is composed of an observer, a feedback controller and a remnant element. An important feature of the model is that the structure is simple, hence a computer simulation requires only a short execution time. A parameter identification program based on the least squares curve fitting method and the Gauss Newton gradient algorithm is developed to determine the parameter values of the gunner model. Thus, a systematic procedure exists for identifying model parameters for a given antiaircraft tracking task. Model predictions of tracking errors are compared with human tracking data obtained from manned simulation experiments. Model predictions are in excellent agreement with the empirical data for several flyby and maneuvering target trajectories.

A model of interval timing by neural integration.

PubMed

Simen, Patrick; Balci, Fuat; de Souza, Laura; Cohen, Jonathan D; Holmes, Philip

2011-06-22

We show that simple assumptions about neural processing lead to a model of interval timing as a temporal integration process, in which a noisy firing-rate representation of time rises linearly on average toward a response threshold over the course of an interval. Our assumptions include: that neural spike trains are approximately independent Poisson processes, that correlations among them can be largely cancelled by balancing excitation and inhibition, that neural populations can act as integrators, and that the objective of timed behavior is maximal accuracy and minimal variance. The model accounts for a variety of physiological and behavioral findings in rodents, monkeys, and humans, including ramping firing rates between the onset of reward-predicting cues and the receipt of delayed rewards, and universally scale-invariant response time distributions in interval timing tasks. It furthermore makes specific, well-supported predictions about the skewness of these distributions, a feature of timing data that is usually ignored. The model also incorporates a rapid (potentially one-shot) duration-learning procedure. Human behavioral data support the learning rule's predictions regarding learning speed in sequences of timed responses. These results suggest that simple, integration-based models should play as prominent a role in interval timing theory as they do in theories of perceptual decision making, and that a common neural mechanism may underlie both types of behavior.

Building predictive in vitro pulmonary toxicity assays using high-throughput imaging and artificial intelligence.

PubMed

Lee, Jia-Ying Joey; Miller, James Alastair; Basu, Sreetama; Kee, Ting-Zhen Vanessa; Loo, Lit-Hsin

2018-06-01

Human lungs are susceptible to the toxicity induced by soluble xenobiotics. However, the direct cellular effects of many pulmonotoxic chemicals are not always clear, and thus, a general in vitro assay for testing pulmonotoxicity applicable to a wide variety of chemicals is not currently available. Here, we report a study that uses high-throughput imaging and artificial intelligence to build an in vitro pulmonotoxicity assay by automatically comparing and selecting human lung-cell lines and their associated quantitative phenotypic features most predictive of in vivo pulmonotoxicity. This approach is called "High-throughput In vitro Phenotypic Profiling for Toxicity Prediction" (HIPPTox). We found that the resulting assay based on two phenotypic features of a human bronchial epithelial cell line, BEAS-2B, can accurately classify 33 reference chemicals with human pulmonotoxicity information (88.8% balance accuracy, 84.6% sensitivity, and 93.0% specificity). In comparison, the predictivity of a standard cell-viability assay on the same set of chemicals is much lower (77.1% balanced accuracy, 84.6% sensitivity, and 69.5% specificity). We also used the assay to evaluate 17 additional test chemicals with unknown/unclear human pulmonotoxicity, and experimentally confirmed that many of the pulmonotoxic reference and predicted-positive test chemicals induce DNA strand breaks and/or activation of the DNA-damage response (DDR) pathway. Therefore, HIPPTox helps us to uncover these common modes-of-action of pulmonotoxic chemicals. HIPPTox may also be applied to other cell types or models, and accelerate the development of predictive in vitro assays for other cell-type- or organ-specific toxicities.

Spatial Attention, Motor Intention, and Bayesian Cue Predictability in the Human Brain.

PubMed

Kuhns, Anna B; Dombert, Pascasie L; Mengotti, Paola; Fink, Gereon R; Vossel, Simone

2017-05-24

Predictions about upcoming events influence how we perceive and respond to our environment. There is increasing evidence that predictions may be generated based upon previous observations following Bayesian principles, but little is known about the underlying cortical mechanisms and their specificity for different cognitive subsystems. The present study aimed at identifying common and distinct neural signatures of predictive processing in the spatial attentional and motor intentional system. Twenty-three female and male healthy human volunteers performed two probabilistic cueing tasks with either spatial or motor cues while lying in the fMRI scanner. In these tasks, the percentage of cue validity changed unpredictably over time. Trialwise estimates of cue predictability were derived from a Bayesian observer model of behavioral responses. These estimates were included as parametric regressors for analyzing the BOLD time series. Parametric effects of cue predictability in valid and invalid trials were considered to reflect belief updating by precision-weighted prediction errors. The brain areas exhibiting predictability-dependent effects dissociated between the spatial attention and motor intention task, with the right temporoparietal cortex being involved during spatial attention and the left angular gyrus and anterior cingulate cortex during motor intention. Connectivity analyses revealed that all three areas showed predictability-dependent coupling with the right hippocampus. These results suggest that precision-weighted prediction errors of stimulus locations and motor responses are encoded in distinct brain regions, but that crosstalk with the hippocampus may be necessary to integrate new trialwise outcomes in both cognitive systems. SIGNIFICANCE STATEMENT The brain is able to infer the environments' statistical structure and responds strongly to expectancy violations. In the spatial attentional domain, it has been shown that parts of the attentional networks are sensitive to the predictability of stimuli. It remains unknown, however, whether these effects are ubiquitous or if they are specific for different cognitive systems. The present study compared the influence of model-derived cue predictability on brain activity in the spatial attentional and motor intentional system. We identified areas with distinct predictability-dependent activation for spatial attention and motor intention, but also common connectivity changes of these regions with the hippocampus. These findings provide novel insights into the generality and specificity of predictive processing signatures in the human brain. Copyright © 2017 the authors 0270-6474/17/375334-11$15.00/0.

CD4/CD8 Ratio and KT Ratio Predict Yellow Fever Vaccine Immunogenicity in HIV-Infected Patients

PubMed Central

Hunt, Peter W.; Huang, Yong; Simoes, Marisol; Lima, Sheila B.; Freire, Marcos S.; Caiaffa-Filho, Helio H.; Hong, Marisa A.; Costa, Dayane Alves; Dias, Juliana Zanatta C.; Cerqueira, Natalia B.; Nishiya, Anna Shoko; Sabino, Ester Cerdeira; Sartori, Ana M.; Kallas, Esper G.

2016-01-01

Background HIV-infected individuals have deficient responses to Yellow Fever vaccine (YFV) and may be at higher risk for adverse events (AE). Chronic immune activation–characterized by low CD4/CD8 ratio or high indoleamine 2,3-dioxygenase-1 (IDO) activity—may influence vaccine response in this population. Methods We prospectively assessed AE, viremia by the YFV virus and YF-specific neutralizing antibodies (NAb) in HIV-infected (CD4>350) and -uninfected adults through 1 year after vaccination. The effect of HIV status on initial antibody response to YFV was measured during the first 3 months following vaccination, while the effect on persistence of antibody response was measured one year following vaccination. We explored CD4/CD8 ratio, IDO activity (plasma kynurenine/tryptophan [KT] ratio) and viremia by Human Pegivirus as potential predictors of NAb response to YFV among HIV-infected participants with linear mixed models. Results 12 HIV-infected and 45-uninfected participants were included in the final analysis. HIV was not significantly associated with AE, YFV viremia or NAb titers through the first 3 months following vaccination. However, HIV–infected participants had 0.32 times the NAb titers observed for HIV-uninfected participants at 1 year following YFV (95% CI 0.13 to 0.83, p = 0.021), independent of sex, age and prior vaccination. In HIV-infected participants, each 10% increase in CD4/CD8 ratio predicted a mean 21% higher post-baseline YFV Nab titer (p = 0.024). Similarly, each 10% increase in KT ratio predicted a mean 21% lower post-baseline YFV Nab titer (p = 0.009). Viremia by Human Pegivirus was not significantly associated with NAb titers. Conclusions HIV infection appears to decrease the durability of NAb responses to YFV, an effect that may be predicted by lower CD4/CD8 ratio or higher KT ratio. PMID:27941965

CD4/CD8 Ratio and KT Ratio Predict Yellow Fever Vaccine Immunogenicity in HIV-Infected Patients.

PubMed

Avelino-Silva, Vivian I; Miyaji, Karina T; Hunt, Peter W; Huang, Yong; Simoes, Marisol; Lima, Sheila B; Freire, Marcos S; Caiaffa-Filho, Helio H; Hong, Marisa A; Costa, Dayane Alves; Dias, Juliana Zanatta C; Cerqueira, Natalia B; Nishiya, Anna Shoko; Sabino, Ester Cerdeira; Sartori, Ana M; Kallas, Esper G

2016-12-01

HIV-infected individuals have deficient responses to Yellow Fever vaccine (YFV) and may be at higher risk for adverse events (AE). Chronic immune activation-characterized by low CD4/CD8 ratio or high indoleamine 2,3-dioxygenase-1 (IDO) activity-may influence vaccine response in this population. We prospectively assessed AE, viremia by the YFV virus and YF-specific neutralizing antibodies (NAb) in HIV-infected (CD4>350) and -uninfected adults through 1 year after vaccination. The effect of HIV status on initial antibody response to YFV was measured during the first 3 months following vaccination, while the effect on persistence of antibody response was measured one year following vaccination. We explored CD4/CD8 ratio, IDO activity (plasma kynurenine/tryptophan [KT] ratio) and viremia by Human Pegivirus as potential predictors of NAb response to YFV among HIV-infected participants with linear mixed models. 12 HIV-infected and 45-uninfected participants were included in the final analysis. HIV was not significantly associated with AE, YFV viremia or NAb titers through the first 3 months following vaccination. However, HIV-infected participants had 0.32 times the NAb titers observed for HIV-uninfected participants at 1 year following YFV (95% CI 0.13 to 0.83, p = 0.021), independent of sex, age and prior vaccination. In HIV-infected participants, each 10% increase in CD4/CD8 ratio predicted a mean 21% higher post-baseline YFV Nab titer (p = 0.024). Similarly, each 10% increase in KT ratio predicted a mean 21% lower post-baseline YFV Nab titer (p = 0.009). Viremia by Human Pegivirus was not significantly associated with NAb titers. HIV infection appears to decrease the durability of NAb responses to YFV, an effect that may be predicted by lower CD4/CD8 ratio or higher KT ratio.

Early stress and human behavioral development: emerging evolutionary perspectives.

PubMed

Del Giudice, M

2014-08-01

Stress experienced early in life exerts a powerful, lasting influence on development. Converging empirical findings show that stressful experiences become deeply embedded in the child's neurobiology, with an astonishing range of long-term effects on cognition, emotion, and behavior. In contrast with the prevailing view that such effects are the maladaptive outcomes of 'toxic' stress, adaptive models regard them as manifestations of evolved developmental plasticity. In this paper, I offer a brief introduction to adaptive models of early stress and human behavioral development, with emphasis on recent theoretical contributions and emerging concepts in the field. I begin by contrasting dysregulation models of early stress with their adaptive counterparts; I then introduce life history theory as a unifying framework, and review recent work on predictive adaptive responses (PARs) in human life history development. In particular, I discuss the distinction between forecasting the future state of the environment (external prediction) and forecasting the future state of the organism (internal prediction). Next, I present the adaptive calibration model, an integrative model of individual differences in stress responsivity based on life history concepts. I conclude by examining how maternal-fetal conflict may shape the physiology of prenatal stress and its adaptive and maladaptive effects on postnatal development. In total, I aim to show how theoretical work from evolutionary biology is reshaping the way we think about the role of stress in human development, and provide researchers with an up-to-date conceptual map of this fascinating and rapidly evolving field.

On the same wavelength: predictable language enhances speaker-listener brain-to-brain synchrony in posterior superior temporal gyrus.

PubMed

Dikker, Suzanne; Silbert, Lauren J; Hasson, Uri; Zevin, Jason D

2014-04-30

Recent research has shown that the degree to which speakers and listeners exhibit similar brain activity patterns during human linguistic interaction is correlated with communicative success. Here, we used an intersubject correlation approach in fMRI to test the hypothesis that a listener's ability to predict a speaker's utterance increases such neural coupling between speakers and listeners. Nine subjects listened to recordings of a speaker describing visual scenes that varied in the degree to which they permitted specific linguistic predictions. In line with our hypothesis, the temporal profile of listeners' brain activity was significantly more synchronous with the speaker's brain activity for highly predictive contexts in left posterior superior temporal gyrus (pSTG), an area previously associated with predictive auditory language processing. In this region, predictability differentially affected the temporal profiles of brain responses in the speaker and listeners respectively, in turn affecting correlated activity between the two: whereas pSTG activation increased with predictability in the speaker, listeners' pSTG activity instead decreased for more predictable sentences. Listeners additionally showed stronger BOLD responses for predictive images before sentence onset, suggesting that highly predictable contexts lead comprehenders to preactivate predicted words.

The thing that should not be: predictive coding and the uncanny valley in perceiving human and humanoid robot actions

PubMed Central

Chaminade, Thierry; Ishiguro, Hiroshi; Driver, Jon; Frith, Chris

2012-01-01

Using functional magnetic resonance imaging (fMRI) repetition suppression, we explored the selectivity of the human action perception system (APS), which consists of temporal, parietal and frontal areas, for the appearance and/or motion of the perceived agent. Participants watched body movements of a human (biological appearance and movement), a robot (mechanical appearance and movement) or an android (biological appearance, mechanical movement). With the exception of extrastriate body area, which showed more suppression for human like appearance, the APS was not selective for appearance or motion per se. Instead, distinctive responses were found to the mismatch between appearance and motion: whereas suppression effects for the human and robot were similar to each other, they were stronger for the android, notably in bilateral anterior intraparietal sulcus, a key node in the APS. These results could reflect increased prediction error as the brain negotiates an agent that appears human, but does not move biologically, and help explain the ‘uncanny valley’ phenomenon. PMID:21515639

The effect of human activities and their associated noise on ungulate behavior.

PubMed

Brown, Casey L; Hardy, Amanda R; Barber, Jesse R; Fristrup, Kurt M; Crooks, Kevin R; Angeloni, Lisa M

2012-01-01

The effect of anthropogenic noise on terrestrial wildlife is a relatively new area of study with broad ranging management implications. Noise has been identified as a disturbance that has the potential to induce behavioral responses in animals similar to those associated with predation risk. This study investigated potential impacts of a variety of human activities and their associated noise on the behavior of elk (Cervus elaphus) and pronghorn (Antilocapra americana) along a transportation corridor in Grand Teton National Park. We conducted roadside scan surveys and focal observations of ungulate behavior while concurrently recording human activity and anthropogenic noise. Although we expected ungulates to be more responsive with greater human activity and noise, as predicted by the risk disturbance hypothesis, they were actually less responsive (less likely to perform vigilant, flight, traveling and defensive behaviors) with increasing levels of vehicle traffic, the human activity most closely associated with noise. Noise levels themselves had relatively little effect on ungulate behavior, although there was a weak negative relationship between noise and responsiveness in our scan samples. In contrast, ungulates did increase their responsiveness with other forms of anthropogenic disturbance; they reacted to the presence of pedestrians (in our scan samples) and to passing motorcycles (in our focal observations). These findings suggest that ungulates did not consistently associate noise and human activity with an increase in predation risk or that they could not afford to maintain responsiveness to the most frequent human stimuli. Although reduced responsiveness to certain disturbances may allow for greater investment in fitness-enhancing activities, it may also decrease detections of predators and other environmental cues and increase conflict with humans.

The Effect of Human Activities and Their Associated Noise on Ungulate Behavior

PubMed Central

Brown, Casey L.; Hardy, Amanda R.; Barber, Jesse R.; Fristrup, Kurt M.; Crooks, Kevin R.; Angeloni, Lisa M.

2012-01-01

Background The effect of anthropogenic noise on terrestrial wildlife is a relatively new area of study with broad ranging management implications. Noise has been identified as a disturbance that has the potential to induce behavioral responses in animals similar to those associated with predation risk. This study investigated potential impacts of a variety of human activities and their associated noise on the behavior of elk (Cervus elaphus) and pronghorn (Antilocapra americana) along a transportation corridor in Grand Teton National Park. Methodology/Principal Findings We conducted roadside scan surveys and focal observations of ungulate behavior while concurrently recording human activity and anthropogenic noise. Although we expected ungulates to be more responsive with greater human activity and noise, as predicted by the risk disturbance hypothesis, they were actually less responsive (less likely to perform vigilant, flight, traveling and defensive behaviors) with increasing levels of vehicle traffic, the human activity most closely associated with noise. Noise levels themselves had relatively little effect on ungulate behavior, although there was a weak negative relationship between noise and responsiveness in our scan samples. In contrast, ungulates did increase their responsiveness with other forms of anthropogenic disturbance; they reacted to the presence of pedestrians (in our scan samples) and to passing motorcycles (in our focal observations). Conclusions These findings suggest that ungulates did not consistently associate noise and human activity with an increase in predation risk or that they could not afford to maintain responsiveness to the most frequent human stimuli. Although reduced responsiveness to certain disturbances may allow for greater investment in fitness-enhancing activities, it may also decrease detections of predators and other environmental cues and increase conflict with humans. PMID:22808175

Differences in the subjective and motivational properties of alcohol across alcohol use severity: application of a novel translational human laboratory paradigm.

PubMed

Bujarski, Spencer; Jentsch, J David; Roche, Daniel J O; Ramchandani, Vijay A; Miotto, Karen; Ray, Lara A

2018-05-08

The Allostatic Model proposes that Alcohol Use Disorder (AUD) is associated with a transition in the motivational structure of alcohol drinking: from positive reinforcement in early-stage drinking to negative reinforcement in late-stage dependence. However, direct empirical support for this preclinical model from human experiments is limited. This study tests predictions derived from the Allostatic Model in humans. Specifically, this study tested whether alcohol use severity (1) independently predicts subjective responses to alcohol (SR; comprised of stimulation/hedonia, negative affect, sedation and craving domains), and alcohol self-administration and 2) moderates associations between domains of SR and alcohol self-administration. Heavy drinking participants ranging in severity of alcohol use and problems (N = 67) completed an intravenous alcohol administration paradigm combining an alcohol challenge (target BrAC = 60 mg%), with progressive ratio self-administration. Alcohol use severity was associated with greater baseline negative affect, sedation, and craving but did not predict changes in any SR domain during the alcohol challenge. Alcohol use severity also predicted greater self-administration. Craving during the alcohol challenge strongly predicted self-administration and sedation predicted lower self-administration. Neither stimulation, nor negative affect predicted self-administration. This study represents a novel approach to translating preclinical neuroscientific theories to the human laboratory. As expected, craving predicted self-administration and sedation was protective. Contrary to the predictions of the Allostatic Model, however, these results were inconsistent with a transition from positively to negatively reinforced alcohol consumption in severe AUD. Future studies that assess negative reinforcement in the context of an acute stressor are warranted.

Publications in acoustic and noise control from NASA Langley Research Center during 1940-1979. [bibliographies

NASA Technical Reports Server (NTRS)

Fryer, B. A. (Compiler)

1980-01-01

Reference lists of approximately 900 published Langley Research Center reports in various areas of acoustics and noise control for the period 1940-1979 are presented. Specific topic areas covered include: duct acoustics; propagation and operations; rotating blade noise; jet noise; sonic boom; flow surface interaction noise; structural response/interior noise; human response; and noise prediction.

Hierarchical dose response of E. coli O157:H7 from human outbreaks incorporating heterogeneity in exposure.

PubMed

Teunis, P F M; Ogden, I D; Strachan, N J C

2008-06-01

The infectivity of pathogenic microorganisms is a key factor in the transmission of an infectious disease in a susceptible population. Microbial infectivity is generally estimated from dose-response studies in human volunteers. This can only be done with mildly pathogenic organisms. Here a hierarchical Beta-Poisson dose-response model is developed utilizing data from human outbreaks. On the lowest level each outbreak is modelled separately and these are then combined at a second level to produce a group dose-response relation. The distribution of foodborne pathogens often shows strong heterogeneity and this is incorporated by introducing an additional parameter to the dose-response model, accounting for the degree of overdispersion relative to Poisson distribution. It was found that heterogeneity considerably influences the shape of the dose-response relationship and increases uncertainty in predicted risk. This uncertainty is greater than previously reported surrogate and outbreak models using a single level of analysis. Monte Carlo parameter samples (alpha, beta of the Beta-Poisson model) can be readily incorporated in risk assessment models built using tools such as S-plus and @ Risk.

Machine Learning of Human Pluripotent Stem Cell-Derived Engineered Cardiac Tissue Contractility for Automated Drug Classification.

PubMed

Lee, Eugene K; Tran, David D; Keung, Wendy; Chan, Patrick; Wong, Gabriel; Chan, Camie W; Costa, Kevin D; Li, Ronald A; Khine, Michelle

2017-11-14

Accurately predicting cardioactive effects of new molecular entities for therapeutics remains a daunting challenge. Immense research effort has been focused toward creating new screening platforms that utilize human pluripotent stem cell (hPSC)-derived cardiomyocytes and three-dimensional engineered cardiac tissue constructs to better recapitulate human heart function and drug responses. As these new platforms become increasingly sophisticated and high throughput, the drug screens result in larger multidimensional datasets. Improved automated analysis methods must therefore be developed in parallel to fully comprehend the cellular response across a multidimensional parameter space. Here, we describe the use of machine learning to comprehensively analyze 17 functional parameters derived from force readouts of hPSC-derived ventricular cardiac tissue strips (hvCTS) electrically paced at a range of frequencies and exposed to a library of compounds. A generated metric is effective for then determining the cardioactivity of a given drug. Furthermore, we demonstrate a classification model that can automatically predict the mechanistic action of an unknown cardioactive drug. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Predictive and tempo-flexible synchronization to a visual metronome in monkeys.

PubMed

Takeya, Ryuji; Kameda, Masashi; Patel, Aniruddh D; Tanaka, Masaki

2017-07-21

Predictive and tempo-flexible synchronization to an auditory beat is a fundamental component of human music. To date, only certain vocal learning species show this behaviour spontaneously. Prior research training macaques (vocal non-learners) to tap to an auditory or visual metronome found their movements to be largely reactive, not predictive. Does this reflect the lack of capacity for predictive synchronization in monkeys, or lack of motivation to exhibit this behaviour? To discriminate these possibilities, we trained monkeys to make synchronized eye movements to a visual metronome. We found that monkeys could generate predictive saccades synchronized to periodic visual stimuli when an immediate reward was given for every predictive movement. This behaviour generalized to novel tempi, and the monkeys could maintain the tempo internally. Furthermore, monkeys could flexibly switch from predictive to reactive saccades when a reward was given for each reactive response. In contrast, when humans were asked to make a sequence of reactive saccades to a visual metronome, they often unintentionally generated predictive movements. These results suggest that even vocal non-learners may have the capacity for predictive and tempo-flexible synchronization to a beat, but that only certain vocal learning species are intrinsically motivated to do it.

CRH-stimulated cortisol release and food intake in healthy, non-obese adults.

PubMed

George, Sophie A; Khan, Samir; Briggs, Hedieh; Abelson, James L

2010-05-01

There is considerable anecdotal and some scientific evidence that stress triggers eating behavior, but underlying physiological mechanisms remain uncertain. The hypothalamic-pituitary-adrenal (HPA) axis is a key mediator of physiological stress responses and may play a role in the link between stress and food intake. Cortisol responses to laboratory stressors predict consumption but it is unclear whether such responses mark a vulnerability to stress-related eating or whether cortisol directly stimulates eating in humans. We infused healthy adults with corticotropin-releasing hormone (CRH) at a dose that is subjectively undetectable but elicits a robust endogenous cortisol response, and measured subsequent intake of snack foods, allowing analysis of HPA reactivity effects on food intake without the complex psychological effects of a stress paradigm. CRH elevated cortisol levels relative to placebo but did not impact subjective anxious distress. Subjects ate more following CRH than following placebo and peak cortisol response to CRH was strongly related to both caloric intake and total consumption. These data show that HPA axis reactivity to pharmacological stimulation predicts subsequent food intake and suggest that cortisol itself may directly stimulate food consumption in humans. Understanding the physiological mechanisms that underlie stress-related eating may prove useful in efforts to attack the public health crises created by obesity. Copyright 2009 Elsevier Ltd. All rights reserved.

Prediction as a humanitarian and pragmatic contribution from human cognitive neuroscience.

PubMed

Gabrieli, John D E; Ghosh, Satrajit S; Whitfield-Gabrieli, Susan

2015-01-07

Neuroimaging has greatly enhanced the cognitive neuroscience understanding of the human brain and its variation across individuals (neurodiversity) in both health and disease. Such progress has not yet, however, propelled changes in educational or medical practices that improve people's lives. We review neuroimaging findings in which initial brain measures (neuromarkers) are correlated with or predict future education, learning, and performance in children and adults; criminality; health-related behaviors; and responses to pharmacological or behavioral treatments. Neuromarkers often provide better predictions (neuroprognosis), alone or in combination with other measures, than traditional behavioral measures. With further advances in study designs and analyses, neuromarkers may offer opportunities to personalize educational and clinical practices that lead to better outcomes for people. Copyright © 2015 Elsevier Inc. All rights reserved.

An Exercise Health Simulation Method Based on Integrated Human Thermophysiological Model

PubMed Central

Chen, Xiaohui; Yu, Liang; Yang, Kaixing

2017-01-01

Research of healthy exercise has garnered a keen research for the past few years. It is known that participation in a regular exercise program can help improve various aspects of cardiovascular function and reduce the risk of suffering from illness. But some exercise accidents like dehydration, exertional heatstroke, and even sudden death need to be brought to attention. If these exercise accidents can be analyzed and predicted before they happened, it will be beneficial to alleviate or avoid disease or mortality. To achieve this objective, an exercise health simulation approach is proposed, in which an integrated human thermophysiological model consisting of human thermal regulation model and a nonlinear heart rate regulation model is reported. The human thermoregulatory mechanism as well as the heart rate response mechanism during exercise can be simulated. On the basis of the simulated physiological indicators, a fuzzy finite state machine is constructed to obtain the possible health transition sequence and predict the exercise health status. The experiment results show that our integrated exercise thermophysiological model can numerically simulate the thermal and physiological processes of the human body during exercise and the predicted exercise health transition sequence from finite state machine can be used in healthcare. PMID:28702074

Integrated deployment architecture for predictive real-time traffic routing incorporating human factors considerations.

DOT National Transportation Integrated Search

2014-05-01

As Advanced Traveler Information Systems (ATIS) are being more widely accessed by drivers, understanding drivers behavioral responses to real-time travel information through ATIS and its consequential benefits are important to the widespread deplo...

MATHEMATICAL MODEL OF METABOLIC PATHWAYS OF STEROIDOGENESIS TO PREDICT MOLECULAR RESPONSE FOR ENDOCRINE DISRUPTING CHEMICALS.

EPA Science Inventory

There is increasing evidence that exposure to endocrine disrupting chemicals (EDCs) in the environment can induce adverse effects on reproduction and development in both humans and wildlife, mediated through hormonal disturbances.

EXPOSURE-DOSE-EFFECT LINKAGES FOR CHEMICALLY REACTIVE AIR TOXIC COMPOUNDS

EPA Science Inventory

This project represents a multidisciplinary collaboration to develop and test methods for more precisely predicting human exposure-dose-response relationships of respiratory tract irritants. These irritants have the unique property of reacting chemically with proteins and lipids ...

Cortical oscillatory activity and the induction of plasticity in the human motor cortex.

PubMed

McAllister, Suzanne M; Rothwell, John C; Ridding, Michael C

2011-05-01

Repetitive transcranial magnetic stimulation paradigms such as continuous theta burst stimulation (cTBS) induce long-term potentiation- and long-term depression-like plasticity in the human motor cortex. However, responses to cTBS are highly variable and may depend on the activity of the cortex at the time of stimulation. We investigated whether power in different electroencephalogram (EEG) frequency bands predicted the response to subsequent cTBS, and conversely whether cTBS had after-effects on the EEG. cTBS may utilize similar mechanisms of plasticity to motor learning; thus, we conducted a parallel set of experiments to test whether ongoing electroencephalography could predict performance of a visuomotor training task, and whether training itself had effects on the EEG. Motor evoked potentials (MEPs) provided an index of cortical excitability pre- and post-intervention. The EEG was recorded over the motor cortex pre- and post-intervention, and power spectra were computed. cTBS reduced MEP amplitudes; however, baseline power in the delta, theta, alpha or beta frequencies did not predict responses to cTBS or learning of the visuomotor training task. cTBS had no effect on delta, theta, alpha or beta power. In contrast, there was an increase in alpha power following visuomotor training that was positively correlated with changes in MEP amplitude post-training. The results suggest that the EEG is not a useful state-marker for predicting responses to plasticity-inducing paradigms. The correlation between alpha power and changes in corticospinal excitability following visuomotor training requires further investigation, but may be related to disengagement of the somatosensory system important for motor memory consolidation. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Guns, germs, and stealing: exploring the link between infectious disease and crime.

PubMed

Shrira, Ilan; Wisman, Arnaud; Webster, Gregory

2013-03-27

Can variation in crime rates be traced to the threat of infectious disease? Pathogens pose an ongoing challenge to survival, leading humans to adapt defenses to manage this threat. In addition to the biological immune system, humans have psychological and behavioral responses designed to protect against disease. Under persistent disease threat, xenophobia increases and people constrict social interactions to known in-group members. Though these responses reduce disease transmission, they can generate favorable crime conditions in two ways. First, xenophobia reduces inhibitions against harming and exploiting out-group members. Second, segregation into in-group factions erodes people's concern for the welfare of their community and weakens the collective ability to prevent crime. The present study examined the effects of infection incidence on crime rates across the United States. Infection rates predicted violent and property crime more strongly than other crime covariates. Infections also predicted homicides against strangers but not family or acquaintances, supporting the hypothesis that in-group-out-group discrimination was responsible for the infections-crime link. Overall, the results add to evidence that disease threat shapes interpersonal behavior and structural characteristics of groups.

Porphyrin metabolisms in human skin commensal Propionibacterium acnes bacteria: potential application to monitor human radiation risk.

PubMed

Shu, M; Kuo, S; Wang, Y; Jiang, Y; Liu, Y-T; Gallo, R L; Huang, C-M

2013-01-01

Propionibacterium acnes (P. acnes), a Gram-positive anaerobic bacterium, is a commensal organism in human skin. Like human cells, the bacteria produce porphyrins, which exhibit fluorescence properties and make bacteria visible with a Wood's lamp. In this review, we compare the porphyrin biosynthesis in humans and P. acnes. Also, since P. acnes living on the surface of skin receive the same radiation exposure as humans, we envision that the changes in porphyrin profiles (the absorption spectra and/or metabolism) of P. acnes by radiation may mirror the response of human cells to radiation. The porphyrin profiles of P. acnes may be a more accurate reflection of radiation risk to the patient than other biodosimeters/biomarkers such as gene up-/down-regulation, which may be non-specific due to patient related factors such as autoimmune diseases. Lastly, we discuss the challenges and possible solutions for using the P. acnes response to predict the radiation risk.

Presentation of a dummy representing suit for simulation of huMAN heatloss (DRESSMAN).

PubMed

Mayer, E; Schwab, R

2004-09-01

DRESSMAN designates a novel dummy for climate measurements that allows predicting the human thermal comfort experienced inside rooms (buildings, vehicles, aircraft, railway compartments etc.) on the basis of indoor climate measurements. Measurements can be listed in tabular form and can also be represented by way of color gradations in a virtual 3D human model. Optionally, visualization may be rendered during or after measurement. Due to its very quick response, DRESSMAN is particularly suited for nonstationary processes.

Great Expectations: Is there Evidence for Predictive Coding in Auditory Cortex?

PubMed

Heilbron, Micha; Chait, Maria

2017-08-04

Predictive coding is possibly one of the most influential, comprehensive, and controversial theories of neural function. While proponents praise its explanatory potential, critics object that key tenets of the theory are untested or even untestable. The present article critically examines existing evidence for predictive coding in the auditory modality. Specifically, we identify five key assumptions of the theory and evaluate each in the light of animal, human and modeling studies of auditory pattern processing. For the first two assumptions - that neural responses are shaped by expectations and that these expectations are hierarchically organized - animal and human studies provide compelling evidence. The anticipatory, predictive nature of these expectations also enjoys empirical support, especially from studies on unexpected stimulus omission. However, for the existence of separate error and prediction neurons, a key assumption of the theory, evidence is lacking. More work exists on the proposed oscillatory signatures of predictive coding, and on the relation between attention and precision. However, results on these latter two assumptions are mixed or contradictory. Looking to the future, more collaboration between human and animal studies, aided by model-based analyses will be needed to test specific assumptions and implementations of predictive coding - and, as such, help determine whether this popular grand theory can fulfill its expectations. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Effects of static orientation upon human optokinetic afternystagmus

NASA Technical Reports Server (NTRS)

Wall, C. 3rd; Merfeld, D. M.; Zupan, L.

1999-01-01

"Normal" human subjects were placed in a series of 5 static orientations with respect to gravity and were asked to view an optokinetic display moving at a constant angular velocity. The axis of rotation coincided with the subject's rostro-caudal axis and produced horizontal optokinetic nystagmus and afternystagmus. Wall (1) previously reported that these optokinetic afternystagmus responses were not well characterized by parametric fits to slow component velocity. The response for nose-up, however, was larger than for nose-down. This suggested that the horizontal eye movements measured during optokinetic stimulation might include an induced linear VOR component as presented in the body of this paper. To investigate this hypothesis, another analysis of these data has been made using cumulative slow component eye position. Some subjects' responses had reversals in afternystagmus direction. These reversals were "filled in" by a zero slow component velocity. This method of analysis gives a much more consistent result across subjects and shows that, on average, responses from the nose-down horizontal (prone) orientation are greatly reduced (p < 0.05) compared to other horizontal and vertical orientations. Average responses are compared to responses predicted by a model previously used to predict successfully the responses to post-rotatory nystagmus after earth horizontal axis rotation. Ten of 11 subjects had larger responses in their supine than their prone orientation. Application of horizontal axis optokinetic afternystagmus for clinical otolith function testing, and implications for altered gravity experiments are discussed.

Visual detection following retinal damage: predictions of an inhomogeneous retino-cortical model

NASA Astrophysics Data System (ADS)

Arnow, Thomas L.; Geisler, Wilson S.

1996-04-01

A model of human visual detection performance has been developed, based on available anatomical and physiological data for the primate visual system. The inhomogeneous retino- cortical (IRC) model computes detection thresholds by comparing simulated neural responses to target patterns with responses to a uniform background of the same luminance. The model incorporates human ganglion cell sampling distributions; macaque monkey ganglion cell receptive field properties; macaque cortical cell contrast nonlinearities; and a optical decision rule based on ideal observer theory. Spatial receptive field properties of cortical neurons were not included. Two parameters were allowed to vary while minimizing the squared error between predicted and observed thresholds. One parameter was decision efficiency, the other was the relative strength of the ganglion-cell center and surround. The latter was only allowed to vary within a small range consistent with known physiology. Contrast sensitivity was measured for sinewave gratings as a function of spatial frequency, target size and eccentricity. Contrast sensitivity was also measured for an airplane target as a function of target size, with and without artificial scotomas. The results of these experiments, as well as contrast sensitivity data from the literature were compared to predictions of the IRC model. Predictions were reasonably good for grating and airplane targets.

Prediction of human errors by maladaptive changes in event-related brain networks.

PubMed

Eichele, Tom; Debener, Stefan; Calhoun, Vince D; Specht, Karsten; Engel, Andreas K; Hugdahl, Kenneth; von Cramon, D Yves; Ullsperger, Markus

2008-04-22

Humans engaged in monotonous tasks are susceptible to occasional errors that may lead to serious consequences, but little is known about brain activity patterns preceding errors. Using functional MRI and applying independent component analysis followed by deconvolution of hemodynamic responses, we studied error preceding brain activity on a trial-by-trial basis. We found a set of brain regions in which the temporal evolution of activation predicted performance errors. These maladaptive brain activity changes started to evolve approximately 30 sec before the error. In particular, a coincident decrease of deactivation in default mode regions of the brain, together with a decline of activation in regions associated with maintaining task effort, raised the probability of future errors. Our findings provide insights into the brain network dynamics preceding human performance errors and suggest that monitoring of the identified precursor states may help in avoiding human errors in critical real-world situations.

Prediction of human errors by maladaptive changes in event-related brain networks

PubMed Central

Eichele, Tom; Debener, Stefan; Calhoun, Vince D.; Specht, Karsten; Engel, Andreas K.; Hugdahl, Kenneth; von Cramon, D. Yves; Ullsperger, Markus

2008-01-01

Humans engaged in monotonous tasks are susceptible to occasional errors that may lead to serious consequences, but little is known about brain activity patterns preceding errors. Using functional MRI and applying independent component analysis followed by deconvolution of hemodynamic responses, we studied error preceding brain activity on a trial-by-trial basis. We found a set of brain regions in which the temporal evolution of activation predicted performance errors. These maladaptive brain activity changes started to evolve ≈30 sec before the error. In particular, a coincident decrease of deactivation in default mode regions of the brain, together with a decline of activation in regions associated with maintaining task effort, raised the probability of future errors. Our findings provide insights into the brain network dynamics preceding human performance errors and suggest that monitoring of the identified precursor states may help in avoiding human errors in critical real-world situations. PMID:18427123

Three predictions of the economic concept of unit price in a choice context.

PubMed

Madden, G J; Bickel, W K; Jacobs, E A

2000-01-01

Economic theory makes three predictions about consumption and response output in a choice situation: (a) When plotted on logarithmic coordinates, total consumption (i.e., summed across concurrent sources of reinforcement) should be a positively decelerating function, and total response output should be a bitonic function of unit price increases; (b) total consumption and response output should be determined by the value of the unit price ratio, independent of its cost and benefit components; and (c) when a reinforcer is available at the same unit price across all sources of reinforcement, consumption should be equal between these sources. These predictions were assessed in human cigarette smokers who earned cigarette puffs in a two-choice situation at a range of unit prices. In some sessions, smokers chose between different amounts of puffs, both available at identical unit prices. Individual subjects' data supported the first two predictions but failed to support the third. Instead, at low unit prices, the relatively larger reinforcer (and larger response requirement) was preferred, whereas at high unit prices, the smaller reinforcer (and smaller response requirement) was preferred. An expansion of unit price is proposed in which handling costs and the discounted value of reinforcers available according to ratio schedules are incorporated.

Multivariate Brain Prediction of Heart Rate and Skin Conductance Responses to Social Threat.

PubMed

Eisenbarth, Hedwig; Chang, Luke J; Wager, Tor D

2016-11-23

Psychosocial stressors induce autonomic nervous system (ANS) responses in multiple body systems that are linked to health risks. Much work has focused on the common effects of stress, but ANS responses in different body systems are dissociable and may result from distinct patterns of cortical-subcortical interactions. Here, we used machine learning to develop multivariate patterns of fMRI activity predictive of heart rate (HR) and skin conductance level (SCL) responses during social threat in humans (N = 18). Overall, brain patterns predicted both HR and SCL in cross-validated analyses successfully (r HR = 0.54, r SCL = 0.58, both p < 0.0001). These patterns partly reflected central stress mechanisms common to both responses because each pattern predicted the other signal to some degree (r HR→SCL = 0.21 and r SCL→HR = 0.22, both p < 0.01), but they were largely physiological response specific. Both patterns included positive predictive weights in dorsal anterior cingulate and cerebellum and negative weights in ventromedial PFC and local pattern similarity analyses within these regions suggested that they encode common central stress mechanisms. However, the predictive maps and searchlight analysis suggested that the patterns predictive of HR and SCL were substantially different across most of the brain, including significant differences in ventromedial PFC, insula, lateral PFC, pre-SMA, and dmPFC. Overall, the results indicate that specific patterns of cerebral activity track threat-induced autonomic responses in specific body systems. Physiological measures of threat are not interchangeable, but rather reflect specific interactions among brain systems. We show that threat-induced increases in heart rate and skin conductance share some common representations in the brain, located mainly in the vmPFC, temporal and parahippocampal cortices, thalamus, and brainstem. However, despite these similarities, the brain patterns that predict these two autonomic responses are largely distinct. This evidence for largely output-measure-specific regulation of autonomic responses argues against a common system hypothesis and provides evidence that different autonomic measures reflect distinct, measurable patterns of cortical-subcortical interactions. Copyright © 2016 the authors 0270-6474/16/3611987-12$15.00/0.

Development of a Zealand White Rabbit Deposition Model to Study Inhalation Anthrax

PubMed Central

Asgharian, Bahman; Price, Owen; Kabilan, Senthil; Jacob, Richard E.; Einstein, Daniel R.; Kuprat, A.P.; Corley, Richard A.

2016-01-01

Despite using rabbits in several inhalation exposure experiments to study diseases such as anthrax, there is a lack of understanding regarding deposition characteristics and fate of inhaled particles (bio-aerosols and viruses) in the respiratory tracts of rabbits. Such information allows dosimetric extrapolation to humans to inform human outcomes. The lung geometry of the New Zealand white rabbit (referred to simply as rabbits throughout the article) was constructed using recently acquired scanned images of the conducting airways of rabbits and available information on its acinar region. In addition, functional relationships were developed for the lung and breathing parameters of rabbits as a function of body weight. The lung geometry and breathing parameters were used to extend the existing deposition model for humans and several other species to rabbits. Evaluation of the deposition model for rabbits was made by comparing predictions with available measurements in the literature. Deposition predictions in the lungs of rabbits indicated smaller deposition fractions compared to those found in humans across various particle diameter ranges. The application of the deposition model for rabbits was demonstrated by extrapolating deposition predictions in rabbits to find equivalent human exposure concentrations assuming the same dose-response relationship between the two species. Human equivalent exposure concentration levels were found to be much smaller than those for rabbits. PMID:26895308

Global and domestic legal preparedness and response: 2014 Ebola outbreak.

PubMed

Hodge, James G

2015-02-01

The global rise of Ebola viral diseases in 2014 necessitates legal responses that promote effective public health responses and respect for the health and human rights of populations. Compulsory public health interventions, approval and administration of experimental drugs or vaccines, and allocation of finite resources require difficult choices in law and policy. Crafting legal decisions in real-time emergencies is neither easy nor predictable, but it is essential to controlling epidemics and saving lives.

Mapping Frequency-Specific Tone Predictions in the Human Auditory Cortex at High Spatial Resolution.

PubMed

Berlot, Eva; Formisano, Elia; De Martino, Federico

2018-05-23

Auditory inputs reaching our ears are often incomplete, but our brains nevertheless transform them into rich and complete perceptual phenomena such as meaningful conversations or pleasurable music. It has been hypothesized that our brains extract regularities in inputs, which enables us to predict the upcoming stimuli, leading to efficient sensory processing. However, it is unclear whether tone predictions are encoded with similar specificity as perceived signals. Here, we used high-field fMRI to investigate whether human auditory regions encode one of the most defining characteristics of auditory perception: the frequency of predicted tones. Two pairs of tone sequences were presented in ascending or descending directions, with the last tone omitted in half of the trials. Every pair of incomplete sequences contained identical sounds, but was associated with different expectations about the last tone (a high- or low-frequency target). This allowed us to disambiguate predictive signaling from sensory-driven processing. We recorded fMRI responses from eight female participants during passive listening to complete and incomplete sequences. Inspection of specificity and spatial patterns of responses revealed that target frequencies were encoded similarly during their presentations, as well as during omissions, suggesting frequency-specific encoding of predicted tones in the auditory cortex (AC). Importantly, frequency specificity of predictive signaling was observed already at the earliest levels of auditory cortical hierarchy: in the primary AC. Our findings provide evidence for content-specific predictive processing starting at the earliest cortical levels. SIGNIFICANCE STATEMENT Given the abundance of sensory information around us in any given moment, it has been proposed that our brain uses contextual information to prioritize and form predictions about incoming signals. However, there remains a surprising lack of understanding of the specificity and content of such prediction signaling; for example, whether a predicted tone is encoded with similar specificity as a perceived tone. Here, we show that early auditory regions encode the frequency of a tone that is predicted yet omitted. Our findings contribute to the understanding of how expectations shape sound processing in the human auditory cortex and provide further insights into how contextual information influences computations in neuronal circuits. Copyright © 2018 the authors 0270-6474/18/384934-09$15.00/0.

Entertainment-education and recruitment of cornea donors: the role of emotion and issue involvement.

PubMed

Bae, Hyuhn-Suhck

2008-01-01

This study examined the role of emotional responses and viewer's level of issue involvement to an entertainment-education show about cornea donation in order to predict intention to register as cornea donors. Results confirmed that sympathy and empathy responses operated as a catalyst for issue involvement, which emerged as an important intermediary in the persuasion process. Issue involvement also was found to be a common causal antecedent of attitude, subjective norm, and perceived behavioral control, the last two of which predict intentions unlike attitude, which does not. The revised path model confirmed that involvement directly influences intention. The findings of this study suggest that adding emotion and involvement in the Theory of Planned Behavior (TPB) enhances the explanatory power of the theory in predicting intentions, which indicates the possibility of combining the Elaboration Likelihood Model (ELM) and the TPB in the prediction of human behaviors.

Human endogenous retrovirus K(HML-2) Gag and Env specific T-cell responses are not detected in HTLV-I-infected subjects using standard peptide screening methods.

PubMed

Jones, R Brad; Leal, Fabio E; Hasenkrug, Aaron M; Segurado, Aluisio C; Nixon, Douglas F; Ostrowski, Mario A; Kallas, Esper G

2013-01-10

An estimated 10-20 million individuals are infected with the retrovirus human T-cell leukemia virus type 1 (HTLV-1). While the majority of these individuals remain asymptomatic, 0.3-4% develop a neurodegenerative inflammatory disease, termed HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP results in the progressive demyelination of the central nervous system and is a differential diagnosis of multiple sclerosis (MS). The etiology of HAM/TSP is unclear, but evidence points to a role for CNS-inflitrating T-cells in pathogenesis. Recently, the HTLV-1-Tax protein has been shown to induce transcription of the human endogenous retrovirus (HERV) families W, H and K. Intriguingly, numerous studies have implicated these same HERV families in MS, though this association remains controversial. Here, we explore the hypothesis that HTLV-1-infection results in the induction of HERV antigen expression and the elicitation of HERV-specific T-cells responses which, in turn, may be reactive against neurons and other tissues. PBMC from 15 HTLV-1-infected subjects, 5 of whom presented with HAM/TSP, were comprehensively screened for T-cell responses to overlapping peptides spanning HERV-K(HML-2) Gag and Env. In addition, we screened for responses to peptides derived from diverse HERV families, selected based on predicted binding to predicted optimal epitopes. We observed a lack of responses to each of these peptide sets. Thus, although the limited scope of our screening prevents us from conclusively disproving our hypothesis, the current study does not provide data supporting a role for HERV-specific T-cell responses in HTLV-1 associated immunopathology.

Utilizing population variation, vaccination, and systems biology to study human immunology

PubMed Central

Tsang, John S.

2016-01-01

The move toward precision medicine has highlighted the importance of understanding biological variability within and across individuals in the human population. In particular, given the prevalent involvement of the immune system in diverse pathologies, an important question is how much and what information about the state of the immune system is required to enable accurate prediction of future health and response to medical interventions. Towards addressing this question, recent studies using vaccination as a model perturbation and systems-biology approaches are beginning to provide a glimpse of how natural population variation together with multiplexed, high-throughput measurement and computational analysis can be used to uncover predictors of immune response quality in humans. Here I discuss recent developments in this emerging field, with emphasis on baseline correlates of vaccination responses, sources of immune-state variability, as well as relevant features of study design, data generation, and computational analysis. PMID:26187853

Human cold stress of strong local-wind "Hijikawa-arashi" in Japan, based on the UTCI index and thermo-physiological responses

NASA Astrophysics Data System (ADS)

Ohashi, Yukitaka; Katsuta, Takumi; Tani, Haruka; Okabayashi, Taiki; Miyahara, Satoshi; Miyashita, Ryoji

2018-03-01

We investigated the cold stress caused by a strong local wind called "Hijikawa-arashi," through in situ vital measurements and the Universal Thermal Climate Index (UTCI). This wind is a very interesting winter phenomenon, localized in an area within 1 km of the seashore in Ozu City, Ehime Prefecture in Japan. When a strong Hijikawa-arashi (HA) occurred at 14-15 m s-1, the UTCI decreased to - 30 °C along the bridge where commuting residents are the most exposed to strong and cold winds. On the bridge, most participants in our experiment felt "very cold" or "extremely cold." The UTCI of HA can be predicted from a multiple regression equation using wind speed and air temperature. The cold HA wind is also harmful to human thermo-physiological responses. It leads to higher blood pressure and increased heart rate, both of which act as cardiovascular stress triggers. Increases of 6-10 mmHg and 3-6 bpm for every 10 °C reduction in UTCI were seen on all observational days, including HA and non-HA days. In fact, the participants' body skin temperatures decreased by approximately 1.2 to 1.7 °C for every 10 °C reduction in UTCI. Thus, the UTCI variation due to the HA outbreak corresponded well with the cold sensation and thermo-physiological responses in humans. This result suggests that daily UTCI monitoring enables the prediction of thermo-physiological responses to the HA cold stress.

Evaluating the Toxicity Pathways Using High-Throughput Environmental Chemical Data

EPA Science Inventory

The application of HTS methods to the characterization of human phenotypic response to environmental chemicals is a largely unexplored area of pharmacogenomics. The U.S. Environmental Protection Agency (EPA), through its ToxCast program, is developing predictive toxicity approach...

UTCI-Fiala multi-node model of human heat transfer and temperature regulation

NASA Astrophysics Data System (ADS)

Fiala, Dusan; Havenith, George; Bröde, Peter; Kampmann, Bernhard; Jendritzky, Gerd

2012-05-01

The UTCI-Fiala mathematical model of human temperature regulation forms the basis of the new Universal Thermal Climate Index (UTC). Following extensive validation tests, adaptations and extensions, such as the inclusion of an adaptive clothing model, the model was used to predict human temperature and regulatory responses for combinations of the prevailing outdoor climate conditions. This paper provides an overview of the underlying algorithms and methods that constitute the multi-node dynamic UTCI-Fiala model of human thermal physiology and comfort. Treated topics include modelling heat and mass transfer within the body, numerical techniques, modelling environmental heat exchanges, thermoregulatory reactions of the central nervous system, and perceptual responses. Other contributions of this special issue describe the validation of the UTCI-Fiala model against measured data and the development of the adaptive clothing model for outdoor climates.

Predicting Pilot Performance in Off-Nominal Conditions: A Meta-Analysis and Model Validation

NASA Technical Reports Server (NTRS)

Wickens, C.D.; Hooey, B.L.; Gore, B.F.; Sebok, A.; Koenecke, C.; Salud, E.

2009-01-01

Pilot response to off-nominal (very rare) events represents a critical component to understanding the safety of next generation airspace technology and procedures. We describe a meta-analysis designed to integrate the existing data regarding pilot accuracy of detecting rare, unexpected events such as runway incursions in realistic flight simulations. Thirty-five studies were identified and pilot responses were categorized by expectancy, event location, and whether the pilot was flying with a highway-in-the-sky display. All three dichotomies produced large, significant effects on event miss rate. A model of human attention and noticing, N-SEEV, was then used to predict event noticing performance as a function of event salience and expectancy, and retinal eccentricity. Eccentricity is predicted from steady state scanning by the SEEV model of attention allocation. The model was used to predict miss rates for the expectancy, location and highway-in-the-sky (HITS) effects identified in the meta-analysis. The correlation between model-predicted results and data from the meta-analysis was 0.72.

Material Properties of the Posterior Human Sclera☆

PubMed Central

Grytz, Rafael; Fazio, Massimo A.; Girard, Michael J.A.; Libertiaux, Vincent; Bruno, Luigi; Gardiner, Stuart; Girkin, Christopher A.; Downs, J. Crawford

2013-01-01

To characterize the material properties of posterior and peripapillary sclera from human donors, and to investigate the macro- and micro-scale strains as potential control mechanisms governing mechanical homeostasis. Posterior scleral shells from 9 human donors aged 57–90 years were subjected to IOP elevations from 5 to 45 mmHg and the resulting full-field displacements were recorded using laser speckle interferometry. Eye-specific finite element models were generated based on experimentally measured scleral shell surface geometry and thickness. Inverse numerical analyses were performed to identify material parameters for each eye by matching experimental deformation measurements to model predictions using a microstructure-based constitutive formulation that incorporates the crimp response and anisotropic architecture of scleral collagen fibrils. The material property fitting produced models that fit both the overall and local deformation responses of posterior scleral shells very well. The nonlinear stiffening of the sclera with increasing IOP was well reproduced by the uncrimping of scleral collagen fibrils, and a circumferentially-aligned ring of collagen fibrils around the scleral canal was predicted in all eyes. Macroscopic in-plane strains were significantly higher in peripapillary region then in the mid-periphery. In contrast, the meso- and micro-scale strains at the collagen network and collagen fibril level were not significantly different between regions. The elastic response of the posterior human sclera can be characterized by the anisotropic architecture and crimp response of scleral collagen fibrils. The similar collagen fibril strains in the peripapillary and mid-peripheral regions support the notion that the scleral collagen architecture including the circumpapillary ring of collagen fibrils evolved to establish optimal load bearing conditions at the collagen fibril level. PMID:23684352

A conceptual connectivity framework for understanding geomorphic change in human-impacted fluvial systems

NASA Astrophysics Data System (ADS)

Pöppl, Ronald; Keesstra, Saskia; Maroulis, Jerry

2017-04-01

Human-induced landscape change is difficult to predict due to the complexity inherent in both geomorphic and social systems as well as due to emerging coupling relationships between them. To better understand system complexity and system response to change, connectivity has become an important research paradigm within various disciplines including geomorphology, hydrology and ecology. With the proposed conceptual connectivity framework on geomorphic change in human-impacted fluvial systems a cautionary note is flagged regarding the need (i) to include and to systematically conceptualise the role of different types of human agency in altering connectivity relationships in geomorphic systems and (ii) to integrate notions of human-environment interactions to connectivity concepts in geomorphology to better explain causes and trajectories of landscape change. Underpinned by case study examples, the presented conceptual framework is able to explain how geomorphic response of fluvial systems to human disturbance is determined by system-specific boundary conditions (incl. system history, related legacy effects and lag times), vegetation dynamics and human-induced functional relationships (i.e. feedback mechanisms) between the different spatial dimensions of connectivity. It is further demonstrated how changes in social systems can trigger a process-response feedback loop between social and geomorphic systems that further governs the trajectory of landscape change in coupled human-geomorphic systems.

Distinct Contributions of Ventromedial and Dorsolateral Subregions of the Human Substantia Nigra to Appetitive and Aversive Learning

PubMed Central

Larsen, Tobias; Collette, Sven; Tyszka, Julian M.; Seymour, Ben; O'Doherty, John P.

2015-01-01

The role of neurons in the substantia nigra (SN) and ventral tegmental area (VTA) of the midbrain in contributing to the elicitation of reward prediction errors during appetitive learning has been well established. Less is known about the differential contribution of these midbrain regions to appetitive versus aversive learning, especially in humans. Here we scanned human participants with high-resolution fMRI focused on the SN and VTA while they participated in a sequential Pavlovian conditioning paradigm involving an appetitive outcome (a pleasant juice), as well as an aversive outcome (an unpleasant bitter and salty flavor). We found a degree of regional specialization within the SN: Whereas a region of ventromedial SN correlated with a temporal difference reward prediction error during appetitive Pavlovian learning, a dorsolateral area correlated instead with an aversive expected value signal in response to the most distal cue, and to a reward prediction error in response to the most proximal cue to the aversive outcome. Furthermore, participants' affective reactions to both the appetitive and aversive conditioned stimuli more than 1 year after the fMRI experiment was conducted correlated with activation in the ventromedial and dorsolateral SN obtained during the experiment, respectively. These findings suggest that, whereas the human ventromedial SN contributes to long-term learning about rewards, the dorsolateral SN may be particularly important for long-term learning in aversive contexts. SIGNIFICANCE STATEMENT The role of the substantia nigra (SN) and ventral tegmental area (VTA) in appetitive learning is well established, but less is known about their contribution to aversive compared with appetitive learning, especially in humans. We used high-resolution fMRI to measure activity in the SN and VTA while participants underwent higher-order Pavlovian learning. We found a regional specialization within the SN: a ventromedial area was selectively engaged during appetitive learning, and a dorsolateral area during aversive learning. Activity in these areas predicted affective reactions to appetitive and aversive conditioned stimuli over 1 year later. These findings suggest that, whereas the human ventromedial SN contributes to long-term learning about rewards, the dorsolateral SN may be particularly important for long-term learning in aversive contexts. PMID:26490862

The utility of the new generation of humanized mice to study HIV-1 infection: transmission, prevention, pathogenesis, and treatment

PubMed Central

2011-01-01

Substantial improvements have been made in recent years in the ability to engraft human cells and tissues into immunodeficient mice. The use of human hematopoietic stem cells (HSCs) leads to multi-lineage human hematopoiesis accompanied by production of a variety of human immune cell types. Population of murine primary and secondary lymphoid organs with human cells occurs, and long-term engraftment has been achieved. Engrafted cells are capable of producing human innate and adaptive immune responses, making these models the most physiologically relevant humanized animal models to date. New models have been successfully infected by a variety of strains of Human Immunodeficiency Virus Type 1 (HIV-1), accompanied by virus replication in lymphoid and non-lymphoid organs, including the gut-associated lymphoid tissue, the male and female reproductive tracts, and the brain. Multiple forms of virus-induced pathogenesis are present, and human T cell and antibody responses to HIV-1 are detected. These humanized mice are susceptible to a high rate of rectal and vaginal transmission of HIV-1 across an intact epithelium, indicating the potential to study vaccines and microbicides. Antiviral drugs, siRNAs, and hematopoietic stem cell gene therapy strategies have all been shown to be effective at reducing viral load and preventing or reversing helper T cell loss in humanized mice, indicating that they will serve as an important preclinical model to study new therapeutic modalities. HIV-1 has also been shown to evolve in response to selective pressures in humanized mice, thus showing that the model will be useful to study and/or predict viral evolution in response to drug or immune pressures. The purpose of this review is to summarize the findings reported to date on all new humanized mouse models (those transplanted with human HSCs) in regards to HIV-1 sexual transmission, pathogenesis, anti-HIV-1 immune responses, viral evolution, pre- and post-exposure prophylaxis, and gene therapeutic strategies. PMID:21835012

Early spatiotemporal-specific changes in intermediate signals are predictive of cytotoxic sensitivity to TNFα and co-treatments

NASA Astrophysics Data System (ADS)

Loo, Lit-Hsin; Bougen-Zhukov, Nicola Michelle; Tan, Wei-Ling Cecilia

2017-03-01

Signaling pathways can generate different cellular responses to the same cytotoxic agents. Current quantitative models for predicting these differential responses are usually based on large numbers of intracellular gene products or signals at different levels of signaling cascades. Here, we report a study to predict cellular sensitivity to tumor necrosis factor alpha (TNFα) using high-throughput cellular imaging and machine-learning methods. We measured and compared 1170 protein phosphorylation events in a panel of human lung cancer cell lines based on different signals, subcellular regions, and time points within one hour of TNFα treatment. We found that two spatiotemporal-specific changes in an intermediate signaling protein, p90 ribosomal S6 kinase (RSK), are sufficient to predict the TNFα sensitivity of these cell lines. Our models could also predict the combined effects of TNFα and other kinase inhibitors, many of which are not known to target RSK directly. Therefore, early spatiotemporal-specific changes in intermediate signals are sufficient to represent the complex cellular responses to these perturbations. Our study provides a general framework for the development of rapid, signaling-based cytotoxicity screens that may be used to predict cellular sensitivity to a cytotoxic agent, or identify co-treatments that may sensitize or desensitize cells to the agent.

Early spatiotemporal-specific changes in intermediate signals are predictive of cytotoxic sensitivity to TNFα and co-treatments

PubMed Central

Loo, Lit-Hsin; Bougen-Zhukov, Nicola Michelle; Tan, Wei-Ling Cecilia

2017-01-01

Signaling pathways can generate different cellular responses to the same cytotoxic agents. Current quantitative models for predicting these differential responses are usually based on large numbers of intracellular gene products or signals at different levels of signaling cascades. Here, we report a study to predict cellular sensitivity to tumor necrosis factor alpha (TNFα) using high-throughput cellular imaging and machine-learning methods. We measured and compared 1170 protein phosphorylation events in a panel of human lung cancer cell lines based on different signals, subcellular regions, and time points within one hour of TNFα treatment. We found that two spatiotemporal-specific changes in an intermediate signaling protein, p90 ribosomal S6 kinase (RSK), are sufficient to predict the TNFα sensitivity of these cell lines. Our models could also predict the combined effects of TNFα and other kinase inhibitors, many of which are not known to target RSK directly. Therefore, early spatiotemporal-specific changes in intermediate signals are sufficient to represent the complex cellular responses to these perturbations. Our study provides a general framework for the development of rapid, signaling-based cytotoxicity screens that may be used to predict cellular sensitivity to a cytotoxic agent, or identify co-treatments that may sensitize or desensitize cells to the agent. PMID:28272488

Systems biology from micro-organisms to human metabolic diseases: the role of detailed kinetic models.

PubMed

Bakker, Barbara M; van Eunen, Karen; Jeneson, Jeroen A L; van Riel, Natal A W; Bruggeman, Frank J; Teusink, Bas

2010-10-01

Human metabolic diseases are typically network diseases. This holds not only for multifactorial diseases, such as metabolic syndrome or Type 2 diabetes, but even when a single gene defect is the primary cause, where the adaptive response of the entire network determines the severity of disease. The latter may differ between individuals carrying the same mutation. Understanding the adaptive responses of human metabolism naturally requires a systems biology approach. Modelling of metabolic pathways in micro-organisms and some mammalian tissues has yielded many insights, qualitative as well as quantitative, into their control and regulation. Yet, even for a well-known pathway such as glycolysis, precise predictions of metabolite dynamics from experimentally determined enzyme kinetics have been only moderately successful. In the present review, we compare kinetic models of glycolysis in three cell types (African trypanosomes, yeast and skeletal muscle), evaluate their predictive power and identify limitations in our understanding. Although each of these models has its own merits and shortcomings, they also share common features. For example, in each case independently measured enzyme kinetic parameters were used as input. Based on these 'lessons from glycolysis', we will discuss how to make best use of kinetic computer models to advance our understanding of human metabolic diseases.

Nano-immunosafety: issues in assay validation

NASA Astrophysics Data System (ADS)

Boraschi, Diana; Oostingh, Gertie J.; Casals, Eudald; Italiani, Paola; Nelissen, Inge; Puntes, Victor F.; Duschl, Albert

2011-07-01

Assessing the safety of engineered nanomaterials for human health must include a thorough evaluation of their effects on the immune system, which is responsible for defending the integrity of our body from damage and disease. An array of robust and representative assays should be set up and validated, which could be predictive of the effects of nanomaterials on immune responses. In a trans-European collaborative work, in vitro assays have been developed to this end. In vitro tests have been preferred for their suitability to standardisation and easier applicability. Adapting classical assays to testing the immunotoxicological effects of nanoparticulate materials has raised a series of issues that needed to be appropriately addressed in order to ensure reliability of results. Besides the exquisitely immunological problem of selecting representative endpoints predictive of the risk of developing disease, assay results turned out to be significantly biased by artefactual interference of the nanomaterials or contaminating agents with the assay protocol. Having addressed such problems, a series of robust and representative assays have been developed that describe the effects of engineered nanoparticles on professional and non-professional human defence cells. Two of such assays are described here, one based on primary human monocytes and the other employing human lung epithelial cells transfected with a reporter gene.

Recapitulating physiological and pathological shear stress and oxygen to model vasculature in health and disease

NASA Astrophysics Data System (ADS)

Abaci, Hasan Erbil; Shen, Yu-I.; Tan, Scott; Gerecht, Sharon

2014-05-01

Studying human vascular disease in conventional cell cultures and in animal models does not effectively mimic the complex vascular microenvironment and may not accurately predict vascular responses in humans. We utilized a microfluidic device to recapitulate both shear stress and O2 levels in health and disease, establishing a microfluidic vascular model (μVM). Maintaining human endothelial cells (ECs) in healthy-mimicking conditions resulted in conversion to a physiological phenotype namely cell elongation, reduced proliferation, lowered angiogenic gene expression and formation of actin cortical rim and continuous barrier. We next examined the responses of the healthy μVM to a vasotoxic cancer drug, 5-Fluorouracil (5-FU), in comparison with an in vivo mouse model. We found that 5-FU does not induce apoptosis rather vascular hyperpermeability, which can be alleviated by Resveratrol treatment. This effect was confirmed by in vivo findings identifying a vasoprotecting strategy by the adjunct therapy of 5-FU with Resveratrol. The μVM of ischemic disease demonstrated the transition of ECs from a quiescent to an activated state, with higher proliferation rate, upregulation of angiogenic genes, and impaired barrier integrity. The μVM offers opportunities to study and predict human ECs with physiologically relevant phenotypes in healthy, pathological and drug-treated environments.

A model of interval timing by neural integration

PubMed Central

Simen, Patrick; Balci, Fuat; deSouza, Laura; Cohen, Jonathan D.; Holmes, Philip

2011-01-01

We show that simple assumptions about neural processing lead to a model of interval timing as a temporal integration process, in which a noisy firing-rate representation of time rises linearly on average toward a response threshold over the course of an interval. Our assumptions include: that neural spike trains are approximately independent Poisson processes; that correlations among them can be largely cancelled by balancing excitation and inhibition; that neural populations can act as integrators; and that the objective of timed behavior is maximal accuracy and minimal variance. The model accounts for a variety of physiological and behavioral findings in rodents, monkeys and humans, including ramping firing rates between the onset of reward-predicting cues and the receipt of delayed rewards, and universally scale-invariant response time distributions in interval timing tasks. It furthermore makes specific, well-supported predictions about the skewness of these distributions, a feature of timing data that is usually ignored. The model also incorporates a rapid (potentially one-shot) duration-learning procedure. Human behavioral data support the learning rule’s predictions regarding learning speed in sequences of timed responses. These results suggest that simple, integration-based models should play as prominent a role in interval timing theory as they do in theories of perceptual decision making, and that a common neural mechanism may underlie both types of behavior. PMID:21697374

Human operator response to error-likely situations in complex engineering systems

NASA Technical Reports Server (NTRS)

Morris, Nancy M.; Rouse, William B.

1988-01-01

The causes of human error in complex systems are examined. First, a conceptual framework is provided in which two broad categories of error are discussed: errors of action, or slips, and errors of intention, or mistakes. Conditions in which slips and mistakes might be expected to occur are identified, based on existing theories of human error. Regarding the role of workload, it is hypothesized that workload may act as a catalyst for error. Two experiments are presented in which humans' response to error-likely situations were examined. Subjects controlled PLANT under a variety of conditions and periodically provided subjective ratings of mental effort. A complex pattern of results was obtained, which was not consistent with predictions. Generally, the results of this research indicate that: (1) humans respond to conditions in which errors might be expected by attempting to reduce the possibility of error, and (2) adaptation to conditions is a potent influence on human behavior in discretionary situations. Subjects' explanations for changes in effort ratings are also explored.

Development of structural and material clavicle response corridors under axial compression and three point bending loading for clavicle finite element model validation.

PubMed

Zhang, Qi; Kindig, Matthew; Li, Zuoping; Crandall, Jeff R; Kerrigan, Jason R

2014-08-22

Clavicle injuries were frequently observed in automotive side and frontal crashes. Finite element (FE) models have been developed to understand the injury mechanism, although no clavicle loading response corridors yet exist in the literature to ensure the model response biofidelity. Moreover, the typically developed structural level (e.g., force-deflection) response corridors were shown to be insufficient for verifying the injury prediction capacity of FE model, which usually is based on strain related injury criteria. Therefore, the purpose of this study is to develop both the structural (force vs deflection) and material level (strain vs force) clavicle response corridors for validating FE models for injury risk modeling. 20 Clavicles were loaded to failure under loading conditions representative of side and frontal crashes respectively, half of which in axial compression, and the other half in three point bending. Both structural and material response corridors were developed for each loading condition. FE model that can accurately predict structural response and strain level provides a more useful tool in injury risk modeling and prediction. The corridor development method in this study could also be extended to develop corridors for other components of the human body. Copyright © 2014 Elsevier Ltd. All rights reserved.

Aeroacoustics of Flight Vehicles: Theory and Practice. Volume 2: Noise Control

NASA Technical Reports Server (NTRS)

Hubbard, Harvey H. (Editor)

1991-01-01

Flight vehicles and the underlying concepts of noise generation, noise propagation, noise prediction, and noise control are studied. This volume includes those chapters that relate to flight vehicle noise control and operations: human response to aircraft noise; atmospheric propagation; theoretical models for duct acoustic propagation and radiation; design and performance of duct acoustic treatment; jet noise suppression; interior noise; flyover noise measurement and prediction; and quiet aircraft design and operational characteristics.

Residential Simulation Tool

DOE Office of Scientific and Technical Information (OSTI.GOV)

Starke, Michael R; Abdelaziz, Omar A; Jackson, Rogerick K

Residential Simulation Tool was developed to understand the impact of residential load consumption on utilities including the role of demand response. This is complicated as many different residential loads exist and are utilized for different purposes. The tool models human behavior and contributes this to load utilization, which contributes to the electrical consumption prediction by the tool. The tool integrates a number of different databases from Department of Energy and other Government websites to support the load consumption prediction.

Management Styles, Mediating Variables, and Stress among HRD Professionals.

ERIC Educational Resources Information Center

Lind, Susan L.; Otte, Fred L.

1994-01-01

Data from 355 valid responses from 1,000 human resource professionals showed that specific variables predicted stress according to the management style of respondents' managers (authoritative, benevolent, consultative, participative). Self-esteem, locus of control, and Type A behavior were consistent predictors. (SK)

Using integrated environmental modeling to automate a process-based Quantitative Microbial Risk Assessment

USDA-ARS?s Scientific Manuscript database

Integrated Environmental Modeling (IEM) organizes multidisciplinary knowledge that explains and predicts environmental-system response to stressors. A Quantitative Microbial Risk Assessment (QMRA) is an approach integrating a range of disparate data (fate/transport, exposure, and human health effect...

A Host Transcriptional Signature for Presymptomatic Detection of Infection in Humans Exposed to Influenza H1N1 or H3N2

DTIC Science & Technology

2013-01-09

specificity. The majority of the top 50 predictive genes contained in each factor are known to characterize host response to viral infection, and include...RSAD2, the OAS family, multiple interferon response elements, the myxovirus- resistance gene MX1, cytokine response pathways and others [16,17,18]. Many...antiviral pathways (Fig. s4). Furthermore, the high degree of similarity and cross- applicability of the two signatures permit the mathematical

Attention and prediction in human audition: a lesson from cognitive psychophysiology

PubMed Central

Schröger, Erich; Marzecová, Anna; SanMiguel, Iria

2015-01-01

Attention is a hypothetical mechanism in the service of perception that facilitates the processing of relevant information and inhibits the processing of irrelevant information. Prediction is a hypothetical mechanism in the service of perception that considers prior information when interpreting the sensorial input. Although both (attention and prediction) aid perception, they are rarely considered together. Auditory attention typically yields enhanced brain activity, whereas auditory prediction often results in attenuated brain responses. However, when strongly predicted sounds are omitted, brain responses to silence resemble those elicited by sounds. Studies jointly investigating attention and prediction revealed that these different mechanisms may interact, e.g. attention may magnify the processing differences between predicted and unpredicted sounds. Following the predictive coding theory, we suggest that prediction relates to predictions sent down from predictive models housed in higher levels of the processing hierarchy to lower levels and attention refers to gain modulation of the prediction error signal sent up to the higher level. As predictions encode contents and confidence in the sensory data, and as gain can be modulated by the intention of the listener and by the predictability of the input, various possibilities for interactions between attention and prediction can be unfolded. From this perspective, the traditional distinction between bottom-up/exogenous and top-down/endogenous driven attention can be revisited and the classic concepts of attentional gain and attentional trace can be integrated. PMID:25728182

The effects of genetic polymorphism on treatment response of recombinant human growth hormone.

PubMed

Chen, Shi; You, Hanxiao; Pan, Hui; Zhu, Huijuan; Yang, Hongbo; Gong, Fengying; Wang, Linjie; Jiang, Yu; Yan, Chengsheng

2017-12-06

Recombinant human growth hormone (rhGH) has been widely used in clinical treatment of growth hormone deficiency (GHD) or non GHD since 1985 and technology have achieved a great development in different long-acting formulations. Although the mathematical models for predicting the growth hormone response could help clinicians get to an individual personalized growth dose, many patients just can't reach the target height and the growth hormone responses differed.Genetic polymorphisms may play a role in the varies of individual responses in this treatment process.This article gives an overview of the genetic polymorphisms research of growth hormone in recent years, in order to give some potential suggestion and guide for the dose titration during treatment. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Validation of an individualised model of human thermoregulation for predicting responses to cold air

NASA Astrophysics Data System (ADS)

van Marken Lichtenbelt, Wouter D.; Frijns, Arjan J. H.; van Ooijen, Marieke J.; Fiala, Dusan; Kester, Arnold M.; van Steenhoven, Anton A.

2007-01-01

Most computer models of human thermoregulation are population based. Here, we individualised the Fiala model [Fiala et al. (2001) Int J Biometeorol 45:143 159] with respect to anthropometrics, body fat, and metabolic rate. The predictions of the adapted multisegmental thermoregulatory model were compared with measured skin temperatures of individuals. Data from two experiments, in which reclining subjects were suddenly exposed to mild to moderate cold environmental conditions, were used to study the effect on dynamic skin temperature responses. Body fat was measured by the three-compartment method combining underwater weighing and deuterium dilution. Metabolic rate was determined by indirect calorimetry. In experiment 1, the bias (mean difference) between predicted and measured mean skin temperature decreased from 1.8°C to -0.15°C during cold exposure. The standard deviation of the mean difference remained of the same magnitude (from 0.7°C to 0.9°C). In experiment 2 the bias of the skin temperature changed from 2.0±1.09°C using the standard model to 1.3±0.93°C using individual characteristics in the model. The inclusion of individual characteristics thus improved the predictions for an individual and led to a significantly smaller systematic error. However, a large part of the discrepancies in individual response to cold remained unexplained. Possible further improvements to the model accomplished by inclusion of more subject characteristics (i.e. body fat distribution, body shape) and model refinements on the level of (skin) blood perfusion, and control functions, are discussed.

A Trajectory Forecast Model as an Event Response Tool: Tracking an Anhydrous Ammonia Spill in Tampa Bay

NASA Astrophysics Data System (ADS)

Havens, H.; Luther, M. E.; Meyers, S. D.

2008-12-01

Response time is critical following a hazardous spill in a marine environment and rapid assessment of circulation patterns can mitigate the damage. Tampa Bay Physical Oceanographic Real-Time System (TB- PORTS) data are used to drive a numerical circulation model of the bay for the purpose of hazardous material spill response, monitoring of human health risks, and environmental protection and management. The model is capable of rapidly producing forecast simulations that, in the event of a human health or ecosystem threat, can alert authorities to areas in Tampa Bay with a high probability of being affected by the material. Responders to an anhydrous ammonia spill in November 2007 in Tampa Bay utilized the numerical model of circulation in the estuary to predict where the spill was likely to be transported. The model quickly generated a week-long simulation predicting how winds and currents might move the spill around the bay. The physical mechanisms transporting ammonium alternated from being tidally driven for the initial two days following the spill to a more classical two-layered circulation for the remainder of the simulation. Velocity profiles of Tampa Bay reveal a strong outward flowing current present at the time of the simulation which acted as a significant transport mechanism for ammonium within the bay. Probability distributions, calculated from the predicted model trajectories, guided sampling in the days after the spill resulting in the detection of a toxic Pseudo-nitzschia bloom that likely was initiated as a result of the anhydrous ammonia spill. The prediction system at present is only accessible to scientists in the Ocean Monitoring and Prediction Lab (OMPL) at the University of South Florida. The forecast simulations are compiled into an animation that is provided to end users at their request. In the future, decision makers will be allowed access to an online component of the coastal prediction system that can be used to manage response and mitigation efforts in order to reduce the risk from such disasters as a hazardous material spills or ship groundings.

A two-layer composite model of the vocal fold lamina propria for fundamental frequency regulation.

PubMed

Zhang, Kai; Siegmund, Thomas; Chan, Roger W

2007-08-01

The mechanical properties of the vocal fold lamina propria, including the vocal fold cover and the vocal ligament, play an important role in regulating the fundamental frequency of human phonation. This study examines the equilibrium hyperelastic tensile deformation behavior of cover and ligament specimens isolated from excised human larynges. Ogden's hyperelastic model is used to characterize the tensile stress-stretch behaviors at equilibrium. Several statistically significant differences in the mechanical response differentiating cover and ligament, as well as gender are found. Fundamental frequencies are predicted from a string model and a beam model, both accounting for the cover and the ligament. The beam model predicts nonzero F(0) for the unstretched state of the vocal fold. It is demonstrated that bending stiffness significantly contributes to the predicted F(0), with the ligament contributing to a higher F(0), especially in females. Despite the availability of only a small data set, the model predicts an age dependence of F(0) in males in agreement with experimental findings. Accounting for two mechanisms of fundamental frequency regulation--vocal fold posturing (stretching) and extended clamping--brings predicted F(0) close to the lower bound of the human phonatory range. Advantages and limitations of the current model are discussed.

New Paradigm for Translational Modeling to Predict Long‐term Tuberculosis Treatment Response

PubMed Central

Bartelink, IH; Zhang, N; Keizer, RJ; Strydom, N; Converse, PJ; Dooley, KE; Nuermberger, EL

2017-01-01

Abstract Disappointing results of recent tuberculosis chemotherapy trials suggest that knowledge gained from preclinical investigations was not utilized to maximal effect. A mouse‐to‐human translational pharmacokinetics (PKs) – pharmacodynamics (PDs) model built on a rich mouse database may improve clinical trial outcome predictions. The model included Mycobacterium tuberculosis growth function in mice, adaptive immune response effect on bacterial growth, relationships among moxifloxacin, rifapentine, and rifampin concentrations accelerating bacterial death, clinical PK data, species‐specific protein binding, drug‐drug interactions, and patient‐specific pathology. Simulations of recent trials testing 4‐month regimens predicted 65% (95% confidence interval [CI], 55–74) relapse‐free patients vs. 80% observed in the REMox‐TB trial, and 79% (95% CI, 72–87) vs. 82% observed in the Rifaquin trial. Simulation of 6‐month regimens predicted 97% (95% CI, 93–99) vs. 92% and 95% observed in 2RHZE/4RH control arms, and 100% predicted and observed in the 35 mg/kg rifampin arm of PanACEA MAMS. These results suggest that the model can inform regimen optimization and predict outcomes of ongoing trials. PMID:28561946

How learning shapes the empathic brain.

PubMed

Hein, Grit; Engelmann, Jan B; Vollberg, Marius C; Tobler, Philippe N

2016-01-05

Deficits in empathy enhance conflicts and human suffering. Thus, it is crucial to understand how empathy can be learned and how learning experiences shape empathy-related processes in the human brain. As a model of empathy deficits, we used the well-established suppression of empathy-related brain responses for the suffering of out-groups and tested whether and how out-group empathy is boosted by a learning intervention. During this intervention, participants received costly help equally often from an out-group member (experimental group) or an in-group member (control group). We show that receiving help from an out-group member elicits a classical learning signal (prediction error) in the anterior insular cortex. This signal in turn predicts a subsequent increase of empathy for a different out-group member (generalization). The enhancement of empathy-related insula responses by the neural prediction error signal was mediated by an establishment of positive emotions toward the out-group member. Finally, we show that surprisingly few positive learning experiences are sufficient to increase empathy. Our results specify the neural and psychological mechanisms through which learning interacts with empathy, and thus provide a neurobiological account for the plasticity of empathic reactions.

How learning shapes the empathic brain

PubMed Central

Hein, Grit; Vollberg, Marius C.; Tobler, Philippe N.

2016-01-01

Deficits in empathy enhance conflicts and human suffering. Thus, it is crucial to understand how empathy can be learned and how learning experiences shape empathy-related processes in the human brain. As a model of empathy deficits, we used the well-established suppression of empathy-related brain responses for the suffering of out-groups and tested whether and how out-group empathy is boosted by a learning intervention. During this intervention, participants received costly help equally often from an out-group member (experimental group) or an in-group member (control group). We show that receiving help from an out-group member elicits a classical learning signal (prediction error) in the anterior insular cortex. This signal in turn predicts a subsequent increase of empathy for a different out-group member (generalization). The enhancement of empathy-related insula responses by the neural prediction error signal was mediated by an establishment of positive emotions toward the out-group member. Finally, we show that surprisingly few positive learning experiences are sufficient to increase empathy. Our results specify the neural and psychological mechanisms through which learning interacts with empathy, and thus provide a neurobiological account for the plasticity of empathic reactions. PMID:26699464

A Simple Proteomics-Based Approach to Identification of Immunodominant Antigens from a Complex Pathogen: Application to the CD4 T Cell Response against Human Herpesvirus 6B

PubMed Central

Becerra-Artiles, Aniuska; Dominguez-Amorocho, Omar; Stern, Lawrence J.; Calvo-Calle, J. Mauricio

2015-01-01

Most of humanity is chronically infected with human herpesvirus 6 (HHV-6), with viral replication controlled at least in part by a poorly characterized CD4 T cell response. Identification of viral epitopes recognized by CD4 T cells is complicated by the large size of the herpesvirus genome and a low frequency of circulating T cells responding to the virus. Here, we present an alternative to classical epitope mapping approaches used to identify major targets of the T cell response to a complex pathogen like HHV-6B. In the approach presented here, extracellular virus preparations or virus-infected cells are fractionated by SDS-PAGE, and eluted fractions are used as source of antigens to study cytokine responses in direct ex vivo T cell activation studies. Fractions inducing significant cytokine responses are analyzed by mass spectrometry to identify viral proteins, and a subset of peptides from these proteins corresponding to predicted HLA-DR binders is tested for IFN-γ production in seropositive donors with diverse HLA haplotypes. Ten HHV-6B viral proteins were identified as immunodominant antigens. The epitope-specific response to HHV-6B virus was complex and variable between individuals. We identified 107 peptides, each recognized by at least one donor, with each donor having a distinctive footprint. Fourteen peptides showed responses in the majority of donors. Responses to these epitopes were validated using in vitro expanded cells and naturally expressed viral proteins. Predicted peptide binding affinities for the eight HLA-DRB1 alleles investigated here correlated only modestly with the observed CD4 T cell responses. Overall, the response to the virus was dominated by peptides from the major capsid protein U57 and major antigenic protein U11, but responses to other proteins including glycoprotein H (U48) and tegument proteins U54 and U14 also were observed. These results provide a means to follow and potentially modulate the CD4 T-cell immune response to HHV-6B. PMID:26599878

A study on the predictability of acute lymphoblastic leukaemia response to treatment using a hybrid oncosimulator.

PubMed

Ouzounoglou, Eleftherios; Kolokotroni, Eleni; Stanulla, Martin; Stamatakos, Georgios S

2018-02-06

Efficient use of Virtual Physiological Human (VPH)-type models for personalized treatment response prediction purposes requires a precise model parameterization. In the case where the available personalized data are not sufficient to fully determine the parameter values, an appropriate prediction task may be followed. This study, a hybrid combination of computational optimization and machine learning methods with an already developed mechanistic model called the acute lymphoblastic leukaemia (ALL) Oncosimulator which simulates ALL progression and treatment response is presented. These methods are used in order for the parameters of the model to be estimated for retrospective cases and to be predicted for prospective ones. The parameter value prediction is based on a regression model trained on retrospective cases. The proposed Hybrid ALL Oncosimulator system has been evaluated when predicting the pre-phase treatment outcome in ALL. This has been correctly achieved for a significant percentage of patient cases tested (approx. 70% of patients). Moreover, the system is capable of denying the classification of cases for which the results are not trustworthy enough. In that case, potentially misleading predictions for a number of patients are avoided, while the classification accuracy for the remaining patient cases further increases. The results obtained are particularly encouraging regarding the soundness of the proposed methodologies and their relevance to the process of achieving clinical applicability of the proposed Hybrid ALL Oncosimulator system and VPH models in general.

Predicting tumor responses to mitomycin C on the basis of DT-diaphorase activity or drug metabolism by tumor homogenates: implications for enzyme-directed bioreductive drug development.

PubMed

Phillips, R M; Burger, A M; Loadman, P M; Jarrett, C M; Swaine, D J; Fiebig, H H

2000-11-15

Mitomycin C (MMC) is a clinically used anticancer drug that is reduced to cytotoxic metabolites by cellular reductases via a process known as bioreductive drug activation. The identification of key enzymes responsible for drug activation has been investigated extensively with the ultimate aim of tailoring drug administration to patients whose tumors possess the biochemical machinery required for drug activation. In the case of MMC, considerable interest has been centered upon the enzyme DT-diaphorase (DTD) although conflicting reports of good and poor correlations between enzyme activity and response in vitro and in vivo have been published. The principle aim of this study was to provide a definitive answer to the question of whether tumor response to MMC could be predicted on the basis of DTD activity in a large panel of human tumor xenografts. DTD levels were measured in 45 human tumor xenografts that had been characterized previously in terms of their sensitivity to MMC in vitro and in vivo (the in vivo response profile to MMC was taken from work published previously). A poor correlation between DTD activity and antitumor activity in vitro as well as in vivo was obtained. This study also assessed the predictive value of an alternative approach based upon the ability of tumor homogenates to metabolize MMC. This approach is based on the premise that the overall rate of MMC metabolism may provide a better indicator of response than single enzyme measurements. MMC metabolism was evaluated in tumor homogenates (clarified by centrifugation at 1000 x g for 1 min) by measuring the disappearance of the parent compound by HPLC. In responsive [T/C <10% (T/C defined as the relative size of treated and control tumors)] and resistant (T/C >50%) tumors, the mean half life of MMC was 75+/-48.3 and 280+/-129.6 min, respectively. The difference between the two groups was statistically significant (P < 0.005). In conclusion, these results unequivocally demonstrate that response to MMC in vivo cannot be predicted on the basis of DTD activity. Measurement of MMC metabolism by tumor homogenates on the other hand may provide a better indicator of tumor response, and further studies are required to determine whether this approach has real clinical potential in terms of individualizing patient chemotherapy.

Using changes in agricultural utility to quantify future climate-induced risk to conservation.

PubMed

Estes, Lyndon D; Paroz, Lydie-Line; Bradley, Bethany A; Green, Jonathan M H; Hole, David G; Holness, Stephen; Ziv, Guy; Oppenheimer, Michael G; Wilcove, David S

2014-04-01

Much of the biodiversity-related climate change impacts research has focused on the direct effects to species and ecosystems. Far less attention has been paid to the potential ecological consequences of human efforts to address the effects of climate change, which may equal or exceed the direct effects of climate change on biodiversity. One of the most significant human responses is likely to be mediated through changes in the agricultural utility of land. As farmers adapt their practices to changing climates, they may increase pressure on some areas that are important to conserve (conservation lands) whereas lessening it on others. We quantified how the agricultural utility of South African conservation lands may be altered by climate change. We assumed that the probability of an area being farmed is linked to the economic benefits of doing so, using land productivity values to represent production benefit and topographic ruggedness as a proxy for costs associated with mechanical workability. We computed current and future values of maize and wheat production in key conservation lands using the DSSAT4.5 model and 36 crop-climate response scenarios. Most conservation lands had, and were predicted to continue to have, low agricultural utility because of their location in rugged terrain. However, several areas were predicted to maintain or gain high agricultural utility and may therefore be at risk of near-term or future conversion to cropland. Conversely, some areas were predicted to decrease in agricultural utility and may therefore prove easier to protect from conversion. Our study provides an approximate but readily transferable method for incorporating potential human responses to climate change into conservation planning. © 2013 Society for Conservation Biology.

Human adaptation responses to a rapidly changing Arctic: A research context for building system resilience

NASA Astrophysics Data System (ADS)

Chapin, T.; Brinkman, T. J.

2016-12-01

Although human behavior accounts for more uncertainty in future trajectories in climate change than do biophysical processes, most climate-change research fails to include human actions in research design and implementation. This is well-illustrated in the Arctic. At the global scale, arctic processes strongly influence the strength of biophysical feedbacks between global human emissions and the rate of climate warming. However, most human actions in the arctic have little effect on these feedbacks, so research can contribute most effectively to reduction in arctic warming through improved understanding of the strength of arctic-global biophysical feedbacks, as in NASA's ABoVE program, and its effective communication to policy makers and the public. In contrast, at the local to regional scale within the arctic, human actions may influence the ecological and societal consequences of arctic warming, so research benefits from active stakeholder engagement in research design and implementation. Human communities and other stakeholders (government and NGOs) respond heterogeneously to socioeconomic and environmental change, so research that documents the range of historical and current adaptive responses to change provides insights on the resilience (flexibility of future options) of social-ecological processes in the arctic. Alaskan communities have attempted a range of adaptive responses to coastal erosion (e.g., seasonal migration, protection in place, relocation), wildfire (fire suppression to use of fire to manage wildlife habitat or landscape heterogeneity), declining sea ice (e.g., new hunting technology, sea ice observations and predictions), and changes in wildlife and fish availability (e.g., switch to harvest of alternative species, harvest times, or harvest locations). Research that draws on both traditional and western knowledge facilitates adaptation and predictions of the likely societal consequences of climate change in the Arctic. Effective inclusion of these actors in the research process could strongly influence the resilience of arctic social-ecological systems to climate change.

Editor's Highlight: Development of an In vitro Assay Measuring Uterine-Specific Estrogenic Responses for Use in Chemical Safety Assessment.

PubMed

Miller, Michelle M; Alyea, Rebecca A; LeSommer, Caroline; Doheny, Daniel L; Rowley, Sean M; Childs, Kristin M; Balbuena, Pergentino; Ross, Susan M; Dong, Jian; Sun, Bin; Andersen, Melvin A; Clewell, Rebecca A

2016-11-01

A toxicity pathway approach was taken to develop an in vitro assay using human uterine epithelial adenocarcinoma (Ishikawa) cells as a replacement for measuring an in vivo uterotrophic response to estrogens. The Ishikawa cell was determined to be fit for the purpose of recapitulating in vivo uterine response by verifying fidelity of the biological pathway components and the dose-response predictions to women of child-bearing age. Expression of the suite of estrogen receptors that control uterine proliferation (ERα66, ERα46, ERα36, ERβ, G-protein coupled estrogen receptor (GPER)) were confirmed across passages and treatment conditions. Phenotypic responses to ethinyl estradiol (EE) from transcriptional activation of ER-mediated genes, to ALP enzyme induction and cellular proliferation occurred at concentrations consistent with estrogenic activity in adult women (low picomolar). To confirm utility of this model to predict concentration-response for uterine proliferation with xenobiotics, we tested the concentration-response for compounds with known uterine estrogenic activity in humans and compared the results to assays from the ToxCast and Tox21 suite of estrogen assays. The Ishikawa proliferation assay was consistent with in vivo responses and was a more sensitive measure of uterine response. Because this assay was constructed by first mapping the key molecular events for cellular response, and then ensuring that the assay incorporated these events, the resulting cellular assay should be a reliable tool for identifying estrogenic compounds and may provide improved quantitation of chemical concentration response for in vitro-based safety assessments. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology.

Neural Correlates of the Binaural Masking Level Difference in Human Frequency-Following Responses.

PubMed

Clinard, Christopher G; Hodgson, Sarah L; Scherer, Mary Ellen

2017-04-01

The binaural masking level difference (BMLD) is an auditory phenomenon where binaural tone-in-noise detection is improved when the phase of either signal or noise is inverted in one of the ears (S π N o or S o N π , respectively), relative to detection when signal and noise are in identical phase at each ear (S o N o ). Processing related to BMLDs and interaural time differences has been confirmed in the auditory brainstem of non-human mammals; in the human auditory brainstem, phase-locked neural responses elicited by BMLD stimuli have not been systematically examined across signal-to-noise ratio. Behavioral and physiological testing was performed in three binaural stimulus conditions: S o N o , S π N o , and S o N π . BMLDs at 500 Hz were obtained from 14 young, normal-hearing adults (ages 21-26). Physiological BMLDs used the frequency-following response (FFR), a scalp-recorded auditory evoked potential dependent on sustained phase-locked neural activity; FFR tone-in-noise detection thresholds were used to calculate physiological BMLDs. FFR BMLDs were significantly smaller (poorer) than behavioral BMLDs, and FFR BMLDs did not reflect a physiological release from masking, on average. Raw FFR amplitude showed substantial reductions in the S π N o condition relative to S o N o and S o N π conditions, consistent with negative effects of phase summation from left and right ear FFRs. FFR amplitude differences between stimulus conditions (e.g., S o N o amplitude-S π N o amplitude) were significantly predictive of behavioral S π N o BMLDs; individuals with larger amplitude differences had larger (better) behavioral B MLDs and individuals with smaller amplitude differences had smaller (poorer) behavioral B MLDs. These data indicate a role for sustained phase-locked neural activity in BMLDs of humans and are the first to show predictive relationships between behavioral BMLDs and human brainstem responses.

Appropriate clinical use of human leukocyte antigen typing for coeliac disease: an Australasian perspective

PubMed Central

Tye-Din, J A; Cameron, D J S; Daveson, A J; Day, A S; Dellsperger, P; Hogan, C; Newnham, E D; Shepherd, S J; Steele, R H; Wienholt, L; Varney, M D

2015-01-01

The past decade has seen human leukocyte antigen (HLA) typing emerge as a remarkably popular test for the diagnostic work-up of coeliac disease with high patient acceptance. Although limited in its positive predictive value for coeliac disease, the strong disease association with specific HLA genes imparts exceptional negative predictive value to HLA typing, enabling a negative result to exclude coeliac disease confidently. In response to mounting evidence that the clinical use and interpretation of HLA typing often deviates from best practice, this article outlines an evidence-based approach to guide clinically appropriate use of HLA typing, and establishes a reporting template for pathology providers to improve communication of results. PMID:25827511

Open source machine-learning algorithms for the prediction of optimal cancer drug therapies.

PubMed

Huang, Cai; Mezencev, Roman; McDonald, John F; Vannberg, Fredrik

2017-01-01

Precision medicine is a rapidly growing area of modern medical science and open source machine-learning codes promise to be a critical component for the successful development of standardized and automated analysis of patient data. One important goal of precision cancer medicine is the accurate prediction of optimal drug therapies from the genomic profiles of individual patient tumors. We introduce here an open source software platform that employs a highly versatile support vector machine (SVM) algorithm combined with a standard recursive feature elimination (RFE) approach to predict personalized drug responses from gene expression profiles. Drug specific models were built using gene expression and drug response data from the National Cancer Institute panel of 60 human cancer cell lines (NCI-60). The models are highly accurate in predicting the drug responsiveness of a variety of cancer cell lines including those comprising the recent NCI-DREAM Challenge. We demonstrate that predictive accuracy is optimized when the learning dataset utilizes all probe-set expression values from a diversity of cancer cell types without pre-filtering for genes generally considered to be "drivers" of cancer onset/progression. Application of our models to publically available ovarian cancer (OC) patient gene expression datasets generated predictions consistent with observed responses previously reported in the literature. By making our algorithm "open source", we hope to facilitate its testing in a variety of cancer types and contexts leading to community-driven improvements and refinements in subsequent applications.

Evaluating Nextgen Closely Spaced Parallel Operations Concepts with Validated Human Performance Models: Flight Deck Guidelines

NASA Technical Reports Server (NTRS)

Hooey, Becky Lee; Gore, Brian Francis; Mahlstedt, Eric; Foyle, David C.

2013-01-01

The objectives of the current research were to develop valid human performance models (HPMs) of approach and land operations; use these models to evaluate the impact of NextGen Closely Spaced Parallel Operations (CSPO) on pilot performance; and draw conclusions regarding flight deck display design and pilot-ATC roles and responsibilities for NextGen CSPO concepts. This document presents guidelines and implications for flight deck display designs and candidate roles and responsibilities. A companion document (Gore, Hooey, Mahlstedt, & Foyle, 2013) provides complete scenario descriptions and results including predictions of pilot workload, visual attention and time to detect off-nominal events.

Emulation as an Integrating Principle for Cognition

PubMed Central

Colder, Brian

2011-01-01

Emulations, defined as ongoing internal representations of potential actions and the futures those actions are expected to produce, play a critical role in directing human bodily activities. Studies of gross motor behavior, perception, allocation of attention, response to errors, interoception, and homeostatic activities, and higher cognitive reasoning suggest that the proper execution of all these functions relies on emulations. Further evidence supports the notion that reinforcement learning in humans is aimed at updating emulations, and that action selection occurs via the advancement of preferred emulations toward realization of their action and environmental prediction. Emulations are hypothesized to exist as distributed active networks of neurons in cortical and sub-cortical structures. This manuscript ties together previously unrelated theories of the role of prediction in different aspects of human information processing to create an integrated framework for cognition. PMID:21660288

Predicting the safety and efficacy of buffer therapy to raise tumour pHe: an integrative modelling study.

PubMed

Martin, N K; Robey, I F; Gaffney, E A; Gillies, R J; Gatenby, R A; Maini, P K

2012-03-27

Clinical positron emission tomography imaging has demonstrated the vast majority of human cancers exhibit significantly increased glucose metabolism when compared with adjacent normal tissue, resulting in an acidic tumour microenvironment. Recent studies demonstrated reducing this acidity through systemic buffers significantly inhibits development and growth of metastases in mouse xenografts. We apply and extend a previously developed mathematical model of blood and tumour buffering to examine the impact of oral administration of bicarbonate buffer in mice, and the potential impact in humans. We recapitulate the experimentally observed tumour pHe effect of buffer therapy, testing a model prediction in vivo in mice. We parameterise the model to humans to determine the translational safety and efficacy, and predict patient subgroups who could have enhanced treatment response, and the most promising combination or alternative buffer therapies. The model predicts a previously unseen potentially dangerous elevation in blood pHe resulting from bicarbonate therapy in mice, which is confirmed by our in vivo experiments. Simulations predict limited efficacy of bicarbonate, especially in humans with more aggressive cancers. We predict buffer therapy would be most effectual: in elderly patients or individuals with renal impairments; in combination with proton production inhibitors (such as dichloroacetate), renal glomular filtration rate inhibitors (such as non-steroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors), or with an alternative buffer reagent possessing an optimal pK of 7.1-7.2. Our mathematical model confirms bicarbonate acts as an effective agent to raise tumour pHe, but potentially induces metabolic alkalosis at the high doses necessary for tumour pHe normalisation. We predict use in elderly patients or in combination with proton production inhibitors or buffers with a pK of 7.1-7.2 is most promising.

Mapping the Human Toxome by Systems Toxicology

PubMed Central

Bouhifd, Mounir; Hogberg, Helena T.; Kleensang, Andre; Maertens, Alexandra; Zhao, Liang; Hartung, Thomas

2014-01-01

Toxicity testing typically involves studying adverse health outcomes in animals subjected to high doses of toxicants with subsequent extrapolation to expected human responses at lower doses. The low-throughput of current toxicity testing approaches (which are largely the same for industrial chemicals, pesticides and drugs) has led to a backlog of more than 80,000 chemicals to which human beings are potentially exposed whose potential toxicity remains largely unknown. Employing new testing strategies that employ the use of predictive, high-throughput cell-based assays (of human origin) to evaluate perturbations in key pathways, referred as pathways of toxicity, and to conduct targeted testing against those pathways, we can begin to greatly accelerate our ability to test the vast “storehouses” of chemical compounds using a rational, risk-based approach to chemical prioritization, and provide test results that are more predictive of human toxicity than current methods. The NIH Transformative Research Grant project Mapping the Human Toxome by Systems Toxicology aims at developing the tools for pathway mapping, annotation and validation as well as the respective knowledge base to share this information. PMID:24443875

Spatial Prediction of Coxiella burnetii Outbreak Exposure via Notified Case Counts in a Dose-Response Model.

PubMed

Brooke, Russell J; Kretzschmar, Mirjam E E; Hackert, Volker; Hoebe, Christian J P A; Teunis, Peter F M; Waller, Lance A

2017-01-01

We develop a novel approach to study an outbreak of Q fever in 2009 in the Netherlands by combining a human dose-response model with geostatistics prediction to relate probability of infection and associated probability of illness to an effective dose of Coxiella burnetii. The spatial distribution of the 220 notified cases in the at-risk population are translated into a smooth spatial field of dose. Based on these symptomatic cases, the dose-response model predicts a median of 611 asymptomatic infections (95% range: 410, 1,084) for the 220 reported symptomatic cases in the at-risk population; 2.78 (95% range: 1.86, 4.93) asymptomatic infections for each reported case. The low attack rates observed during the outbreak range from (Equation is included in full-text article.)to (Equation is included in full-text article.). The estimated peak levels of exposure extend to the north-east from the point source with an increasing proportion of asymptomatic infections further from the source. Our work combines established methodology from model-based geostatistics and dose-response modeling allowing for a novel approach to study outbreaks. Unobserved infections and the spatially varying effective dose can be predicted using the flexible framework without assuming any underlying spatial structure of the outbreak process. Such predictions are important for targeting interventions during an outbreak, estimating future disease burden, and determining acceptable risk levels.

Peritraumatic startle response predicts the vulnerability to develop PTSD-like behaviors in rats: a model for peritraumatic dissociation

PubMed Central

Dong, Xinwen; Li, Yonghui

2014-01-01

Peritraumatic dissociation, a state characterized by alteration in perception and reduced awareness of surroundings, is considered to be a risk factor for the development of post-traumatic stress disorder (PTSD). However, the predictive ability of peritraumatic dissociation is questioned for the inconsistent results in different time points of assessment. The startle reflex is an objective behavioral measurement of defensive response to abrupt and intense sensory stimulus of surroundings, with potential to be used as an assessment on the dissociative status in both humans and rodents. The present study examined the predictive effect of acoustic startle response (ASR) in different time points around the traumatic event in an animal model of PTSD. The PTSD-like symptoms, including hyperarousal, avoidance, and contextual fear, were assessed 2–3 weeks post-trauma. The results showed that (1) the startle amplitude attenuated immediate after intense footshock in almost half of the stress animals, and (2) the attenuated startle responses at 1 h but not 24 h after stress predicted the development of severe PTSD-like symptoms. These data indicate that the startle alteration at the immediate period after trauma, including 1 h, is more important in PTSD prediction than 24 h after trauma. Our study also suggests that the startle attenuation immediate after intense stress may serve as an objective measurement of peritraumatic dissociation in rats. PMID:24478660

Predicting novel histopathological microlesions in human epileptic brain through transcriptional clustering.

PubMed

Dachet, Fabien; Bagla, Shruti; Keren-Aviram, Gal; Morton, Andrew; Balan, Karina; Saadat, Laleh; Valyi-Nagy, Tibor; Kupsky, William; Song, Fei; Dratz, Edward; Loeb, Jeffrey A

2015-02-01

Although epilepsy is associated with a variety of abnormalities, exactly why some brain regions produce seizures and others do not is not known. We developed a method to identify cellular changes in human epileptic neocortex using transcriptional clustering. A paired analysis of high and low spiking tissues recorded in vivo from 15 patients predicted 11 cell-specific changes together with their 'cellular interactome'. These predictions were validated histologically revealing millimetre-sized 'microlesions' together with a global increase in vascularity and microglia. Microlesions were easily identified in deeper cortical layers using the neuronal marker NeuN, showed a marked reduction in neuronal processes, and were associated with nearby activation of MAPK/CREB signalling, a marker of epileptic activity, in superficial layers. Microlesions constitute a common, undiscovered layer-specific abnormality of neuronal connectivity in human neocortex that may be responsible for many 'non-lesional' forms of epilepsy. The transcriptional clustering approach used here could be applied more broadly to predict cellular differences in other brain and complex tissue disorders. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Patterns and Limitations of Urban Human Mobility Resilience under the Influence of Multiple Types of Natural Disaster

PubMed Central

Wang, Qi; Taylor, John E.

2016-01-01

Natural disasters pose serious threats to large urban areas, therefore understanding and predicting human movements is critical for evaluating a population’s vulnerability and resilience and developing plans for disaster evacuation, response and relief. However, only limited research has been conducted into the effect of natural disasters on human mobility. This study examines how natural disasters influence human mobility patterns in urban populations using individuals’ movement data collected from Twitter. We selected fifteen destructive cases across five types of natural disaster and analyzed the human movement data before, during, and after each event, comparing the perturbed and steady state movement data. The results suggest that the power-law can describe human mobility in most cases and that human mobility patterns observed in steady states are often correlated with those in perturbed states, highlighting their inherent resilience. However, the quantitative analysis shows that this resilience has its limits and can fail in more powerful natural disasters. The findings from this study will deepen our understanding of the interaction between urban dwellers and civil infrastructure, improve our ability to predict human movement patterns during natural disasters, and facilitate contingency planning by policymakers. PMID:26820404

Patterns and Limitations of Urban Human Mobility Resilience under the Influence of Multiple Types of Natural Disaster.

PubMed

Wang, Qi; Taylor, John E

2016-01-01

Natural disasters pose serious threats to large urban areas, therefore understanding and predicting human movements is critical for evaluating a population's vulnerability and resilience and developing plans for disaster evacuation, response and relief. However, only limited research has been conducted into the effect of natural disasters on human mobility. This study examines how natural disasters influence human mobility patterns in urban populations using individuals' movement data collected from Twitter. We selected fifteen destructive cases across five types of natural disaster and analyzed the human movement data before, during, and after each event, comparing the perturbed and steady state movement data. The results suggest that the power-law can describe human mobility in most cases and that human mobility patterns observed in steady states are often correlated with those in perturbed states, highlighting their inherent resilience. However, the quantitative analysis shows that this resilience has its limits and can fail in more powerful natural disasters. The findings from this study will deepen our understanding of the interaction between urban dwellers and civil infrastructure, improve our ability to predict human movement patterns during natural disasters, and facilitate contingency planning by policymakers.

Phylogeny, Traits, and Biodiversity of a Neotropical Bat Assemblage: Close Relatives Show Similar Responses to Local Deforestation.

PubMed

Frank, Hannah K; Frishkoff, Luke O; Mendenhall, Chase D; Daily, Gretchen C; Hadly, Elizabeth A

2017-08-01

If species' evolutionary pasts predetermine their responses to evolutionarily novel stressors, then phylogeny could predict species survival in an increasingly human-dominated world. To understand the role of phylogenetic relatedness in structuring responses to rapid environmental change, we focused on assemblages of Neotropical bats, an ecologically diverse and functionally important group. We examined how taxonomic and phylogenetic diversity shift between tropical forest and farmland. We then explored the importance of evolutionary history by ascertaining whether close relatives share similar responses to environmental change and which species traits might mediate these trends. We analyzed a 5-year data set (5,011 captures) from 18 sites in a countryside landscape in southern Costa Rica using statistical models that account and correct for imperfect detection of species across sites, spatial autocorrelation, and consideration of spatial scale. Taxonomic and phylogenetic diversity decreased with deforestation, and assemblages became more phylogenetically clustered. Species' responses to deforestation were strongly phylogenetically correlated. Body mass and absolute wing loading explained a substantial portion of species variation in species' habitat preferences, likely related to these traits' influence on maneuverability in cluttered forest environments. Our findings highlight the role that evolutionary history plays in determining which species will survive human impacts and the need to consider diversity metrics, evolutionary history, and traits together when making predictions about species persistence for conservation or ecosystem functioning.

Coupling of a finite element human head model with a lumped parameter Hybrid III dummy model: preliminary results.

PubMed

Ruan, J S; Prasad, P

1995-08-01

A skull-brain finite element model of the human head has been coupled with a multilink rigid body model of the Hybrid III dummy. The experimental coupled model is intended to represent anatomically a 50th percentile human to the extent the dummy and the skull-brain model represent a human. It has been verified by simulating several human cadaver head impact tests as well as dummy head 'impacts" during barrier crashes in an automotive environment. Skull-isostress and brain-isostrain response curves were established based on model calibration of experimental human cadaver tolerance data. The skull-isostress response curve agrees with the JARI Human Head Impact Tolerance Curve for skull fracture. The brain-isostrain response curve predicts a higher G level for concussion than does the JARI concussion curve and the Wayne State Tolerance Curve at the longer time duration range. Barrier crash simulations consist of belted dummies impacting an airbag, a hard and soft steering wheel hub, and no head contact with vehicle interior components. Head impact force, intracranial pressures and strains, skull stress, and head center-of-gravity acceleration were investigated as injury parameters. Head injury criterion (HIC) was also calculated along with these parameters. Preliminary results of the model simulations in those impact conditions are discussed.

Identification and experimental validation of damping ratios of different human body segments through anthropometric vibratory model in standing posture.

PubMed

Gupta, T C

2007-08-01

A 15 degrees of freedom lumped parameter vibratory model of human body is developed, for vertical mode vibrations, using anthropometric data of the 50th percentile US male. The mass and stiffness of various segments are determined from the elastic modulii of bones and tissues and from the anthropometric data available, assuming the shape of all the segments is ellipsoidal. The damping ratio of each segment is estimated on the basis of the physical structure of the body in a particular posture. Damping constants of various segments are calculated from these damping ratios. The human body is modeled as a linear spring-mass-damper system. The optimal values of the damping ratios of the body segments are estimated, for the 15 degrees of freedom model of the 50th percentile US male, by comparing the response of the model with the experimental response. Formulating a similar vibratory model of the 50th percentile Indian male and comparing the frequency response of the model with the experimental response of the same group of subjects validate the modeling procedure. A range of damping ratios has been considered to develop a vibratory model, which can predict the vertical harmonic response of the human body.

Adaptive Responses to Prochloraz Exposure in the Hypothalamic-Pituitary Gonadal Axis of Fathead Minnows

EPA Science Inventory

Exposure to endocrine disrupting chemicals can affect reproduction and development in both humans and wildlife. We are developing a mechanistic mathematical model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict doseresponse and time-course ...

GIS and crop simulation modelling applications in climate change research

USDA-ARS?s Scientific Manuscript database

The challenges that climate change presents humanity require an unprecedented ability to predict the responses of crops to environment and management. Geographic information systems (GIS) and crop simulation models are two powerful and highly complementary tools that are increasingly used for such p...

THE ROLE OF MAMMALIAN DATA IN DETERMINING PHARMACEUTICAL RESPONSES IN AQUATIC ORGANISMS

EPA Science Inventory

The limitations surrounding application of pharmaceutical data are restricted to extrapolation of the animal and human data across phyla. Experience dictates that mammalian data are most likely to extrapolate predictably to fish and other aquatic vertebrates (e.g. Amphibia), and ...

Buffered Qualitative Stability explains the robustness and evolvability of transcriptional networks

PubMed Central

Albergante, Luca; Blow, J Julian; Newman, Timothy J

2014-01-01

The gene regulatory network (GRN) is the central decision‐making module of the cell. We have developed a theory called Buffered Qualitative Stability (BQS) based on the hypothesis that GRNs are organised so that they remain robust in the face of unpredictable environmental and evolutionary changes. BQS makes strong and diverse predictions about the network features that allow stable responses under arbitrary perturbations, including the random addition of new connections. We show that the GRNs of E. coli, M. tuberculosis, P. aeruginosa, yeast, mouse, and human all verify the predictions of BQS. BQS explains many of the small- and large‐scale properties of GRNs, provides conditions for evolvable robustness, and highlights general features of transcriptional response. BQS is severely compromised in a human cancer cell line, suggesting that loss of BQS might underlie the phenotypic plasticity of cancer cells, and highlighting a possible sequence of GRN alterations concomitant with cancer initiation. DOI: http://dx.doi.org/10.7554/eLife.02863.001 PMID:25182846

Assessing large-scale wildlife responses to human infrastructure development

PubMed Central

Torres, Aurora; Jaeger, Jochen A. G.; Alonso, Juan Carlos

2016-01-01

Habitat loss and deterioration represent the main threats to wildlife species, and are closely linked to the expansion of roads and human settlements. Unfortunately, large-scale effects of these structures remain generally overlooked. Here, we analyzed the European transportation infrastructure network and found that 50% of the continent is within 1.5 km of transportation infrastructure. We present a method for assessing the impacts from infrastructure on wildlife, based on functional response curves describing density reductions in birds and mammals (e.g., road-effect zones), and apply it to Spain as a case study. The imprint of infrastructure extends over most of the country (55.5% in the case of birds and 97.9% for mammals), with moderate declines predicted for birds (22.6% of individuals) and severe declines predicted for mammals (46.6%). Despite certain limitations, we suggest the approach proposed is widely applicable to the evaluation of effects of planned infrastructure developments under multiple scenarios, and propose an internationally coordinated strategy to update and improve it in the future. PMID:27402749

Assessing large-scale wildlife responses to human infrastructure development.

PubMed

Torres, Aurora; Jaeger, Jochen A G; Alonso, Juan Carlos

2016-07-26

Habitat loss and deterioration represent the main threats to wildlife species, and are closely linked to the expansion of roads and human settlements. Unfortunately, large-scale effects of these structures remain generally overlooked. Here, we analyzed the European transportation infrastructure network and found that 50% of the continent is within 1.5 km of transportation infrastructure. We present a method for assessing the impacts from infrastructure on wildlife, based on functional response curves describing density reductions in birds and mammals (e.g., road-effect zones), and apply it to Spain as a case study. The imprint of infrastructure extends over most of the country (55.5% in the case of birds and 97.9% for mammals), with moderate declines predicted for birds (22.6% of individuals) and severe declines predicted for mammals (46.6%). Despite certain limitations, we suggest the approach proposed is widely applicable to the evaluation of effects of planned infrastructure developments under multiple scenarios, and propose an internationally coordinated strategy to update and improve it in the future.

Fetus-derived DLK1 is required for maternal metabolic adaptations to pregnancy and is associated with fetal growth restriction.

PubMed

Cleaton, Mary A M; Dent, Claire L; Howard, Mark; Corish, Jennifer A; Gutteridge, Isabelle; Sovio, Ulla; Gaccioli, Francesca; Takahashi, Nozomi; Bauer, Steven R; Charnock-Jones, D Steven; Powell, Theresa L; Smith, Gordon C S; Ferguson-Smith, Anne C; Charalambous, Marika

2016-12-01

Pregnancy is a state of high metabolic demand. Fasting diverts metabolism to fatty acid oxidation, and the fasted response occurs much more rapidly in pregnant women than in non-pregnant women. The product of the imprinted DLK1 gene (delta-like homolog 1) is an endocrine signaling molecule that reaches a high concentration in the maternal circulation during late pregnancy. By using mouse models with deleted Dlk1, we show that the fetus is the source of maternal circulating DLK1. In the absence of fetally derived DLK1, the maternal fasting response is impaired. Furthermore, we found that maternal circulating DLK1 levels predict embryonic mass in mice and can differentiate healthy small-for-gestational-age (SGA) infants from pathologically small infants in a human cohort. Therefore, measurement of DLK1 concentration in maternal blood may be a valuable method for diagnosing human disorders associated with impaired DLK1 expression and to predict poor intrauterine growth and complications of pregnancy.

Buffered Qualitative Stability explains the robustness and evolvability of transcriptional networks.

PubMed

Albergante, Luca; Blow, J Julian; Newman, Timothy J

2014-09-02

The gene regulatory network (GRN) is the central decision-making module of the cell. We have developed a theory called Buffered Qualitative Stability (BQS) based on the hypothesis that GRNs are organised so that they remain robust in the face of unpredictable environmental and evolutionary changes. BQS makes strong and diverse predictions about the network features that allow stable responses under arbitrary perturbations, including the random addition of new connections. We show that the GRNs of E. coli, M. tuberculosis, P. aeruginosa, yeast, mouse, and human all verify the predictions of BQS. BQS explains many of the small- and large-scale properties of GRNs, provides conditions for evolvable robustness, and highlights general features of transcriptional response. BQS is severely compromised in a human cancer cell line, suggesting that loss of BQS might underlie the phenotypic plasticity of cancer cells, and highlighting a possible sequence of GRN alterations concomitant with cancer initiation. Copyright © 2014, Albergante et al.

Evaluation of internal noise methods for Hotelling observers

NASA Astrophysics Data System (ADS)

Zhang, Yani; Pham, Binh T.; Eckstein, Miguel P.

2005-04-01

Including internal noise in computer model observers to degrade model observer performance to human levels is a common method to allow for quantitatively comparisons of human and model performance. In this paper, we studied two different types of methods for injecting internal noise to Hotelling model observers. The first method adds internal noise to the output of the individual channels: a) Independent non-uniform channel noise, b) Independent uniform channel noise. The second method adds internal noise to the decision variable arising from the combination of channel responses: a) internal noise standard deviation proportional to decision variable's standard deviation due to the external noise, b) internal noise standard deviation proportional to decision variable's variance caused by the external noise. We tested the square window Hotelling observer (HO), channelized Hotelling observer (CHO), and Laguerre-Gauss Hotelling observer (LGHO). The studied task was detection of a filling defect of varying size/shape in one of four simulated arterial segment locations with real x-ray angiography backgrounds. Results show that the internal noise method that leads to the best prediction of human performance differs across the studied models observers. The CHO model best predicts human observer performance with the channel internal noise. The HO and LGHO best predict human observer performance with the decision variable internal noise. These results might help explain why previous studies have found different results on the ability of each Hotelling model to predict human performance. Finally, the present results might guide researchers with the choice of method to include internal noise into their Hotelling models.

Prediction, Assessment of the Rift Valley Fever Activity in East and Southern Africa 2006–2008 and Possible Vector Control Strategies

PubMed Central

Anyamba, Assaf; Linthicum, Kenneth J.; Small, Jennifer; Britch, Seth C.; Pak, Edwin; de La Rocque, Stephane; Formenty, Pierre; Hightower, Allen W.; Breiman, Robert F.; Chretien, Jean-Paul; Tucker, Compton J.; Schnabel, David; Sang, Rosemary; Haagsma, Karl; Latham, Mark; Lewandowski, Henry B.; Magdi, Salih Osman; Mohamed, Mohamed Ally; Nguku, Patrick M.; Reynes, Jean-Marc; Swanepoel, Robert

2010-01-01

Historical outbreaks of Rift Valley fever (RVF) since the early 1950s have been associated with cyclical patterns of the El Niño/Southern Oscillation (ENSO) phenomenon, which results in elevated and widespread rainfall over the RVF endemic areas of Africa. Using satellite measurements of global and regional elevated sea surface temperatures, elevated rainfall, and satellite derived-normalized difference vegetation index data, we predicted with lead times of 2–4 months areas where outbreaks of RVF in humans and animals were expected and occurred in the Horn of Africa, Sudan, and Southern Africa at different time periods from September 2006 to March 2008. Predictions were confirmed by entomological field investigations of virus activity and by reported cases of RVF in human and livestock populations. This represents the first series of prospective predictions of RVF outbreaks and provides a baseline for improved early warning, control, response planning, and mitigation into the future. PMID:20682905

Evaluation of geometrically personalized THUMS pedestrian model response against sedan-pedestrian PMHS impact test data.

PubMed

Chen, Huipeng; Poulard, David; Forman, Jason; Crandall, Jeff; Panzer, Matthew B

2018-07-04

Evaluating the biofidelity of pedestrian finite element models (PFEM) using postmortem human subjects (PMHS) is a challenge because differences in anthropometry between PMHS and PFEM could limit a model's capability to accurately capture cadaveric responses. Geometrical personalization via morphing can modify the PFEM geometry to match the specific PMHS anthropometry, which could alleviate this issue. In this study, the Total Human Model for Safety (THUMS) PFEM (Ver 4.01) was compared to the cadaveric response in vehicle-pedestrian impacts using geometrically personalized models. The AM50 THUMS PFEM was used as the baseline model, and 2 morphed PFEM were created to the anthropometric specifications of 2 obese PMHS used in a previous pedestrian impact study with a mid-size sedan. The same measurements as those obtained during the PMHS tests were calculated from the simulations (kinematics, accelerations, strains), and biofidelity metrics based on signals correlation (correlation and analysis, CORA) were established to compare the response of the models to the experiments. Injury outcomes were predicted deterministically (through strain-based threshold) and probabilistically (with injury risk functions) and compared with the injuries reported in the necropsy. The baseline model could not accurately capture all aspects of the PMHS kinematics, strain, and injury risks, whereas the morphed models reproduced biofidelic response in terms of trajectory (CORA score = 0.927 ± 0.092), velocities (0.975 ± 0.027), accelerations (0.862 ± 0.072), and strains (0.707 ± 0.143). The personalized THUMS models also generally predicted injuries consistent with those identified during posttest autopsy. The study highlights the need to control for pedestrian anthropometry when validating pedestrian human body models against PMHS data. The information provided in the current study could be useful for improving model biofidelity for vehicle-pedestrian impact scenarios.

Cortical Brain Activity Reflecting Attentional Biasing Toward Reward-Predicting Cues Covaries with Economic Decision-Making Performance

PubMed Central

San Martín, René; Appelbaum, Lawrence G.; Huettel, Scott A.; Woldorff, Marty G.

2016-01-01

Adaptive choice behavior depends critically on identifying and learning from outcome-predicting cues. We hypothesized that attention may be preferentially directed toward certain outcome-predicting cues. We studied this possibility by analyzing event-related potential (ERP) responses in humans during a probabilistic decision-making task. Participants viewed pairs of outcome-predicting visual cues and then chose to wager either a small (i.e., loss-minimizing) or large (i.e., gain-maximizing) amount of money. The cues were bilaterally presented, which allowed us to extract the relative neural responses to each cue by using a contralateral-versus-ipsilateral ERP contrast. We found an early lateralized ERP response, whose features matched the attention-shift-related N2pc component and whose amplitude scaled with the learned reward-predicting value of the cues as predicted by an attention-for-reward model. Consistently, we found a double dissociation involving the N2pc. Across participants, gain-maximization positively correlated with the N2pc amplitude to the most reliable gain-predicting cue, suggesting an attentional bias toward such cues. Conversely, loss-minimization was negatively correlated with the N2pc amplitude to the most reliable loss-predicting cue, suggesting an attentional avoidance toward such stimuli. These results indicate that learned stimulus–reward associations can influence rapid attention allocation, and that differences in this process are associated with individual differences in economic decision-making performance. PMID:25139941

Development of a human body finite element model with multiple muscles and their controller for estimating occupant motions and impact responses in frontal crash situations.

PubMed

Iwamoto, Masami; Nakahira, Yuko; Kimpara, Hideyuki; Sugiyama, Takahiko; Min, Kyuengbo

2012-10-01

A few reports suggest differences in injury outcomes between cadaver tests and real-world accidents under almost similar conditions. This study hypothesized that muscle activity could primarily cause the differences, and then developed a human body finite element (FE) model with individual muscles. Each muscle was modeled as a hybrid model of bar elements with active properties and solid elements with passive properties. The model without muscle activation was firstly validated against five series of cadaver test data on impact responses in the anterior-posterior direction. The model with muscle activation levels estimated based on electromyography (EMG) data was secondly validated against four series of volunteer test data on bracing effects for stiffness and thickness of an upper arm muscle, and braced driver's responses under a static environment and a brake deceleration. A muscle controller using reinforcement learning (RL), which is a mathematical model of learning process in the basal ganglia associated with human postural controls, were newly proposed to estimate muscle activity in various occupant conditions including inattentive and attentive conditions. Control of individual muscles predicted by RL reproduced more human like head-neck motions than conventional control of two groups of agonist and antagonist muscles. The model and the controller demonstrated that head-neck motions of an occupant under an impact deceleration of frontal crash were different in between a bracing condition with maximal braking force and an occupant condition predicted by RL. The model and the controller have the potential to investigate muscular effects in various occupant conditions during frontal crashes.

Development of a Zealand white rabbit deposition model to study inhalation anthrax

DOE Office of Scientific and Technical Information (OSTI.GOV)

Asgharian, Bahman; Price, Owen; Kabilan, Senthil

Despite using rabbits in several inhalation exposure experiments to study diseases such as anthrax, there is a lack of understanding regarding deposition characteristics and fate of inhaled particles (bio-aerosols and viruses) in the respiratory tracts of rabbits. Such information allows dosimetric extrapolation to humans to inform human outcomes. The lung geometry of the New Zealand white rabbit (referred to simply as rabbits throughout the article) was constructed using recently acquired scanned images of the conducting airways of rabbits and available information on its acinar region. In addition, functional relationships were developed for the lung and breathing parameters of rabbits asmore » a function of body weight. The lung geometry and breathing parameters were used to extend the existing deposition model for humans and several other species to rabbits. Evaluation of the deposition model for rabbits was made by comparing predictions with available measurements in the literature. Deposition predictions in the lungs of rabbits indicated smaller deposition fractions compared to those found in humans across various particle diameter ranges. The application of the deposition model for rabbits was demonstrated by extrapolating deposition predictions in rabbits to find equivalent human exposure concentrations assuming the same dose-response relationship between the two species. Human equivalent exposure concentration levels were found to be much smaller than those for rabbits.« less

Human milk peptides differentiate between the preterm and term infant and across varying lactational stages.

PubMed

Dingess, Kelly A; de Waard, Marita; Boeren, Sjef; Vervoort, Jacques; Lambers, Tim T; van Goudoever, Johannes B; Hettinga, Kasper

2017-10-18

Variations in endogenous peptide profiles, functionality, and the enzymes responsible for the formation of these peptides in human milk are understudied. Additionally, there is a lack of knowledge regarding peptides in donor human milk, which is used to feed preterm infants when mother's own milk is not (sufficiently) available. To assess this, 29 human milk samples from the Dutch Human Milk Bank were analyzed as three groups, preterm late lactation stage (LS) (n = 12), term early (n = 8) and term late LS (n = 9). Gestational age (GA) groups were defined as preterm (24-36 weeks) and term (≥37 weeks). LS was determined as days postpartum as early (16-36 days) or late (55-88 days). Peptides, analyzed by LC-MS/MS, and parent proteins (proteins from matched peptide sequences) were identified and quantified, after which peptide functionality and the enzymes responsible for protein cleavage were determined. A total of 16 different parent proteins were identified from human milk, with no differences by GA or LS. We identified 1104 endogenous peptides, of which, the majority were from the parent proteins β-casein, polymeric immunoglobulin receptor, α s1 -casein, osteopontin, and κ-casein. The absolute number of peptides differed by GA and LS with 30 and 41 differing sequences respectively (p < 0.05) Odds likelihood tests determined that 32 peptides had a predicted bioactive functionality, with no significant differences between groups. Enzyme prediction analysis showed that plasmin/trypsin enzymes most likely cleaved the identified human milk peptides. These results explain some of the variation in endogenous peptides in human milk, leading to future targets that may be studied for functionality.

Frequency response function-based explicit framework for dynamic identification in human-structure systems

NASA Astrophysics Data System (ADS)

Wei, Xiaojun; Živanović, Stana

2018-05-01

The aim of this paper is to propose a novel theoretical framework for dynamic identification in a structure occupied by a single human. The framework enables the prediction of the dynamics of the human-structure system from the known properties of the individual system components, the identification of human body dynamics from the known dynamics of the empty structure and the human-structure system and the identification of the properties of the structure from the known dynamics of the human and the human-structure system. The novelty of the proposed framework is the provision of closed-form solutions in terms of frequency response functions obtained by curve fitting measured data. The advantages of the framework over existing methods are that there is neither need for nonlinear optimisation nor need for spatial/modal models of the empty structure and the human-structure system. In addition, the second-order perturbation method is employed to quantify the effect of uncertainties in human body dynamics on the dynamic identification of the empty structure and the human-structure system. The explicit formulation makes the method computationally efficient and straightforward to use. A series of numerical examples and experiments are provided to illustrate the working of the method.

Definition of Human Epitopes Recognized in Tetanus Toxoid and Development of an Assay Strategy to Detect Ex Vivo Tetanus CD4+ T Cell Responses

PubMed Central

da Silva Antunes, Ricardo; Paul, Sinu; Sidney, John; Weiskopf, Daniela; Dan, Jennifer M.; Phillips, Elizabeth; Mallal, Simon; Crotty, Shane; Sette, Alessandro; Lindestam Arlehamn, Cecilia S.

2017-01-01

Despite widespread uses of tetanus toxoid (TT) as a vaccine, model antigen and protein carrier, TT epitopes have been poorly characterized. Herein we defined the human CD4+ T cell epitope repertoire by reevaluation of previously described epitopes and evaluation of those derived from prediction of HLA Class II binding. Forty-seven epitopes were identified following in vitro TT stimulation, with 28 epitopes accounting for 90% of the total response. Despite this diverse range of epitopes, individual responses were associated with only a few immunodominant epitopes, with each donor responding on average to 3 epitopes. For the top 14 epitopes, HLA restriction could be inferred based on HLA typing of the responding donors. HLA binding predictions re-identified the vast majority of known epitopes, and identified 24 additional novel epitopes. With these epitopes, we created a TT epitope pool, which allowed us to characterize TT responses directly ex vivo using a cytokine-independent Activation Induced Marker (AIM) assay. These TT responses were highly Th1 or Th2 polarized, which was dependent upon the original priming vaccine, either the cellular DTwP or acellular DTaP formulation. This polarization remained despite the original priming having occurred decades past and a recent booster immunization with a reduced acellular vaccine formulation. While TT responses following booster vaccination were not durably increased in magnitude, they were associated with a relative expansion of CD4+ effector memory T cells. PMID:28081174

Can we predict the blood pressure response to renal denervation?

PubMed Central

Fink, Gregory D.; Phelps, Jeremiah T.

2016-01-01

Renal denervation (RDN) is a new therapy used to treat drug-resistant hypertension in the clinical setting. Published human trials show substantial inter-individual variability in the blood pressure (BP) response to RDN, even when technical aspects of the treatment are standardized as much as possible between patients. Widespread acceptance of RDN for treating hypertension will require accurate identification of patients likely to respond to RDN with a fall in BP that is clinically significant in magnitude, well-maintained over time and does not cause adverse consequences. In this paper we review and evaluate clinical studies that address possible predictors of the BP response to RDN. We conclude that only one generally reliable predictor has been identified to date, namely pre-RDN BP level, although there is some evidence for a few other factors. Experimental interventions in laboratory animals provide the opportunity to explore potential predictors that are difficult to investigate in human patients. Therefore we also describe results (from our lab and others) with RDN in spontaneously hypertensive rats. Since virtually all patients receiving RDN are taking three or more antihypertensive drugs, a particular focus of our work was on how ongoing antihypertensive drug treatment might alter the BP response to RDN. We conclude that patient age (or duration of hypertension) and concomitant treatment with certain drugs can affect the blood pressure response to RDN and that this information could help predict a favorable clinical response. PMID:27530600

Definition of Human Epitopes Recognized in Tetanus Toxoid and Development of an Assay Strategy to Detect Ex Vivo Tetanus CD4+ T Cell Responses.

PubMed

da Silva Antunes, Ricardo; Paul, Sinu; Sidney, John; Weiskopf, Daniela; Dan, Jennifer M; Phillips, Elizabeth; Mallal, Simon; Crotty, Shane; Sette, Alessandro; Lindestam Arlehamn, Cecilia S

2017-01-01

Despite widespread uses of tetanus toxoid (TT) as a vaccine, model antigen and protein carrier, TT epitopes have been poorly characterized. Herein we defined the human CD4+ T cell epitope repertoire by reevaluation of previously described epitopes and evaluation of those derived from prediction of HLA Class II binding. Forty-seven epitopes were identified following in vitro TT stimulation, with 28 epitopes accounting for 90% of the total response. Despite this diverse range of epitopes, individual responses were associated with only a few immunodominant epitopes, with each donor responding on average to 3 epitopes. For the top 14 epitopes, HLA restriction could be inferred based on HLA typing of the responding donors. HLA binding predictions re-identified the vast majority of known epitopes, and identified 24 additional novel epitopes. With these epitopes, we created a TT epitope pool, which allowed us to characterize TT responses directly ex vivo using a cytokine-independent Activation Induced Marker (AIM) assay. These TT responses were highly Th1 or Th2 polarized, which was dependent upon the original priming vaccine, either the cellular DTwP or acellular DTaP formulation. This polarization remained despite the original priming having occurred decades past and a recent booster immunization with a reduced acellular vaccine formulation. While TT responses following booster vaccination were not durably increased in magnitude, they were associated with a relative expansion of CD4+ effector memory T cells.

Radiation Effect on Human Tissue

NASA Technical Reports Server (NTRS)

Richmond, Robert C.; Cruz, Angela; Bors, Karen; Curreri, Peter A. (Technical Monitor)

2002-01-01

Predicting the occurrence of human cancer following exposure of an epidemiologic population to any agent causing genetic damage is a difficult task. To an approximation, this is because the uncertainty of uniform exposure to the damaging agent, and the uncertainty of uniform processing of that damage within a complex set of biological variables, degrade the confidence of predicting the delayed expression of cancer as a relatively rare event within clinically normal individuals. This situation begs the need for alternate controlled experimental models that are predictive for the development of human cancer following exposures to agents causing genetic damage. Such models historically have not been of substantial proven value. It is more recently encouraging, however, that developments in molecular and cell biology have led to an expanded knowledge of human carcinogenesis, and of molecular markers associated with that process. It is therefore appropriate to consider new laboratory models developed to accomodate that expanded knowledge in order to assess the cancer risks associated with exposures to genotoxic agents. When ionizing radiation of space is the genotoxic agent, then a series of additional considerations for human cancer risk assessment must also be applied. These include the dose of radiation absorbed by tissue at different locations in the body, the quality of the absorbed radiation, the rate at which absorbed dose accumulates in tissue, the way in which absorbed dose is measured and calculated, and the alterations in incident radiation caused by shielding materials. It is clear that human cancer risk assessment for damage caused by ionizing radiation is a multidisciplinary responsibility, and that within this responsibility no single discipline can hold disproportionate sway if a risk assessment model of radiation-induced human cancer is to be developed that has proven value. Biomolecular and cellular markers from the work reported here are considered for use in assessing human cancer risk related to exposure to space radiation. This potential use must be integrated within the specified multidisciplinary context in order to create a new tool of molecular epidemiology that can hopefully then realistically assess this cancer risk.

Development, Evaluation, and Sensitivity Analysis of Parametric Finite Element Whole-Body Human Models in Side Impacts.

PubMed

Hwang, Eunjoo; Hu, Jingwen; Chen, Cong; Klein, Katelyn F; Miller, Carl S; Reed, Matthew P; Rupp, Jonathan D; Hallman, Jason J

2016-11-01

Occupant stature and body shape may have significant effects on injury risks in motor vehicle crashes, but the current finite element (FE) human body models (HBMs) only represent occupants with a few sizes and shapes. Our recent studies have demonstrated that, by using a mesh morphing method, parametric FE HBMs can be rapidly developed for representing a diverse population. However, the biofidelity of those models across a wide range of human attributes has not been established. Therefore, the objectives of this study are 1) to evaluate the accuracy of HBMs considering subject-specific geometry information, and 2) to apply the parametric HBMs in a sensitivity analysis for identifying the specific parameters affecting body responses in side impact conditions. Four side-impact tests with two male post-mortem human subjects (PMHSs) were selected to evaluate the accuracy of the geometry and impact responses of the morphed HBMs. For each PMHS test, three HBMs were simulated to compare with the test results: the original Total Human Model for Safety (THUMS) v4.01 (O-THUMS), a parametric THUMS (P-THUMS), and a subject-specific THUMS (S-THUMS). The P-THUMS geometry was predicted from only age, sex, stature, and BMI using our statistical geometry models of skeleton and body shape, while the S-THUMS geometry was based on each PMHS's CT data. The simulation results showed a preliminary trend that the correlations between the PTHUMS- predicted impact responses and the four PMHS tests (mean-CORA: 0.84, 0.78, 0.69, 0.70) were better than those between the O-THUMS and the normalized PMHS responses (mean-CORA: 0.74, 0.72, 0.55, 0.63), while they are similar to the correlations between S-THUMS and the PMHS tests (mean-CORA: 0.85, 0.85, 0.67, 0.72). The sensitivity analysis using the PTHUMS showed that, in side impact conditions, the HBM skeleton and body shape geometries as well as the body posture were more important in modeling the occupant impact responses than the bone and soft tissue material properties and the padding stiffness with the given parameter ranges. More investigations are needed to further support these findings.

Genetic determinants of freckle occurrence in the Spanish population: Towards ephelides prediction from human DNA samples.

PubMed

Hernando, Barbara; Ibañez, Maria Victoria; Deserio-Cuesta, Julio Alberto; Soria-Navarro, Raquel; Vilar-Sastre, Inca; Martinez-Cadenas, Conrado

2018-03-01

Prediction of human pigmentation traits, one of the most differentiable externally visible characteristics among individuals, from biological samples represents a useful tool in the field of forensic DNA phenotyping. In spite of freckling being a relatively common pigmentation characteristic in Europeans, little is known about the genetic basis of this largely genetically determined phenotype in southern European populations. In this work, we explored the predictive capacity of eight freckle and sunlight sensitivity-related genes in 458 individuals (266 non-freckled controls and 192 freckled cases) from Spain. Four loci were associated with freckling (MC1R, IRF4, ASIP and BNC2), and female sex was also found to be a predictive factor for having a freckling phenotype in our population. After identifying the most informative genetic variants responsible for human ephelides occurrence in our sample set, we developed a DNA-based freckle prediction model using a multivariate regression approach. Once developed, the capabilities of the prediction model were tested by a repeated 10-fold cross-validation approach. The proportion of correctly predicted individuals using the DNA-based freckle prediction model was 74.13%. The implementation of sex into the DNA-based freckle prediction model slightly improved the overall prediction accuracy by 2.19% (76.32%). Further evaluation of the newly-generated prediction model was performed by assessing the model's performance in a new cohort of 212 Spanish individuals, reaching a classification success rate of 74.61%. Validation of this prediction model may be carried out in larger populations, including samples from different European populations. Further research to validate and improve this newly-generated freckle prediction model will be needed before its forensic application. Together with DNA tests already validated for eye and hair colour prediction, this freckle prediction model may lead to a substantially more detailed physical description of unknown individuals from DNA found at the crime scene. Copyright © 2017 Elsevier B.V. All rights reserved.

Prediction of biodiversity hotspots in the Anthropocene: The case of veteran oaks.

PubMed

Skarpaas, Olav; Blumentrath, Stefan; Evju, Marianne; Sverdrup-Thygeson, Anne

2017-10-01

Over the past centuries, humans have transformed large parts of the biosphere, and there is a growing need to understand and predict the distribution of biodiversity hotspots influenced by the presence of humans. Our basic hypothesis is that human influence in the Anthropocene is ubiquitous, and we predict that biodiversity hot spot modeling can be improved by addressing three challenges raised by the increasing ecological influence of humans: (i) anthropogenically modified responses to individual ecological factors, (ii) fundamentally different processes and predictors in landscape types shaped by different land use histories and (iii) a multitude and complexity of natural and anthropogenic processes that may require many predictors and even multiple models in different landscape types. We modeled the occurrence of veteran oaks in Norway, and found, in accordance with our basic hypothesis and predictions, that humans influence the distribution of veteran oaks throughout its range, but in different ways in forests and open landscapes. In forests, geographical and topographic variables related to the oak niche are still important, but the occurrence of veteran oaks is shifted toward steeper slopes, where logging is difficult. In open landscapes, land cover variables are more important, and veteran oaks are more common toward the north than expected from the fundamental oak niche. In both landscape types, multiple predictor variables representing ecological and human-influenced processes were needed to build a good model, and several models performed almost equally well. Models accounting for the different anthropogenic influences on landscape structure and processes consistently performed better than models based exclusively on natural biogeographical and ecological predictors. Thus, our results for veteran oaks clearly illustrate the challenges to distribution modeling raised by the ubiquitous influence of humans, even in a moderately populated region, but also show that predictions can be improved by explicitly addressing these anthropogenic complexities.

Human cold stress of strong local-wind "Hijikawa-arashi" in Japan, based on the UTCI index and thermo-physiological responses.

PubMed

Ohashi, Yukitaka; Katsuta, Takumi; Tani, Haruka; Okabayashi, Taiki; Miyahara, Satoshi; Miyashita, Ryoji

2018-03-30

We investigated the cold stress caused by a strong local wind called "Hijikawa-arashi," through in situ vital measurements and the Universal Thermal Climate Index (UTCI). This wind is a very interesting winter phenomenon, localized in an area within 1 km of the seashore in Ozu City, Ehime Prefecture in Japan. When a strong Hijikawa-arashi (HA) occurred at 14-15 m s -1 , the UTCI decreased to - 30 °C along the bridge where commuting residents are the most exposed to strong and cold winds. On the bridge, most participants in our experiment felt "very cold" or "extremely cold." The UTCI of HA can be predicted from a multiple regression equation using wind speed and air temperature. The cold HA wind is also harmful to human thermo-physiological responses. It leads to higher blood pressure and increased heart rate, both of which act as cardiovascular stress triggers. Increases of 6-10 mmHg and 3-6 bpm for every 10 °C reduction in UTCI were seen on all observational days, including HA and non-HA days. In fact, the participants' body skin temperatures decreased by approximately 1.2 to 1.7 °C for every 10 °C reduction in UTCI. Thus, the UTCI variation due to the HA outbreak corresponded well with the cold sensation and thermo-physiological responses in humans. This result suggests that daily UTCI monitoring enables the prediction of thermo-physiological responses to the HA cold stress.

Predicting cancer rates in astronauts from animal carcinogenesis studies and cellular markers

NASA Technical Reports Server (NTRS)

Williams, J. R.; Zhang, Y.; Zhou, H.; Osman, M.; Cha, D.; Kavet, R.; Cuccinotta, F.; Dicello, J. F.; Dillehay, L. E.

1999-01-01

The radiation space environment includes particles such as protons and multiple species of heavy ions, with much of the exposure to these radiations occurring at extremely low average dose-rates. Limitations in databases needed to predict cancer hazards in human beings from such radiations are significant and currently do not provide confidence that such predictions are acceptably precise or accurate. In this article, we outline the need for animal carcinogenesis data based on a more sophisticated understanding of the dose-response relationship for induction of cancer and correlative cellular endpoints by representative space radiations. We stress the need for a model that can interrelate human and animal carcinogenesis data with cellular mechanisms. Using a broad model for dose-response patterns which we term the "subalpha-alpha-omega (SAO) model", we explore examples in the literature for radiation-induced cancer and for radiation-induced cellular events to illustrate the need for data that define the dose-response patterns more precisely over specific dose ranges, with special attention to low dose, low dose-rate exposure. We present data for multiple endpoints in cells, which vary in their radiosensitivity, that also support the proposed model. We have measured induction of complex chromosome aberrations in multiple cell types by two space radiations, Fe-ions and protons, and compared these to photons delivered at high dose-rate or low dose-rate. Our data demonstrate that at least three factors modulate the relative efficacy of Fe-ions compared to photons: (i) intrinsic radiosensitivity of irradiated cells; (ii) dose-rate; and (iii) another unspecified effect perhaps related to reparability of DNA lesions. These factors can produce respectively up to at least 7-, 6- and 3-fold variability. These data demonstrate the need to understand better the role of intrinsic radiosensitivity and dose-rate effects in mammalian cell response to ionizing radiation. Such understanding is critical in extrapolating databases between cellular response, animal carcinogenesis and human carcinogenesis, and we suggest that the SAO model is a useful tool for such extrapolation.

Mechanical characterization of human brain tissue.

PubMed

Budday, S; Sommer, G; Birkl, C; Langkammer, C; Haybaeck, J; Kohnert, J; Bauer, M; Paulsen, F; Steinmann, P; Kuhl, E; Holzapfel, G A

2017-01-15

Mechanics are increasingly recognized to play an important role in modulating brain form and function. Computational simulations are a powerful tool to predict the mechanical behavior of the human brain in health and disease. The success of these simulations depends critically on the underlying constitutive model and on the reliable identification of its material parameters. Thus, there is an urgent need to thoroughly characterize the mechanical behavior of brain tissue and to identify mathematical models that capture the tissue response under arbitrary loading conditions. However, most constitutive models have only been calibrated for a single loading mode. Here, we perform a sequence of multiple loading modes on the same human brain specimen - simple shear in two orthogonal directions, compression, and tension - and characterize the loading-mode specific regional and directional behavior. We complement these three individual tests by combined multiaxial compression/tension-shear tests and discuss effects of conditioning and hysteresis. To explore to which extent the macrostructural response is a result of the underlying microstructural architecture, we supplement our biomechanical tests with diffusion tensor imaging and histology. We show that the heterogeneous microstructure leads to a regional but not directional dependence of the mechanical properties. Our experiments confirm that human brain tissue is nonlinear and viscoelastic, with a pronounced compression-tension asymmetry. Using our measurements, we compare the performance of five common constitutive models, neo-Hookean, Mooney-Rivlin, Demiray, Gent, and Ogden, and show that only the isotropic modified one-term Ogden model is capable of representing the hyperelastic behavior under combined shear, compression, and tension loadings: with a shear modulus of 0.4-1.4kPa and a negative nonlinearity parameter it captures the compression-tension asymmetry and the increase in shear stress under superimposed compression but not tension. Our results demonstrate that material parameters identified for a single loading mode fail to predict the response under arbitrary loading conditions. Our systematic characterization of human brain tissue will lead to more accurate computational simulations, which will allow us to determine criteria for injury, to develop smart protection systems, and to predict brain development and disease progression. There is a pressing need to characterize the mechanical behavior of human brain tissue under multiple loading conditions, and to identify constitutive models that are able to capture the tissue response under these conditions. We perform a sequence of experimental tests on the same brain specimen to characterize the regional and directional behavior, and we supplement our tests with DTI and histology to explore to which extent the macrostructural response is a result of the underlying microstructure. Results demonstrate that human brain tissue is nonlinear and viscoelastic, with a pronounced compression-tension asymmetry, and we show that the multiaxial data can best be captured by a modified version of the one-term Ogden model. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Merck Ad5/HIV induces broad innate immune activation that predicts CD8⁺ T-cell responses but is attenuated by preexisting Ad5 immunity.

PubMed

Zak, Daniel E; Andersen-Nissen, Erica; Peterson, Eric R; Sato, Alicia; Hamilton, M Kristina; Borgerding, Joleen; Krishnamurty, Akshay T; Chang, Joanne T; Adams, Devin J; Hensley, Tiffany R; Salter, Alexander I; Morgan, Cecilia A; Duerr, Ann C; De Rosa, Stephen C; Aderem, Alan; McElrath, M Juliana

2012-12-11

To better understand how innate immune responses to vaccination can lead to lasting protective immunity, we used a systems approach to define immune signatures in humans over 1 wk following MRKAd5/HIV vaccination that predicted subsequent HIV-specific T-cell responses. Within 24 h, striking increases in peripheral blood mononuclear cell gene expression associated with inflammation, IFN response, and myeloid cell trafficking occurred, and lymphocyte-specific transcripts decreased. These alterations were corroborated by marked serum inflammatory cytokine elevations and egress of circulating lymphocytes. Responses of vaccinees with preexisting adenovirus serotype 5 (Ad5) neutralizing antibodies were strongly attenuated, suggesting that enhanced HIV acquisition in Ad5-seropositive subgroups in the Step Study may relate to the lack of appropriate innate activation rather than to increased systemic immune activation. Importantly, patterns of chemoattractant cytokine responses at 24 h and alterations in 209 peripheral blood mononuclear cell transcripts at 72 h were predictive of subsequent induction and magnitude of HIV-specific CD8(+) T-cell responses. This systems approach provides a framework to compare innate responses induced by vectors, as shown here by contrasting the more rapid, robust response to MRKAd5/HIV with that to yellow fever vaccine. When applied iteratively, the findings may permit selection of HIV vaccine candidates eliciting innate immune response profiles more likely to drive HIV protective immunity.

Microdose-induced Drug-DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice

PubMed Central

Zimmermann, Maike; Wang, Si-Si; Zhang, Hongyong; Lin, Tzu-yin; Malfatti, Michael; Haack, Kurt; Ognibene, Ted; Yang, Hongyuan; Airhart, Susan; Turteltaub, Kenneth W.; Cimino, George D.; Tepper, Clifford G.; Drakaki, Alexandra; Chamie, Karim; de Vere White, Ralph; Pan, Chong-xian; Henderson, Paul T.

2017-01-01

We report progress on predicting tumor response to platinum-based chemotherapy with a novel mass spectrometry approach. Fourteen bladder cancer patients were administered one diagnostic microdose each of [14C]carboplatin (1% of the therapeutic dose). Carboplatin-DNA adducts were quantified by accelerator mass spectrometry (AMS) in blood and tumor samples collected within 24 hours, and compared to subsequent chemotherapy response. Patients with the highest adduct levels were responders, but not all responders had high adduct levels. Four patient-derived bladder cancer xenograft mouse models were used to test the possibility that another drug in the regimen could cause a response. The mice were dosed with [14C]carboplatin or [14C]gemcitabine and the resulting drug-DNA adduct levels were compared to tumor response to chemotherapy. At least one of the drugs had to induce high drug-DNA adduct levels or create a synergistic increase in overall adducts to prompt a corresponding therapeutic response, demonstrating proof-of-principle for drug-DNA adducts as predictive biomarkers. PMID:27903751

Revisiting the Role of Bad News in Maintaining Human Observing Behavior

ERIC Educational Resources Information Center

Fantino, Edmund; Silberberg, Alan

2010-01-01

Results from studies of observing responses have suggested that stimuli maintain observing owing to their special relationship to primary reinforcement (the conditioned- reinforcement hypothesis), and not because they predict the availability and nonavailability of reinforcement (the information hypothesis). The present article first reviews a…

Developing Predictive Approaches to Characterize Adaptive Responses of the Reproductive Endocrine Axis to Aromatase Inhibition II: Computational Modeling

EPA Science Inventory

ABSTRACT Exposure to endocrine disrupting chemicals can affect reproduction and development in both humans and wildlife. We developed a mechanistic mathematical model of the hypothalamic­ pituitary-gonadal (HPG) axis in female fathead minnows to predic...

Symptom patterns in dissociative identity disorder patients and the general population.

PubMed

Ross, Colin A; Ness, Laura

2010-01-01

The authors used the Dissociative Disorders Interview Schedule to compare structured interview symptom patterns in a general population sample (N= 502) and a sample of patients with clinical diagnoses of dissociative identity disorder (N= 303). Based on the Trauma Model, the authors predicted that the patterns would be similar in the 2 samples and that symptom scores would be higher in participants reporting childhood sexual abuse in both samples. They predicted that symptom scores would be higher among women with dissociative identity disorder reporting sexual abuse than among women in the general population reporting sexual abuse, with the clinical sample reporting more severe abuse. These predictions were supported by the data. The authors conclude that symptom patterns in dissociative identity disorder are typical of the normal human response to severe, chronic childhood trauma and have ecological validity for the human race in general.

Physiologically based pharmacokinetic modeling of tea catechin mixture in rats and humans.

PubMed

Law, Francis C P; Yao, Meicun; Bi, Hui-Chang; Lam, Stephen

2017-06-01

Although green tea ( Camellia sinensis) (GT) contains a large number of polyphenolic compounds with anti-oxidative and anti-proliferative activities, little is known of the pharmacokinetics and tissue dose of tea catechins (TCs) as a chemical mixture in humans. The objectives of this study were to develop and validate a physiologically based pharmacokinetic (PBPK) model of tea catechin mixture (TCM) in rats and humans, and to predict an integrated or total concentration of TCM in the plasma of humans after consuming GT or Polyphenon E (PE). To this end, a PBPK model of epigallocatechin gallate (EGCg) consisting of 13 first-order, blood flow-limited tissue compartments was first developed in rats. The rat model was scaled up to humans by replacing its physiological parameters, pharmacokinetic parameters and tissue/blood partition coefficients (PCs) with human-specific values. Both rat and human EGCg models were then extrapolated to other TCs by substituting its physicochemical parameters, pharmacokinetic parameters, and PCs with catechin-specific values. Finally, a PBPK model of TCM was constructed by linking three rat (or human) tea catechin models together without including a description for pharmacokinetic interaction between the TCs. The mixture PBPK model accurately predicted the pharmacokinetic behaviors of three individual TCs in the plasma of rats and humans after GT or PE consumption. Model-predicted total TCM concentration in the plasma was linearly related to the dose consumed by humans. The mixture PBPK model is able to translate an external dose of TCM into internal target tissue doses for future safety assessment and dose-response analysis studies in humans. The modeling framework as described in this paper is also applicable to the bioactive chemical in other plant-based health products.

Disease and thermal acclimation in a more variable and unpredictable climate

NASA Astrophysics Data System (ADS)

Raffel, Thomas R.; Romansic, John M.; Halstead, Neal T.; McMahon, Taegan A.; Venesky, Matthew D.; Rohr, Jason R.

2013-02-01

Global climate change is shifting the distribution of infectious diseases of humans and wildlife with potential adverse consequences for disease control. As well as increasing mean temperatures, climate change is expected to increase climate variability, making climate less predictable. However, few empirical or theoretical studies have considered the effects of climate variability or predictability on disease, despite it being likely that hosts and parasites will have differential responses to climatic shifts. Here we present a theoretical framework for how temperature variation and its predictability influence disease risk by affecting host and parasite acclimation responses. Laboratory experiments conducted in 80 independent incubators, and field data on disease-associated frog declines in Latin America, support the framework and provide evidence that unpredictable temperature fluctuations, on both monthly and diurnal timescales, decrease frog resistance to the pathogenic chytrid fungus Batrachochytrium dendrobatidis. Furthermore, the pattern of temperature-dependent growth of the fungus on frogs was opposite to the pattern of growth in culture, emphasizing the importance of accounting for the host-parasite interaction when predicting climate-dependent disease dynamics. If similar acclimation responses influence other host-parasite systems, as seems likely, then present models, which generally ignore small-scale temporal variability in climate, might provide poor predictions for climate effects on disease.

Collective behaviour, uncertainty and environmental change.

PubMed

Bentley, R Alexander; O'Brien, Michael J

2015-11-28

A central aspect of cultural evolutionary theory concerns how human groups respond to environmental change. Although we are painting with a broad brush, it is fair to say that prior to the twenty-first century, adaptation often happened gradually over multiple human generations, through a combination of individual and social learning, cumulative cultural evolution and demographic shifts. The result was a generally resilient and sustainable population. In the twenty-first century, however, considerable change happens within small portions of a human generation, on a vastly larger range of geographical and population scales and involving a greater degree of horizontal learning. As a way of gauging the complexity of societal response to environmental change in a globalized future, we discuss several theoretical tools for understanding how human groups adapt to uncertainty. We use our analysis to estimate the limits of predictability of future societal change, in the belief that knowing when to hedge bets is better than relying on a false sense of predictability. © 2015 The Author(s).

Publications in acoustics and noise control from the NASA Langley Research Center during 1940-1976

NASA Technical Reports Server (NTRS)

Fryer, B. A. (Compiler)

1977-01-01

Reference lists are presented of published research papers in various areas of acoustics and noise control for the period 1940-1976. The references are listed chronologically and are grouped under the following general headings: (1) Duct acoustics; (2) propagation and operations; (3) rotating blade noise; (4) jet noise; (5) sonic boom; (6) flow-surface interaction noise; (7) human response; (8) structural response; (9) prediction; and (10) miscellaneous.

Determinants of ventilation and pulmonary artery pressure during early acclimatization to hypoxia in humans

PubMed Central

Fatemian, Marzieh; Herigstad, Mari; Croft, Quentin P. P.; Formenti, Federico; Cardenas, Rosa; Wheeler, Carly; Smith, Thomas G.; Friedmannova, Maria; Dorrington, Keith L.

2015-01-01

Key points Lung ventilation and pulmonary artery pressure rise progressively in response to 8 h of hypoxia, changes described as ‘acclimatization to hypoxia’. Acclimatization responses differ markedly between humans for unknown reasons.We explored whether the magnitudes of the ventilatory and vascular responses were related, and whether the degree of acclimatization could be predicted by acute measurements of ventilatory and vascular sensitivities.In 80 healthy human volunteers measurements of acclimatization were made before, during, and after a sustained exposure to 8 h of isocapnic hypoxia.No correlation was found between measures of ventilatory and pulmonary vascular acclimatization.The ventilatory chemoreflex sensitivities to acute hypoxia and hypercapnia all increased in proportion to their pre‐acclimatization values following 8 h of hypoxia. The peripheral (rapid) chemoreflex sensitivity to CO2, measured before sustained hypoxia against a background of hyperoxia, was a modest predictor of ventilatory acclimatization to hypoxia. This finding has relevance to predicting human acclimatization to the hypoxia of altitude. Abstract Pulmonary ventilation and pulmonary arterial pressure both rise progressively during the first few hours of human acclimatization to hypoxia. These responses are highly variable between individuals, but the origin of this variability is unknown. Here, we sought to determine whether the variabilities between different measures of response to sustained hypoxia were related, which would suggest a common source of variability. Eighty volunteers individually underwent an 8‐h isocapnic exposure to hypoxia (end‐tidal P O2=55 Torr) in a purpose‐built chamber. Measurements of ventilation and pulmonary artery systolic pressure (PASP) assessed by Doppler echocardiography were made during the exposure. Before and after the exposure, measurements were made of the ventilatory sensitivities to acute isocapnic hypoxia (GpO2) and hyperoxic hypercapnia, the latter divided into peripheral (G pC O2) and central (G cC O2) components. Substantial acclimatization was observed in both ventilation and PASP, the latter being 40% greater in women than men. No correlation was found between the magnitudes of pulmonary ventilatory and pulmonary vascular responses. For GpO2, G pC O2 and G cC O2, but not the sensitivity of PASP to acute hypoxia, the magnitude of the increase during acclimatization was proportional to the pre‐acclimatization value. Additionally, the change in GpO2 during acclimatization to hypoxia correlated well with most other measures of ventilatory acclimatization. Of the initial measurements prior to sustained hypoxia, only G pC O2 predicted the subsequent rise in ventilation and change in GpO2 during acclimatization. We conclude that the magnitudes of the ventilatory and pulmonary vascular responses to sustained hypoxia are predominantly determined by different factors and that the initial G pC O2 is a modest predictor of ventilatory acclimatization. PMID:25907672

Free energy, precision and learning: the role of cholinergic neuromodulation

PubMed Central

Moran, Rosalyn J.; Campo, Pablo; Symmonds, Mkael; Stephan, Klaas E.; Dolan, Raymond J.; Friston, Karl J.

2014-01-01

Acetylcholine (ACh) is a neuromodulatory transmitter implicated in perception and learning under uncertainty. This study combined computational simulations and pharmaco-electroencephalography in humans, to test a formulation of perceptual inference based upon the free energy principle. This formulation suggests that acetylcholine enhances the precision of bottom-up synaptic transmission in cortical hierarchies by optimising the gain of supragranular pyramidal cells. Simulations of a mismatch negativity paradigm predicted a rapid trial-by-trial suppression of evoked sensory prediction error (PE) responses that is attenuated by cholinergic neuromodulation. We confirmed this prediction empirically with a placebo-controlled study of cholinesterase inhibition. Furthermore – using dynamic causal modelling – we found that drug-induced differences in PE responses could be explained by gain modulation in supragranular pyramidal cells in primary sensory cortex. This suggests that acetylcholine adaptively enhances sensory precision by boosting bottom-up signalling when stimuli are predictable, enabling the brain to respond optimally under different levels of environmental uncertainty. PMID:23658161

Integrated analysis of drug-induced gene expression profiles predicts novel hERG inhibitors.

PubMed

Babcock, Joseph J; Du, Fang; Xu, Kaiping; Wheelan, Sarah J; Li, Min

2013-01-01

Growing evidence suggests that drugs interact with diverse molecular targets mediating both therapeutic and toxic effects. Prediction of these complex interactions from chemical structures alone remains challenging, as compounds with different structures may possess similar toxicity profiles. In contrast, predictions based on systems-level measurements of drug effect may reveal pharmacologic similarities not evident from structure or known therapeutic indications. Here we utilized drug-induced transcriptional responses in the Connectivity Map (CMap) to discover such similarities among diverse antagonists of the human ether-à-go-go related (hERG) potassium channel, a common target of promiscuous inhibition by small molecules. Analysis of transcriptional profiles generated in three independent cell lines revealed clusters enriched for hERG inhibitors annotated using a database of experimental measurements (hERGcentral) and clinical indications. As a validation, we experimentally identified novel hERG inhibitors among the unannotated drugs in these enriched clusters, suggesting transcriptional responses may serve as predictive surrogates of cardiotoxicity complementing existing functional assays.

Integrated Analysis of Drug-Induced Gene Expression Profiles Predicts Novel hERG Inhibitors

PubMed Central

Babcock, Joseph J.; Du, Fang; Xu, Kaiping; Wheelan, Sarah J.; Li, Min

2013-01-01

Growing evidence suggests that drugs interact with diverse molecular targets mediating both therapeutic and toxic effects. Prediction of these complex interactions from chemical structures alone remains challenging, as compounds with different structures may possess similar toxicity profiles. In contrast, predictions based on systems-level measurements of drug effect may reveal pharmacologic similarities not evident from structure or known therapeutic indications. Here we utilized drug-induced transcriptional responses in the Connectivity Map (CMap) to discover such similarities among diverse antagonists of the human ether-à-go-go related (hERG) potassium channel, a common target of promiscuous inhibition by small molecules. Analysis of transcriptional profiles generated in three independent cell lines revealed clusters enriched for hERG inhibitors annotated using a database of experimental measurements (hERGcentral) and clinical indications. As a validation, we experimentally identified novel hERG inhibitors among the unannotated drugs in these enriched clusters, suggesting transcriptional responses may serve as predictive surrogates of cardiotoxicity complementing existing functional assays. PMID:23936032

Human Biomarker Discovery and Predictive Models for Disease Progression for Idiopathic Pneumonia Syndrome Following Allogeneic Stem Cell Transplantation*

PubMed Central

Schlatzer, Daniela M.; Dazard, Jean-Eudes; Ewing, Rob M.; Ilchenko, Serguei; Tomcheko, Sara E.; Eid, Saada; Ho, Vincent; Yanik, Greg; Chance, Mark R.; Cooke, Kenneth R.

2012-01-01

Allogeneic hematopoietic stem cell transplantation (SCT) is the only curative therapy for many malignant and nonmalignant conditions. Idiopathic pneumonia syndrome (IPS) is a frequently fatal complication that limits successful outcomes. Preclinical models suggest that IPS represents an immune mediated attack on the lung involving elements of both the adaptive and the innate immune system. However, the etiology of IPS in humans is less well understood. To explore the disease pathway and uncover potential biomarkers of disease, we performed two separate label-free, proteomics experiments defining the plasma protein profiles of allogeneic SCT patients with IPS. Samples obtained from SCT recipients without complications served as controls. The initial discovery study, intended to explore the disease pathway in humans, identified a set of 81 IPS-associated proteins. These data revealed similarities between the known IPS pathways in mice and the condition in humans, in particular in the acute phase response. In addition, pattern recognition pathways were judged to be significant as a function of development of IPS, and from this pathway we chose the lipopolysaccaharide-binding protein (LBP) protein as a candidate molecular diagnostic for IPS, and verified its increase as a function of disease using an ELISA assay. In a separately designed study, we identified protein-based classifiers that could predict, at day 0 of SCT, patients who: 1) progress to IPS and 2) respond to cytokine neutralization therapy. Using cross-validation strategies, we built highly predictive classifier models of both disease progression and therapeutic response. In sum, data generated in this report confirm previous clinical and experimental findings, provide new insights into the pathophysiology of IPS, identify potential molecular classifiers of the condition, and uncover a set of markers potentially of interest for patient stratification as a basis for individualized therapy. PMID:22337588

Dynamic imaging of adaptive stress response pathway activation for prediction of drug induced liver injury.

PubMed

Wink, Steven; Hiemstra, Steven W; Huppelschoten, Suzanne; Klip, Janna E; van de Water, Bob

2018-05-01

Drug-induced liver injury remains a concern during drug treatment and development. There is an urgent need for improved mechanistic understanding and prediction of DILI liabilities using in vitro approaches. We have established and characterized a panel of liver cell models containing mechanism-based fluorescent protein toxicity pathway reporters to quantitatively assess the dynamics of cellular stress response pathway activation at the single cell level using automated live cell imaging. We have systematically evaluated the application of four key adaptive stress pathway reporters for the prediction of DILI liability: SRXN1-GFP (oxidative stress), CHOP-GFP (ER stress/UPR response), p21 (p53-mediated DNA damage-related response) and ICAM1 (NF-κB-mediated inflammatory signaling). 118 FDA-labeled drugs in five human exposure relevant concentrations were evaluated for reporter activation using live cell confocal imaging. Quantitative data analysis revealed activation of single or multiple reporters by most drugs in a concentration and time dependent manner. Hierarchical clustering of time course dynamics and refined single cell analysis allowed the allusion of key events in DILI liability. Concentration response modeling was performed to calculate benchmark concentrations (BMCs). Extracted temporal dynamic parameters and BMCs were used to assess the predictive power of sub-lethal adaptive stress pathway activation. Although cellular adaptive responses were activated by non-DILI and severe-DILI compounds alike, dynamic behavior and lower BMCs of pathway activation were sufficiently distinct between these compound classes. The high-level detailed temporal- and concentration-dependent evaluation of the dynamics of adaptive stress pathway activation adds to the overall understanding and prediction of drug-induced liver liabilities.

Improving Upon an Empirical Procedure for Characterizing Magnetospheric States

NASA Astrophysics Data System (ADS)

Fung, S. F.; Neufeld, J.; Shao, X.

2012-12-01

Work is being performed to improve upon an empirical procedure for describing and predicting the states of the magnetosphere [Fung and Shao, 2008]. We showed in our previous paper that the state of the magnetosphere can be described by a quantity called the magnetospheric state vector (MS vector) consisting of a concatenation of a set of driver-state and a set of response-state parameters. The response state parameters are time-shifted individually to account for their nominal response times so that time does not appear as an explicit parameter in the MS prescription. The MS vector is thus conceptually analogous to the set of vital signs for describing the state of health of a human body. In that previous study, we further demonstrated that since response states are results of driver states, then there should be a correspondence between driver and response states. Such correspondence can be used to predict the subsequent response state from any known driver state with a few hours' lead time. In this paper, we investigate a few possible ways to improve the magnetospheric state descriptions and prediction efficiency by including additional driver state parameters, such as solar activity, IMF-Bx and -By, and optimizing parameter bin sizes. Fung, S. F. and X. Shao, Specification of multiple geomagnetic responses to variable solar wind and IMF input, Ann. Geophys., 26, 639-652, 2008.

How We Choose One over Another: Predicting Trial-by-Trial Preference Decision

PubMed Central

Bhushan, Vidya; Saha, Goutam; Lindsen, Job; Shimojo, Shinsuke; Bhattacharya, Joydeep

2012-01-01

Preference formation is a complex problem as it is subjective, involves emotion, is led by implicit processes, and changes depending on the context even within the same individual. Thus, scientific attempts to predict preference are challenging, yet quite important for basic understanding of human decision making mechanisms, but prediction in a group-average sense has only a limited significance. In this study, we predicted preferential decisions on a trial by trial basis based on brain responses occurring before the individuals made their decisions explicit. Participants made a binary preference decision of approachability based on faces while their electrophysiological responses were recorded. An artificial neural network based pattern-classifier was used with time-frequency resolved patterns of a functional connectivity measure as features for the classifier. We were able to predict preference decisions with a mean accuracy of 74.3±2.79% at participant-independent level and of 91.4±3.8% at participant-dependent level. Further, we revealed a causal role of the first impression on final decision and demonstrated the temporal trajectory of preference decision formation. PMID:22912859

Computational Models of Human Performance: Validation of Memory and Procedural Representation in Advanced Air/Ground Simulation

NASA Technical Reports Server (NTRS)

Corker, Kevin M.; Labacqz, J. Victor (Technical Monitor)

1997-01-01

The Man-Machine Interaction Design and Analysis System (MIDAS) under joint U.S. Army and NASA cooperative is intended to assist designers of complex human/automation systems in successfully incorporating human performance capabilities and limitations into decision and action support systems. MIDAS is a computational representation of multiple human operators, selected perceptual, cognitive, and physical functions of those operators, and the physical/functional representation of the equipment with which they operate. MIDAS has been used as an integrated predictive framework for the investigation of human/machine systems, particularly in situations with high demands on the operators. We have extended the human performance models to include representation of both human operators and intelligent aiding systems in flight management, and air traffic service. The focus of this development is to predict human performance in response to aiding system developed to identify aircraft conflict and to assist in the shared authority for resolution. The demands of this application requires representation of many intelligent agents sharing world-models, coordinating action/intention, and cooperative scheduling of goals and action in an somewhat unpredictable world of operations. In recent applications to airborne systems development, MIDAS has demonstrated an ability to predict flight crew decision-making and procedural behavior when interacting with automated flight management systems and Air Traffic Control. In this paper, we describe two enhancements to MIDAS. The first involves the addition of working memory in the form of an articulatory buffer for verbal communication protocols and a visuo-spatial buffer for communications via digital datalink. The second enhancement is a representation of multiple operators working as a team. This enhanced model was used to predict the performance of human flight crews and their level of compliance with commercial aviation communication procedures. We show how the data produced by MIDAS compares with flight crew performance data from full mission simulations. Finally, we discuss the use of these features to study communication issues connected with aircraft-based separation assurance.

Utilizing population variation, vaccination, and systems biology to study human immunology.

PubMed

Tsang, John S

2015-08-01

The move toward precision medicine has highlighted the importance of understanding biological variability within and across individuals in the human population. In particular, given the prevalent involvement of the immune system in diverse pathologies, an important question is how much and what information about the state of the immune system is required to enable accurate prediction of future health and response to medical interventions. Towards addressing this question, recent studies using vaccination as a model perturbation and systems-biology approaches are beginning to provide a glimpse of how natural population variation together with multiplexed, high-throughput measurement and computational analysis can be used to uncover predictors of immune response quality in humans. Here I discuss recent developments in this emerging field, with emphasis on baseline correlates of vaccination responses, sources of immune-state variability, as well as relevant features of study design, data generation, and computational analysis. Copyright © 2015 The Author. Published by Elsevier Ltd.. All rights reserved.

Regret and Responsibility Resolved? Evaluating Ordóñez and Connolly's (2000) Conclusions.

PubMed

Zeelenberg; van Dijk WW; Manstead

2000-01-01

T. Connolly, L. D. Ordo;aan;atez, and R. Coughlan (1997, Organizational Behavior and Human Decision Processes, 70, 73-85) argued, on the basis of 5 experiments, that regret need not be related to a sense of responsibility for the regretted outcome. We (M. Zeelenberg, W. W. van Dijk, & A. S. R. Manstead, 1998, Organizational Behavior and Human Decision Processes, 74, 254-272) showed in 2 experiments that this conclusion was premature, because it was based on an indirect measure of regret (i.e., overall happiness with the decision outcome). When regret was directly measured, the predicted effects of responsibility were found. L. D. Ordo;aan;atez and T. Connolly (2000, Organizational Behavior and Human Decision Processes, 81, 132-142) replicated our findings in 2 experiments. Based on their findings they arrived at 4 conclusions. In this rejoinder we first discuss Ordóñez and Connolly's new studies and we then discuss the validity of their 4 conclusions. Copyright 2000 Academic Press.

Using kinematic analysis of movement to predict the time occurrence of an evoked potential associated with a motor command.

PubMed

O'Reilly, Christian; Plamondon, Réjean; Landou, Mohamed K; Stemmer, Brigitte

2013-01-01

This article presents an exploratory study investigating the possibility of predicting the time occurrence of a motor event related potential (ERP) from a kinematic analysis of human movements. Although the response-locked motor potential may link the ERP components to the recorded response, to our knowledge no previous attempt has been made to predict a priori (i.e. before any contact with the electroencephalographic data) the time occurrence of an ERP component based only on the modeling of an overt response. The proposed analysis relies on the delta-lognormal modeling of velocity, as proposed by the kinematic theory of rapid human movement used in several studies of motor control. Although some methodological aspects of this technique still need to be fine-tuned, the initial results showed that the model-based kinematic analysis allowed the prediction of the time occurrence of a motor command ERP in most participants in the experiment. The average map of the motor command ERPs showed that this signal was stronger in electrodes close to the contra-lateral motor area (Fz, FCz, FC1, and FC3). These results seem to support the claims made by the kinematic theory that a motor command is emitted at time t(0), the time reference parameter of the model. This article proposes a new time marker directly associated with a cerebral event (i.e. the emission of a motor command) that can be used for the development of new data analysis methodologies and for the elaboration of new experimental protocols based on ERP. © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Influence of mesh density, cortical thickness and material properties on human rib fracture prediction.

PubMed

Li, Zuoping; Kindig, Matthew W; Subit, Damien; Kent, Richard W

2010-11-01

The purpose of this paper was to investigate the sensitivity of the structural responses and bone fractures of the ribs to mesh density, cortical thickness, and material properties so as to provide guidelines for the development of finite element (FE) thorax models used in impact biomechanics. Subject-specific FE models of the second, fourth, sixth and tenth ribs were developed to reproduce dynamic failure experiments. Sensitivity studies were then conducted to quantify the effects of variations in mesh density, cortical thickness, and material parameters on the model-predicted reaction force-displacement relationship, cortical strains, and bone fracture locations for all four ribs. Overall, it was demonstrated that rib FE models consisting of 2000-3000 trabecular hexahedral elements (weighted element length 2-3mm) and associated quadrilateral cortical shell elements with variable thickness more closely predicted the rib structural responses and bone fracture force-failure displacement relationships observed in the experiments (except the fracture locations), compared to models with constant cortical thickness. Further increases in mesh density increased computational cost but did not markedly improve model predictions. A ±30% change in the major material parameters of cortical bone lead to a -16.7 to 33.3% change in fracture displacement and -22.5 to +19.1% change in the fracture force. The results in this study suggest that human rib structural responses can be modeled in an accurate and computationally efficient way using (a) a coarse mesh of 2000-3000 solid elements, (b) cortical shells elements with variable thickness distribution and (c) a rate-dependent elastic-plastic material model. Copyright © 2010 IPEM. Published by Elsevier Ltd. All rights reserved.

Mapping Protein Interactions between Dengue Virus and Its Human and Insect Hosts

PubMed Central

Doolittle, Janet M.; Gomez, Shawn M.

2011-01-01

Background Dengue fever is an increasingly significant arthropod-borne viral disease, with at least 50 million cases per year worldwide. As with other viral pathogens, dengue virus is dependent on its host to perform the bulk of functions necessary for viral survival and replication. To be successful, dengue must manipulate host cell biological processes towards its own ends, while avoiding elimination by the immune system. Protein-protein interactions between the virus and its host are one avenue through which dengue can connect and exploit these host cellular pathways and processes. Methodology/Principal Findings We implemented a computational approach to predict interactions between Dengue virus (DENV) and both of its hosts, Homo sapiens and the insect vector Aedes aegypti. Our approach is based on structural similarity between DENV and host proteins and incorporates knowledge from the literature to further support a subset of the predictions. We predict over 4,000 interactions between DENV and humans, as well as 176 interactions between DENV and A. aegypti. Additional filtering based on shared Gene Ontology cellular component annotation reduced the number of predictions to approximately 2,000 for humans and 18 for A. aegypti. Of 19 experimentally validated interactions between DENV and humans extracted from the literature, this method was able to predict nearly half (9). Additional predictions suggest specific interactions between virus and host proteins relevant to interferon signaling, transcriptional regulation, stress, and the unfolded protein response. Conclusions/Significance Dengue virus manipulates cellular processes to its advantage through specific interactions with the host's protein interaction network. The interaction networks presented here provide a set of hypothesis for further experimental investigation into the DENV life cycle as well as potential therapeutic targets. PMID:21358811

Respiratory Syncytial Virus (RSV) Pulmonary Infection in Humanized Mice Induces Human Anti-RSV Immune Responses and Pathology

PubMed Central

Sharma, Anurag; Wu, Wenzhu; Sung, Biin; Huang, Jing; Tsao, Tiffany; Li, Xiangming; Gomi, Rika; Tsuji, Moriya

2016-01-01

ABSTRACT Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract disease, which causes high rates of morbidity and mortality in infants and the elderly. Models of human RSV pulmonary disease are needed to better understand RSV pathogenesis and to assess the efficacy of RSV vaccines. We assessed the RSV-specific human innate, humoral, and cellular immune responses in humanized mice (mice with a human immune system [HIS mice]) with functional human CD4+ T and B cells. These mice were generated by introduction of HLA class II genes, various human cytokines, and human B cell activation factor into immunodeficient NOD scid gamma (NSG) mice by the use of an adeno-associated virus vector, followed by engraftment of human hematopoietic stem cells. During the first 3 days of infection, HIS mice lost more weight and cleared RSV faster than NSG mice. Human chemokine (C-C motif) ligand 3 (CCL3) and human interleukin-1β (IL-1β) expression was detected in the RSV-infected HIS mice. The pathological features induced by RSV infection in HIS mice included peribronchiolar inflammation, neutrophil predominance in the bronchioalveolar lavage fluid, and enhanced airway mucus production. Human anti-RSV IgG and RSV-neutralizing antibodies were detected in serum and human anti-RSV mucosal IgA was detected in bronchioalveolar lavage fluid for up to 6 weeks. RSV infection induced an RSV-specific human gamma interferon response in HIS mouse splenocytes. These results indicate that human immune cells can induce features of RSV lung disease, including mucus hyperplasia, in murine lungs and that HIS mice can be used to elicit human anti-RSV humoral and cellular immunity. IMPORTANCE Infections with respiratory syncytial virus (RSV) are common and can cause severe lung disease in infants and the elderly. The lack of a suitable animal model with disease features similar to those in humans has hampered efforts to predict the efficacy of novel anti-RSV therapies and vaccines for use in humans. A murine model consisting of mice with a human immune system (HIS mice) could be useful for assessment of RSV disease and anti-RSV responses specific to humans. This study investigates an HIS mouse model to imitate human RSV disease and immune responses. We found that RSV lung infection in HIS mice results in an RSV-specific pathology that mimics RSV disease in humans and induces human anti-RSV immune responses. This model could be useful for better understanding of human RSV disease and for the development of RSV therapies. PMID:26962219

Response of dorsomedial prefrontal cortex predicts altruistic behavior

PubMed Central

Waytz, Adam; Zaki, Jamil; Mitchell, Jason P.

2012-01-01

Human beings have an unusual proclivity for altruistic behavior, and recent commentators have suggested that these prosocial tendencies arise from our unique capacity to understand the minds of others (i.e., to mentalize). The current studies test this hypothesis by examining the relation between altruistic behavior and the reflexive engagement of a neural system reliably associated with mentalizing. Results indicated that activity in the dorsomedial prefrontal cortex (dorsal MPFC)—a region consistently involved in understanding others’ mental states—predicts both monetary donations to others and time spent helping others. These findings address long-standing questions about the proximate source of human altruism by suggesting that prosocial behavior results, in part, from our broader tendency for social-cognitive thought. PMID:22649243

ADDME – Avoiding Drug Development Mistakes Early: central nervous system drug discovery perspective

PubMed Central

Tsaioun, Katya; Bottlaender, Michel; Mabondzo, Aloise

2009-01-01

The advent of early absorption, distribution, metabolism, excretion, and toxicity (ADMET) screening has increased the attrition rate of weak drug candidates early in the drug-discovery process, and decreased the proportion of compounds failing in clinical trials for ADMET reasons. This paper reviews the history of ADMET screening and its place in pharmaceutical development, and central nervous system drug discovery in particular. Assays that have been developed in response to specific needs and improvements in technology that result in higher throughput and greater accuracy of prediction of human mechanisms of absorption and toxicity are discussed. The paper concludes with the authors' forecast of new models that will better predict human efficacy and toxicity. PMID:19534730

Organs-on-chips at the frontiers of drug discovery

PubMed Central

Esch, Eric W.; Bahinski, Anthony; Huh, Dongeun

2016-01-01

Improving the effectiveness of preclinical predictions of human drug responses is critical to reducing costly failures in clinical trials. Recent advances in cell biology, microfabrication and microfluidics have enabled the development of microengineered models of the functional units of human organs — known as organs-on-chips — that could provide the basis for preclinical assays with greater predictive power. Here, we examine the new opportunities for the application of organ-on-chip technologies in a range of areas in preclinical drug discovery, such as target identification and validation, target-based screening, and phenotypic screening. We also discuss emerging drug discovery opportunities enabled by organs-on-chips, as well as important challenges in realizing the full potential of this technology. PMID:25792263

Predicting disease onset in clinically healthy people

PubMed Central

2016-01-01

Virtually all human disease is induced by oxidative stress. Oxidative stress, which is caused by toxic environmental exposure, the presence of disease, lifestyle choices, stress, chronic inflammation or combinations of these, is responsible for most disease. Oxidative stress from all sources is additive and it is the total oxidative stress from all sources that induces the onset of most disease. Oxidative stress leads to lipid peroxidation, which in turn produces Malondialdehyde. Serum malondialdehyde level is an additive parameter resulting from all sources of oxidative stress and, therefore, is a reliable indicator of total oxidative stress which can be used to predict the onset of disease in clinically asymptomatic individuals and to suggest the need for treatment that can prevent much human disease. PMID:28652846

Educational and Ecological Correlates of IQ: A Cross-National Investigation

ERIC Educational Resources Information Center

Barber, N.

2005-01-01

The new paradigm of evolutionary social science suggests that humans adjust rapidly to changing economic conditions, including cognitive changes in response to the economic significance of education. This research tested the predictions that cross-national differences in IQ scores would be positively correlated with education and negatively…

Computational Systems Toxicology: recapitulating the logistical dynamics of cellular response networks in virtual tissue models (Eurotox_2017)

EPA Science Inventory

Translating in vitro data and biological information into a predictive model for human toxicity poses a significant challenge. This is especially true for complex adaptive systems such as the embryo where cellular dynamics are precisely orchestrated in space and time. Computer ce...

Aerospace Materials and Process Technology Reinvestment Workshop Held in Dayton, Ohio on 18-19 May 1993.

DTIC Science & Technology

1993-05-19

The Laboratories Theory, Modeling and Simulation , • ATP Characterization J Education and Human Resources • MTC Facilities -- NBSR and CNRF MISSION...34 Automiated System for Composite Analysis (ASCA).Y -Basis for usefri(eadly numerical methods to describe composite laminates and predict ?heir response

Detection and Response for Rift Valley fever

USDA-ARS?s Scientific Manuscript database

Rift Valley fever is a viral disease that impacts domestic livestock and humans in Africa and the Middle East, and poses a threat to military operations in these areas. We describe a Rift Valley fever Risk Monitoring website, and its ability to predict risk of disease temporally and spatially. We al...

Conducting Family Interviews for a Course in Human Sexuality.

ERIC Educational Resources Information Center

Stinson, Kandi M.

1987-01-01

Describes a student project that requires students to administer a questionnaire on sexual attitudes to family members and age-peers. Since students predict responses before administering the questionnaires, the results can illustrate the differences between actual and perceived generation gaps and other aspects of sexual socialization and value…

Do Quercus ilex woodlands undergo abrupt non-linear functional changes in response to human disturbance along a climatic gradient?

NASA Astrophysics Data System (ADS)

Bochet, Esther; García-Fayos, Patricio; José Molina, Maria; Moreno de las Heras, Mariano; Espigares, Tíscar; Nicolau, Jose Manuel; Monleon, Vicente

2017-04-01

Theoretical models predict that drylands are particularly prone to suffer critical transitions with abrupt non-linear changes in their structure and functions as a result of the existing complex interactions between climatic fluctuations and human disturbances. However, so far, few studies provide empirical data to validate these models. We aim at determining how holm oak (Quercus ilex) woodlands undergo changes in their functions in response to human disturbance along an aridity gradient (from semi-arid to sub-humid conditions), in eastern Spain. For that purpose, we used (a) remote-sensing estimations of precipitation-use-efficiency (PUE) from enhanced vegetation index (EVI) observations performed in 231x231 m plots of the Moderate Resolution Imaging Spectroradiometer (MODIS); (b) biological and chemical soil parameter determinations (extracellular soil enzyme activity, soil respiration, nutrient cycling processes) from soil sampled in the same plots; (c) vegetation parameter determinations (ratio of functional groups) from vegetation surveys performed in the same plots. We analyzed and compared the shape of the functional change (in terms of PUE and soil and vegetation parameters) in response to human disturbance intensity for our holm oak sites along the aridity gradient. Overall, our results evidenced important differences in the shape of the functional change in response to human disturbance between climatic conditions. Semi-arid areas experienced a more accelerated non-linear decrease with an increasing disturbance intensity than sub-humid ones. The proportion of functional groups (herbaceous vs. woody cover) played a relevant role in the shape of the functional response of the holm oak sites to human disturbance.

Great ape origins of personality maturation and sex differences: a study of orangutans and chimpanzees.

PubMed

Weiss, Alexander; King, James E

2015-04-01

Human personality development evinces increased emotional stability, prosocial tendencies, and responsibility. One hypothesis offered to explain this pattern is Social-Investment Theory, which posits that culturally defined social roles, including marriage and employment, are responsible for the increased maturity. Alternatively, Five-Factor Theory emphasizes the role of biological factors, such as those governing physical development, which may predate the emergence of humans. Five-Factor Theory, unlike Social-Investment Theory, predicts that all or some of the human personality developmental trends should be present in great apes, our closest evolutionary relatives. To test this prediction and to better understand the evolutionary origins of sex differences, we examined age and sex differences in the chimpanzee and orangutan personality domains Extraversion, Dominance, Neuroticism, and Agreeableness. We also examined the Activity and Gregariousness facets of Extraversion and the orangutan Intellect domain. Extraversion and Neuroticism declined across age groups in both species, in common with humans. A significant interaction indicated that Agreeableness declined in orangutans but increased in chimpanzees, as it does in humans, though this may reflect differences in how Agreeableness was defined in each species. Significant interactions indicated that male chimpanzees, unlike male orangutans, displayed higher Neuroticism scores than females and maintained higher levels of Activity and Dominance into old age than female chimpanzees, male orangutans, and female orangutans. Personality-age correlations were comparable across orangutans and chimpanzees and were similar to those reported in human studies. Sex differences were stronger in chimpanzees than in humans or orangutans. These findings support Five-Factor Theory, suggest the role of gene-culture coevolution in shaping personality development, and suggest that sex differences evolved independently in different species. (c) 2015 APA, all rights reserved).

Optimal resource allocation for novelty detection in a human auditory memory.

PubMed

Sinkkonen, J; Kaski, S; Huotilainen, M; Ilmoniemi, R J; Näätänen, R; Kaila, K

1996-11-04

A theory of resource allocation for neuronal low-level filtering is presented, based on an analysis of optimal resource allocation in simple environments. A quantitative prediction of the theory was verified in measurements of the magnetic mismatch response (MMR), an auditory event-related magnetic response of the human brain. The amplitude of the MMR was found to be directly proportional to the information conveyed by the stimulus. To the extent that the amplitude of the MMR can be used to measure resource usage by the auditory cortex, this finding supports our theory that, at least for early auditory processing, energy resources are used in proportion to the information content of incoming stimulus flow.

Response of human populations to large-scale emergencies

NASA Astrophysics Data System (ADS)

Bagrow, James; Wang, Dashun; Barabási, Albert-László

2010-03-01

Until recently, little quantitative data regarding collective human behavior during dangerous events such as bombings and riots have been available, despite its importance for emergency management, safety and urban planning. Understanding how populations react to danger is critical for prediction, detection and intervention strategies. Using a large telecommunications dataset, we study for the first time the spatiotemporal, social and demographic response properties of people during several disasters, including a bombing, a city-wide power outage, and an earthquake. Call activity rapidly increases after an event and we find that, when faced with a truly life-threatening emergency, information rapidly propagates through a population's social network. Other events, such as sports games, do not exhibit this propagation.

Optimal estimator model for human spatial orientation

NASA Technical Reports Server (NTRS)

Borah, J.; Young, L. R.; Curry, R. E.

1979-01-01

A model is being developed to predict pilot dynamic spatial orientation in response to multisensory stimuli. Motion stimuli are first processed by dynamic models of the visual, vestibular, tactile, and proprioceptive sensors. Central nervous system function is then modeled as a steady-state Kalman filter which blends information from the various sensors to form an estimate of spatial orientation. Where necessary, this linear central estimator has been augmented with nonlinear elements to reflect more accurately some highly nonlinear human response characteristics. Computer implementation of the model has shown agreement with several important qualitative characteristics of human spatial orientation, and it is felt that with further modification and additional experimental data the model can be improved and extended. Possible means are described for extending the model to better represent the active pilot with varying skill and work load levels.

Specificities of Human CD4+ T Cell Responses to an Inactivated Flavivirus Vaccine and Infection: Correlation with Structure and Epitope Prediction

PubMed Central

Schwaiger, Julia; Aberle, Judith H.; Stiasny, Karin; Knapp, Bernhard; Schreiner, Wolfgang; Fae, Ingrid; Fischer, Gottfried; Scheinost, Ondrej; Chmelik, Vaclav

2014-01-01

ABSTRACT Tick-borne encephalitis (TBE) virus is endemic in large parts of Europe and Central and Eastern Asia and causes more than 10,000 annual cases of neurological disease in humans. It is closely related to the mosquito-borne yellow fever, dengue, Japanese encephalitis, and West Nile viruses, and vaccination with an inactivated whole-virus vaccine can effectively prevent clinical disease. Neutralizing antibodies are directed to the viral envelope protein (E) and an accepted correlate of immunity. However, data on the specificities of CD4+ T cells that recognize epitopes in the viral structural proteins and thus can provide direct help to the B cells producing E-specific antibodies are lacking. We therefore conducted a study on the CD4+ T cell response against the virion proteins in vaccinated people in comparison to TBE patients. The data obtained with overlapping peptides in interleukin-2 (IL-2) enzyme-linked immunosorbent spot (ELISpot) assays were analyzed in relation to the three-dimensional structures of the capsid (C) and E proteins as well as to epitope predictions based on major histocompatibility complex (MHC) class II peptide affinities. In the C protein, peptides corresponding to two out of four alpha helices dominated the response in both vaccinees and patients, whereas in the E protein concordance of immunodominance was restricted to peptides of a single domain (domain III). Epitope predictions were much better for C than for E and were especially erroneous for the transmembrane regions. Our data provide evidence for a strong impact of protein structural features that influence peptide processing, contributing to the discrepancies observed between experimentally determined and computer-predicted CD4+ T cell epitopes. IMPORTANCE Tick-borne encephalitis virus is endemic in large parts of Europe and Asia and causes more than 10,000 annual cases of neurological disease in humans. It is closely related to yellow fever, dengue, Japanese encephalitis, and West Nile viruses, and vaccination with an inactivated vaccine can effectively prevent disease. Both vaccination and natural infection induce the formation of antibodies to a viral surface protein that neutralize the infectivity of the virus and mediate protection. B lymphocytes synthesizing these antibodies require help from other lymphocytes (helper T cells) which recognize small peptides derived from proteins contained in the viral particle. Which of these peptides dominate immune responses to vaccination and infection, however, was unknown. In our study we demonstrate which parts of the proteins contribute most strongly to the helper T cell response, highlight specific weaknesses of currently available approaches for their prediction, and demonstrate similarities and differences between vaccination and infection. PMID:24789782

Normalizing and scaling of data to derive human response corridors from impact tests.

PubMed

Yoganandan, Narayan; Arun, Mike W J; Pintar, Frank A

2014-06-03

It is well known that variability is inherent in any biological experiment. Human cadavers (Post-Mortem Human Subjects, PMHS) are routinely used to determine responses to impact loading for crashworthiness applications including civilian (motor vehicle) and military environments. It is important to transform measured variables from PMHS tests (accelerations, forces and deflections) to a standard or reference population, termed normalization. The transformation process should account for inter-specimen variations with some underlying assumptions used during normalization. Scaling is a process by which normalized responses are converted from one standard to another (example, mid-size adult male to large-male and small-size female adults, and to pediatric populations). These responses are used to derive corridors to assess the biofidelity of anthropomorphic test devices (crash dummies) used to predict injury in impact environments and design injury mitigating devices. This survey examines the pros and cons of different approaches for obtaining normalized and scaled responses and corridors used in biomechanical studies for over four decades. Specifically, the equal-stress equal-velocity and impulse-momentum methods along with their variations are discussed in this review. Methods ranging from subjective to quasi-static loading to different approaches are discussed for deriving temporal mean and plus minus one standard deviation human corridors of time-varying fundamental responses and cross variables (e.g., force-deflection). The survey offers some insights into the potential efficacy of these approaches with examples from recent impact tests and concludes with recommendations for future studies. The importance of considering various parameters during the experimental design of human impact tests is stressed. Published by Elsevier Ltd.

Membrane Localization of Human Equilibrative Nucleoside Transporter 1 in Tumor Cells May Predict Response to Adjuvant Gemcitabine in Resected Cholangiocarcinoma Patients.

PubMed

Brandi, Giovanni; Deserti, Marzia; Vasuri, Francesco; Farioli, Andrea; Degiovanni, Alessio; Palloni, Andrea; Frega, Giorgio; Barbera, Maria A; de Lorenzo, Stefania; Garajova, Ingrid; Di Marco, Mariacristina; Pinna, Antonio D; Cescon, Matteo; Cucchetti, Alessandro; Ercolani, Giorgio; D'Errico-Grigioni, Antonietta; Pantaleo, Maria A; Biasco, Guido; Tavolari, Simona

2016-05-01

The use of gemcitabine as an adjuvant modality for cholangiocarcinoma (CC) is increasing, but limited data are available on predictive biomarkers of response. Human equilibrative nucleoside transporter 1 (hENT-1) is the major transporter involved in gemcitabine intracellular uptake. This study investigated the putative predictive role of hENT-1 localization in tumor cells of CC patients undergoing treatment with adjuvant gemcitabine. Seventy-one consecutive patients with resected CC receiving adjuvant gemcitabine at our center were retrospectively analyzed by immunohistochemistry for hENT-1 localization in tumor cells. The main outcome measure was disease-free survival (DFS). Hazard ratios (HRs) of relapse and associated 95% confidence intervals (CIs) were obtained from proportional hazards regression models stratified on quintiles of propensity score. Twenty-three (32.4%) cases were negative for hENT-1, 22 (31.0%) were positive in the cytoplasm only, and 26 (36.6%) showed concomitant cytoplasm/membrane staining. Patients with membrane hENT-1 had a longer DFS (HR 0.49, 95% CI 0.24-0.99, p = .046) than those who were negative or positive only in the cytoplasm of tumor cells. Notably, the association between DFS and membrane hENT-1 was dependent on the number of gemcitabine cycles (one to two cycles: HR 0.96, 95% CI 0.34-2.68; three to four cycles: HR 0.99, 95% CI 0.34-2.90; five to six cycles: HR 0.27, 95% CI 0.10-0.77). hENT-1 localization on tumor cell membrane may predict response to adjuvant gemcitabine in CC patients receiving more than four cycles of chemotherapy. Further prospective randomized trials on larger populations are required to confirm these preliminary results, so that optimal gemcitabine-based chemotherapy may be tailored for CC patients in the adjuvant setting. Gemcitabine is becoming an increasingly used adjuvant modality in cholangiocarcinoma (CC), but limited data are available on predictive biomarkers of response. In this study, patients receiving more than four cycles of adjuvant gemcitabine and harboring Human equilibrative nucleoside transporter 1 (hENT-1, the major transporter involved in gemcitabine intracellular uptake) on tumor cell membrane had a longer disease-free survival compared with patients negative or positive for hENT-1 only in the cytoplasm of tumor cells. Overall these results may lay the basis for further prospective randomized trials based on a larger population of patients and may prove useful for tailoring appropriate gemcitabine-based chemotherapy for CC patients in the adjuvant setting. ©AlphaMed Press.

Improved management of small pelagic fisheries through seasonal climate prediction.

PubMed

Tommasi, Désirée; Stock, Charles A; Pegion, Kathleen; Vecchi, Gabriel A; Methot, Richard D; Alexander, Michael A; Checkley, David M

2017-03-01

Populations of small pelagic fish are strongly influenced by climate. The inability of managers to anticipate environment-driven fluctuations in stock productivity or distribution can lead to overfishing and stock collapses, inflexible management regulations inducing shifts in the functional response to human predators, lost opportunities to harvest populations, bankruptcies in the fishing industry, and loss of resilience in the human food supply. Recent advances in dynamical global climate prediction systems allow for sea surface temperature (SST) anomaly predictions at a seasonal scale over many shelf ecosystems. Here we assess the utility of SST predictions at this "fishery relevant" scale to inform management, using Pacific sardine as a case study. The value of SST anomaly predictions to management was quantified under four harvest guidelines (HGs) differing in their level of integration of SST data and predictions. The HG that incorporated stock biomass forecasts informed by skillful SST predictions led to increases in stock biomass and yield, and reductions in the probability of yield and biomass falling below socioeconomic or ecologically acceptable levels. However, to mitigate the risk of collapse in the event of an erroneous forecast, it was important to combine such forecast-informed harvest controls with additional harvest restrictions at low biomass. © 2016 by the Ecological Society of America.

Prediction of air pollutant concentration based on sparse response back-propagation training feedforward neural networks.

PubMed

Ding, Weifu; Zhang, Jiangshe; Leung, Yee

2016-10-01

In this paper, we predict air pollutant concentration using a feedforward artificial neural network inspired by the mechanism of the human brain as a useful alternative to traditional statistical modeling techniques. The neural network is trained based on sparse response back-propagation in which only a small number of neurons respond to the specified stimulus simultaneously and provide a high convergence rate for the trained network, in addition to low energy consumption and greater generalization. Our method is evaluated on Hong Kong air monitoring station data and corresponding meteorological variables for which five air quality parameters were gathered at four monitoring stations in Hong Kong over 4 years (2012-2015). Our results show that our training method has more advantages in terms of the precision of the prediction, effectiveness, and generalization of traditional linear regression algorithms when compared with a feedforward artificial neural network trained using traditional back-propagation.

A Bayesian network to predict coastal vulnerability to sea level rise

USGS Publications Warehouse

Gutierrez, B.T.; Plant, N.G.; Thieler, E.R.

2011-01-01

Sea level rise during the 21st century will have a wide range of effects on coastal environments, human development, and infrastructure in coastal areas. The broad range of complex factors influencing coastal systems contributes to large uncertainties in predicting long-term sea level rise impacts. Here we explore and demonstrate the capabilities of a Bayesian network (BN) to predict long-term shoreline change associated with sea level rise and make quantitative assessments of prediction uncertainty. A BN is used to define relationships between driving forces, geologic constraints, and coastal response for the U.S. Atlantic coast that include observations of local rates of relative sea level rise, wave height, tide range, geomorphic classification, coastal slope, and shoreline change rate. The BN is used to make probabilistic predictions of shoreline retreat in response to different future sea level rise rates. Results demonstrate that the probability of shoreline retreat increases with higher rates of sea level rise. Where more specific information is included, the probability of shoreline change increases in a number of cases, indicating more confident predictions. A hindcast evaluation of the BN indicates that the network correctly predicts 71% of the cases. Evaluation of the results using Brier skill and log likelihood ratio scores indicates that the network provides shoreline change predictions that are better than the prior probability. Shoreline change outcomes indicating stability (-1 1 m/yr) was not well predicted. We find that BNs can assimilate important factors contributing to coastal change in response to sea level rise and can make quantitative, probabilistic predictions that can be applied to coastal management decisions. Copyright ?? 2011 by the American Geophysical Union.

Inter-species pathway perturbation prediction via data-driven detection of functional homology.

PubMed

Hafemeister, Christoph; Romero, Roberto; Bilal, Erhan; Meyer, Pablo; Norel, Raquel; Rhrissorrakrai, Kahn; Bonneau, Richard; Tarca, Adi L

2015-02-15

Experiments in animal models are often conducted to infer how humans will respond to stimuli by assuming that the same biological pathways will be affected in both organisms. The limitations of this assumption were tested in the IMPROVER Species Translation Challenge, where 52 stimuli were applied to both human and rat cells and perturbed pathways were identified. In the Inter-species Pathway Perturbation Prediction sub-challenge, multiple teams proposed methods to use rat transcription data from 26 stimuli to predict human gene set and pathway activity under the same perturbations. Submissions were evaluated using three performance metrics on data from the remaining 26 stimuli. We present two approaches, ranked second in this challenge, that do not rely on sequence-based orthology between rat and human genes to translate pathway perturbation state but instead identify transcriptional response orthologs across a set of training conditions. The translation from rat to human accomplished by these so-called direct methods is not dependent on the particular analysis method used to identify perturbed gene sets. In contrast, machine learning-based methods require performing a pathway analysis initially and then mapping the pathway activity between organisms. Unlike most machine learning approaches, direct methods can be used to predict the activation of a human pathway for a new (test) stimuli, even when that pathway was never activated by a training stimuli. Gene expression data are available from ArrayExpress (accession E-MTAB-2091), while software implementations are available from http://bioinformaticsprb.med.wayne.edu?p=50 and http://goo.gl/hJny3h. christoph.hafemeister@nyu.edu or atarca@med.wayne.edu. Supplementary data are available at Bioinformatics online. Published by Oxford University Press 2014. This work is written by US Government employees and is in the public domain in the US.

Pigeons acquire multiple categories in parallel via associative learning: A parallel to human word learning?

PubMed Central

Wasserman, Edward A.; Brooks, Daniel I.; McMurray, Bob

2014-01-01

Might there be parallels between category learning in animals and word learning in children? To examine this possibility, we devised a new associative learning technique for teaching pigeons to sort 128 photographs of objects into 16 human language categories. We found that pigeons learned all 16 categories in parallel, they perceived the perceptual coherence of the different object categories, and they generalized their categorization behavior to novel photographs from the training categories. More detailed analyses of the factors that predict trial-by-trial learning implicated a number of factors that may shape learning. First, we found considerable trial-by-trial dependency of pigeons’ categorization responses, consistent with several recent studies that invoke this dependency to claim that humans acquire words via symbolic or inferential mechanisms; this finding suggests that such dependencies may also arise in associative systems. Second, our trial-by-trial analyses divulged seemingly irrelevant aspects of the categorization task, like the spatial location of the report responses, which influenced learning. Third, those trial-by-trial analyses also supported the possibility that learning may be determined both by strengthening correct stimulus-response associations and by weakening incorrect stimulus-response associations. The parallel between all these findings and important aspects of human word learning suggests that associative learning mechanisms may play a much stronger part in complex human behavior than is commonly believed. PMID:25497520

Prediction modeling of physiological responses and human performance in the heat with application to space operations

NASA Technical Reports Server (NTRS)

Pandolf, Kent B.; Stroschein, Leander A.; Gonzalez, Richard R.; Sawka, Michael N.

1994-01-01

This institute has developed a comprehensive USARIEM heat strain model for predicting physiological responses and soldier performance in the heat which has been programmed for use by hand-held calculators, personal computers, and incorporated into the development of a heat strain decision aid. This model deals directly with five major inputs: the clothing worn, the physical work intensity, the state of heat acclimation, the ambient environment (air temperature, relative humidity, wind speed, and solar load), and the accepted heat casualty level. In addition to predicting rectal temperature, heart rate, and sweat loss given the above inputs, our model predicts the expected physical work/rest cycle, the maximum safe physical work time, the estimated recovery time from maximal physical work, and the drinking water requirements associated with each of these situations. This model provides heat injury risk management guidance based on thermal strain predictions from the user specified environmental conditions, soldier characteristics, clothing worn, and the physical work intensity. If heat transfer values for space operations' clothing are known, NASA can use this prediction model to help avoid undue heat strain in astronauts during space flight.

Long latency postural responses are functionally modified by cognitive set.

PubMed

Beckley, D J; Bloem, B R; Remler, M P; Roos, R A; Van Dijk, J G

1991-10-01

We examined how cognitive set influences the long latency components of normal postural responses in the legs. We disturbed the postural stability of standing human subjects with sudden toe-up ankle rotations. To influence the subjects' cognitive set, we varied the rotation amplitude either predictably (serial 4 degrees versus serial 10 degrees) or unpredictably (random mixture of 4 degrees and 10 degrees). The subjects' responses to these ankle rotations were assessed from the EMG activity of the tibialis anterior, the medial gastrocnemius, and the vastus lateralis muscles of the left leg. The results indicate that, when the rotation amplitude is predictable, only the amplitude of the long latency (LL) response in tibialis anterior and vastus lateralis varied directly with perturbation size. Furthermore, when the rotation amplitude is unpredictable, the central nervous system selects a default amplitude for the LL response in the tibialis anterior. When normal subjects are exposed to 2 perturbation amplitudes which include the potential risk of falling, the default LL response in tibialis anterior appropriately anticipates the larger amplitude perturbation rather than the smaller or an intermediate one.

Human vulnerability to stress depends on amygdala's predisposition and hippocampal plasticity

PubMed Central

Admon, Roee; Lubin, Gad; Stern, Orit; Rosenberg, Keren; Sela, Lee; Ben-Ami, Haim; Hendler, Talma

2009-01-01

Variations in people's vulnerability to stressful life events may rise from a predated neural sensitivity as well as from differential neural modifications in response to the event. Because the occurrence of a stressful life event cannot be foreseen, characterizing the temporal trajectory of its neural manifestations in humans has been a real challenge. The current prospective study examined the emotional experience and brain responses of 50 a priori healthy new recruits to the Israeli Defense Forces at 2 time points: before they entered their mandatory military service and after their subsequent exposure to stressful events while deployed in combat units. Over time, soldiers reported on increase in stress symptoms that was correlated with greater amygdala and hippocampus responsiveness to stress-related content. However, these closely situated core limbic regions exhibited different temporal trajectories with regard to the stress effect; whereas amygdala's reactivity before stress predicted the increase in stress symptoms, the hippocampal change in activation over time correlated with the increase in such symptoms. Hippocampal plasticity was also reflected by a modification over time of its functional coupling with the ventromedial prefrontal cortex, and this coupling magnitude was again predicted by predated amygdala reactivity. Together, these findings suggest that variations in human's likelihood to develop symptomatic phenomena following stressful life events may depend on a balanced interplay between their amygdala's predisposing reactivity and hippocampal posteriori intra- and interregional plasticity. Accordingly, an individually tailored therapeutic approach for trauma survivors should target these 2 neural probes while considering their unique temporal prints. PMID:19666562

The influence of visual training on predicting complex action sequences.

PubMed

Cross, Emily S; Stadler, Waltraud; Parkinson, Jim; Schütz-Bosbach, Simone; Prinz, Wolfgang

2013-02-01

Linking observed and executable actions appears to be achieved by an action observation network (AON), comprising parietal, premotor, and occipitotemporal cortical regions of the human brain. AON engagement during action observation is thought to aid in effortless, efficient prediction of ongoing movements to support action understanding. Here, we investigate how the AON responds when observing and predicting actions we cannot readily reproduce before and after visual training. During pre- and posttraining neuroimaging sessions, participants watched gymnasts and wind-up toys moving behind an occluder and pressed a button when they expected each agent to reappear. Between scanning sessions, participants visually trained to predict when a subset of stimuli would reappear. Posttraining scanning revealed activation of inferior parietal, superior temporal, and cerebellar cortices when predicting occluded actions compared to perceiving them. Greater activity emerged when predicting untrained compared to trained sequences in occipitotemporal cortices and to a lesser degree, premotor cortices. The occipitotemporal responses when predicting untrained agents showed further specialization, with greater responses within body-processing regions when predicting gymnasts' movements and in object-selective cortex when predicting toys' movements. The results suggest that (1) select portions of the AON are recruited to predict the complex movements not easily mapped onto the observer's body and (2) greater recruitment of these AON regions supports prediction of less familiar sequences. We suggest that the findings inform both the premotor model of action prediction and the predictive coding account of AON function. Copyright © 2011 Wiley Periodicals, Inc.

Human In Silico Drug Trials Demonstrate Higher Accuracy than Animal Models in Predicting Clinical Pro-Arrhythmic Cardiotoxicity.

PubMed

Passini, Elisa; Britton, Oliver J; Lu, Hua Rong; Rohrbacher, Jutta; Hermans, An N; Gallacher, David J; Greig, Robert J H; Bueno-Orovio, Alfonso; Rodriguez, Blanca

2017-01-01

Early prediction of cardiotoxicity is critical for drug development. Current animal models raise ethical and translational questions, and have limited accuracy in clinical risk prediction. Human-based computer models constitute a fast, cheap and potentially effective alternative to experimental assays, also facilitating translation to human. Key challenges include consideration of inter-cellular variability in drug responses and integration of computational and experimental methods in safety pharmacology. Our aim is to evaluate the ability of in silico drug trials in populations of human action potential (AP) models to predict clinical risk of drug-induced arrhythmias based on ion channel information, and to compare simulation results against experimental assays commonly used for drug testing. A control population of 1,213 human ventricular AP models in agreement with experimental recordings was constructed. In silico drug trials were performed for 62 reference compounds at multiple concentrations, using pore-block drug models (IC 50 /Hill coefficient). Drug-induced changes in AP biomarkers were quantified, together with occurrence of repolarization/depolarization abnormalities. Simulation results were used to predict clinical risk based on reports of Torsade de Pointes arrhythmias, and further evaluated in a subset of compounds through comparison with electrocardiograms from rabbit wedge preparations and Ca 2+ -transient recordings in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). Drug-induced changes in silico vary in magnitude depending on the specific ionic profile of each model in the population, thus allowing to identify cell sub-populations at higher risk of developing abnormal AP phenotypes. Models with low repolarization reserve (increased Ca 2+ /late Na + currents and Na + /Ca 2+ -exchanger, reduced Na + /K + -pump) are highly vulnerable to drug-induced repolarization abnormalities, while those with reduced inward current density (fast/late Na + and Ca 2+ currents) exhibit high susceptibility to depolarization abnormalities. Repolarization abnormalities in silico predict clinical risk for all compounds with 89% accuracy. Drug-induced changes in biomarkers are in overall agreement across different assays: in silico AP duration changes reflect the ones observed in rabbit QT interval and hiPS-CMs Ca 2+ -transient, and simulated upstroke velocity captures variations in rabbit QRS complex. Our results demonstrate that human in silico drug trials constitute a powerful methodology for prediction of clinical pro-arrhythmic cardiotoxicity, ready for integration in the existing drug safety assessment pipelines.

Accounting for inter-annual and seasonal variability in regionalization of hydrologic response in the Great Lakes basin

NASA Astrophysics Data System (ADS)

Kult, J. M.; Fry, L. M.; Gronewold, A. D.

2012-12-01

Methods for predicting streamflow in areas with limited or nonexistent measures of hydrologic response typically invoke the concept of regionalization, whereby knowledge pertaining to gauged catchments is transferred to ungauged catchments. In this study, we identify watershed physical characteristics acting as primary drivers of hydrologic response throughout the US portion of the Great Lakes basin. Relationships between watershed physical characteristics and hydrologic response are generated from 166 catchments spanning a variety of climate, soil, land cover, and land form regimes through regression tree analysis, leading to a grouping of watersheds exhibiting similar hydrologic response characteristics. These groupings are then used to predict response in ungauged watersheds in an uncertainty framework. Results from this method are assessed alongside one historical regionalization approach which, while simple, has served as a cornerstone of Great Lakes regional hydrologic research for several decades. Our approach expands upon previous research by considering multiple temporal characterizations of hydrologic response. Due to the substantial inter-annual and seasonal variability in hydrologic response observed over the Great Lakes basin, results from the regression tree analysis differ considerably depending on the level of temporal aggregation used to define the response. Specifically, higher levels of temporal aggregation for the response metric (for example, indices derived from long-term means of climate and streamflow observations) lead to improved watershed groupings with lower within-group variance. However, this perceived improvement in model skill occurs at the cost of understated uncertainty when applying the regression to time series simulations or as a basis for model calibration. In such cases, our results indicate that predictions based on long-term characterizations of hydrologic response can produce misleading conclusions when applied at shorter time steps. This study suggests that measures of hydrologic response quantified at these shorter time steps may provide a more robust basis for making predictions in applications of water resource management, model calibration and simulations, and human health and safety.

How glitter relates to gold: similarity-dependent reward prediction errors in the human striatum.

PubMed

Kahnt, Thorsten; Park, Soyoung Q; Burke, Christopher J; Tobler, Philippe N

2012-11-14

Optimal choices benefit from previous learning. However, it is not clear how previously learned stimuli influence behavior to novel but similar stimuli. One possibility is to generalize based on the similarity between learned and current stimuli. Here, we use neuroscientific methods and a novel computational model to inform the question of how stimulus generalization is implemented in the human brain. Behavioral responses during an intradimensional discrimination task showed similarity-dependent generalization. Moreover, a peak shift occurred, i.e., the peak of the behavioral generalization gradient was displaced from the rewarded conditioned stimulus in the direction away from the unrewarded conditioned stimulus. To account for the behavioral responses, we designed a similarity-based reinforcement learning model wherein prediction errors generalize across similar stimuli and update their value. We show that this model predicts a similarity-dependent neural generalization gradient in the striatum as well as changes in responding during extinction. Moreover, across subjects, the width of generalization was negatively correlated with functional connectivity between the striatum and the hippocampus. This result suggests that hippocampus-striatal connections contribute to stimulus-specific value updating by controlling the width of generalization. In summary, our results shed light onto the neurobiology of a fundamental, similarity-dependent learning principle that allows learning the value of stimuli that have never been encountered.

Natural innate cytokine response to immunomodulators and adjuvants in human precision-cut lung slices.

PubMed

Switalla, S; Lauenstein, L; Prenzler, F; Knothe, S; Förster, C; Fieguth, H-G; Pfennig, O; Schaumann, F; Martin, C; Guzman, C A; Ebensen, T; Müller, M; Hohlfeld, J M; Krug, N; Braun, A; Sewald, K

2010-08-01

Prediction of lung innate immune responses is critical for developing new drugs. Well-established immune modulators like lipopolysaccharides (LPS) can elicit a wide range of immunological effects. They are involved in acute lung diseases such as infections or chronic airway diseases such as COPD. LPS has a strong adjuvant activity, but its pyrogenicity has precluded therapeutic use. The bacterial lipopeptide MALP-2 and its synthetic derivative BPPcysMPEG are better tolerated. We have compared the effects of LPS and BPPcysMPEG on the innate immune response in human precision-cut lung slices. Cytokine responses were quantified by ELISA, Luminex, and Meso Scale Discovery technology. The initial response to LPS and BPPcysMPEG was marked by coordinated and significant release of the mediators IL-1β, MIP-1β, and IL-10 in viable PCLS. Stimulation of lung tissue with BPPcysMPEG, however, induced a differential response. While LPS upregulated IFN-γ, BPPcysMPEG did not. This traces back to their signaling pathways via TLR4 and TLR2/6. The calculated exposure doses selected for LPS covered ranges occurring in clinical studies with human beings. Correlation of obtained data with data from human BAL fluid after segmental provocation with endotoxin showed highly comparable effects, resulting in a coefficient of correlation >0.9. Furthermore, we were interested in modulating the response to LPS. Using dexamethasone as an immunosuppressive drug for anti-inflammatory therapy, we found a significant reduction of GM-CSF, IL-1β, and IFN-γ. The PCLS-model offers the unique opportunity to test the efficacy and toxicity of biological agents intended for use by inhalation in a complex setting in humans. Copyright © 2010 Elsevier Inc. All rights reserved.

Natural innate cytokine response to immunomodulators and adjuvants in human precision-cut lung slices

DOE Office of Scientific and Technical Information (OSTI.GOV)

Switalla, S.; Lauenstein, L.; Prenzler, F.

Prediction of lung innate immune responses is critical for developing new drugs. Well-established immune modulators like lipopolysaccharides (LPS) can elicit a wide range of immunological effects. They are involved in acute lung diseases such as infections or chronic airway diseases such as COPD. LPS has a strong adjuvant activity, but its pyrogenicity has precluded therapeutic use. The bacterial lipopeptide MALP-2 and its synthetic derivative BPPcysMPEG are better tolerated. We have compared the effects of LPS and BPPcysMPEG on the innate immune response in human precision-cut lung slices. Cytokine responses were quantified by ELISA, Luminex, and Meso Scale Discovery technology. Themore » initial response to LPS and BPPcysMPEG was marked by coordinated and significant release of the mediators IL-1{beta}, MIP-1{beta}, and IL-10 in viable PCLS. Stimulation of lung tissue with BPPcysMPEG, however, induced a differential response. While LPS upregulated IFN-{gamma}, BPPcysMPEG did not. This traces back to their signaling pathways via TLR4 and TLR2/6. The calculated exposure doses selected for LPS covered ranges occurring in clinical studies with human beings. Correlation of obtained data with data from human BAL fluid after segmental provocation with endotoxin showed highly comparable effects, resulting in a coefficient of correlation > 0.9. Furthermore, we were interested in modulating the response to LPS. Using dexamethasone as an immunosuppressive drug for anti-inflammatory therapy, we found a significant reduction of GM-CSF, IL-1{beta}, and IFN-{gamma}. The PCLS-model offers the unique opportunity to test the efficacy and toxicity of biological agents intended for use by inhalation in a complex setting in humans.« less

Diffuse optical measurements of head and neck tumor hemodynamics for early prediction of chemoradiation therapy outcomes

NASA Astrophysics Data System (ADS)

Dong, Lixin; Kudrimoti, Mahesh; Irwin, Daniel; Chen, Li; Kumar, Sameera; Shang, Yu; Huang, Chong; Johnson, Ellis L.; Stevens, Scott D.; Shelton, Brent J.; Yu, Guoqiang

2016-08-01

This study used a hybrid near-infrared diffuse optical instrument to monitor tumor hemodynamic responses to chemoradiation therapy for early prediction of treatment outcomes in patients with head and neck cancer. Forty-seven patients were measured once per week to evaluate the hemodynamic status of clinically involved cervical lymph nodes as surrogates for the primary tumor response. Patients were classified into two groups: complete response (CR) (n=29) and incomplete response (IR) (n=18). Tumor hemodynamic responses were found to be associated with clinical outcomes (CR/IR), wherein the associations differed depending on human papillomavirus (HPV-16) status. In HPV-16 positive patients, significantly lower levels in tumor oxygenated hemoglobin concentration ([HbO2]) at weeks 1 to 3, total hemoglobin concentration at week 3, and blood oxygen saturation (StO2) at week 3 were found in the IR group. In HPV-16 negative patients, significantly higher levels in tumor blood flow index and reduced scattering coefficient (μs‧) at week 3 were observed in the IR group. These hemodynamic parameters exhibited significantly high accuracy for early prediction of clinical outcomes, within the first three weeks of therapy, with the areas under the receiver operating characteristic curves (AUCs) ranging from 0.83 to 0.96.

Sleep hygiene behaviours: an application of the theory of planned behaviour and the investigation of perceived autonomy support, past behaviour and response inhibition.

PubMed

Kor, Kenny; Mullan, Barbara Ann

2011-09-01

This study investigated the sleep hygiene behaviour of university students within the framework of the Theory of Planned Behaviour (TPB [Ajzen, I. (1991). The theory of planned behavior. Organizational Behavior and Human Decision Processes, 50, 179-211.]), and examined the predictive validity of additional variables including perceived autonomy support, past behaviour and response inhibition. A total of 257 undergraduate students from an Australian university were administered two online questionnaires at two time points. At time 1, participants completed the TPB questionnaire and the Go/NoGo task as a measure of response inhibition. A week later at time 2, participants completed a questionnaire measuring the performance of sleep hygiene behaviours. Multiple and hierarchical regression analyses showed that the TPB model significantly predicted intention and behaviour. Although intention and perceived behavioural control were statistically significant in predicting behaviour, past behaviour and response inhibition accounted for more variance when added to the TPB model. Subjective norm was found to be the strongest predictor of intention implying the importance of normative influences in sleep hygiene behaviours. Response inhibition was the strongest predictor of behaviour, reinforcing the argument that the performance of health protective behaviours requires self-regulatory ability. Therefore, interventions should be targeted at enhancing self-regulatory capacity.

Diffuse optical measurements of head and neck tumor hemodynamics for early prediction of chemoradiation therapy outcomes

PubMed Central

Dong, Lixin; Kudrimoti, Mahesh; Irwin, Daniel; Chen, Li; Kumar, Sameera; Shang, Yu; Huang, Chong; Johnson, Ellis L.; Stevens, Scott D.; Shelton, Brent J.; Yu, Guoqiang

2016-01-01

Abstract. This study used a hybrid near-infrared diffuse optical instrument to monitor tumor hemodynamic responses to chemoradiation therapy for early prediction of treatment outcomes in patients with head and neck cancer. Forty-seven patients were measured once per week to evaluate the hemodynamic status of clinically involved cervical lymph nodes as surrogates for the primary tumor response. Patients were classified into two groups: complete response (CR) (n=29) and incomplete response (IR) (n=18). Tumor hemodynamic responses were found to be associated with clinical outcomes (CR/IR), wherein the associations differed depending on human papillomavirus (HPV-16) status. In HPV-16 positive patients, significantly lower levels in tumor oxygenated hemoglobin concentration ([HbO2]) at weeks 1 to 3, total hemoglobin concentration at week 3, and blood oxygen saturation (StO2) at week 3 were found in the IR group. In HPV-16 negative patients, significantly higher levels in tumor blood flow index and reduced scattering coefficient (μs′) at week 3 were observed in the IR group. These hemodynamic parameters exhibited significantly high accuracy for early prediction of clinical outcomes, within the first three weeks of therapy, with the areas under the receiver operating characteristic curves (AUCs) ranging from 0.83 to 0.96. PMID:27564315

Using APEX to Model Anticipated Human Error: Analysis of a GPS Navigational Aid

NASA Technical Reports Server (NTRS)

VanSelst, Mark; Freed, Michael; Shefto, Michael (Technical Monitor)

1997-01-01

The interface development process can be dramatically improved by predicting design facilitated human error at an early stage in the design process. The approach we advocate is to SIMULATE the behavior of a human agent carrying out tasks with a well-specified user interface, ANALYZE the simulation for instances of human error, and then REFINE the interface or protocol to minimize predicted error. This approach, incorporated into the APEX modeling architecture, differs from past approaches to human simulation in Its emphasis on error rather than e.g. learning rate or speed of response. The APEX model consists of two major components: (1) a powerful action selection component capable of simulating behavior in complex, multiple-task environments; and (2) a resource architecture which constrains cognitive, perceptual, and motor capabilities to within empirically demonstrated limits. The model mimics human errors arising from interactions between limited human resources and elements of the computer interface whose design falls to anticipate those limits. We analyze the design of a hand-held Global Positioning System (GPS) device used for radical and navigational decisions in small yacht recalls. The analysis demonstrates how human system modeling can be an effective design aid, helping to accelerate the process of refining a product (or procedure).

Cortical Brain Activity Reflecting Attentional Biasing Toward Reward-Predicting Cues Covaries with Economic Decision-Making Performance.

PubMed

San Martín, René; Appelbaum, Lawrence G; Huettel, Scott A; Woldorff, Marty G

2016-01-01

Adaptive choice behavior depends critically on identifying and learning from outcome-predicting cues. We hypothesized that attention may be preferentially directed toward certain outcome-predicting cues. We studied this possibility by analyzing event-related potential (ERP) responses in humans during a probabilistic decision-making task. Participants viewed pairs of outcome-predicting visual cues and then chose to wager either a small (i.e., loss-minimizing) or large (i.e., gain-maximizing) amount of money. The cues were bilaterally presented, which allowed us to extract the relative neural responses to each cue by using a contralateral-versus-ipsilateral ERP contrast. We found an early lateralized ERP response, whose features matched the attention-shift-related N2pc component and whose amplitude scaled with the learned reward-predicting value of the cues as predicted by an attention-for-reward model. Consistently, we found a double dissociation involving the N2pc. Across participants, gain-maximization positively correlated with the N2pc amplitude to the most reliable gain-predicting cue, suggesting an attentional bias toward such cues. Conversely, loss-minimization was negatively correlated with the N2pc amplitude to the most reliable loss-predicting cue, suggesting an attentional avoidance toward such stimuli. These results indicate that learned stimulus-reward associations can influence rapid attention allocation, and that differences in this process are associated with individual differences in economic decision-making performance. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Modeling human target acquisition in ground-to-air weapon systems

NASA Technical Reports Server (NTRS)

Phatak, A. V.; Mohr, R. L.; Vikmanis, M.; Wei, K. C.

1982-01-01

The problems associated with formulating and validating mathematical models for describing and predicting human target acquisition response are considered. In particular, the extension of the human observer model to include the acquisition phase as well as the tracking segment is presented. Relationship of the Observer model structure to the more complex Standard Optimal Control model formulation and to the simpler Transfer Function/Noise representation is discussed. Problems pertinent to structural identifiability and the form of the parameterization are elucidated. A systematic approach toward the identification of the observer acquisition model parameters from ensemble tracking error data is presented.

A predictive in vitro model of the impact of drugs with anticholinergic properties on human neuronal and astrocytic systems.

PubMed

Woehrling, Elizabeth K; Parri, H Rheinallt; Tse, Erin H Y; Hill, Eric J; Maidment, Ian D; Fox, G Christopher; Coleman, Michael D

2015-01-01

The link between off-target anticholinergic effects of medications and acute cognitive impairment in older adults requires urgent investigation. We aimed to determine whether a relevant in vitro model may aid the identification of anticholinergic responses to drugs and the prediction of anticholinergic risk during polypharmacy. In this preliminary study we employed a co-culture of human-derived neurons and astrocytes (NT2.N/A) derived from the NT2 cell line. NT2.N/A cells possess much of the functionality of mature neurons and astrocytes, key cholinergic phenotypic markers and muscarinic acetylcholine receptors (mAChRs). The cholinergic response of NT2 astrocytes to the mAChR agonist oxotremorine was examined using the fluorescent dye fluo-4 to quantitate increases in intracellular calcium [Ca2+]i. Inhibition of this response by drugs classified as severe (dicycloverine, amitriptyline), moderate (cyclobenzaprine) and possible (cimetidine) on the Anticholinergic Cognitive Burden (ACB) scale, was examined after exposure to individual and pairs of compounds. Individually, dicycloverine had the most significant effect regarding inhibition of the astrocytic cholinergic response to oxotremorine, followed by amitriptyline then cyclobenzaprine and cimetidine, in agreement with the ACB scale. In combination, dicycloverine with cyclobenzaprine had the most significant effect, followed by dicycloverine with amitriptyline. The order of potency of the drugs in combination frequently disagreed with predicted ACB scores derived from summation of the individual drug scores, suggesting current scales may underestimate the effect of polypharmacy. Overall, this NT2.N/A model may be appropriate for further investigation of adverse anticholinergic effects of multiple medications, in order to inform clinical choices of suitable drug use in the elderly.

A Predictive In Vitro Model of the Impact of Drugs with Anticholinergic Properties on Human Neuronal and Astrocytic Systems

PubMed Central

Woehrling, Elizabeth K.; Parri, H. Rheinallt; Tse, Erin H. Y.; Hill, Eric J.; Maidment, Ian D.; Fox, G. Christopher; Coleman, Michael D.

2015-01-01

The link between off-target anticholinergic effects of medications and acute cognitive impairment in older adults requires urgent investigation. We aimed to determine whether a relevant in vitro model may aid the identification of anticholinergic responses to drugs and the prediction of anticholinergic risk during polypharmacy. In this preliminary study we employed a co-culture of human-derived neurons and astrocytes (NT2.N/A) derived from the NT2 cell line. NT2.N/A cells possess much of the functionality of mature neurons and astrocytes, key cholinergic phenotypic markers and muscarinic acetylcholine receptors (mAChRs). The cholinergic response of NT2 astrocytes to the mAChR agonist oxotremorine was examined using the fluorescent dye fluo-4 to quantitate increases in intracellular calcium [Ca2+]i. Inhibition of this response by drugs classified as severe (dicycloverine, amitriptyline), moderate (cyclobenzaprine) and possible (cimetidine) on the Anticholinergic Cognitive Burden (ACB) scale, was examined after exposure to individual and pairs of compounds. Individually, dicycloverine had the most significant effect regarding inhibition of the astrocytic cholinergic response to oxotremorine, followed by amitriptyline then cyclobenzaprine and cimetidine, in agreement with the ACB scale. In combination, dicycloverine with cyclobenzaprine had the most significant effect, followed by dicycloverine with amitriptyline. The order of potency of the drugs in combination frequently disagreed with predicted ACB scores derived from summation of the individual drug scores, suggesting current scales may underestimate the effect of polypharmacy. Overall, this NT2.N/A model may be appropriate for further investigation of adverse anticholinergic effects of multiple medications, in order to inform clinical choices of suitable drug use in the elderly. PMID:25738989

Modeling ultrasound propagation through material of increasing geometrical complexity.

PubMed

Odabaee, Maryam; Odabaee, Mostafa; Pelekanos, Matthew; Leinenga, Gerhard; Götz, Jürgen

2018-06-01

Ultrasound is increasingly being recognized as a neuromodulatory and therapeutic tool, inducing a broad range of bio-effects in the tissue of experimental animals and humans. To achieve these effects in a predictable manner in the human brain, the thick cancellous skull presents a problem, causing attenuation. In order to overcome this challenge, as a first step, the acoustic properties of a set of simple bone-modeling resin samples that displayed an increasing geometrical complexity (increasing step sizes) were analyzed. Using two Non-Destructive Testing (NDT) transducers, we found that Wiener deconvolution predicted the Ultrasound Acoustic Response (UAR) and attenuation caused by the samples. However, whereas the UAR of samples with step sizes larger than the wavelength could be accurately estimated, the prediction was not accurate when the sample had a smaller step size. Furthermore, a Finite Element Analysis (FEA) performed in ANSYS determined that the scattering and refraction of sound waves was significantly higher in complex samples with smaller step sizes compared to simple samples with a larger step size. Together, this reveals an interaction of frequency and geometrical complexity in predicting the UAR and attenuation. These findings could in future be applied to poro-visco-elastic materials that better model the human skull. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Strategies for Controlling Non-Transmissible Infection Outbreaks Using a Large Human Movement Data Set

PubMed Central

Hancock, Penelope A.; Rehman, Yasmin; Hall, Ian M.; Edeghere, Obaghe; Danon, Leon; House, Thomas A.; Keeling, Matthew J.

2014-01-01

Prediction and control of the spread of infectious disease in human populations benefits greatly from our growing capacity to quantify human movement behavior. Here we develop a mathematical model for non-transmissible infections contracted from a localized environmental source, informed by a detailed description of movement patterns of the population of Great Britain. The model is applied to outbreaks of Legionnaires' disease, a potentially life-threatening form of pneumonia caused by the bacteria Legionella pneumophilia. We use case-report data from three recent outbreaks that have occurred in Great Britain where the source has already been identified by public health agencies. We first demonstrate that the amount of individual-level heterogeneity incorporated in the movement data greatly influences our ability to predict the source location. The most accurate predictions were obtained using reported travel histories to describe movements of infected individuals, but using detailed simulation models to estimate movement patterns offers an effective fast alternative. Secondly, once the source is identified, we show that our model can be used to accurately determine the population likely to have been exposed to the pathogen, and hence predict the residential locations of infected individuals. The results give rise to an effective control strategy that can be implemented rapidly in response to an outbreak. PMID:25211122

Screening and evaluation of anticancer agents.

PubMed

Zee-Cheng, R K; Cheng, C C

1988-02-01

The screening and evaluation procedures for the development of anticancer agents indicated that the entire process is a rather difficult task. This is particularly true in choosing screening models and criteria for activity. If the criteria were set too low, then some clinically false-positive results may be faced; and if the criteria were set too high, some agents could be missed which might be effective against certain types of human cancer. Presently, active compounds are selected by prescreening and screening against transplanted mouse tumors and human tumor xenografts as well as by the in vitro systems. Xenografts of human tumor in athymic nude animals represent metabolic characteristics of human malignant disease which appear to be of value in the preclinical screening. Human tumor cloning assays have gained increased attention as a promising in vitro test system for the screening as well as for the prediction of patient responses. Application of chemosensitivity tests in the prediction of the responses of individuals to chemotherapy, especially in the identification of drug resistant tumors are, in general, quite reliable. Human tumor xenografts, human tumor cloning assays and chemosensitivity tests may be regarded as the major impetus in screening during the past decade. After promising agents are selected from the screening procedures, before the filing of an investigational new drug application, the preclinical toxicology and pharmacology should be completed. Information on the nature of toxicity, dose-response effects, and dose schedule are necessary for predicting the effects of the drug in man. The new drugs then go through three phases of clinical trials to assure safety, effectiveness, and reliability of the drugs. During the past fifteen years eight-three antineoplastic drugs were evaluated clinically under the NCI sponsorship and twenty-four are active in at least one disease. Among these active drugs, eleven possess novel clinical structure, the remaining thirteen are analogues of known active compounds already in clinical trials. After an investigational anticancer drug is approved by the U.S. Food and Drug Administration it becomes a commercial product on the market and the benefits can be shared by the general public. The time required for evaluation and development from the first discovery of activity to final FDA approval for fifty-two therapeutic drugs are tabled. The average interval is 8.8 years, but in the 1950s the average was only 2.8 years, in the 1960s, 6.5 years; in the 1970s, 13.9 years; and in the 1980s, 16.0 years. This reflects the increasing stricter requirements for an antineoplastic drug to be officially recognize

Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses

PubMed Central

Rusk, Anthony W.; Tung, David; Miller, Maria; Roix, Jeffrey; Khanna, Kristen V.; Murthy, Ravi; Benjamin, Robert S.; Helgason, Thorunn; Szvalb, Ariel D.; Bird, Justin E.; Roy-Chowdhuri, Sinchita; Zhang, Halle H.; Qiao, Yuan; Karim, Baktiar; McDaniel, Jennifer; Elpiner, Amanda; Sahora, Alexandra; Lachowicz, Joshua; Phillips, Brenda; Turner, Avenelle; Klein, Mary K.; Post, Gerald; Diaz, Luis A.; Riggins, Gregory J.; Papadopoulos, Nickolas; Kinzler, Kenneth W.; Vogelstein, Bert; Bettegowda, Chetan; Huso, David L.; Varterasian, Mary

2015-01-01

Species of Clostridium bacteria are notable for their ability to lyse tumor cells growing in hypoxic environments. We show that an attenuated strain of Clostridium novyi (C. novyi-NT) induces a microscopically precise, tumor-localized response in a rat orthotopic brain tumor model after intratumoral injection. It is well known, however, that experimental models often do not reliably predict the responses of human patients to therapeutic agents. We therefore used naturally occurring canine tumors as a translational bridge to human trials. Canine tumors are more like those of humans because they occur in animals with heterogeneous genetic backgrounds, are of host origin, and are due to spontaneous rather than engineered mutations. We found that intratumoral injection of C. novyi-NT spores was well tolerated in companion dogs bearing spontaneous solid tumors, with the most common toxicities being the expected symptoms associated with bacterial infections. Objective responses were observed in 6 of 16 dogs (37.5%), with three complete and three partial responses. On the basis of these encouraging results, we treated a human patient who had an advanced leiomyosarcoma with an intratumoral injection of C. novyi-NT spores. This treatment reduced the tumor within and surrounding the bone. Together, these results show that C. novyi-NT can precisely eradicate neoplastic tissues and suggest that further clinical trials of this agent in selected patients are warranted. PMID:25122639

Concentration Addition, Independent Action and Generalized Concentration Addition Models for Mixture Effect Prediction of Sex Hormone Synthesis In Vitro

PubMed Central

Hadrup, Niels; Taxvig, Camilla; Pedersen, Mikael; Nellemann, Christine; Hass, Ulla; Vinggaard, Anne Marie

2013-01-01

Humans are concomitantly exposed to numerous chemicals. An infinite number of combinations and doses thereof can be imagined. For toxicological risk assessment the mathematical prediction of mixture effects, using knowledge on single chemicals, is therefore desirable. We investigated pros and cons of the concentration addition (CA), independent action (IA) and generalized concentration addition (GCA) models. First we measured effects of single chemicals and mixtures thereof on steroid synthesis in H295R cells. Then single chemical data were applied to the models; predictions of mixture effects were calculated and compared to the experimental mixture data. Mixture 1 contained environmental chemicals adjusted in ratio according to human exposure levels. Mixture 2 was a potency adjusted mixture containing five pesticides. Prediction of testosterone effects coincided with the experimental Mixture 1 data. In contrast, antagonism was observed for effects of Mixture 2 on this hormone. The mixtures contained chemicals exerting only limited maximal effects. This hampered prediction by the CA and IA models, whereas the GCA model could be used to predict a full dose response curve. Regarding effects on progesterone and estradiol, some chemicals were having stimulatory effects whereas others had inhibitory effects. The three models were not applicable in this situation and no predictions could be performed. Finally, the expected contributions of single chemicals to the mixture effects were calculated. Prochloraz was the predominant but not sole driver of the mixtures, suggesting that one chemical alone was not responsible for the mixture effects. In conclusion, the GCA model seemed to be superior to the CA and IA models for the prediction of testosterone effects. A situation with chemicals exerting opposing effects, for which the models could not be applied, was identified. In addition, the data indicate that in non-potency adjusted mixtures the effects cannot always be accounted for by single chemicals. PMID:23990906

Modeling startle eyeblink electromyogram to assess fear learning.

PubMed

Khemka, Saurabh; Tzovara, Athina; Gerster, Samuel; Quednow, Boris B; Bach, Dominik R

2017-02-01

Pavlovian fear conditioning is widely used as a laboratory model of associative learning in human and nonhuman species. In this model, an organism is trained to predict an aversive unconditioned stimulus from initially neutral events (conditioned stimuli, CS). In humans, fear memory is typically measured via conditioned autonomic responses or fear-potentiated startle. For the latter, various analysis approaches have been developed, but a systematic comparison of competing methodologies is lacking. Here, we investigate the suitability of a model-based approach to startle eyeblink analysis for assessment of fear memory, and compare this to extant analysis strategies. First, we build a psychophysiological model (PsPM) on a generic startle response. Then, we optimize and validate this PsPM on three independent fear-conditioning data sets. We demonstrate that our model can robustly distinguish aversive (CS+) from nonaversive stimuli (CS-, i.e., has high predictive validity). Importantly, our model-based approach captures fear-potentiated startle during fear retention as well as fear acquisition. Our results establish a PsPM-based approach to assessment of fear-potentiated startle, and qualify previous peak-scoring methods. Our proposed model represents a generic startle response and can potentially be used beyond fear conditioning, for example, to quantify affective startle modulation or prepulse inhibition of the acoustic startle response. © 2016 The Authors. Psychophysiology published by Wiley Periodicals, Inc. on behalf of Society for Psychophysiological Research.

Surprise responses in the human brain demonstrate statistical learning under high concurrent cognitive demand

NASA Astrophysics Data System (ADS)

Garrido, Marta Isabel; Teng, Chee Leong James; Taylor, Jeremy Alexander; Rowe, Elise Genevieve; Mattingley, Jason Brett

2016-06-01

The ability to learn about regularities in the environment and to make predictions about future events is fundamental for adaptive behaviour. We have previously shown that people can implicitly encode statistical regularities and detect violations therein, as reflected in neuronal responses to unpredictable events that carry a unique prediction error signature. In the real world, however, learning about regularities will often occur in the context of competing cognitive demands. Here we asked whether learning of statistical regularities is modulated by concurrent cognitive load. We compared electroencephalographic metrics associated with responses to pure-tone sounds with frequencies sampled from narrow or wide Gaussian distributions. We showed that outliers evoked a larger response than those in the centre of the stimulus distribution (i.e., an effect of surprise) and that this difference was greater for physically identical outliers in the narrow than in the broad distribution. These results demonstrate an early neurophysiological marker of the brain's ability to implicitly encode complex statistical structure in the environment. Moreover, we manipulated concurrent cognitive load by having participants perform a visual working memory task while listening to these streams of sounds. We again observed greater prediction error responses in the narrower distribution under both low and high cognitive load. Furthermore, there was no reliable reduction in prediction error magnitude under high-relative to low-cognitive load. Our findings suggest that statistical learning is not a capacity limited process, and that it proceeds automatically even when cognitive resources are taxed by concurrent demands.

Intermittent control: a computational theory of human control.

PubMed

Gawthrop, Peter; Loram, Ian; Lakie, Martin; Gollee, Henrik

2011-02-01

The paradigm of continuous control using internal models has advanced understanding of human motor control. However, this paradigm ignores some aspects of human control, including intermittent feedback, serial ballistic control, triggered responses and refractory periods. It is shown that event-driven intermittent control provides a framework to explain the behaviour of the human operator under a wider range of conditions than continuous control. Continuous control is included as a special case, but sampling, system matched hold, an intermittent predictor and an event trigger allow serial open-loop trajectories using intermittent feedback. The implementation here may be described as "continuous observation, intermittent action". Beyond explaining unimodal regulation distributions in common with continuous control, these features naturally explain refractoriness and bimodal stabilisation distributions observed in double stimulus tracking experiments and quiet standing, respectively. Moreover, given that human control systems contain significant time delays, a biological-cybernetic rationale favours intermittent over continuous control: intermittent predictive control is computationally less demanding than continuous predictive control. A standard continuous-time predictive control model of the human operator is used as the underlying design method for an event-driven intermittent controller. It is shown that when event thresholds are small and sampling is regular, the intermittent controller can masquerade as the underlying continuous-time controller and thus, under these conditions, the continuous-time and intermittent controller cannot be distinguished. This explains why the intermittent control hypothesis is consistent with the continuous control hypothesis for certain experimental conditions.

Identifying protein phosphorylation sites with kinase substrate specificity on human viruses.

PubMed

Bretaña, Neil Arvin; Lu, Cheng-Tsung; Chiang, Chiu-Yun; Su, Min-Gang; Huang, Kai-Yao; Lee, Tzong-Yi; Weng, Shun-Long

2012-01-01

Viruses infect humans and progress inside the body leading to various diseases and complications. The phosphorylation of viral proteins catalyzed by host kinases plays crucial regulatory roles in enhancing replication and inhibition of normal host-cell functions. Due to its biological importance, there is a desire to identify the protein phosphorylation sites on human viruses. However, the use of mass spectrometry-based experiments is proven to be expensive and labor-intensive. Furthermore, previous studies which have identified phosphorylation sites in human viruses do not include the investigation of the responsible kinases. Thus, we are motivated to propose a new method to identify protein phosphorylation sites with its kinase substrate specificity on human viruses. The experimentally verified phosphorylation data were extracted from virPTM--a database containing 301 experimentally verified phosphorylation data on 104 human kinase-phosphorylated virus proteins. In an attempt to investigate kinase substrate specificities in viral protein phosphorylation sites, maximal dependence decomposition (MDD) is employed to cluster a large set of phosphorylation data into subgroups containing significantly conserved motifs. The experimental human phosphorylation sites are collected from Phospho.ELM, grouped according to its kinase annotation, and compared with the virus MDD clusters. This investigation identifies human kinases such as CK2, PKB, CDK, and MAPK as potential kinases for catalyzing virus protein substrates as confirmed by published literature. Profile hidden Markov model is then applied to learn a predictive model for each subgroup. A five-fold cross validation evaluation on the MDD-clustered HMMs yields an average accuracy of 84.93% for Serine, and 78.05% for Threonine. Furthermore, an independent testing data collected from UniProtKB and Phospho.ELM is used to make a comparison of predictive performance on three popular kinase-specific phosphorylation site prediction tools. In the independent testing, the high sensitivity and specificity of the proposed method demonstrate the predictive effectiveness of the identified substrate motifs and the importance of investigating potential kinases for viral protein phosphorylation sites.

Improving the forecast for biodiversity under climate change.

PubMed

Urban, M C; Bocedi, G; Hendry, A P; Mihoub, J-B; Pe'er, G; Singer, A; Bridle, J R; Crozier, L G; De Meester, L; Godsoe, W; Gonzalez, A; Hellmann, J J; Holt, R D; Huth, A; Johst, K; Krug, C B; Leadley, P W; Palmer, S C F; Pantel, J H; Schmitz, A; Zollner, P A; Travis, J M J

2016-09-09

New biological models are incorporating the realistic processes underlying biological responses to climate change and other human-caused disturbances. However, these more realistic models require detailed information, which is lacking for most species on Earth. Current monitoring efforts mainly document changes in biodiversity, rather than collecting the mechanistic data needed to predict future changes. We describe and prioritize the biological information needed to inform more realistic projections of species' responses to climate change. We also highlight how trait-based approaches and adaptive modeling can leverage sparse data to make broader predictions. We outline a global effort to collect the data necessary to better understand, anticipate, and reduce the damaging effects of climate change on biodiversity. Copyright © 2016, American Association for the Advancement of Science.

Systemic effects of ionizing radiation at the proteome and metabolome levels in the blood of cancer patients treated with radiotherapy: the influence of inflammation and radiation toxicity.

PubMed

Jelonek, Karol; Pietrowska, Monika; Widlak, Piotr

2017-07-01

Blood is the most common replacement tissue used to study systemic responses of organisms to different types of pathological conditions and environmental insults. Local irradiation during cancer radiotherapy induces whole body responses that can be observed at the blood proteome and metabolome levels. Hence, comparative blood proteomics and metabolomics are emerging approaches used in the discovery of radiation biomarkers. These techniques enable the simultaneous measurement of hundreds of molecules and the identification of sets of components that can discriminate different physiological states of the human body. Radiation-induced changes are affected by the dose and volume of irradiated tissues; hence, the molecular composition of blood is a hypothetical source of biomarkers for dose assessment and the prediction and monitoring of systemic responses to radiation. This review aims to provide a comprehensive overview on the available evidence regarding molecular responses to ionizing radiation detected at the level of the human blood proteome and metabolome. It focuses on patients exposed to radiation during cancer radiotherapy and emphasizes effects related to radiation-induced toxicity and inflammation. Systemic responses to radiation detected at the blood proteome and metabolome levels are primarily related to the intensity of radiation-induced toxicity, including inflammatory responses. Thus, several inflammation-associated molecules can be used to monitor or even predict radiation-induced toxicity. However, these abundant molecular features have a rather limited applicability as universal biomarkers for dose assessment, reflecting the individual predisposition of the immune system and tissue-specific mechanisms involved in radiation-induced damage.

Activity in the human brain predicting differential heart rate responses to emotional facial expressions.

PubMed

Critchley, Hugo D; Rotshtein, Pia; Nagai, Yoko; O'Doherty, John; Mathias, Christopher J; Dolan, Raymond J

2005-02-01

The James-Lange theory of emotion proposes that automatically generated bodily reactions not only color subjective emotional experience of stimuli, but also necessitate a mechanism by which these bodily reactions are differentially generated to reflect stimulus quality. To examine this putative mechanism, we simultaneously measured brain activity and heart rate to identify regions where neural activity predicted the magnitude of heart rate responses to emotional facial expressions. Using a forewarned reaction time task, we showed that orienting heart rate acceleration to emotional face stimuli was modulated as a function of the emotion depicted. The magnitude of evoked heart rate increase, both across the stimulus set and within each emotion category, was predicted by level of activity within a matrix of interconnected brain regions, including amygdala, insula, anterior cingulate, and brainstem. We suggest that these regions provide a substrate for translating visual perception of emotional facial expression into differential cardiac responses and thereby represent an interface for selective generation of visceral reactions that contribute to the embodied component of emotional reaction.

Characterization of recent and minimally passaged Brazilian dengue viruses inducing robust infection in rhesus macaques.

PubMed

Borges, Maria Beatriz; Marchevsky, Renato Sergio; Mendes, Ygara S; Mendes, Luiz Gustavo; Duarte, Ana Claudia; Cruz, Michael; de Filippis, Ana Maria Bispo; Vasconcelos, Pedro Fernando C; Freire, Marcos; Homma, Akira; Mossman, Sally; Lepine, Edith; Vanloubbeeck, Yannick; Lorin, Clarisse; Malice, Marie-Pierre; Caride, Elena; Warter, Lucile

2018-01-01

The macaque is widely accepted as a suitable model for preclinical characterization of dengue vaccine candidates. However, the only vaccine for which both preclinical and clinical efficacy results were reported so far showed efficacy levels that were substantially different between macaques and humans. We hypothesized that this model's predictive capacity may be improved using recent and minimally passaged dengue virus isolates, and by assessing vaccine efficacy by characterizing not only the post-dengue virus challenge viremia/RNAemia but also the associated-cytokine profile. Ten recent and minimally passaged Brazilian clinical isolates from the four dengue virus serotypes were tested for their infectivity in rhesus macaques. For the strains showing robust replication capacity, the associated-changes in soluble mediator levels, and the elicited dengue virus-neutralizing antibody responses, were also characterized. Three isolates from dengue virus serotypes 1, 2 and 4 induced viremia of high magnitude and longer duration relative to previously reported viremia kinetics in this model, and robust dengue virus-neutralizing antibody responses. Consistent with observations in humans, increased MCP-1, IFN-γ and VEGF-A levels, and transiently decreased IL-8 levels were detected after infection with the selected isolates. These results may contribute to establishing a dengue macaque model showing a higher predictability for vaccine efficacy in humans.

Characterization of recent and minimally passaged Brazilian dengue viruses inducing robust infection in rhesus macaques

PubMed Central

Borges, Maria Beatriz; Marchevsky, Renato Sergio; Mendes, Ygara S.; Mendes, Luiz Gustavo; Duarte, Ana Claudia; Cruz, Michael; de Filippis, Ana Maria Bispo; Vasconcelos, Pedro Fernando C.; Freire, Marcos; Homma, Akira; Mossman, Sally; Lepine, Edith; Vanloubbeeck, Yannick; Lorin, Clarisse; Malice, Marie-Pierre; Caride, Elena

2018-01-01

The macaque is widely accepted as a suitable model for preclinical characterization of dengue vaccine candidates. However, the only vaccine for which both preclinical and clinical efficacy results were reported so far showed efficacy levels that were substantially different between macaques and humans. We hypothesized that this model’s predictive capacity may be improved using recent and minimally passaged dengue virus isolates, and by assessing vaccine efficacy by characterizing not only the post-dengue virus challenge viremia/RNAemia but also the associated-cytokine profile. Ten recent and minimally passaged Brazilian clinical isolates from the four dengue virus serotypes were tested for their infectivity in rhesus macaques. For the strains showing robust replication capacity, the associated-changes in soluble mediator levels, and the elicited dengue virus-neutralizing antibody responses, were also characterized. Three isolates from dengue virus serotypes 1, 2 and 4 induced viremia of high magnitude and longer duration relative to previously reported viremia kinetics in this model, and robust dengue virus-neutralizing antibody responses. Consistent with observations in humans, increased MCP-1, IFN-γ and VEGF-A levels, and transiently decreased IL-8 levels were detected after infection with the selected isolates. These results may contribute to establishing a dengue macaque model showing a higher predictability for vaccine efficacy in humans. PMID:29694440

Predictive systems ecology

PubMed Central

Evans, Matthew R.; Bithell, Mike; Cornell, Stephen J.; Dall, Sasha R. X.; Díaz, Sandra; Emmott, Stephen; Ernande, Bruno; Grimm, Volker; Hodgson, David J.; Lewis, Simon L.; Mace, Georgina M.; Morecroft, Michael; Moustakas, Aristides; Murphy, Eugene; Newbold, Tim; Norris, K. J.; Petchey, Owen; Smith, Matthew; Travis, Justin M. J.; Benton, Tim G.

2013-01-01

Human societies, and their well-being, depend to a significant extent on the state of the ecosystems that surround them. These ecosystems are changing rapidly usually in response to anthropogenic changes in the environment. To determine the likely impact of environmental change on ecosystems and the best ways to manage them, it would be desirable to be able to predict their future states. We present a proposal to develop the paradigm of predictive systems ecology, explicitly to understand and predict the properties and behaviour of ecological systems. We discuss the necessary and desirable features of predictive systems ecology models. There are places where predictive systems ecology is already being practised and we summarize a range of terrestrial and marine examples. Significant challenges remain but we suggest that ecology would benefit both as a scientific discipline and increase its impact in society if it were to embrace the need to become more predictive. PMID:24089332

Predictive systems ecology.

PubMed

Evans, Matthew R; Bithell, Mike; Cornell, Stephen J; Dall, Sasha R X; Díaz, Sandra; Emmott, Stephen; Ernande, Bruno; Grimm, Volker; Hodgson, David J; Lewis, Simon L; Mace, Georgina M; Morecroft, Michael; Moustakas, Aristides; Murphy, Eugene; Newbold, Tim; Norris, K J; Petchey, Owen; Smith, Matthew; Travis, Justin M J; Benton, Tim G

2013-11-22

Human societies, and their well-being, depend to a significant extent on the state of the ecosystems that surround them. These ecosystems are changing rapidly usually in response to anthropogenic changes in the environment. To determine the likely impact of environmental change on ecosystems and the best ways to manage them, it would be desirable to be able to predict their future states. We present a proposal to develop the paradigm of predictive systems ecology, explicitly to understand and predict the properties and behaviour of ecological systems. We discuss the necessary and desirable features of predictive systems ecology models. There are places where predictive systems ecology is already being practised and we summarize a range of terrestrial and marine examples. Significant challenges remain but we suggest that ecology would benefit both as a scientific discipline and increase its impact in society if it were to embrace the need to become more predictive.

Principal component analysis of binding energies for single-point mutants of hT2R16 bound to an agonist correlate with experimental mutant cell response.

PubMed

Chen, Derek E; Willick, Darryl L; Ruckel, Joseph B; Floriano, Wely B

2015-01-01

Directed evolution is a technique that enables the identification of mutants of a particular protein that carry a desired property by successive rounds of random mutagenesis, screening, and selection. This technique has many applications, including the development of G protein-coupled receptor-based biosensors and designer drugs for personalized medicine. Although effective, directed evolution is not without challenges and can greatly benefit from the development of computational techniques to predict the functional outcome of single-point amino acid substitutions. In this article, we describe a molecular dynamics-based approach to predict the effects of single amino acid substitutions on agonist binding (salicin) to a human bitter taste receptor (hT2R16). An experimentally determined functional map of single-point amino acid substitutions was used to validate the whole-protein molecular dynamics-based predictive functions. Molecular docking was used to construct a wild-type agonist-receptor complex, providing a starting structure for single-point substitution simulations. The effects of each single amino acid substitution in the functional response of the receptor to its agonist were estimated using three binding energy schemes with increasing inclusion of solvation effects. We show that molecular docking combined with molecular mechanics simulations of single-point mutants of the agonist-receptor complex accurately predicts the functional outcome of single amino acid substitutions in a human bitter taste receptor.

Human Immunity and the Design of Multi-Component, Single Target Vaccines

PubMed Central

Saul, Allan; Fay, Michael P.

2007-01-01

Background Inclusion of multiple immunogens to target a single organism is a strategy being pursued for many experimental vaccines, especially where it is difficult to generate a strongly protective response from a single immunogen. Although there are many human vaccines that contain multiple defined immunogens, in almost every case each component targets a different pathogen. As a consequence, there is little practical experience for deciding where the increased complexity of vaccines with multiple defined immunogens vaccines targeting single pathogens will be justifiable. Methodology/Principal Findings A mathematical model, with immunogenicity parameters derived from a database of human responses to established vaccines, was used to predict the increase in the efficacy and the proportion of the population protected resulting from addition of further immunogens. The gains depended on the relative protection and the range of responses in the population to each immunogen and also to the correlation of the responses between immunogens. In most scenarios modeled, the gain in overall efficacy obtained by adding more immunogens was comparable to gains obtained from a single immunogen through the use of better formulations or adjuvants. Multi-component single target vaccines were more effective at decreasing the proportion of poor responders than increasing the overall efficacy of the vaccine in a population. Conclusions/Significance Inclusion of limited number of antigens in a vaccine aimed at targeting a single organism will increase efficacy, but the gains are relatively modest and for a practical vaccine there are constraints that are likely to limit multi-component single target vaccines to a small number of key antigens. The model predicts that this type of vaccine will be most useful where the critical issue is the reduction in proportion of poor responders. PMID:17786221

Cell Host Response to Infection with Novel Human Coronavirus EMC Predicts Potential Antivirals and Important Differences with SARS Coronavirus

PubMed Central

Josset, Laurence; Menachery, Vineet D.; Gralinski, Lisa E.; Agnihothram, Sudhakar; Sova, Pavel; Carter, Victoria S.; Yount, Boyd L.; Graham, Rachel L.; Baric, Ralph S.; Katze, Michael G.

2013-01-01

ABSTRACT A novel human coronavirus (HCoV-EMC) was recently identified in the Middle East as the causative agent of a severe acute respiratory syndrome (SARS) resembling the illness caused by SARS coronavirus (SARS-CoV). Although derived from the CoV family, the two viruses are genetically distinct and do not use the same receptor. Here, we investigated whether HCoV-EMC and SARS-CoV induce similar or distinct host responses after infection of a human lung epithelial cell line. HCoV-EMC was able to replicate as efficiently as SARS-CoV in Calu-3 cells and similarly induced minimal transcriptomic changes before 12 h postinfection. Later in infection, HCoV-EMC induced a massive dysregulation of the host transcriptome, to a much greater extent than SARS-CoV. Both viruses induced a similar activation of pattern recognition receptors and the interleukin 17 (IL-17) pathway, but HCoV-EMC specifically down-regulated the expression of several genes within the antigen presentation pathway, including both type I and II major histocompatibility complex (MHC) genes. This could have an important impact on the ability of the host to mount an adaptive host response. A unique set of 207 genes was dysregulated early and permanently throughout infection with HCoV-EMC, and was used in a computational screen to predict potential antiviral compounds, including kinase inhibitors and glucocorticoids. Overall, HCoV-EMC and SARS-CoV elicit distinct host gene expression responses, which might impact in vivo pathogenesis and could orient therapeutic strategies against that emergent virus. PMID:23631916

Anomaly Detection in Host Signaling Pathways for the Early Prognosis of Acute Infection.

PubMed

Wang, Kun; Langevin, Stanley; O'Hern, Corey S; Shattuck, Mark D; Ogle, Serenity; Forero, Adriana; Morrison, Juliet; Slayden, Richard; Katze, Michael G; Kirby, Michael

2016-01-01

Clinical diagnosis of acute infectious diseases during the early stages of infection is critical to administering the appropriate treatment to improve the disease outcome. We present a data driven analysis of the human cellular response to respiratory viruses including influenza, respiratory syncytia virus, and human rhinovirus, and compared this with the response to the bacterial endotoxin, Lipopolysaccharides (LPS). Using an anomaly detection framework we identified pathways that clearly distinguish between asymptomatic and symptomatic patients infected with the four different respiratory viruses and that accurately diagnosed patients exposed to a bacterial infection. Connectivity pathway analysis comparing the viral and bacterial diagnostic signatures identified host cellular pathways that were unique to patients exposed to LPS endotoxin indicating this type of analysis could be used to identify host biomarkers that can differentiate clinical etiologies of acute infection. We applied the Multivariate State Estimation Technique (MSET) on two human influenza (H1N1 and H3N2) gene expression data sets to define host networks perturbed in the asymptomatic phase of infection. Our analysis identified pathways in the respiratory virus diagnostic signature as prognostic biomarkers that triggered prior to clinical presentation of acute symptoms. These early warning pathways correctly predicted that almost half of the subjects would become symptomatic in less than forty hours post-infection and that three of the 18 subjects would become symptomatic after only 8 hours. These results provide a proof-of-concept for utility of anomaly detection algorithms to classify host pathway signatures that can identify presymptomatic signatures of acute diseases and differentiate between etiologies of infection. On a global scale, acute respiratory infections cause a significant proportion of human co-morbidities and account for 4.25 million deaths annually. The development of clinical diagnostic tools to distinguish between acute viral and bacterial respiratory infections is critical to improve patient care and limit the overuse of antibiotics in the medical community. The identification of prognostic respiratory virus biomarkers provides an early warning system that is capable of predicting which subjects will become symptomatic to expand our medical diagnostic capabilities and treatment options for acute infectious diseases. The host response to acute infection may be viewed as a deterministic signaling network responsible for maintaining the health of the host organism. We identify pathway signatures that reflect the very earliest perturbations in the host response to acute infection. These pathways provide a monitor the health state of the host using anomaly detection to quantify and predict health outcomes to pathogens.

Anomaly Detection in Host Signaling Pathways for the Early Prognosis of Acute Infection

PubMed Central

O’Hern, Corey S.; Shattuck, Mark D.; Ogle, Serenity; Forero, Adriana; Morrison, Juliet; Slayden, Richard; Katze, Michael G.

2016-01-01

Clinical diagnosis of acute infectious diseases during the early stages of infection is critical to administering the appropriate treatment to improve the disease outcome. We present a data driven analysis of the human cellular response to respiratory viruses including influenza, respiratory syncytia virus, and human rhinovirus, and compared this with the response to the bacterial endotoxin, Lipopolysaccharides (LPS). Using an anomaly detection framework we identified pathways that clearly distinguish between asymptomatic and symptomatic patients infected with the four different respiratory viruses and that accurately diagnosed patients exposed to a bacterial infection. Connectivity pathway analysis comparing the viral and bacterial diagnostic signatures identified host cellular pathways that were unique to patients exposed to LPS endotoxin indicating this type of analysis could be used to identify host biomarkers that can differentiate clinical etiologies of acute infection. We applied the Multivariate State Estimation Technique (MSET) on two human influenza (H1N1 and H3N2) gene expression data sets to define host networks perturbed in the asymptomatic phase of infection. Our analysis identified pathways in the respiratory virus diagnostic signature as prognostic biomarkers that triggered prior to clinical presentation of acute symptoms. These early warning pathways correctly predicted that almost half of the subjects would become symptomatic in less than forty hours post-infection and that three of the 18 subjects would become symptomatic after only 8 hours. These results provide a proof-of-concept for utility of anomaly detection algorithms to classify host pathway signatures that can identify presymptomatic signatures of acute diseases and differentiate between etiologies of infection. On a global scale, acute respiratory infections cause a significant proportion of human co-morbidities and account for 4.25 million deaths annually. The development of clinical diagnostic tools to distinguish between acute viral and bacterial respiratory infections is critical to improve patient care and limit the overuse of antibiotics in the medical community. The identification of prognostic respiratory virus biomarkers provides an early warning system that is capable of predicting which subjects will become symptomatic to expand our medical diagnostic capabilities and treatment options for acute infectious diseases. The host response to acute infection may be viewed as a deterministic signaling network responsible for maintaining the health of the host organism. We identify pathway signatures that reflect the very earliest perturbations in the host response to acute infection. These pathways provide a monitor the health state of the host using anomaly detection to quantify and predict health outcomes to pathogens. PMID:27532264

Genetic differences in transcript responses to low-dose ionizing radiation identify tissue functions associated with breast cancer susceptibility.

PubMed

Snijders, Antoine M; Marchetti, Francesco; Bhatnagar, Sandhya; Duru, Nadire; Han, Ju; Hu, Zhi; Mao, Jian-Hua; Gray, Joe W; Wyrobek, Andrew J

2012-01-01

High dose ionizing radiation (IR) is a well-known risk factor for breast cancer but the health effects after low-dose (LD, <10 cGy) exposures remain highly uncertain. We explored a systems approach that compared LD-induced chromosome damage and transcriptional responses in strains of mice with genetic differences in their sensitivity to radiation-induced mammary cancer (BALB/c and C57BL/6) for the purpose of identifying mechanisms of mammary cancer susceptibility. Unirradiated mammary and blood tissues of these strains differed significantly in baseline expressions of DNA repair, tumor suppressor, and stress response genes. LD exposures of 7.5 cGy (weekly for 4 weeks) did not induce detectable genomic instability in either strain. However, the mammary glands of the sensitive strain but not the resistant strain showed early transcriptional responses involving: (a) diminished immune response, (b) increased cellular stress, (c) altered TGFβ-signaling, and (d) inappropriate expression of developmental genes. One month after LD exposure, the two strains showed opposing responses in transcriptional signatures linked to proliferation, senescence, and microenvironment functions. We also discovered a pre-exposure expression signature in both blood and mammary tissues that is predictive for poor survival among human cancer patients (p = 0.0001), and a post-LD-exposure signature also predictive for poor patient survival (p<0.0001). There is concordant direction of expression in the LD-exposed sensitive mouse strain, in biomarkers of human DCIS and in biomarkers of human breast tumors. Our findings support the hypothesis that genetic mechanisms that determine susceptibility to LD radiation induced mammary cancer in mice are similar to the tissue mechanisms that determine poor-survival in breast cancer patients. We observed non-linearity of the LD responses providing molecular evidence against the LNT risk model and obtained new evidence that LD responses are strongly influenced by genotype. Our findings suggest that the biological assumptions concerning the mechanisms by which LD radiation is translated into breast cancer risk should be reexamined and suggest a new strategy to identify genetic features that predispose or protect individuals from LD-induced breast cancer.

Human amygdala engagement moderated by early life stress exposure is a biobehavioral target for predicting recovery on antidepressants.

PubMed

Goldstein-Piekarski, Andrea N; Korgaonkar, Mayuresh S; Green, Erin; Suppes, Trisha; Schatzberg, Alan F; Hastie, Trevor; Nemeroff, Charles B; Williams, Leanne M

2016-10-18

Amygdala circuitry and early life stress (ELS) are both strongly and independently implicated in the neurobiology of depression. Importantly, animal models have revealed that the contribution of ELS to the development and maintenance of depression is likely a consequence of structural and physiological changes in amygdala circuitry in response to stress hormones. Despite these mechanistic foundations, amygdala engagement and ELS have not been investigated as biobehavioral targets for predicting functional remission in translational human studies of depression. Addressing this question, we integrated human neuroimaging and measurement of ELS within a controlled trial of antidepressant outcomes. Here we demonstrate that the interaction between amygdala activation engaged by emotional stimuli and ELS predicts functional remission on antidepressants with a greater than 80% cross-validated accuracy. Our model suggests that in depressed people with high ELS, the likelihood of remission is highest with greater amygdala reactivity to socially rewarding stimuli, whereas for those with low-ELS exposure, remission is associated with lower amygdala reactivity to both rewarding and threat-related stimuli. This full model predicted functional remission over and above the contribution of demographics, symptom severity, ELS, and amygdala reactivity alone. These findings identify a human target for elucidating the mechanisms of antidepressant functional remission and offer a target for developing novel therapeutics. The results also offer a proof-of-concept for using neuroimaging as a target for guiding neuroscience-informed intervention decisions at the level of the individual person.

Model of human dynamic orientation. Ph.D. Thesis; [associated with vestibular stimuli

NASA Technical Reports Server (NTRS)

Ormsby, C. C.

1974-01-01

The dynamics associated with the perception of orientation were modelled for near-threshold and suprathreshold vestibular stimuli. A model of the information available at the peripheral sensors which was consistent with available neurophysiologic data was developed and served as the basis for the models of the perceptual responses. The central processor was assumed to utilize the information from the peripheral sensors in an optimal (minimum mean square error) manner to produce the perceptual estimates of dynamic orientation. This assumption, coupled with the models of sensory information, determined the form of the model for the central processor. The problem of integrating information from the semi-circular canals and the otoliths to predict the perceptual response to motions which stimulated both organs was studied. A model was developed which was shown to be useful in predicting the perceptual response to multi-sensory stimuli.

Prospective Molecular Profiling of Melanoma Metastases Suggests Classifiers of Immune Responsiveness

PubMed Central

Wang, Ena; Miller, Lance D.; Ohnmacht, Galen A.; Mocellin, Simone; Perez-Diez, Ainhoa; Petersen, David; Zhao, Yingdong; Simon, Richard; Powell, John I.; Asaki, Esther; Alexander, H. Richard; Duray, Paul H.; Herlyn, Meenhard; Restifo, Nicholas P.; Liu, Edison T.; Rosenberg, Steven A.; Marincola, Francesco M.

2008-01-01

We amplified RNAs from 63 fine needle aspiration (FNA) samples from 37 s.c. melanoma metastases from 25 patients undergoing immunotherapy for hybridization to a 6108-gene human cDNA chip. By prospectively following the history of the lesions, we could correlate transcript patterns with clinical outcome. Cluster analysis revealed a tight relationship among autologous synchronously sampled tumors compared with unrelated lesions (average Pearson's r = 0.83 and 0.7, respectively, P < 0.0003). As reported previously, two subgroups of metastatic melanoma lesions were identified that, however, had no predictive correlation with clinical outcome. Ranking of gene expression data from pretreatment samples identified ∼30 genes predictive of clinical response (P < 0.001). Analysis of their annotations denoted that approximately half of them were related to T-cell regulation, suggesting that immune responsiveness might be predetermined by a tumor microenvironment conducive to immune recognition. PMID:12097256

Dynamic modulation of decision biases by brainstem arousal systems.

PubMed

de Gee, Jan Willem; Colizoli, Olympia; Kloosterman, Niels A; Knapen, Tomas; Nieuwenhuis, Sander; Donner, Tobias H

2017-04-11

Decision-makers often arrive at different choices when faced with repeated presentations of the same evidence. Variability of behavior is commonly attributed to noise in the brain's decision-making machinery. We hypothesized that phasic responses of brainstem arousal systems are a significant source of this variability. We tracked pupil responses (a proxy of phasic arousal) during sensory-motor decisions in humans, across different sensory modalities and task protocols. Large pupil responses generally predicted a reduction in decision bias. Using fMRI, we showed that the pupil-linked bias reduction was (i) accompanied by a modulation of choice-encoding pattern signals in parietal and prefrontal cortex and (ii) predicted by phasic, pupil-linked responses of a number of neuromodulatory brainstem centers involved in the control of cortical arousal state, including the noradrenergic locus coeruleus. We conclude that phasic arousal suppresses decision bias on a trial-by-trial basis, thus accounting for a significant component of the variability of choice behavior.

Dynamic modulation of decision biases by brainstem arousal systems

PubMed Central

de Gee, Jan Willem; Colizoli, Olympia; Kloosterman, Niels A; Knapen, Tomas; Nieuwenhuis, Sander; Donner, Tobias H

2017-01-01

Decision-makers often arrive at different choices when faced with repeated presentations of the same evidence. Variability of behavior is commonly attributed to noise in the brain’s decision-making machinery. We hypothesized that phasic responses of brainstem arousal systems are a significant source of this variability. We tracked pupil responses (a proxy of phasic arousal) during sensory-motor decisions in humans, across different sensory modalities and task protocols. Large pupil responses generally predicted a reduction in decision bias. Using fMRI, we showed that the pupil-linked bias reduction was (i) accompanied by a modulation of choice-encoding pattern signals in parietal and prefrontal cortex and (ii) predicted by phasic, pupil-linked responses of a number of neuromodulatory brainstem centers involved in the control of cortical arousal state, including the noradrenergic locus coeruleus. We conclude that phasic arousal suppresses decision bias on a trial-by-trial basis, thus accounting for a significant component of the variability of choice behavior. DOI: http://dx.doi.org/10.7554/eLife.23232.001 PMID:28383284

Naturally Occurring Canine Melanoma as a Predictive Comparative Oncology Model for Human Mucosal and Other Triple Wild-Type Melanomas

PubMed Central

Hernandez, Belen; Wei, Bih-Rong; Michael, Helen T.; Merlino, Glenn; Simpson, R. Mark

2018-01-01

Melanoma remains mostly an untreatable fatal disease despite advances in decoding cancer genomics and developing new therapeutic modalities. Progress in patient care would benefit from additional predictive models germane for human disease mechanisms, tumor heterogeneity, and therapeutic responses. Toward this aim, this review documents comparative aspects of human and naturally occurring canine melanomas. Clinical presentation, pathology, therapies, and genetic alterations are highlighted in the context of current basic and translational research in comparative oncology. Somewhat distinct from sun exposure-related human cutaneous melanomas, there is growing evidence that a variety of gene copy number alterations and protein structure/function mutations play roles in canine melanomas, in circumstances more analogous to human mucosal melanomas and to some extent other melanomas with murine sarcoma viral oncogene homolog B (BRAF), Neuroblastoma RAS Viral (V-Ras) Oncogene Homolog (NRAS), and neurofibromin 1 tumor suppressor NF1 triple wild-type genotype. Gaps in canine genome annotation, as well as an insufficient number and depth of sequences covered, remain considerable barriers to progress and should be collectively addressed. Preclinical approaches can be designed to include canine clinical trials addressing immune modulation as well as combined-targeted inhibition of Rat Sarcoma Superfamily/Mitogen-activated protein kinase (RAS/MAPK) and/or Phosphatidylinositol-3-Kinase/Protein Kinase B/Mammalian target of rapamycin (PI3K/AKT/mTOR) signal transduction, pathways frequently activated in both human and canine melanomas. Future investment should be aimed towards improving understanding of canine melanoma as a predictive preclinical surrogate for human melanoma and for mutually benefiting these uniquely co-dependent species. PMID:29385676

CCL11 (Eotaxin-1) Levels Predict Long-Term Functional Outcomes in Patients Following Ischemic Stroke.

PubMed

Roy-O'Reilly, Meaghan; Ritzel, Rodney M; Conway, Sarah E; Staff, Ilene; Fortunato, Gilbert; McCullough, Louise D

2017-12-01

Circulating levels of the pro-inflammatory cytokine C-C motif chemokine 11 (CCL11, also known as eotaxin-1) are increased in several animal models of neuroinflammation, including traumatic brain injury and Alzheimer's disease. Increased levels of CCL11 have also been linked to decreased neurogenesis in mice. We hypothesized that circulating CCL11 levels would increase following ischemic stroke in mice and humans, and that higher CCL11 levels would correlate with poor long-term recovery in patients. As predicted, circulating levels of CCL11 in both young and aged mice increased significantly 24 h after experimental stroke. However, ischemic stroke patients showed decreased CCL11 levels compared to controls 24 h after stroke. Interestingly, lower post-stroke CCL11 levels were predictive of increased stroke severity and independently predictive of poorer functional outcomes in patients 12 months after ischemic stroke. These results illustrate important differences in the peripheral inflammatory response to ischemic stroke between mice and human patients. In addition, it suggests CCL11 as a candidate biomarker for the prediction of acute and long-term functional outcomes in ischemic stroke patients.

Computational Model of the Fathead Minnow Hypothalamic-Pituitary-Gonadal Axis: Incorporating Protein Synthesis in Improving Predictability of Responses to Endocrine Active Chemicals

EPA Science Inventory

There is international concern about chemicals that alter endocrine system function in humans and/or wildlife and subsequently cause adverse effects. We previously developed a mechanistic computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minno...

Effect of chemical compounds on electronic tongue response to citrus juices

USDA-ARS?s Scientific Manuscript database

The electronic tongue system mimics the process of taste detection by human taste buds and recognition by the brain, hence helping in prediction of taste. With this unique capability, the electronic tongue has been used for taste detection of a wide range of food products. As a preliminary step in p...

Hydrological model parameterization using NDVI values to account for the effects of land-cover change on the rainfall-runoff response

USDA-ARS?s Scientific Manuscript database

Classic rainfall-runoff models usually use historical data to estimate model parameters and mean values of parameters are considered for predictions. However, due to climate changes and human effects, the parameters of model change temporally. To overcome this problem, Normalized Difference Vegetati...

Genetic data: The new challenge of personalized medicine, insights for rheumatoid arthritis patients.

PubMed

Goulielmos, George N; Zervou, Maria I; Myrthianou, Effie; Burska, Agata; Niewold, Timothy B; Ponchel, Frederique

2016-06-01

Rapid advances in genotyping technology, analytical methods, and the establishment of large cohorts for population genetic studies have resulted in a large new body of information about the genetic basis of human rheumatoid arthritis (RA). Improved understanding of the root pathogenesis of the disease holds the promise of improved diagnostic and prognostic tools based upon this information. In this review, we summarize the nature of new genetic findings in human RA, including susceptibility loci and gene-gene and gene-environment interactions, as well as genetic loci associated with sub-groups of patients and those associated with response to therapy. Possible uses of these data are discussed, such as prediction of disease risk as well as personalized therapy and prediction of therapeutic response and risk of adverse events. While these applications are largely not refined to the point of clinical utility in RA, it seems likely that multi-parameter datasets including genetic, clinical, and biomarker data will be employed in the future care of RA patients. Copyright © 2016 Elsevier B.V. All rights reserved.

The effect of clustering on perceived quantity in humans (Homo sapiens) and in chicks (Gallus gallus).

PubMed

Bertamini, Marco; Guest, Martin; Vallortigara, Giorgio; Rugani, Rosa; Regolin, Lucia

2018-04-30

Animals can perceive the numerosity of sets of visual elements. Qualitative and quantitative similarities in different species suggest the existence of a shared system (approximate number system). Biases associated with sensory properties are informative about the underlying mechanisms. In humans, regular spacing increases perceived numerosity (regular-random numerosity illusion). This has led to a model that predicts numerosity based on occupancy (a measure that decreases when elements are close together). We used a procedure in which observers selected one of two stimuli and were given feedback with respect to whether the choice was correct. One configuration had 20 elements and the other 40, randomly placed inside a circular region. Participants had to discover the rule based on feedback. Because density and clustering covaried with numerosity, different dimensions could be used. After reaching a criterion, test trials presented two types of configurations with 30 elements. One type had a larger interelement distance than the other (high or low clustering). If observers had adopted a numerosity strategy, they would choose low clustering (if reinforced with 40) and high clustering (if reinforced with 20). A clustering or density strategy predicts the opposite. Human adults used a numerosity strategy. Chicks were tested using a similar procedure. There were two behavioral measures: first approach response and final circumnavigation (walking behind the screen). The prediction based on numerosity was confirmed by the first approach data. For chicks, one clear pattern from both responses was a preference for the configurations with higher clustering. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Encoding model of temporal processing in human visual cortex.

PubMed

Stigliani, Anthony; Jeska, Brianna; Grill-Spector, Kalanit

2017-12-19

How is temporal information processed in human visual cortex? Visual input is relayed to V1 through segregated transient and sustained channels in the retina and lateral geniculate nucleus (LGN). However, there is intense debate as to how sustained and transient temporal channels contribute to visual processing beyond V1. The prevailing view associates transient processing predominately with motion-sensitive regions and sustained processing with ventral stream regions, while the opposing view suggests that both temporal channels contribute to neural processing beyond V1. Using fMRI, we measured cortical responses to time-varying stimuli and then implemented a two temporal channel-encoding model to evaluate the contributions of each channel. Different from the general linear model of fMRI that predicts responses directly from the stimulus, the encoding approach first models neural responses to the stimulus from which fMRI responses are derived. This encoding approach not only predicts cortical responses to time-varying stimuli from milliseconds to seconds but also, reveals differential contributions of temporal channels across visual cortex. Consistent with the prevailing view, motion-sensitive regions and adjacent lateral occipitotemporal regions are dominated by transient responses. However, ventral occipitotemporal regions are driven by both sustained and transient channels, with transient responses exceeding the sustained. These findings propose a rethinking of temporal processing in the ventral stream and suggest that transient processing may contribute to rapid extraction of the content of the visual input. Importantly, our encoding approach has vast implications, because it can be applied with fMRI to decipher neural computations in millisecond resolution in any part of the brain. Copyright © 2017 the Author(s). Published by PNAS.

Predicting the safety and efficacy of buffer therapy to raise tumour pHe: an integrative modelling study

PubMed Central

Martin, N K; Robey, I F; Gaffney, E A; Gillies, R J; Gatenby, R A; Maini, P K

2012-01-01

Background: Clinical positron emission tomography imaging has demonstrated the vast majority of human cancers exhibit significantly increased glucose metabolism when compared with adjacent normal tissue, resulting in an acidic tumour microenvironment. Recent studies demonstrated reducing this acidity through systemic buffers significantly inhibits development and growth of metastases in mouse xenografts. Methods: We apply and extend a previously developed mathematical model of blood and tumour buffering to examine the impact of oral administration of bicarbonate buffer in mice, and the potential impact in humans. We recapitulate the experimentally observed tumour pHe effect of buffer therapy, testing a model prediction in vivo in mice. We parameterise the model to humans to determine the translational safety and efficacy, and predict patient subgroups who could have enhanced treatment response, and the most promising combination or alternative buffer therapies. Results: The model predicts a previously unseen potentially dangerous elevation in blood pHe resulting from bicarbonate therapy in mice, which is confirmed by our in vivo experiments. Simulations predict limited efficacy of bicarbonate, especially in humans with more aggressive cancers. We predict buffer therapy would be most effectual: in elderly patients or individuals with renal impairments; in combination with proton production inhibitors (such as dichloroacetate), renal glomular filtration rate inhibitors (such as non-steroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors), or with an alternative buffer reagent possessing an optimal pK of 7.1–7.2. Conclusion: Our mathematical model confirms bicarbonate acts as an effective agent to raise tumour pHe, but potentially induces metabolic alkalosis at the high doses necessary for tumour pHe normalisation. We predict use in elderly patients or in combination with proton production inhibitors or buffers with a pK of 7.1–7.2 is most promising. PMID:22382688

Predicting the threshold of pulse-train electrical stimuli using a stochastic auditory nerve model: the effects of stimulus noise.

PubMed

Xu, Yifang; Collins, Leslie M

2004-04-01

The incorporation of low levels of noise into an electrical stimulus has been shown to improve auditory thresholds in some human subjects (Zeng et al., 2000). In this paper, thresholds for noise-modulated pulse-train stimuli are predicted utilizing a stochastic neural-behavioral model of ensemble fiber responses to bi-phasic stimuli. The neural refractory effect is described using a Markov model for a noise-free pulse-train stimulus and a closed-form solution for the steady-state neural response is provided. For noise-modulated pulse-train stimuli, a recursive method using the conditional probability is utilized to track the neural responses to each successive pulse. A neural spike count rule has been presented for both threshold and intensity discrimination under the assumption that auditory perception occurs via integration over a relatively long time period (Bruce et al., 1999). An alternative approach originates from the hypothesis of the multilook model (Viemeister and Wakefield, 1991), which argues that auditory perception is based on several shorter time integrations and may suggest an NofM model for prediction of pulse-train threshold. This motivates analyzing the neural response to each individual pulse within a pulse train, which is considered to be the brief look. A logarithmic rule is hypothesized for pulse-train threshold. Predictions from the multilook model are shown to match trends in psychophysical data for noise-free stimuli that are not always matched by the long-time integration rule. Theoretical predictions indicate that threshold decreases as noise variance increases. Theoretical models of the neural response to pulse-train stimuli not only reduce calculational overhead but also facilitate utilization of signal detection theory and are easily extended to multichannel psychophysical tasks.

An active learning approach for rapid characterization of endothelial cells in human tumors.

PubMed

Padmanabhan, Raghav K; Somasundar, Vinay H; Griffith, Sandra D; Zhu, Jianliang; Samoyedny, Drew; Tan, Kay See; Hu, Jiahao; Liao, Xuejun; Carin, Lawrence; Yoon, Sam S; Flaherty, Keith T; Dipaola, Robert S; Heitjan, Daniel F; Lal, Priti; Feldman, Michael D; Roysam, Badrinath; Lee, William M F

2014-01-01

Currently, no available pathological or molecular measures of tumor angiogenesis predict response to antiangiogenic therapies used in clinical practice. Recognizing that tumor endothelial cells (EC) and EC activation and survival signaling are the direct targets of these therapies, we sought to develop an automated platform for quantifying activity of critical signaling pathways and other biological events in EC of patient tumors by histopathology. Computer image analysis of EC in highly heterogeneous human tumors by a statistical classifier trained using examples selected by human experts performed poorly due to subjectivity and selection bias. We hypothesized that the analysis can be optimized by a more active process to aid experts in identifying informative training examples. To test this hypothesis, we incorporated a novel active learning (AL) algorithm into FARSIGHT image analysis software that aids the expert by seeking out informative examples for the operator to label. The resulting FARSIGHT-AL system identified EC with specificity and sensitivity consistently greater than 0.9 and outperformed traditional supervised classification algorithms. The system modeled individual operator preferences and generated reproducible results. Using the results of EC classification, we also quantified proliferation (Ki67) and activity in important signal transduction pathways (MAP kinase, STAT3) in immunostained human clear cell renal cell carcinoma and other tumors. FARSIGHT-AL enables characterization of EC in conventionally preserved human tumors in a more automated process suitable for testing and validating in clinical trials. The results of our study support a unique opportunity for quantifying angiogenesis in a manner that can now be tested for its ability to identify novel predictive and response biomarkers.

Computational substrates of norms and their violations during social exchange.

PubMed

Xiang, Ting; Lohrenz, Terry; Montague, P Read

2013-01-16

Social norms in humans constrain individual behaviors to establish shared expectations within a social group. Previous work has probed social norm violations and the feelings that such violations engender; however, a computational rendering of the underlying neural and emotional responses has been lacking. We probed norm violations using a two-party, repeated fairness game (ultimatum game) where proposers offer a split of a monetary resource to a responder who either accepts or rejects the offer. Using a norm-training paradigm where subject groups are preadapted to either high or low offers, we demonstrate that unpredictable shifts in expected offers creates a difference in rejection rates exhibited by the two responder groups for otherwise identical offers. We constructed an ideal observer model that identified neural correlates of norm prediction errors in the ventral striatum and anterior insula, regions that also showed strong responses to variance-prediction errors generated by the same model. Subjective feelings about offers correlated with these norm prediction errors, and the two signals displayed overlapping, but not identical, neural correlates in striatum, insula, and medial orbitofrontal cortex. These results provide evidence for the hypothesis that responses in anterior insula can encode information about social norm violations that correlate with changes in overt behavior (changes in rejection rates). Together, these results demonstrate that the brain regions involved in reward prediction and risk prediction are also recruited in signaling social norm violations.

Computational Substrates of Norms and Their Violations during Social Exchange

PubMed Central

Xiang, Ting; Lohrenz, Terry; Montague, P. Read

2013-01-01

Social norms in humans constrain individual behaviors to establish shared expectations within a social group. Previous work has probed social norm violations and the feelings that such violations engender; however, a computational rendering of the underlying neural and emotional responses has been lacking. We probed norm violations using a two-party, repeated fairness game (ultimatum game) where proposers offer a split of a monetary resource to a responder who either accepts or rejects the offer. Using a norm-training paradigm where subject groups are preadapted to either high or low offers, we demonstrate that unpredictable shifts in expected offers creates a difference in rejection rates exhibited by the two responder groups for otherwise identical offers. We constructed an ideal observer model that identified neural correlates of norm prediction errors in the ventral striatum and anterior insula, regions that also showed strong responses to variance-prediction errors generated by the same model. Subjective feelings about offers correlated with these norm prediction errors, and the two signals displayed overlapping, but not identical, neural correlates in striatum, insula, and medial orbitofrontal cortex. These results provide evidence for the hypothesis that responses in anterior insula can encode information about social norm violations that correlate with changes in overt behavior (changes in rejection rates). Together, these results demonstrate that the brain regions involved in reward prediction and risk prediction are also recruited in signaling social norm violations. PMID:23325247

Development of companion diagnostics

DOE PAGES

Mankoff, David A.; Edmonds, Christine E.; Farwell, Michael D.; ...

2015-12-12

The goal of individualized and targeted treatment and precision medicine requires the assessment of potential therapeutic targets to direct treatment selection. The biomarkers used to direct precision medicine, often termed companion diagnostics, for highly targeted drugs have thus far been almost entirely based on in vitro assay of biopsy material. Molecular imaging companion diagnostics offer a number of features complementary to those from in vitro assay, including the ability to measure the heterogeneity of each patient’s cancer across the entire disease burden and to measure early changes in response to treatment. We discuss the use of molecular imaging methods asmore » companion diagnostics for cancer therapy with the goal of predicting response to targeted therapy and measuring early (pharmacodynamic) response as an indication of whether the treatment has “hit” the target. We also discuss considerations for probe development for molecular imaging companion diagnostics, including both small-molecule probes and larger molecules such as labeled antibodies and related constructs. We then describe two examples where both predictive and pharmacodynamic molecular imaging markers have been tested in humans: endocrine therapy for breast cancer and human epidermal growth factor receptor type 2–targeted therapy. Lastly, the review closes with a summary of the items needed to move molecular imaging companion diagnostics from early studies into multicenter trials and into the clinic.« less

Development of companion diagnostics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mankoff, David A.; Edmonds, Christine E.; Farwell, Michael D.

The goal of individualized and targeted treatment and precision medicine requires the assessment of potential therapeutic targets to direct treatment selection. The biomarkers used to direct precision medicine, often termed companion diagnostics, for highly targeted drugs have thus far been almost entirely based on in vitro assay of biopsy material. Molecular imaging companion diagnostics offer a number of features complementary to those from in vitro assay, including the ability to measure the heterogeneity of each patient’s cancer across the entire disease burden and to measure early changes in response to treatment. We discuss the use of molecular imaging methods asmore » companion diagnostics for cancer therapy with the goal of predicting response to targeted therapy and measuring early (pharmacodynamic) response as an indication of whether the treatment has “hit” the target. We also discuss considerations for probe development for molecular imaging companion diagnostics, including both small-molecule probes and larger molecules such as labeled antibodies and related constructs. We then describe two examples where both predictive and pharmacodynamic molecular imaging markers have been tested in humans: endocrine therapy for breast cancer and human epidermal growth factor receptor type 2–targeted therapy. Lastly, the review closes with a summary of the items needed to move molecular imaging companion diagnostics from early studies into multicenter trials and into the clinic.« less

Development of Companion Diagnostics

PubMed Central

Mankoff, David A.; Edmonds, Christine E.; Farwell, Michael D.; Pryma, Daniel A.

2016-01-01

The goal of individualized and targeted treatment and precision medicine requires the assessment of potential therapeutic targets to direct treatment selection. The biomarkers used to direct precision medicine, often termed companion diagnostics, for highly targeted drugs have thus far been almost entirely based on in vitro assay of biopsy material. Molecular imaging companion diagnostics offer a number of features complementary to those from in vitro assay, including the ability to measure the heterogeneity of each patient’s cancer across the entire disease burden and to measure early changes in response to treatment. We discuss the use of molecular imaging methods as companion diagnostics for cancer therapy with the goal of predicting response to targeted therapy and measuring early (pharmacodynamic) response as an indication of whether the treatment has “hit” the target. We also discuss considerations for probe development for molecular imaging companion diagnostics, including both small-molecule probes and larger molecules such as labeled antibodies and related constructs. We then describe two examples where both predictive and pharmacodynamic molecular imaging markers have been tested in humans: endocrine therapy for breast cancer and human epidermal growth factor receptor type 2–targeted therapy. The review closes with a summary of the items needed to move molecular imaging companion diagnostics from early studies into multicenter trials and into the clinic. PMID:26687857

A Human Thrifty Phenotype Associated With Less Weight Loss During Caloric Restriction

PubMed Central

Thearle, Marie S.; Ibrahim, Mostafa; Hohenadel, Maximilian G.; Bogardus, Clifton; Krakoff, Jonathan; Votruba, Susanne B.

2015-01-01

Successful weight loss is variable for reasons not fully elucidated. Whether effective weight loss results from smaller reductions in energy expenditure during caloric restriction is not known. We analyzed whether obese individuals with a “thrifty” phenotype, that is, greater reductions in 24-h energy expenditure during fasting and smaller increases with overfeeding, lose less weight during caloric restriction than those with a “spendthrift” phenotype. During a weight-maintaining period, 24-h energy expenditure responses to fasting and 200% overfeeding were measured in a whole-room indirect calorimeter. Volunteers then underwent 6 weeks of 50% caloric restriction. We calculated the daily energy deficit (kilocalories per day) during caloric restriction, incorporating energy intake and waste, energy expenditure, and daily activity. We found that a smaller reduction in 24-h energy expenditure during fasting and a larger response to overfeeding predicted more weight loss over 6 weeks, even after accounting for age, sex, race, and baseline weight, as well as a greater rate of energy deficit accumulation. The success of dietary weight loss efforts is influenced by the energy expenditure response to caloric restriction. Greater decreases in energy expenditure during caloric restriction predict less weight loss, indicating the presence of thrifty and spendthrift phenotypes in obese humans. PMID:25964395

A Study in a New Test Facility on Indoor Annoyance Caused by Sonic Booms

NASA Technical Reports Server (NTRS)

Rathsam, Jonathan; Loubeau, Alexandra; Klos, Jacob

2012-01-01

A sonic-boom simulator at NASA Langley Research Center has been constructed to research the indoor human response to low-amplitude sonic booms. The research goal is the development of a psychoacoustic model for individual sonic booms to be validated by future community studies. The study in this report assessed the suitability of existing noise metrics for predicting indoor human annoyance. The test signals included a wide range of synthesized and recorded sonic-boom waveforms. Results indicated that no noise metric predicts indoor annoyance to sonic-boom sounds better than Perceived Level, PL. During the study it became apparent that structural vibrations induced by the test signals were contributing to annoyance, so the relationship between sound and vibration at levels of equivalent annoyance has been quantified.

Predicting “Airborne” Influenza Viruses: (Trans-) mission Impossible?

PubMed Central

Sorrell, E.M.; Schrauwen, E.J.A.; Linster, M.; De Graaf, M.; Herfst, S.; Fouchier, R.A.M.

2011-01-01

Repeated transmission of animal influenza viruses to humans has prompted investigation of the viral, host, and environmental factors responsible for transmission via aerosols or respiratory droplets. How do we determine – out of thousands of influenza virus isolates collected in animal surveillance studies each year – which viruses have the potential to become “airborne”, and hence pose a pandemic threat? Here, using knowledge from pandemic, zoonotic and epidemic viruses, we postulate that the minimal requirements for efficient transmission of an animal influenza virus between humans are: efficient virus attachment to (upper) respiratory tissues, replication to high titers in these tissues, and release and aerosolization of single virus particles. Investigating “airborne” transmission of influenza viruses is key to understand – and predict – influenza pandemics. PMID:22440921

Microgravity

NASA Image and Video Library

2003-01-22

One concern about human adaptation to space is how returning from the microgravity of orbit to Earth can affect an astronaut's ability to fly safely. There are monitors and infrared video cameras to measure eye movements without having to affect the crew member. A computer screen provides moving images which the eye tracks while the brain determines what it is seeing. A video camera records movement of the subject's eyes. Researchers can then correlate perception and response. Test subjects perceive different images when a moving object is covered by a mask that is visible or invisible (above). Early results challenge the accepted theory that smooth pursuit -- the fluid eye movement that humans and primates have -- does not involve the higher brain. NASA results show that: Eye movement can predict human perceptual performance, smooth pursuit and saccadic (quick or ballistic) movement share some signal pathways, and common factors can make both smooth pursuit and visual perception produce errors in motor responses.

Persistent neuronal activity in human prefrontal cortex links perception and action

PubMed Central

Haller, Matar; Case, John; Crone, Nathan E.; Chang, Edward F.; King-Stephens, David; Laxer, Kenneth D.; Weber, Peter B.; Parvizi, Josef; Knight, Robert T.; Shestyuk, Avgusta Y.

2017-01-01

How do humans flexibly respond to changing environmental demands on a sub-second temporal scale? Extensive research has highlighted the key role of the prefrontal cortex in flexible decision-making and adaptive behavior, yet the core mechanisms that translate sensory information into behavior remain undefined. Utilizing direct human cortical recordings, we investigated the temporal and spatial evolution of neuronal activity, indexed by the broadband gamma signal, while sixteen participants performed a broad range of self-paced cognitive tasks. Here we describe a robust domain- and modality-independent pattern of persistent stimulus-to-response neural activation that encodes stimulus features and predicts motor output on a trial-by-trial basis with near-perfect accuracy. Observed across a distributed network of brain areas, this persistent neural activation is centered in the prefrontal cortex and is required for successful response implementation, providing a functional substrate for domain-general transformation of perception into action, critical for flexible behavior.

The Individual and Population Genetics of Antibody Immunity.

PubMed

Watson, Corey T; Glanville, Jacob; Marasco, Wayne A

2017-07-01

Antibodies (Abs) produced by immunoglobulin (IG) genes are the most diverse proteins expressed in humans. While part of this diversity is generated by recombination during B-cell development and mutations during affinity maturation, the germ-line IG loci are also diverse across human populations and ethnicities. Recently, proof-of-concept studies have demonstrated genotype-phenotype correlations between specific IG germ-line variants and the quality of Ab responses during vaccination and disease. However, the functional consequences of IG genetic variation in Ab function and immunological outcomes remain underexplored. In this opinion article, we outline interconnections between IG genomic diversity and Ab-expressed repertoires and structure. We further propose a strategy for integrating IG genotyping with functional Ab profiling data as a means to better predict and optimize humoral responses in genetically diverse human populations, with immediate implications for personalized medicine. Copyright © 2017 Elsevier Ltd. All rights reserved.

Multi-platform ’Omics Analysis of Human Ebola Virus Disease Pathogenesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Eisfeld, Amie J.; Halfmann, Peter J.; Wendler, Jason P.

The pathogenesis of human Ebola virus disease (EVD) is complex. EVD is characterized by high levels of virus replication and dissemination, dysregulated immune responses, extensive virus- and host-mediated tissue damage, and disordered coagulation. To clarify how host responses contribute to EVD pathophysiology, we performed multi-platform ’omics analysis of peripheral blood mononuclear cells and plasma from EVD patients. Our results indicate that EVD molecular signatures overlap with those of sepsis, imply that pancreatic enzymes contribute to tissue damage in fatal EVD, and suggest that Ebola virus infection may induce aberrant neutrophils whose activity could explain hallmarks of fatal EVD. Moreover, integratedmore » biomarker prediction identified putative biomarkers from different data platforms that differentiated survivors and fatalities early after infection. This work reveals insight into EVD pathogenesis, suggests an effective approach for biomarker identification, and provides an important community resource for further analysis of human EVD severity.« less

Understanding Visible Perception

NASA Technical Reports Server (NTRS)

2003-01-01

One concern about human adaptation to space is how returning from the microgravity of orbit to Earth can affect an astronaut's ability to fly safely. There are monitors and infrared video cameras to measure eye movements without having to affect the crew member. A computer screen provides moving images which the eye tracks while the brain determines what it is seeing. A video camera records movement of the subject's eyes. Researchers can then correlate perception and response. Test subjects perceive different images when a moving object is covered by a mask that is visible or invisible (above). Early results challenge the accepted theory that smooth pursuit -- the fluid eye movement that humans and primates have -- does not involve the higher brain. NASA results show that: Eye movement can predict human perceptual performance, smooth pursuit and saccadic (quick or ballistic) movement share some signal pathways, and common factors can make both smooth pursuit and visual perception produce errors in motor responses.

Multi-platform 'Omics Analysis of Human Ebola Virus Disease Pathogenesis.

PubMed

Eisfeld, Amie J; Halfmann, Peter J; Wendler, Jason P; Kyle, Jennifer E; Burnum-Johnson, Kristin E; Peralta, Zuleyma; Maemura, Tadashi; Walters, Kevin B; Watanabe, Tokiko; Fukuyama, Satoshi; Yamashita, Makoto; Jacobs, Jon M; Kim, Young-Mo; Casey, Cameron P; Stratton, Kelly G; Webb-Robertson, Bobbie-Jo M; Gritsenko, Marina A; Monroe, Matthew E; Weitz, Karl K; Shukla, Anil K; Tian, Mingyuan; Neumann, Gabriele; Reed, Jennifer L; van Bakel, Harm; Metz, Thomas O; Smith, Richard D; Waters, Katrina M; N'jai, Alhaji; Sahr, Foday; Kawaoka, Yoshihiro

2017-12-13

The pathogenesis of human Ebola virus disease (EVD) is complex. EVD is characterized by high levels of virus replication and dissemination, dysregulated immune responses, extensive virus- and host-mediated tissue damage, and disordered coagulation. To clarify how host responses contribute to EVD pathophysiology, we performed multi-platform 'omics analysis of peripheral blood mononuclear cells and plasma from EVD patients. Our results indicate that EVD molecular signatures overlap with those of sepsis, imply that pancreatic enzymes contribute to tissue damage in fatal EVD, and suggest that Ebola virus infection may induce aberrant neutrophils whose activity could explain hallmarks of fatal EVD. Moreover, integrated biomarker prediction identified putative biomarkers from different data platforms that differentiated survivors and fatalities early after infection. This work reveals insight into EVD pathogenesis, suggests an effective approach for biomarker identification, and provides an important community resource for further analysis of human EVD severity. Copyright © 2017 Elsevier Inc. All rights reserved.

Characterization of the SOS meta-regulon in the human gut microbiome.

PubMed

Cornish, Joseph P; Sanchez-Alberola, Neus; O'Neill, Patrick K; O'Keefe, Ronald; Gheba, Jameel; Erill, Ivan

2014-05-01

Data from metagenomics projects remain largely untapped for the analysis of transcriptional regulatory networks. Here, we provide proof-of-concept that metagenomic data can be effectively leveraged to analyze regulatory networks by characterizing the SOS meta-regulon in the human gut microbiome. We combine well-established in silico and in vitro techniques to mine the human gut microbiome data and determine the relative composition of the SOS network in a natural setting. Our analysis highlights the importance of translesion synthesis as a primary function of the SOS response. We predict the association of this network with three novel protein clusters involved in cell wall biogenesis, chromosome partitioning and restriction modification, and we confirm binding of the SOS response transcriptional repressor to sites in the promoter of a cell wall biogenesis enzyme, a phage integrase and a death-on-curing protein. We discuss the implications of these findings and the potential for this approach for metagenome analysis.

Large Scale Immune Profiling of Infected Humans and Goats Reveals Differential Recognition of Brucella melitensis Antigens

PubMed Central

Liang, Li; Leng, Diana; Burk, Chad; Nakajima-Sasaki, Rie; Kayala, Matthew A.; Atluri, Vidya L.; Pablo, Jozelyn; Unal, Berkay; Ficht, Thomas A.; Gotuzzo, Eduardo; Saito, Mayuko; Morrow, W. John W.; Liang, Xiaowu; Baldi, Pierre; Gilman, Robert H.; Vinetz, Joseph M.; Tsolis, Renée M.; Felgner, Philip L.

2010-01-01

Brucellosis is a widespread zoonotic disease that is also a potential agent of bioterrorism. Current serological assays to diagnose human brucellosis in clinical settings are based on detection of agglutinating anti-LPS antibodies. To better understand the universe of antibody responses that develop after B. melitensis infection, a protein microarray was fabricated containing 1,406 predicted B. melitensis proteins. The array was probed with sera from experimentally infected goats and naturally infected humans from an endemic region in Peru. The assay identified 18 antigens differentially recognized by infected and non-infected goats, and 13 serodiagnostic antigens that differentiate human patients proven to have acute brucellosis from syndromically similar patients. There were 31 cross-reactive antigens in healthy goats and 20 cross-reactive antigens in healthy humans. Only two of the serodiagnostic antigens and eight of the cross-reactive antigens overlap between humans and goats. Based on these results, a nitrocellulose line blot containing the human serodiagnostic antigens was fabricated and applied in a simple assay that validated the accuracy of the protein microarray results in the diagnosis of humans. These data demonstrate that an experimentally infected natural reservoir host produces a fundamentally different immune response than a naturally infected accidental human host. PMID:20454614

Immunogenicity of a meningococcal native outer membrane vesicle vaccine with attenuated endotoxin and over-expressed factor H binding protein in infant rhesus monkeys

PubMed Central

Koeberling, Oliver; Seubert, Anja; Santos, George; Colaprico, Annalisa; Ugozzoli, Mildred; Donnelly, John; Granoff, Dan M.

2011-01-01

We previously investigated immunogenicity of meningococcal native outer membrane vesicle (NOMV) vaccines prepared from recombinant strains with attenuated endotoxin (ΔLpxL1) and over-expressed factor H binding protein (fHbp) in a mouse model. The vaccines elicited broad serum bactericidal antibody responses. While human toll-like receptor 4 (TLR-4) is mainly stimulated by wildtype meningococcal endotoxin, mouse TLR-4 is stimulated by both the wildtype and mutant endotoxin. An adjuvant effect in mice of the mutant endotoxin would be expected to be much less in humans, and may have contributed to the broad mouse bactericidal responses. Here we show that as previously reported for humans, rhesus primate peripheral blood mononuclear cells incubated with a NOMV vaccine from ΔLpxL1 recombinant strains had lower proinflammatory cytokine responses than with a control wildtype NOMV vaccine. The cytokine responses to the mutant vaccine were similar to those elicited by a detergent-treated, wildtype outer membrane vesicle vaccine that had been safely administered to humans. Monkeys (N=4) were immunized beginning at ages 2 to 3 months with three doses of a NOMV vaccine prepared from ΔLpxL1 recombinant strains with over-expressed fHbp in the variant 1 and 2 groups. The mutant NOMV vaccine elicited serum bactericidal titers ≥1:4 against all 10 genetically diverse strains tested, including 9 with heterologous PorA to those in the vaccine. Negative-control animals had serum bactericidal titers <1:4. Thus, the mutant NOMV vaccine elicited broadly protective serum antibodies in a non-human infant primate model that is more relevant for predicting human antibody responses than mice. PMID:21571025

In vitro screening for population variability in toxicity of pesticide-containing mixtures

PubMed Central

Abdo, Nour; Wetmore, Barbara A.; Chappell, Grace A.; Shea, Damian; Wright, Fred A.; Rusyna, Ivan

2016-01-01

Population-based human in vitro models offer exceptional opportunities for evaluating the potential hazard and mode of action of chemicals, as well as variability in responses to toxic insults among individuals. This study was designed to test the hypothesis that comparative population genomics with efficient in vitro experimental design can be used for evaluation of the potential for hazard, mode of action, and the extent of population variability in responses to chemical mixtures. We selected 146 lymphoblast cell lines from 4 ancestrally and geographically diverse human populations based on the availability of genome sequence and basal RNA-seq data. Cells were exposed to two pesticide mixtures – an environmental surface water sample comprised primarily of organochlorine pesticides and a laboratory-prepared mixture of 36 currently used pesticides – in concentration response and evaluated for cytotoxicity. On average, the two mixtures exhibited a similar range of in vitro cytotoxicity and showed considerable inter-individual variability across screened cell lines. However, when in vitroto-in vivo extrapolation (IVIVE) coupled with reverse dosimetry was employed to convert the in vitro cytotoxic concentrations to oral equivalent doses and compared to the upper bound of predicted human exposure, we found that a nominally more cytotoxic chlorinated pesticide mixture is expected to have greater margin of safety (more than 5 orders of magnitude) as compared to the current use pesticide mixture (less than 2 orders of magnitude) due primarily to differences in exposure predictions. Multivariate genome-wide association mapping revealed an association between the toxicity of current use pesticide mixture and a polymorphism in rs1947825 in C17orf54. We conclude that a combination of in vitro human population-based cytotoxicity screening followed by dosimetric adjustment and comparative population genomics analyses enables quantitative evaluation of human health hazard from complex environmental mixtures. Additionally, such an approach yields testable hypotheses regarding potential toxicity mechanisms. PMID:26386728

Sonic Boom Modeling Technical Challenge

NASA Technical Reports Server (NTRS)

Sullivan, Brenda M.

2007-01-01

This viewgraph presentation reviews the technical challenges in modeling sonic booms. The goal of this program is to develop knowledge, capabilities and technologies to enable overland supersonic flight. The specific objectives of the modeling are: (1) Develop and validate sonic boom propagation model through realistic atmospheres, including effects of turbulence (2) Develop methods enabling prediction of response of and acoustic transmission into structures impacted by sonic booms (3) Develop and validate psychoacoustic model of human response to sonic booms under both indoor and outdoor listening conditions, using simulators.

Free will and punishment: a mechanistic view of human nature reduces retribution.

PubMed

Shariff, Azim F; Greene, Joshua D; Karremans, Johan C; Luguri, Jamie B; Clark, Cory J; Schooler, Jonathan W; Baumeister, Roy F; Vohs, Kathleen D

2014-08-01

If free-will beliefs support attributions of moral responsibility, then reducing these beliefs should make people less retributive in their attitudes about punishment. Four studies tested this prediction using both measured and manipulated free-will beliefs. Study 1 found that people with weaker free-will beliefs endorsed less retributive, but not consequentialist, attitudes regarding punishment of criminals. Subsequent studies showed that learning about the neural bases of human behavior, through either lab-based manipulations or attendance at an undergraduate neuroscience course, reduced people's support for retributive punishment (Studies 2-4). These results illustrate that exposure to debates about free will and to scientific research on the neural basis of behavior may have consequences for attributions of moral responsibility. © The Author(s) 2014.

Connectivity Predicts Deep Brain Stimulation Outcome in Parkinson Disease

PubMed Central

Horn, Andreas; Reich, Martin; Vorwerk, Johannes; Li, Ningfei; Wenzel, Gregor; Fang, Qianqian; Schmitz-Hübsch, Tanja; Nickl, Robert; Kupsch, Andreas; Volkmann, Jens; Kühn, Andrea A.; Fox, Michael D.

2018-01-01

Objective The benefit of deep brain stimulation (DBS) for Parkinson disease (PD) may depend on connectivity between the stimulation site and other brain regions, but which regions and whether connectivity can predict outcome in patients remain unknown. Here, we identify the structural and functional connectivity profile of effective DBS to the subthalamic nucleus (STN) and test its ability to predict outcome in an independent cohort. Methods A training dataset of 51 PD patients with STN DBS was combined with publicly available human connectome data (diffusion tractography and resting state functional connectivity) to identify connections reliably associated with clinical improvement (motor score of the Unified Parkinson Disease Rating Scale [UPDRS]). This connectivity profile was then used to predict outcome in an independent cohort of 44 patients from a different center. Results In the training dataset, connectivity between the DBS electrode and a distributed network of brain regions correlated with clinical response including structural connectivity to supplementary motor area and functional anticorrelation to primary motor cortex (p<0.001). This same connectivity profile predicted response in an independent patient cohort (p<0.01). Structural and functional connectivity were independent predictors of clinical improvement (p<0.001) and estimated response in individual patients with an average error of 15% UPDRS improvement. Results were similar using connectome data from normal subjects or a connectome age, sex, and disease matched to our DBS patients. Interpretation Effective STN DBS for PD is associated with a specific connectivity profile that can predict clinical outcome across independent cohorts. This prediction does not require specialized imaging in PD patients themselves. PMID:28586141

Metabolic enzyme microarray coupled with miniaturized cell-culture array technology for high-throughput toxicity screening.

PubMed

Lee, Moo-Yeal; Dordick, Jonathan S; Clark, Douglas S

2010-01-01

Due to poor drug candidate safety profiles that are often identified late in the drug development process, the clinical progression of new chemical entities to pharmaceuticals remains hindered, thus resulting in the high cost of drug discovery. To accelerate the identification of safer drug candidates and improve the clinical progression of drug candidates to pharmaceuticals, it is important to develop high-throughput tools that can provide early-stage predictive toxicology data. In particular, in vitro cell-based systems that can accurately mimic the human in vivo response and predict the impact of drug candidates on human toxicology are needed to accelerate the assessment of drug candidate toxicity and human metabolism earlier in the drug development process. The in vitro techniques that provide a high degree of human toxicity prediction will be perhaps more important in cosmetic and chemical industries in Europe, as animal toxicity testing is being phased out entirely in the immediate future.We have developed a metabolic enzyme microarray (the Metabolizing Enzyme Toxicology Assay Chip, or MetaChip) and a miniaturized three-dimensional (3D) cell-culture array (the Data Analysis Toxicology Assay Chip, or DataChip) for high-throughput toxicity screening of target compounds and their metabolic enzyme-generated products. The human or rat MetaChip contains an array of encapsulated metabolic enzymes that is designed to emulate the metabolic reactions in the human or rat liver. The human or rat DataChip contains an array of 3D human or rat cells encapsulated in alginate gels for cell-based toxicity screening. By combining the DataChip with the complementary MetaChip, in vitro toxicity results are obtained that correlate well with in vivo rat data.

Chemical combination effects predict connectivity in biological systems

PubMed Central

Lehár, Joseph; Zimmermann, Grant R; Krueger, Andrew S; Molnar, Raymond A; Ledell, Jebediah T; Heilbut, Adrian M; Short, Glenn F; Giusti, Leanne C; Nolan, Garry P; Magid, Omar A; Lee, Margaret S; Borisy, Alexis A; Stockwell, Brent R; Keith, Curtis T

2007-01-01

Efforts to construct therapeutically useful models of biological systems require large and diverse sets of data on functional connections between their components. Here we show that cellular responses to combinations of chemicals reveal how their biological targets are connected. Simulations of pathways with pairs of inhibitors at varying doses predict distinct response surface shapes that are reproduced in a yeast experiment, with further support from a larger screen using human tumour cells. The response morphology yields detailed connectivity constraints between nearby targets, and synergy profiles across many combinations show relatedness between targets in the whole network. Constraints from chemical combinations complement genetic studies, because they probe different cellular components and can be applied to disease models that are not amenable to mutagenesis. Chemical probes also offer increased flexibility, as they can be continuously dosed, temporally controlled, and readily combined. After extending this initial study to cover a wider range of combination effects and pathway topologies, chemical combinations may be used to refine network models or to identify novel targets. This response surface methodology may even apply to non-biological systems where responses to targeted perturbations can be measured. PMID:17332758

Microdose-Induced Drug–DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice

DOE PAGES

Zimmermann, Maike; Wang, Si-Si; Zhang, Hongyong; ...

2016-11-30

Here, we report progress on predicting tumor response to platinum-based chemotherapy with a novel mass spectrometry approach. Fourteen bladder cancer patients were administered one diagnostic microdose each of [ 14C]carboplatin (1% of the therapeutic dose). Carboplatin–DNA adducts were quantified by accelerator mass spectrometry in blood and tumor samples collected within 24 hours, and compared with subsequent chemotherapy response. Patients with the highest adduct levels were responders, but not all responders had high adduct levels. Four patient-derived bladder cancer xenograft mouse models were used to test the possibility that another drug in the regimen could cause a response. The mice weremore » dosed with [ 14C]carboplatin or [ 14C]gemcitabine and the resulting drug–DNA adduct levels were compared with tumor response to chemotherapy. At least one of the drugs had to induce high drug–DNA adduct levels or create a synergistic increase in overall adducts to prompt a corresponding therapeutic response, demonstrating proof-of-principle for drug–DNA adducts as predictive biomarkers.« less

Microdose-Induced Drug–DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zimmermann, Maike; Wang, Si-Si; Zhang, Hongyong

Here, we report progress on predicting tumor response to platinum-based chemotherapy with a novel mass spectrometry approach. Fourteen bladder cancer patients were administered one diagnostic microdose each of [ 14C]carboplatin (1% of the therapeutic dose). Carboplatin–DNA adducts were quantified by accelerator mass spectrometry in blood and tumor samples collected within 24 hours, and compared with subsequent chemotherapy response. Patients with the highest adduct levels were responders, but not all responders had high adduct levels. Four patient-derived bladder cancer xenograft mouse models were used to test the possibility that another drug in the regimen could cause a response. The mice weremore » dosed with [ 14C]carboplatin or [ 14C]gemcitabine and the resulting drug–DNA adduct levels were compared with tumor response to chemotherapy. At least one of the drugs had to induce high drug–DNA adduct levels or create a synergistic increase in overall adducts to prompt a corresponding therapeutic response, demonstrating proof-of-principle for drug–DNA adducts as predictive biomarkers.« less

Microdose-Induced Drug-DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice.

PubMed

Zimmermann, Maike; Wang, Si-Si; Zhang, Hongyong; Lin, Tzu-Yin; Malfatti, Michael; Haack, Kurt; Ognibene, Ted; Yang, Hongyuan; Airhart, Susan; Turteltaub, Kenneth W; Cimino, George D; Tepper, Clifford G; Drakaki, Alexandra; Chamie, Karim; de Vere White, Ralph; Pan, Chong-Xian; Henderson, Paul T

2017-02-01

We report progress on predicting tumor response to platinum-based chemotherapy with a novel mass spectrometry approach. Fourteen bladder cancer patients were administered one diagnostic microdose each of [ 14 C]carboplatin (1% of the therapeutic dose). Carboplatin-DNA adducts were quantified by accelerator mass spectrometry in blood and tumor samples collected within 24 hours, and compared with subsequent chemotherapy response. Patients with the highest adduct levels were responders, but not all responders had high adduct levels. Four patient-derived bladder cancer xenograft mouse models were used to test the possibility that another drug in the regimen could cause a response. The mice were dosed with [ 14 C]carboplatin or [ 14 C]gemcitabine and the resulting drug-DNA adduct levels were compared with tumor response to chemotherapy. At least one of the drugs had to induce high drug-DNA adduct levels or create a synergistic increase in overall adducts to prompt a corresponding therapeutic response, demonstrating proof-of-principle for drug-DNA adducts as predictive biomarkers. Mol Cancer Ther; 16(2); 376-87. ©2016 AACR. ©2016 American Association for Cancer Research.

Refinement of a limit cycle oscillator model of the effects of light on the human circadian pacemaker

NASA Technical Reports Server (NTRS)

Jewett, M. E.; Kronauer, R. E.; Brown, E. N. (Principal Investigator)

1998-01-01

In 1990, Kronauer proposed a mathematical model of the effects of light on the human circadian pacemaker. Although this model predicted many general features of the response of the human circadian pacemaker to light exposure, additional data now available enable us to refine the original model. We first refined the original model by incorporating the results of a dose response curve to light into the model's predicted relationship between light intensity and the strength of the drive onto the pacemaker. Data from three bright light phase resetting experiments were then used to refine the amplitude recovery characteristics of the model. Finally, the model was tested and further refined using data from an extensive phase resetting experiment in which a 3-cycle bright light stimulus was presented against a background of dim light. In order to describe the results of the four resetting experiments, the following major refinements to the original model were necessary: (i) the relationship between light intensity (I) and drive onto the pacemaker was reduced from I1/3 to I0.23 for light levels between 150 and 10,000 lux; (ii) the van der Pol oscillator from the original model was replaced with a higher-order limit cycle oscillator so that amplitude recovery is slower near the singularity and faster near the limit cycle; (iii) a direct effect of light on circadian period (tau x) was incorporated into the model such that as I increases, tau x decreases, which is in accordance with "Aschoff's rule". This refined model generates the following testable predictions: it should be difficult to enhance normal circadian amplitude via bright light; near the critical point of a type 0 phase response curve (PRC) the slope should be steeper than it is in a type 1 PRC; and circadian period measured during forced desynchrony should be directly affected by ambient light intensity.

The evolution of predictive adaptive responses in human life history

PubMed Central

Nettle, Daniel; Frankenhuis, Willem E.; Rickard, Ian J.

2013-01-01

Many studies in humans have shown that adverse experience in early life is associated with accelerated reproductive timing, and there is comparative evidence for similar effects in other animals. There are two different classes of adaptive explanation for associations between early-life adversity and accelerated reproduction, both based on the idea of predictive adaptive responses (PARs). According to external PAR hypotheses, early-life adversity provides a ‘weather forecast’ of the environmental conditions into which the individual will mature, and it is adaptive for the individual to develop an appropriate phenotype for this anticipated environment. In internal PAR hypotheses, early-life adversity has a lasting negative impact on the individual's somatic state, such that her health is likely to fail more rapidly as she gets older, and there is an advantage to adjusting her reproductive schedule accordingly. We use a model of fluctuating environments to derive evolveability conditions for acceleration of reproductive timing in response to early-life adversity in a long-lived organism. For acceleration to evolve via the external PAR process, early-life cues must have a high degree of validity and the level of annual autocorrelation in the individual's environment must be almost perfect. For acceleration to evolve via the internal PAR process requires that early-life experience must determine a significant fraction of the variance in survival prospects in adulthood. The two processes are not mutually exclusive, and mechanisms for calibrating reproductive timing on the basis of early experience could evolve through a combination of the predictive value of early-life adversity for the later environment and its negative impact on somatic state. PMID:23843395

High Proliferation Predicts Pathological Complete Response to Neoadjuvant Chemotherapy in Early Breast Cancer

PubMed Central

Lluch, Ana; Ribelles, Nuria; Anton-Torres, Antonio; Sanchez-Rovira, Pedro; Albanell, Joan; Calvo, Lourdes; García-Asenjo, Jose Antonio Lopez; Palacios, Jose; Chacon, Jose Ignacio; Ruiz, Amparo; De la Haba-Rodriguez, Juan; Segui-Palmer, Miguel A.; Cirauqui, Beatriz; Margeli, Mireia; Plazaola, Arrate; Barnadas, Agusti; Casas, Maribel; Caballero, Rosalia; Carrasco, Eva; Rojo, Federico

2016-01-01

Background. In the neoadjuvant setting, changes in the proliferation marker Ki67 are associated with primary endocrine treatment efficacy, but its value as a predictor of response to chemotherapy is still controversial. Patients and Methods. We analyzed 262 patients with centralized basal Ki67 immunohistochemical evaluation derived from 4 GEICAM (Spanish Breast Cancer Group) clinical trials of neoadjuvant chemotherapy for breast cancer. The objective was to identify the optimal threshold for Ki67 using the receiver-operating characteristic curve method to maximize its predictive value for chemotherapy benefit. We also evaluated the predictive role of the defined Ki67 cutoffs for molecular subtypes defined by estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). Results. A basal Ki67 cutpoint of 50% predicted pathological complete response (pCR). Patients with Ki67 >50% achieved a pCR rate of 40% (36 of 91) versus a pCR rate of 19% in patients with Ki67 ≤50% (33 of 171) (p = .0004). Ki67 predictive value was especially relevant in ER-HER2− and ER-HER2+ patients (pCR rates of 42% and 64%, respectively, in patients with Ki67 >50% versus 15% and 45%, respectively, in patients with Ki67 ≤50%; p = .0337 and .3238, respectively). Both multivariate analyses confirmed the independent predictive value of the Ki67 cutpoint of 50%. Conclusion. Basal Ki67 proliferation index >50% should be considered an independent predictive factor for pCR reached after neoadjuvant chemotherapy, suggesting that cell proliferation is a phenomenon closely related to chemosensitivity. These findings could help to identify a group of patients with a potentially favorable long-term prognosis. Implications for Practice: The use of basal Ki67 status as a predictive factor of chemotherapy benefit could facilitate the identification of a patient subpopulation with high probability of achieving pathological complete response when treated with primary chemotherapy, and thus with a potentially favorable long-term prognosis. PMID:26786263

Predicting the emetic liability of novel chemical entities: a comparative study.

PubMed

du Sert, Nathalie Percie; Holmes, Anthony M; Wallis, Rob; Andrews, Paul Lr

2012-03-01

Emesis is a multi-system reflex, which is usually investigated using in vivo models. The aim of the study is to compare the response induced by emetic compounds across species and investigate whether dogs, ferrets and rats are all similarly predictive of humans. A systematic review was carried out and relevant publications were identified from PubMed. The search was restricted to four species (human, dog, ferret, rat) and ten compounds representative of various mechanisms of emesis induction (apomorphine, cisplatin, cholecystokinin octapeptide, copper sulphate, cyclophosphamide, ipecacuanha, lithium chloride, morphine, nicotine, rolipram). 1046 publications were reviewed, and 311 were included, the main reason for exclusion was the lack of quantitative data. Emetic or pica data were extracted as incidence, intensity or latency. All three animal species identified emetic liability but interspecies differences for dose sensitivity were detected. These results suggest that emetic liability can be reliably identified in a common laboratory species such as the rat. However, to evaluate the characteristics of the emetic response, no animal species is a universal predictor of emetic liability and the choice of species should be an informed decision based on the type of compound investigated. Limitations relating to the conduct and reporting of emesis studies were identified, the main ones being the lack of comparable outcome measures between human and animal data, and the limited availability of human data in the public domain. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chemical reaction vector embeddings: towards predicting drug metabolism in the human gut microbiome.

PubMed

Mallory, Emily K; Acharya, Ambika; Rensi, Stefano E; Turnbaugh, Peter J; Bright, Roselie A; Altman, Russ B

2018-01-01

Bacteria in the human gut have the ability to activate, inactivate, and reactivate drugs with both intended and unintended effects. For example, the drug digoxin is reduced to the inactive metabolite dihydrodigoxin by the gut Actinobacterium E. lenta, and patients colonized with high levels of drug metabolizing strains may have limited response to the drug. Understanding the complete space of drugs that are metabolized by the human gut microbiome is critical for predicting bacteria-drug relationships and their effects on individual patient response. Discovery and validation of drug metabolism via bacterial enzymes has yielded >50 drugs after nearly a century of experimental research. However, there are limited computational tools for screening drugs for potential metabolism by the gut microbiome. We developed a pipeline for comparing and characterizing chemical transformations using continuous vector representations of molecular structure learned using unsupervised representation learning. We applied this pipeline to chemical reaction data from MetaCyc to characterize the utility of vector representations for chemical reaction transformations. After clustering molecular and reaction vectors, we performed enrichment analyses and queries to characterize the space. We detected enriched enzyme names, Gene Ontology terms, and Enzyme Consortium (EC) classes within reaction clusters. In addition, we queried reactions against drug-metabolite transformations known to be metabolized by the human gut microbiome. The top results for these known drug transformations contained similar substructure modifications to the original drug pair. This work enables high throughput screening of drugs and their resulting metabolites against chemical reactions common to gut bacteria.

From Pavlov to PTSD: The extinction of conditioned fear in rodents, humans, and in anxiety disorders

PubMed Central

VanElzakker, Michael B.; Dahlgren, M. Kathryn; Davis, F. Caroline; Dubois, Stacey; Shin, Lisa M.

2014-01-01

Nearly 100 years ago, Ivan Pavlov demonstrated that dogs could learn to use a neutral cue to predict a biologically relevant event: after repeated predictive pairings, Pavlov's dogs were conditioned to anticipate food at the sound of a bell, which caused them to salivate. Like sustenance, danger is biologically relevant, and neutral cues can take on great salience when they predict a threat to survival. In anxiety disorders such as posttraumatic stress disorder (PTSD), this type of conditioned fear fails to extinguish, and reminders of traumatic events can cause pathological conditioned fear responses for decades after danger has passed. In this review, we use fear conditioning and extinction studies to draw a direct line from Pavlov to PTSD and other anxiety disorders. We explain how rodent studies have informed neuroimaging studies of healthy humans and humans with PTSD. We describe several genes that have been linked to both PTSD and fear conditioning and extinction and explain how abnormalities in fear conditioning or extinction may reflect a general biomarker of anxiety disorders. Finally, we explore drug and neuromodulation treatments that may enhance therapeutic extinction in anxiety disorders. PMID:24321650

From Pavlov to PTSD: the extinction of conditioned fear in rodents, humans, and anxiety disorders.

PubMed

VanElzakker, Michael B; Dahlgren, M Kathryn; Davis, F Caroline; Dubois, Stacey; Shin, Lisa M

2014-09-01

Nearly 100 years ago, Ivan Pavlov demonstrated that dogs could learn to use a neutral cue to predict a biologically relevant event: after repeated predictive pairings, Pavlov's dogs were conditioned to anticipate food at the sound of a bell, which caused them to salivate. Like sustenance, danger is biologically relevant, and neutral cues can take on great salience when they predict a threat to survival. In anxiety disorders such as posttraumatic stress disorder (PTSD), this type of conditioned fear fails to extinguish, and reminders of traumatic events can cause pathological conditioned fear responses for decades after danger has passed. In this review, we use fear conditioning and extinction studies to draw a direct line from Pavlov to PTSD and other anxiety disorders. We explain how rodent studies have informed neuroimaging studies of healthy humans and humans with PTSD. We describe several genes that have been linked to both PTSD and fear conditioning and extinction and explain how abnormalities in fear conditioning or extinction may reflect a general biomarker of anxiety disorders. Finally, we explore drug and neuromodulation treatments that may enhance therapeutic extinction in anxiety disorders. Copyright © 2013 Elsevier Inc. All rights reserved.

Transcriptomic characterization of the novel avian-origin influenza A (H7N9) virus: specific host response and responses intermediate between avian (H5N1 and H7N7) and human (H3N2) viruses and implications for treatment options.

PubMed

Josset, Laurence; Zeng, Hui; Kelly, Sara M; Tumpey, Terrence M; Katze, Michael G

2014-02-04

A novel avian-origin H7N9 influenza A virus (IAV) emerged in China in 2013, causing mild to lethal human respiratory infections. H7N9 originated with multiple reassortment events between avian viruses and carries genetic markers of human adaptation. Determining whether H7N9 induces a host response closer to that with human or avian IAV is important in order to better characterize this emerging virus. Here we compared the human lung epithelial cell response to infection with A/Anhui/01/13 (H7N9) or highly pathogenic avian-origin H5N1, H7N7, or human seasonal H3N2 IAV. The transcriptomic response to H7N9 was highly specific to this strain but was more similar to the response to human H3N2 than to that to other avian IAVs. H7N9 and H3N2 both elicited responses related to eicosanoid signaling and chromatin modification, whereas H7N9 specifically induced genes regulating the cell cycle and transcription. Among avian IAVs, the response to H7N9 was closest to that elicited by H5N1 virus. Host responses common to H7N9 and the other avian viruses included the lack of induction of the antigen presentation pathway and reduced proinflammatory cytokine induction compared to that with H3N2. Repression of these responses could have an important impact on the immunogenicity and virulence of H7N9 in humans. Finally, using a genome-based drug repurposing approach, we identified several drugs predicted to regulate the host response to H7N9 that may act as potential antivirals, including several kinase inhibitors, as well as FDA-approved drugs, such as troglitazone and minocycline. Importantly, we validated that minocycline inhibited H7N9 replication in vitro, suggesting that our computational approach holds promise for identifying novel antivirals. Whether H7N9 will be the next pandemic influenza virus or will persist and sporadically infect humans from its avian reservoir, similar to H5N1, is not known yet. High-throughput profiling of the host response to infection allows rapid characterization of virus-host interactions and generates many hypotheses that will accelerate understanding and responsiveness to this potential threat. We show that the cellular response to H7N9 virus is closer to that induced by H3N2 than to that induced by H5N1, reflecting the potential of this new virus for adaptation to humans. Importantly, dissecting the host response to H7N9 may guide host-directed antiviral development.

The value of integrating pre-clinical data to predict nausea and vomiting risk in humans as illustrated by AZD3514, a novel androgen receptor modulator

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grant, Claire, E-mail: claire.grant@astrazeneca.com; Ewart, Lorna; Muthas, Daniel

Nausea and vomiting are components of a complex mechanism that signals food avoidance and protection of the body against the absorption of ingested toxins. This response can also be triggered by pharmaceuticals. Predicting clinical nausea and vomiting liability for pharmaceutical agents based on pre-clinical data can be problematic as no single animal model is a universal predictor. Moreover, efforts to improve models are hampered by the lack of translational animal and human data in the public domain. AZD3514 is a novel, orally-administered compound that inhibits androgen receptor signaling and down-regulates androgen receptor expression. Here we have explored the utility ofmore » integrating data from several pre-clinical models to predict nausea and vomiting in the clinic. Single and repeat doses of AZD3514 resulted in emesis, salivation and gastrointestinal disturbances in the dog, and inhibited gastric emptying in rats after a single dose. AZD3514, at clinically relevant exposures, induced dose-responsive “pica” behaviour in rats after single and multiple daily doses, and induced retching and vomiting behaviour in ferrets after a single dose. We compare these data with the clinical manifestation of nausea and vomiting encountered in patients with castration-resistant prostate cancer receiving AZD3514. Our data reveal a striking relationship between the pre-clinical observations described and the experience of nausea and vomiting in the clinic. In conclusion, the emetic nature of AZD3514 was predicted across a range of pre-clinical models, and the approach presented provides a valuable framework for predicition of clinical nausea and vomiting. - Highlights: • Integrated pre-clinical data can be used to predict clinical nausea and vomiting. • Data integrated from standard toxicology studies is sufficient to make a prediction. • The use of the nausea algorithm developed by Parkinson (2012) aids the prediction. • Additional pre-clinical studies can be used to confirm and quantify the risk.« less

Prenatal stress effects in a wild, long-lived primate: predictive adaptive responses in an unpredictable environment.

PubMed

Berghänel, Andreas; Heistermann, Michael; Schülke, Oliver; Ostner, Julia

2016-09-28

Prenatal maternal stress affects offspring phenotype in numerous species including humans, but it is debated whether these effects are evolutionarily adaptive. Relating stress to adverse conditions, current explanations invoke either short-term developmental constraints on offspring phenotype resulting in decelerated growth to avoid starvation, or long-term predictive adaptive responses (PARs) resulting in accelerated growth and reproduction in response to reduced life expectancies. Two PAR subtypes were proposed, acting either on predicted internal somatic states or predicted external environmental conditions, but because both affect phenotypes similarly, they are largely indistinguishable. Only external (not internal) PARs rely on high environmental stability particularly in long-lived species. We report on a crucial test case in a wild long-lived mammal, the Assamese macaque (Macaca assamensis), which evolved and lives in an unpredictable environment where external PARs are probably not advantageous. We quantified food availability, growth, motor skills, maternal caretaking style and maternal physiological stress from faecal glucocorticoid measures. Prenatal maternal stress was negatively correlated to prenatal food availability and led to accelerated offspring growth accompanied by decelerated motor skill acquisition and reduced immune function. These results support the 'internal PAR' theory, which stresses the role of stable adverse internal somatic states rather than stable external environments. © 2016 The Author(s).

Mathematics as a Conduit for Translational Research in Post-Traumatic Osteoarthritis

PubMed Central

Ayati, Bruce P.; Kapitanov, Georgi I.; Coleman, Mitchell C.; Anderson, Donald D.; Martin, James A.

2016-01-01

Biomathematical models offer a powerful method of clarifying complex temporal interactions and the relationships among multiple variables in a system. We present a coupled in silico biomathematical model of articular cartilage degeneration in response to impact and/or aberrant loading such as would be associated with injury to an articular joint. The model incorporates fundamental biological and mechanical information obtained from explant and small animal studies to predict post-traumatic osteoarthritis (PTOA) progression, with an eye toward eventual application in human patients. In this sense, we refer to the mathematics as a “conduit of translation”. The new in silico framework presented in this paper involves a biomathematical model for the cellular and biochemical response to strains computed using finite element analysis. The model predicts qualitative responses presently, utilizing system parameter values largely taken from the literature. To contribute to accurate predictions, models need to be accurately parameterized with values that are based on solid science. We discuss a parameter identification protocol that will enable us to make increasingly accurate predictions of PTOA progression using additional data from smaller scale explant and small animal assays as they become available. By distilling the data from the explant and animal assays into parameters for biomathematical models, mathematics can translate experimental data to clinically relevant knowledge. PMID:27653021

Neuronal mechanisms underlying differences in spatial resolution between darks and lights in human vision.

PubMed

Pons, Carmen; Mazade, Reece; Jin, Jianzhong; Dul, Mitchell W; Zaidi, Qasim; Alonso, Jose-Manuel

2017-12-01

Artists and astronomers noticed centuries ago that humans perceive dark features in an image differently from light ones; however, the neuronal mechanisms underlying these dark/light asymmetries remained unknown. Based on computational modeling of neuronal responses, we have previously proposed that such perceptual dark/light asymmetries originate from a luminance/response saturation within the ON retinal pathway. Consistent with this prediction, here we show that stimulus conditions that increase ON luminance/response saturation (e.g., dark backgrounds) or its effect on light stimuli (e.g., optical blur) impair the perceptual discrimination and salience of light targets more than dark targets in human vision. We also show that, in cat visual cortex, the magnitude of the ON luminance/response saturation remains relatively constant under a wide range of luminance conditions that are common indoors, and only shifts away from the lowest luminance contrasts under low mesopic light. Finally, we show that the ON luminance/response saturation affects visual salience mostly when the high spatial frequencies of the image are reduced by poor illumination or optical blur. Because both low luminance and optical blur are risk factors in myopia, our results suggest a possible neuronal mechanism linking myopia progression with the function of the ON visual pathway.

Neuronal mechanisms underlying differences in spatial resolution between darks and lights in human vision

PubMed Central

Pons, Carmen; Mazade, Reece; Jin, Jianzhong; Dul, Mitchell W.; Zaidi, Qasim; Alonso, Jose-Manuel

2017-01-01

Artists and astronomers noticed centuries ago that humans perceive dark features in an image differently from light ones; however, the neuronal mechanisms underlying these dark/light asymmetries remained unknown. Based on computational modeling of neuronal responses, we have previously proposed that such perceptual dark/light asymmetries originate from a luminance/response saturation within the ON retinal pathway. Consistent with this prediction, here we show that stimulus conditions that increase ON luminance/response saturation (e.g., dark backgrounds) or its effect on light stimuli (e.g., optical blur) impair the perceptual discrimination and salience of light targets more than dark targets in human vision. We also show that, in cat visual cortex, the magnitude of the ON luminance/response saturation remains relatively constant under a wide range of luminance conditions that are common indoors, and only shifts away from the lowest luminance contrasts under low mesopic light. Finally, we show that the ON luminance/response saturation affects visual salience mostly when the high spatial frequencies of the image are reduced by poor illumination or optical blur. Because both low luminance and optical blur are risk factors in myopia, our results suggest a possible neuronal mechanism linking myopia progression with the function of the ON visual pathway. PMID:29196762

Morphometric Characterization of Rat and Human Alveolar Macrophage Cell Models and their Response to Amiodarone using High Content Image Analysis.

PubMed

Hoffman, Ewelina; Patel, Aateka; Ball, Doug; Klapwijk, Jan; Millar, Val; Kumar, Abhinav; Martin, Abigail; Mahendran, Rhamiya; Dailey, Lea Ann; Forbes, Ben; Hutter, Victoria

2017-12-01

Progress to the clinic may be delayed or prevented when vacuolated or "foamy" alveolar macrophages are observed during non-clinical inhalation toxicology assessment. The first step in developing methods to study this response in vitro is to characterize macrophage cell lines and their response to drug exposures. Human (U937) and rat (NR8383) cell lines and primary rat alveolar macrophages obtained by bronchoalveolar lavage were characterized using high content fluorescence imaging analysis quantification of cell viability, morphometry, and phospholipid and neutral lipid accumulation. Cell health, morphology and lipid content were comparable (p < 0.05) for both cell lines and the primary macrophages in terms of vacuole number, size and lipid content. Responses to amiodarone, a known inducer of phospholipidosis, required analysis of shifts in cell population profiles (the proportion of cells with elevated vacuolation or lipid content) rather than average population data which was insensitive to the changes observed. A high content image analysis assay was developed and used to provide detailed morphological characterization of rat and human alveolar-like macrophages and their response to a phospholipidosis-inducing agent. This provides a basis for development of assays to predict or understand macrophage vacuolation following inhaled drug exposure.

Validation of the thermophysiological model by Fiala for prediction of local skin temperatures

NASA Astrophysics Data System (ADS)

Martínez, Natividad; Psikuta, Agnes; Kuklane, Kalev; Quesada, José Ignacio Priego; de Anda, Rosa María Cibrián Ortiz; Soriano, Pedro Pérez; Palmer, Rosario Salvador; Corberán, José Miguel; Rossi, René Michel; Annaheim, Simon

2016-12-01

The most complete and realistic physiological data are derived from direct measurements during human experiments; however, they present some limitations such as ethical concerns, time and cost burden. Thermophysiological models are able to predict human thermal response in a wide range of environmental conditions, but their use is limited due to lack of validation. The aim of this work was to validate the thermophysiological model by Fiala for prediction of local skin temperatures against a dedicated database containing 43 different human experiments representing a wide range of conditions. The validation was conducted based on root-mean-square deviation (rmsd) and bias. The thermophysiological model by Fiala showed a good precision when predicting core and mean skin temperature (rmsd 0.26 and 0.92 °C, respectively) and also local skin temperatures for most body sites (average rmsd for local skin temperatures 1.32 °C). However, an increased deviation of the predictions was observed for the forehead skin temperature (rmsd of 1.63 °C) and for the thigh during exercising exposures (rmsd of 1.41 °C). Possible reasons for the observed deviations are lack of information on measurement circumstances (hair, head coverage interference) or an overestimation of the sweat evaporative cooling capacity for the head and thigh, respectively. This work has highlighted the importance of collecting details about the clothing worn and how and where the sensors were attached to the skin for achieving more precise results in the simulations.

Resolving the paradox of suboptimal choice.

PubMed

Zentall, Thomas R

2016-01-01

When humans engage in commercial (totally probabilistic) gambling they are making suboptimal choices because the return is generally less than the investment. This review (a) examines the literature on pigeon suboptimal choice, (b) describes the conditions under which it occurs, (c) identifies the mechanisms that appear to be responsible for the effect, and (d) suggests that similar processes may be able to account for analogous suboptimal choice when humans engage in commercial gambling. Pigeons show suboptimal choice when they choose between 1 alternative that 20% of the time provides them with a signal that they will always get fed or 80% of the time with a signal that they will not get fed (overall 20% reinforcement) and a second alternative that 100% of the time provides them with a signal that they will get fed 50% of the time (overall 50% reinforcement). The pigeons' strong preference for the suboptimal choice was investigated in a series of experiments that found the preference for the suboptimal alternative was determined by the value of the signal that predicted reinforcement, rather its frequency and that the frequency of the signal that predicted nonreinforcement had little effect on the suboptimal choice. Paradoxically, this account makes the prediction that pigeons will be indifferent between an alternative that 50% of the time provides a fully predictive stimulus for reinforcement and an alternative that 100% of the time provides a fully predictive stimulus for reinforcement. The similarities and differences of this suboptimal choice task to human gambling are discussed. (c) 2016 APA, all rights reserved).

Development and validation of immune dysfunction score to predict 28-day mortality of sepsis patients

PubMed Central

Fang, Wen-Feng; Douglas, Ivor S.; Chen, Yu-Mu; Lin, Chiung-Yu; Kao, Hsu-Ching; Fang, Ying-Tang; Huang, Chi-Han; Chang, Ya-Ting; Huang, Kuo-Tung; Wang, Yi-His; Wang, Chin-Chou

2017-01-01

Background Sepsis-induced immune dysfunction ranging from cytokines storm to immunoparalysis impacts outcomes. Monitoring immune dysfunction enables better risk stratification and mortality prediction and is mandatory before widely application of immunoadjuvant therapies. We aimed to develop and validate a scoring system according to patients’ immune dysfunction status for 28-day mortality prediction. Methods A prospective observational study from a cohort of adult sepsis patients admitted to ICU between August 2013 and June 2016 at Kaohsiung Chang Gung Memorial Hospital in Taiwan. We evaluated immune dysfunction status through measurement of baseline plasma Cytokine levels, Monocyte human leukocyte-DR expression by flow cytometry, and stimulated immune response using post LPS stimulated cytokine elevation ratio. An immune dysfunction score was created for 28-day mortality prediction and was validated. Results A total of 151 patients were enrolled. Data of the first consecutive 106 septic patients comprised the training cohort, and of other 45 patients comprised the validation cohort. Among the 106 patients, 21 died and 85 were still alive on day 28 after ICU admission. (mortality rate, 19.8%). Independent predictive factors revealed via multivariate logistic regression analysis included segmented neutrophil-to-monocyte ratio, granulocyte-colony stimulating factor, interleukin-10, and monocyte human leukocyte antigen-antigen D–related levels, all of which were selected to construct the score, which predicted 28-day mortality with area under the curve of 0.853 and 0.789 in the training and validation cohorts, respectively. Conclusions The immune dysfunction scoring system developed here included plasma granulocyte-colony stimulating factor level, interleukin-10 level, serum segmented neutrophil-to-monocyte ratio, and monocyte human leukocyte antigen-antigen D–related expression appears valid and reproducible for predicting 28-day mortality. PMID:29073262

Novelty and Inductive Generalization in Human Reinforcement Learning.

PubMed

Gershman, Samuel J; Niv, Yael

2015-07-01

In reinforcement learning (RL), a decision maker searching for the most rewarding option is often faced with the question: What is the value of an option that has never been tried before? One way to frame this question is as an inductive problem: How can I generalize my previous experience with one set of options to a novel option? We show how hierarchical Bayesian inference can be used to solve this problem, and we describe an equivalence between the Bayesian model and temporal difference learning algorithms that have been proposed as models of RL in humans and animals. According to our view, the search for the best option is guided by abstract knowledge about the relationships between different options in an environment, resulting in greater search efficiency compared to traditional RL algorithms previously applied to human cognition. In two behavioral experiments, we test several predictions of our model, providing evidence that humans learn and exploit structured inductive knowledge to make predictions about novel options. In light of this model, we suggest a new interpretation of dopaminergic responses to novelty. Copyright © 2015 Cognitive Science Society, Inc.

Novelty and Inductive Generalization in Human Reinforcement Learning

PubMed Central

Gershman, Samuel J.; Niv, Yael

2015-01-01

In reinforcement learning, a decision maker searching for the most rewarding option is often faced with the question: what is the value of an option that has never been tried before? One way to frame this question is as an inductive problem: how can I generalize my previous experience with one set of options to a novel option? We show how hierarchical Bayesian inference can be used to solve this problem, and describe an equivalence between the Bayesian model and temporal difference learning algorithms that have been proposed as models of reinforcement learning in humans and animals. According to our view, the search for the best option is guided by abstract knowledge about the relationships between different options in an environment, resulting in greater search efficiency compared to traditional reinforcement learning algorithms previously applied to human cognition. In two behavioral experiments, we test several predictions of our model, providing evidence that humans learn and exploit structured inductive knowledge to make predictions about novel options. In light of this model, we suggest a new interpretation of dopaminergic responses to novelty. PMID:25808176

Mesenchymal Inflammation Drives Genotoxic Stress in Hematopoietic Stem Cells and Predicts Disease Evolution in Human Pre-leukemia.

PubMed

Zambetti, Noemi A; Ping, Zhen; Chen, Si; Kenswil, Keane J G; Mylona, Maria A; Sanders, Mathijs A; Hoogenboezem, Remco M; Bindels, Eric M J; Adisty, Maria N; Van Strien, Paulina M H; van der Leije, Cindy S; Westers, Theresia M; Cremers, Eline M P; Milanese, Chiara; Mastroberardino, Pier G; van Leeuwen, Johannes P T M; van der Eerden, Bram C J; Touw, Ivo P; Kuijpers, Taco W; Kanaar, Roland; van de Loosdrecht, Arjan A; Vogl, Thomas; Raaijmakers, Marc H G P

2016-11-03

Mesenchymal niche cells may drive tissue failure and malignant transformation in the hematopoietic system, but the underlying molecular mechanisms and relevance to human disease remain poorly defined. Here, we show that perturbation of mesenchymal cells in a mouse model of the pre-leukemic disorder Shwachman-Diamond syndrome (SDS) induces mitochondrial dysfunction, oxidative stress, and activation of DNA damage responses in hematopoietic stem and progenitor cells. Massive parallel RNA sequencing of highly purified mesenchymal cells in the SDS mouse model and a range of human pre-leukemic syndromes identified p53-S100A8/9-TLR inflammatory signaling as a common driving mechanism of genotoxic stress. Transcriptional activation of this signaling axis in the mesenchymal niche predicted leukemic evolution and progression-free survival in myelodysplastic syndrome (MDS), the principal leukemia predisposition syndrome. Collectively, our findings identify mesenchymal niche-induced genotoxic stress in heterotypic stem and progenitor cells through inflammatory signaling as a targetable determinant of disease outcome in human pre-leukemia. Copyright © 2016 Elsevier Inc. All rights reserved.

ESR (electron spin resonance)-determined osmotic behavior of bull spermatozoa

DOE Office of Scientific and Technical Information (OSTI.GOV)

Du, J.; Kleinhans, F.W.; Spitzer, V.J.

1990-01-01

Our laboratories are pursuing a fundamental approach to the problems of semen cryopreservation. For many cell types (human red cells, yeast, HeLa) it has been demonstrated that there is an optimum cooling rate for cryopreservation. Faster rates allow insufficient time for cell dehydration and result in intracellular ice formation and cell death. It is possible to predict this optimal rate provided that the cell acts as an ideal osmometer and several other cell parameters are known such as the membrane hydraulic conductivity. It is the purpose of this work to examine the osmotic response of bull sperm to sucrose andmore » NaCl utilizing electron spin resonance (ESR) to measure cell volume. For calibration purposes we also measured the ESR response of human red cells (RBC), the osmotic response of which is well documented with other methods. 15 refs., 1 fig.« less

A signal detection model predicts the effects of set size on visual search accuracy for feature, conjunction, triple conjunction, and disjunction displays

NASA Technical Reports Server (NTRS)

Eckstein, M. P.; Thomas, J. P.; Palmer, J.; Shimozaki, S. S.

2000-01-01

Recently, quantitative models based on signal detection theory have been successfully applied to the prediction of human accuracy in visual search for a target that differs from distractors along a single attribute (feature search). The present paper extends these models for visual search accuracy to multidimensional search displays in which the target differs from the distractors along more than one feature dimension (conjunction, disjunction, and triple conjunction displays). The model assumes that each element in the display elicits a noisy representation for each of the relevant feature dimensions. The observer combines the representations across feature dimensions to obtain a single decision variable, and the stimulus with the maximum value determines the response. The model accurately predicts human experimental data on visual search accuracy in conjunctions and disjunctions of contrast and orientation. The model accounts for performance degradation without resorting to a limited-capacity spatially localized and temporally serial mechanism by which to bind information across feature dimensions.

Acoustical transmission-line model of the middle-ear cavities and mastoid air cells.

PubMed

Keefe, Douglas H

2015-04-01

An acoustical transmission line model of the middle-ear cavities and mastoid air cell system (MACS) was constructed for the adult human middle ear with normal function. The air-filled cavities comprised the tympanic cavity, aditus, antrum, and MACS. A binary symmetrical airway branching model of the MACS was constructed using an optimization procedure to match the average total volume and surface area of human temporal bones. The acoustical input impedance of the MACS was calculated using a recursive procedure, and used to predict the input impedance of the middle-ear cavities at the location of the tympanic membrane. The model also calculated the ratio of the acoustical pressure in the antrum to the pressure in the middle-ear cavities at the location of the tympanic membrane. The predicted responses were sensitive to the magnitude of the viscothermal losses within the MACS. These predicted input impedance and pressure ratio functions explained the presence of multiple resonances reported in published data, which were not explained by existing MACS models.

Prediction and prevention of the next pandemic zoonosis

PubMed Central

Morse, Stephen S; Mazet, Jonna A K; Woolhouse, Mark; Parrish, Colin R; Carroll, Dennis; Karesh, William B; Zambrana-Torrelio, Carlos; Lipkin, W Ian; Daszak, Peter

2013-01-01

Most pandemics—eg, HIV/AIDS, severe acute respiratory syndrome, pandemic influenza—originate in animals, are caused by viruses, and are driven to emerge by ecological, behavioural, or socioeconomic changes. Despite their substantial effects on global public health and growing understanding of the process by which they emerge, no pandemic has been predicted before infecting human beings. We review what is known about the pathogens that emerge, the hosts that they originate in, and the factors that drive their emergence. We discuss challenges to their control and new efforts to predict pandemics, target surveillance to the most crucial interfaces, and identify prevention strategies. New mathematical modelling, diagnostic, communications, and informatics technologies can identify and report hitherto unknown microbes in other species, and thus new risk assessment approaches are needed to identify microbes most likely to cause human disease. We lay out a series of research and surveillance opportunities and goals that could help to overcome these challenges and move the global pandemic strategy from response to pre-emption. PMID:23200504

Motion Direction Biases and Decoding in Human Visual Cortex

PubMed Central

Wang, Helena X.; Merriam, Elisha P.; Freeman, Jeremy

2014-01-01

Functional magnetic resonance imaging (fMRI) studies have relied on multivariate analysis methods to decode visual motion direction from measurements of cortical activity. Above-chance decoding has been commonly used to infer the motion-selective response properties of the underlying neural populations. Moreover, patterns of reliable response biases across voxels that underlie decoding have been interpreted to reflect maps of functional architecture. Using fMRI, we identified a direction-selective response bias in human visual cortex that: (1) predicted motion-decoding accuracy; (2) depended on the shape of the stimulus aperture rather than the absolute direction of motion, such that response amplitudes gradually decreased with distance from the stimulus aperture edge corresponding to motion origin; and 3) was present in V1, V2, V3, but not evident in MT+, explaining the higher motion-decoding accuracies reported previously in early visual cortex. These results demonstrate that fMRI-based motion decoding has little or no dependence on the underlying functional organization of motion selectivity. PMID:25209297

Effect of radiation and other cytotoxic agents on the growth of cells cultured from normal and tumor tissues from the female genital tract

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mothersill, C.; Seymour, C.B.; Bonnar, J.

1990-05-01

A technique is presented which allows the response of human gynecological tissue to radiation and cytotoxic drugs to be assessed using a tissue culture explant system. The technique is simple to use and gives results in line with those obtained for human tissues by more complex culture methods. Data are presented showing how the explant technique developed by the group for other tissues can be adapted to yield acceptable results for normal tissue response to radiation. The potential of the technique for use in predictive testing of individual tumor response is then assessed in five cases of gynecological malignancy. Itmore » is clear that variations in sensitivity to different radio- and chemotherapy agents and combinations can be detected. The results obtained require clinical validation and it is hoped that this will come over the next few years from evaluation of patient response to treatment using individually optimized, rather than empirical therapy.« less

The kinetics and location of intra-host HIV evolution to evade cellular immunity are predictable

NASA Astrophysics Data System (ADS)

Barton, John; Goonetilleke, Nilu; Butler, Thomas; Walker, Bruce; McMichael, Andrew; Chakraborty, Arup

Human immunodeficiency virus (HIV) evolves within infected persons to escape targeting and clearance by the host immune system, thereby preventing effective immune control of infection. Knowledge of the timing and pathways of escape that result in loss of control of the virus could aid in the design of effective strategies to overcome the challenge of viral diversification and immune escape. We combined methods from statistical physics and evolutionary dynamics to predict the course of in vivo viral sequence evolution in response to T cell-mediated immune pressure in a cohort of 17 persons with acute HIV infection. Our predictions agree well with both the location of documented escape mutations and the clinically observed time to escape. We also find that that the mutational pathways to escape depend on the viral sequence background due to epistatic interactions. The ability to predict escape pathways, and the duration over which control is maintained by specific immune responses prior to escape, could be exploited for the rational design of immunotherapeutic strategies that may enable long-term control of HIV infection.

Reward Dependent Invigoration Relates to Theta Oscillations and Is Predicted by Dopaminergic Midbrain Integrity in Healthy Elderly.

PubMed

Steiger, Tineke K; Bunzeck, Nico

2017-01-01

Motivation can have invigorating effects on behavior via dopaminergic neuromodulation. While this relationship has mainly been established in theoretical models and studies in younger subjects, the impact of structural declines of the dopaminergic system during healthy aging remains unclear. To investigate this issue, we used electroencephalography (EEG) in healthy young and elderly humans in a reward-learning paradigm. Specifically, scene images were initially encoded by combining them with cues predicting monetary reward (high vs. low reward). Subsequently, recognition memory for the scenes was tested. As a main finding, we can show that response times (RTs) during encoding were faster for high reward predicting images in the young but not elderly participants. This pattern was resembled in power changes in the theta-band (4-7 Hz). Importantly, analyses of structural MRI data revealed that individual reward-related differences in the elderlies' response time could be predicted by the structural integrity of the dopaminergic substantia nigra (SN; as measured by magnetization transfer (MT)). These findings suggest a close relationship between reward-based invigoration, theta oscillations and age-dependent changes of the dopaminergic system.

A community effort to assess and improve drug sensitivity prediction algorithms

PubMed Central

Costello, James C; Heiser, Laura M; Georgii, Elisabeth; Gönen, Mehmet; Menden, Michael P; Wang, Nicholas J; Bansal, Mukesh; Ammad-ud-din, Muhammad; Hintsanen, Petteri; Khan, Suleiman A; Mpindi, John-Patrick; Kallioniemi, Olli; Honkela, Antti; Aittokallio, Tero; Wennerberg, Krister; Collins, James J; Gallahan, Dan; Singer, Dinah; Saez-Rodriguez, Julio; Kaski, Samuel; Gray, Joe W; Stolovitzky, Gustavo

2015-01-01

Predicting the best treatment strategy from genomic information is a core goal of precision medicine. Here we focus on predicting drug response based on a cohort of genomic, epigenomic and proteomic profiling data sets measured in human breast cancer cell lines. Through a collaborative effort between the National Cancer Institute (NCI) and the Dialogue on Reverse Engineering Assessment and Methods (DREAM) project, we analyzed a total of 44 drug sensitivity prediction algorithms. The top-performing approaches modeled nonlinear relationships and incorporated biological pathway information. We found that gene expression microarrays consistently provided the best predictive power of the individual profiling data sets; however, performance was increased by including multiple, independent data sets. We discuss the innovations underlying the top-performing methodology, Bayesian multitask MKL, and we provide detailed descriptions of all methods. This study establishes benchmarks for drug sensitivity prediction and identifies approaches that can be leveraged for the development of new methods. PMID:24880487

A community effort to assess and improve drug sensitivity prediction algorithms.

PubMed

Costello, James C; Heiser, Laura M; Georgii, Elisabeth; Gönen, Mehmet; Menden, Michael P; Wang, Nicholas J; Bansal, Mukesh; Ammad-ud-din, Muhammad; Hintsanen, Petteri; Khan, Suleiman A; Mpindi, John-Patrick; Kallioniemi, Olli; Honkela, Antti; Aittokallio, Tero; Wennerberg, Krister; Collins, James J; Gallahan, Dan; Singer, Dinah; Saez-Rodriguez, Julio; Kaski, Samuel; Gray, Joe W; Stolovitzky, Gustavo

2014-12-01

Predicting the best treatment strategy from genomic information is a core goal of precision medicine. Here we focus on predicting drug response based on a cohort of genomic, epigenomic and proteomic profiling data sets measured in human breast cancer cell lines. Through a collaborative effort between the National Cancer Institute (NCI) and the Dialogue on Reverse Engineering Assessment and Methods (DREAM) project, we analyzed a total of 44 drug sensitivity prediction algorithms. The top-performing approaches modeled nonlinear relationships and incorporated biological pathway information. We found that gene expression microarrays consistently provided the best predictive power of the individual profiling data sets; however, performance was increased by including multiple, independent data sets. We discuss the innovations underlying the top-performing methodology, Bayesian multitask MKL, and we provide detailed descriptions of all methods. This study establishes benchmarks for drug sensitivity prediction and identifies approaches that can be leveraged for the development of new methods.

Human Dose-Response Data for Francisella tularensis and a Dose- and Time-Dependent Mathematical Model of Early-Phase Fever Associated with Tularemia After Inhalation Exposure.

PubMed

McClellan, Gene; Coleman, Margaret; Crary, David; Thurman, Alec; Thran, Brandolyn

2018-04-25

Military health risk assessors, medical planners, operational planners, and defense system developers require knowledge of human responses to doses of biothreat agents to support force health protection and chemical, biological, radiological, nuclear (CBRN) defense missions. This article reviews extensive data from 118 human volunteers administered aerosols of the bacterial agent Francisella tularensis, strain Schu S4, which causes tularemia. The data set includes incidence of early-phase febrile illness following administration of well-characterized inhaled doses of F. tularensis. Supplemental data on human body temperature profiles over time available from de-identified case reports is also presented. A unified, logically consistent model of early-phase febrile illness is described as a lognormal dose-response function for febrile illness linked with a stochastic time profile of fever. Three parameters are estimated from the human data to describe the time profile: incubation period or onset time for fever; rise time of fever; and near-maximum body temperature. Inhaled dose-dependence and variability are characterized for each of the three parameters. These parameters enable a stochastic model for the response of an exposed population through incorporation of individual-by-individual variability by drawing random samples from the statistical distributions of these three parameters for each individual. This model provides risk assessors and medical decisionmakers reliable representations of the predicted health impacts of early-phase febrile illness for as long as one week after aerosol exposures of human populations to F. tularensis. © 2018 Society for Risk Analysis.

Architecture and functional ecology of the human gastrocnemius muscle-tendon unit.

PubMed

Butler, Erin E; Dominy, Nathaniel J

2016-04-01

The gastrocnemius muscle-tendon unit (MTU) is central to human locomotion. Structural variation in the human gastrocnemius MTU is predicted to affect the efficiency of locomotion, a concept most often explored in the context of performance activities. For example, stiffness of the Achilles tendon varies among individuals with different histories of competitive running. Such a finding highlights the functional variation of individuals and raises the possibility of similar variation between populations, perhaps in response to specific ecological or environmental demands. Researchers often assume minimal variation in human populations, or that industrialized populations represent the human species as well as any other. Yet rainforest hunter-gatherers, which often express the human pygmy phenotype, contradict such assumptions. Indeed, the human pygmy phenotype is a potential model system for exploring the range of ecomorphological variation in the architecture of human hindlimb muscles, a concept we review here. © 2015 Anatomical Society.

Human behavior and human performance: Psychomotor demands

NASA Technical Reports Server (NTRS)

1992-01-01

The results of several experiments are presented in abstract form. These studies are critical for the interpretation and acceptance of flight based science to be conducted by the Behavior and Performance project. Some representative titles are as follow: External audio for IBM/PC compatible computers; A comparative assessment of psychomotor performance (target prediction by humans and macaques); Response path (a dependent measure for computer maze solving and other tasks); Behavioral asymmetries of psychomotor performance in Rhesus monkey (a dissociation between hand preference and skill); Testing primates with joystick based automated apparatus; and Environmental enrichment and performance assessment for ground or flight based research with primates;

Species differences in tumour responses to cancer chemotherapy

PubMed Central

Lawrence, Jessica; Cameron, David; Argyle, David

2015-01-01

Despite advances in chemotherapy, radiotherapy and targeted drug development, cancer remains a disease of high morbidity and mortality. The treatment of human cancer patients with chemotherapy has become commonplace and accepted over the past 100 years. In recent years, and with a similar incidence of cancer to people, the use of cancer chemotherapy drugs in veterinary patients such as the dog has also become accepted clinical practice. The poor predictability of tumour responses to cancer chemotherapy drugs in rodent models means that the standard drug development pathway is costly, both in terms of money and time, leading to many drugs failing in Phase I and II clinical trials. This has led to the suggestion that naturally occurring cancers in pet dogs may offer an alternative model system to inform rational drug development in human oncology. In this review, we will explore the species variation in tumour responses to conventional chemotherapy and highlight our understanding of the differences in pharmacodynamics, pharmacokinetics and pharmacogenomics between humans and dogs. Finally, we explore the potential hurdles that need to be overcome to gain the greatest value from comparative oncology studies. PMID:26056373

Generation of human auditory steady-state responses (SSRs). II: Addition of responses to individual stimuli.

PubMed

Santarelli, R; Maurizi, M; Conti, G; Ottaviani, F; Paludetti, G; Pettorossi, V E

1995-03-01

In order to investigate the generation of the 40 Hz steady-state response (SSR), auditory potentials evoked by clicks were recorded in 16 healthy subjects in two stimulating conditions. Firstly, repetition rates of 7.9 and 40 Hz were used to obtain individual middle latency responses (MLRs) and 40 Hz-SSRs, respectively. In the second condition, eight click trains were presented at a 40 Hz repetition rate and an inter-train interval of 126 ms. We extracted from the whole train response: (1) the response-segment taking place after the last click of the train (last click response, LCR), (2) a modified LCR (mLCR) obtained by clearing the LCR from the amplitude enhancement due to the overlapping of the responses to the clicks preceding the last within the stimulus train. In comparison to MLRs, the most relevant feature of the evoked activity following the last click of the train (LCRs, mLCRs) was the appearance in the 50-110 ms latency range of one (in 11 subjects) or two (in 2 subjects) additional positive-negative deflections having the same periodicity as that of MLR waves. The grand average (GA) of the 40 Hz-SSRs was compared with three predictions synthesized by superimposing: (1) the GA of MLRs, (2) the GA of LCRs, (3) the GA of mLCRs. Both the MLR and mLCR predictions reproduced the recorded signal in amplitude while the LCR prediction amplitude resulted almost twice that of the 40 Hz-SSR. With regard to the phase, the MLR, LCR and mLCR closely predicted the recorded signal. Our findings confirm the effectiveness of the linear addition mechanism in the generation of the 40 Hz-SSR. However the responses to individual stimuli within the 40 Hz-SSR differ from MLRs because of additional periodic activity. These results suggest that phenomena related to the resonant frequency of the activated system may play a role in the mechanisms which interact to generate the 40 Hz-SSR.

Antibody responses of Macaca fascicularis against a new inactivated polio vaccine derived from Sabin strains (sIPV) in DTaP-sIPV vaccine.

PubMed

Sato, Y; Shiosaki, K; Goto, Y; Sonoda, K; Kino, Y

2013-05-01

Antibody responses of Macaca fascicularis against a new tetravalent vaccine composed of diphtheria toxoid, tetanus toxoid, acellular pertussis antigens, and inactivated poliovirus derived from Sabin strains (sIPV) was investigated to predict an optimal dose of sIPV in a new tetravalent vaccine (DTaP-sIPV) prior to conducting a dose-defined clinical study. Monkeys were inoculated with DTaP-sIPVs containing three different antigen units of sIPVs: Vaccine A (types 1:2:3 = 3:100:100 DU), Vaccine B (types 1:2:3 = 1.5:50:50 DU), and Vaccine C (types 1:2:3 = 0.75:25:25 DU). There was no difference in the average titers of neutralizing antibody against the attenuated or virulent polioviruses between Vaccines A and B. The average neutralizing antibody titers of Vaccine C tended to be lower than those of Vaccines A and B. The sIPV antigens did not affect the anti-diphtheria or anti-tetanus antibody titers of DTaP-sIPV. Furthermore, the average neutralizing antibody titers of Vaccine A against the attenuated and virulent polioviruses were comparable between M. fascicularis and humans. These results suggest that M. fascicularis may be a useful animal model for predicting the antibody responses to sIPVs in humans, and that it may be likely to reduce the amount of sIPVs contained in DTaP-sIPVs, even for humans. Copyright © 2013 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

Touchscreen-paradigm for mice reveals cross-species evidence for an antagonistic relationship of cognitive flexibility and stability

PubMed Central

Richter, S. Helene; Vogel, Anne S.; Ueltzhöffer, Kai; Muzzillo, Chiara; Vogt, Miriam A.; Lankisch, Katja; Armbruster-Genç, Diana J. N.; Riva, Marco A.; Fiebach, Christian J.; Gass, Peter; Vollmayr, Barbara

2014-01-01

The abilities to either flexibly adjust behavior according to changing demands (cognitive flexibility) or to maintain it in the face of potential distractors (cognitive stability) are critical for adaptive behavior in many situations. Recently, a novel human paradigm has found individual differences of cognitive flexibility and stability to be related to common prefrontal networks. The aims of the present study were, first, to translate this paradigm from humans to mice and, second, to test conceptual predictions of a computational model of prefrontal working memory mechanisms, the Dual State Theory, which assumes an antagonistic relation between cognitive flexibility and stability. Mice were trained in a touchscreen-paradigm to discriminate visual cues. The task involved “ongoing” and cued “switch” trials. In addition distractor cues were interspersed to test the ability to resist distraction, and an ambiguous condition assessed the spontaneous switching between two possible responses without explicit cues. While response times did not differ substantially between conditions, error rates (ER) increased from the “ongoing” baseline condition to the most complex condition, where subjects were required to switch between two responses in the presence of a distracting cue. Importantly, subjects switching more often spontaneously were found to be more distractible by task irrelevant cues, but also more flexible in situations, where switching was required. These results support a dichotomy of cognitive flexibility and stability as predicted by the Dual State Theory. Furthermore, they replicate critical aspects of the human paradigm, which indicates the translational potential of the testing procedure and supports the use of touchscreen procedures in preclinical animal research. PMID:24834036

Vestibular Activation Differentially Modulates Human Early Visual Cortex and V5/MT Excitability and Response Entropy

PubMed Central

Guzman-Lopez, Jessica; Arshad, Qadeer; Schultz, Simon R; Walsh, Vincent; Yousif, Nada

2013-01-01

Head movement imposes the additional burdens on the visual system of maintaining visual acuity and determining the origin of retinal image motion (i.e., self-motion vs. object-motion). Although maintaining visual acuity during self-motion is effected by minimizing retinal slip via the brainstem vestibular-ocular reflex, higher order visuovestibular mechanisms also contribute. Disambiguating self-motion versus object-motion also invokes higher order mechanisms, and a cortical visuovestibular reciprocal antagonism is propounded. Hence, one prediction is of a vestibular modulation of visual cortical excitability and indirect measures have variously suggested none, focal or global effects of activation or suppression in human visual cortex. Using transcranial magnetic stimulation-induced phosphenes to probe cortical excitability, we observed decreased V5/MT excitability versus increased early visual cortex (EVC) excitability, during vestibular activation. In order to exclude nonspecific effects (e.g., arousal) on cortical excitability, response specificity was assessed using information theory, specifically response entropy. Vestibular activation significantly modulated phosphene response entropy for V5/MT but not EVC, implying a specific vestibular effect on V5/MT responses. This is the first demonstration that vestibular activation modulates human visual cortex excitability. Furthermore, using information theory, not previously used in phosphene response analysis, we could distinguish between a specific vestibular modulation of V5/MT excitability from a nonspecific effect at EVC. PMID:22291031

Imaging biomarkers to predict response to anti-HER2 (ErbB2) therapy in preclinical models of breast cancer

PubMed Central

Shah, Chirayu; Miller, Todd W.; Wyatt, Shelby K.; McKinley, Eliot T.; Olivares, Maria Graciela; Sanchez, Violeta; Nolting, Donald D.; Buck, Jason R.; Zhao, Ping; Ansari, M. Sib; Baldwin, Ronald M.; Gore, John C.; Schiff, Rachel; Arteaga, Carlos L.; Manning, H. Charles

2010-01-01

Purpose To evaluate non-invasive imaging methods as predictive biomarkers of response to trastuzumab in mouse models of HER2-overexpressing breast cancer. The correlation between tumor regression and molecular imaging of apoptosis, glucose metabolism, and cellular proliferation was evaluated longitudinally in responding and non-responding tumor-bearing cohorts. Experimental Design Mammary tumors from MMTV/HER2 transgenic female mice were transplanted into syngeneic female mice. BT474 human breast carcinoma cell line xenografts were grown in athymic nude mice. Tumor cell apoptosis (NIR700-Annexin-V accumulation), glucose metabolism ([18F]FDG-PET), and proliferation ([18F]FLT-PET) were evaluated throughout a bi-weekly trastuzumab regimen. Imaging metrics were validated by direct measurement of tumor size and immunohistochemical (IHC) analysis of cleaved caspase-3, phosphorylated AKT (p-AKT) and Ki67. Results NIR700-Annexin-V accumulated significantly in trastuzumab-treated MMTV/HER2 and BT474 tumors that ultimately regressed, but not in non-responding or vehicle-treated tumors. Uptake of [18F]FDG was not affected by trastuzumab treatment in MMTV/HER2 or BT474 tumors. [18F]FLT PET imaging predicted trastuzumab response in BT474 tumors but not in MMTV/HER2 tumors, which exhibited modest uptake of [18F]FLT. Close agreement was observed between imaging metrics and IHC analysis. Conclusions Molecular imaging of apoptosis accurately predicts trastuzumab-induced regression of HER2(+) tumors and may warrant clinical exploration to predict early response to neoadjuvant trastuzumab. Trastuzumab does not appear to alter glucose metabolism substantially enough to afford [18F]FDG-PET significant predictive value in this setting. Although promising in one preclinical model, further studies are required to determine the overall value of [18F]FLT-PET as a biomarker of response to trastuzumab in HER2+ breast cancer. PMID:19584166

Multidimensional Profiling of Task Stress States for Human Factors: A Brief Review.

PubMed

Matthews, Gerald

2016-09-01

This article advocates multidimensional assessment of task stress in human factors and reviews the use of the Dundee Stress State Questionnaire (DSSQ) for evaluation of systems and operators. Contemporary stress research has progressed from an exclusive focus on environmental stressors to transactional perspectives on the stress process. Performance impacts of stress reflect the operator's dynamic attempts to understand and cope with task demands. Multidimensional stress assessments are necessary to gauge the different forms of system-operator interaction. This review discusses the theoretical and practical use of the DSSQ in evaluating multidimensional patterns of stress response. It presents psychometric evidence for the multidimensional perspective and illustrative profiles of subjective state response to task stressors and environments. Evidence is also presented on stress state correlations with related variables, including personality, stress process measures, psychophysiological response, and objective task performance. Evidence supports the validity of the DSSQ as a task stress measure. Studies of various simulated environments show that different tasks elicit different profiles of stress state response. Operator characteristics such as resilience predict individual differences in state response to stressors. Structural equation modeling may be used to understand performance impacts of stress states. Multidimensional assessment affords insight into the stress process in a variety of human factors contexts. Integrating subjective and psychophysiological assessment is a priority for future research. Stress state measurement contributes to evaluating system design, countermeasures to stress and fatigue, and performance vulnerabilities. It may also support personnel selection and diagnostic monitoring of operators. © 2016, Human Factors and Ergonomics Society.

Modeling fear‐conditioned bradycardia in humans

PubMed Central

Tzovara, Athina; Staib, Matthias; Paulus, Philipp C.; Hofer, Nicolas; Bach, Dominik R.

2016-01-01

Abstract Across species, cued fear conditioning is a common experimental paradigm to investigate aversive Pavlovian learning. While fear‐conditioned stimuli (CS+) elicit overt behavior in many mammals, this is not the case in humans. Typically, autonomic nervous system activity is used to quantify fear memory in humans, measured by skin conductance responses (SCR). Here, we investigate whether heart period responses (HPR) evoked by the CS, often observed in humans and small mammals, are suitable to complement SCR as an index of fear memory in humans. We analyze four datasets involving delay and trace conditioning, in which heart beats are identified via electrocardiogram or pulse oximetry, to show that fear‐conditioned heart rate deceleration (bradycardia) is elicited and robustly distinguishes CS+ from CS−. We then develop a psychophysiological model (PsPM) of fear‐conditioned HPR. This PsPM is inverted to yield estimates of autonomic input into the heart. We show that the sensitivity to distinguish CS+ and CS− (predictive validity) is higher for model‐based estimates than peak‐scoring analysis, and compare this with SCR. Our work provides a novel tool to investigate fear memory in humans that allows direct comparison between species. PMID:26950648

Shotgun metaproteomics of the human distal gut microbiota

DOE Office of Scientific and Technical Information (OSTI.GOV)

VerBerkmoes, N.C.; Russell, A.L.; Shah, M.

2008-10-15

The human gut contains a dense, complex and diverse microbial community, comprising the gut microbiome. Metagenomics has recently revealed the composition of genes in the gut microbiome, but provides no direct information about which genes are expressed or functioning. Therefore, our goal was to develop a novel approach to directly identify microbial proteins in fecal samples to gain information about the genes expressed and about key microbial functions in the human gut. We used a non-targeted, shotgun mass spectrometry-based whole community proteomics, or metaproteomics, approach for the first deep proteome measurements of thousands of proteins in human fecal samples, thusmore » demonstrating this approach on the most complex sample type to date. The resulting metaproteomes had a skewed distribution relative to the metagenome, with more proteins for translation, energy production and carbohydrate metabolism when compared to what was earlier predicted from metagenomics. Human proteins, including antimicrobial peptides, were also identified, providing a non-targeted glimpse of the host response to the microbiota. Several unknown proteins represented previously undescribed microbial pathways or host immune responses, revealing a novel complex interplay between the human host and its associated microbes.« less

A Simple Exploration of Complexity at the Climate-Weather-Social-Conflict Nexus

NASA Astrophysics Data System (ADS)

Shaw, M.

2017-12-01

The conceptualization, exploration, and prediction of interplay between climate, weather, important resources, and social and economic - so political - human behavior is cast, and analyzed, in terms familiar from statistical physics and nonlinear dynamics. A simple threshold toy model is presented which emulates human tendencies to either actively engage in responses deriving, in part, from environmental circumstances or to maintain some semblance of status quo, formulated based on efforts drawn from the sociophysics literature - more specifically vis a vis a model akin to spin glass depictions of human behavior - with threshold/switching of individual and collective dynamics influenced by relatively more detailed weather and land surface model (hydrological) analyses via a land data assimilation system (a custom rendition of the NASA GSFC Land Information System). Parameters relevant to human systems' - e.g., individual and collective switching - sensitivity to hydroclimatology are explored towards investigation of overall system behavior; i.e., fixed points/equilibria, oscillations, and bifurcations of systems composed of human interactions and responses to climate and weather through, e.g., agriculture. We discuss implications in terms of conceivable impacts of climate change and associated natural disasters on socioeconomics, politics, and power transfer, drawing from relatively recent literature concerning human conflict.

Finding the Beat: From Socially Coordinated Vocalizations in Songbirds to Rhythmic Entrainment in Humans.

PubMed

Benichov, Jonathan I; Globerson, Eitan; Tchernichovski, Ofer

2016-01-01

Humans and oscine songbirds share the rare capacity for vocal learning. Songbirds have the ability to acquire songs and calls of various rhythms through imitation. In several species, birds can even coordinate the timing of their vocalizations with other individuals in duets that are synchronized with millisecond-accuracy. It is not known, however, if songbirds can perceive rhythms holistically nor if they are capable of spontaneous entrainment to complex rhythms, in a manner similar to humans. Here we review emerging evidence from studies of rhythm generation and vocal coordination across songbirds and humans. In particular, recently developed experimental methods have revealed neural mechanisms underlying the temporal structure of song and have allowed us to test birds' abilities to predict the timing of rhythmic social signals. Surprisingly, zebra finches can readily learn to anticipate the calls of a "vocal robot" partner and alter the timing of their answers to avoid jamming, even in reference to complex rhythmic patterns. This capacity resembles, to some extent, human predictive motor response to an external beat. In songbirds, this is driven, at least in part, by the forebrain song system, which controls song timing and is essential for vocal learning. Building upon previous evidence for spontaneous entrainment in human and non-human vocal learners, we propose a comparative framework for future studies aimed at identifying shared mechanism of rhythm production and perception across songbirds and humans.

Network Controllability in the Inferior Frontal Gyrus Relates to Controlled Language Variability and Susceptibility to TMS.

PubMed

Medaglia, John D; Harvey, Denise Y; White, Nicole; Kelkar, Apoorva; Zimmerman, Jared; Bassett, Danielle S; Hamilton, Roy H

2018-06-08

In language production, humans are confronted with considerable word selection demands. Often, we must select a word from among similar, acceptable, and competing alternative words in order to construct a sentence that conveys an intended meaning. In recent years, the left inferior frontal gyrus (LIFG) has been identified as critical to this ability. Despite a recent emphasis on network approaches to understanding language, how the LIFG interacts with the brain's complex networks to facilitate controlled language performance remains unknown. Here, we take a novel approach to understand word selection as a network control process in the brain. Using an anatomical brain network derived from high-resolution diffusion spectrum imaging (DSI), we computed network controllability underlying the site of transcranial magnetic stimulation in the LIFG between administrations of language tasks that vary in response (cognitive control) demands: open-response (word generation) vs. closed-response (number naming) tasks. We find that a statistic that quantifies the LIFG's theoretically predicted control of communication across modules in the human connectome explains TMS-induced changes in open-response language task performance only. Moreover, we find that a statistic that quantifies the LIFG's theoretically predicted control of difficult-to-reach states explains vulnerability to TMS in the closed-ended (but not open-ended) response task. These findings establish a link between network controllability, cognitive function, and TMS effects. SIGNIFICANCE STATEMENT This work illustrates that network control statistics applied to anatomical connectivity data demonstrate relationships with cognitive variability during controlled language tasks and TMS effects. Copyright © 2018 the authors.

Consequences of contamination of the spacecraft environment: immunologic consequences

NASA Technical Reports Server (NTRS)

Shearer, W. T.

2001-01-01

Long-term space voyages pose numerous known and unknown health hazards, to the human immune system. Well-studied clinical examples of secondary immunodeficiencies created on Earth, lead one to predict that the conditions of prolonged space flight would weaken the human immune responses that normally hold infection and cancer in check. From evidence gathered from humans flown for prolonged periods in space and from human models of space flight studied on Earth it is reasonable to suspect that space travelers to the planet Mars would experience a weakening of immunity. Subtle defects of immune cell structure and function have been observed in astronauts, such as weakening of specific T-lymphocyte recall of specific antigens. Ground-based models also have demonstrated alterations of immune function, such as the elevation of neuroendocrine immune system messengers, interleukin-6, and soluble tumor necrosis factor-alpha receptor in sleep deprivation. Since severe immune compromise the clinical consequences of reactivation of latent virus infections and the development of cancer, has yet to be seen in space flight or in the Earth models, it is extremely important to begin to quantify early changes in immunity to predict the development of immune system collapse with poor clinical outcomes. This approach is designed to validate a number of surrogate markers that will predict trouble ahead. Inherent in this research is the development of countermeasures to reduce the risks of infection and cancer in the first humans going to Mars.

Genetically Engineered Cancer Models, But Not Xenografts, Faithfully Predict Anticancer Drug Exposure in Melanoma Tumors

PubMed Central

Combest, Austin J.; Roberts, Patrick J.; Dillon, Patrick M.; Sandison, Katie; Hanna, Suzan K.; Ross, Charlene; Habibi, Sohrab; Zamboni, Beth; Müller, Markus; Brunner, Martin; Sharpless, Norman E.

2012-01-01

Background. Rodent studies are a vital step in the development of novel anticancer therapeutics and are used in pharmacokinetic (PK), toxicology, and efficacy studies. Traditionally, anticancer drug development has relied on xenograft implantation of human cancer cell lines in immunocompromised mice for efficacy screening of a candidate compound. The usefulness of xenograft models for efficacy testing, however, has been questioned, whereas genetically engineered mouse models (GEMMs) and orthotopic syngeneic transplants (OSTs) may offer some advantages for efficacy assessment. A critical factor influencing the predictability of rodent tumor models is drug PKs, but a comprehensive comparison of plasma and tumor PK parameters among xenograft models, OSTs, GEMMs, and human patients has not been performed. Methods. In this work, we evaluated the plasma and tumor dispositions of an antimelanoma agent, carboplatin, in patients with cutaneous melanoma compared with four different murine melanoma models (one GEMM, one human cell line xenograft, and two OSTs). Results. Using microdialysis to sample carboplatin tumor disposition, we found that OSTs and xenografts were poor predictors of drug exposure in human tumors, whereas the GEMM model exhibited PK parameters similar to those seen in human tumors. Conclusions. The tumor PKs of carboplatin in a GEMM of melanoma more closely resembles the tumor disposition in patients with melanoma than transplanted tumor models. GEMMs show promise in becoming an improved prediction model for intratumoral PKs and response in patients with solid tumors. PMID:22993143

The insertion of human dynamics models in the flight control loops of V/STOL research aircraft. Appendix 2: The optimal control model of a pilot in V/STOL aircraft control loops

NASA Technical Reports Server (NTRS)

Zipf, Mark E.

1989-01-01

An overview is presented of research work focussed on the design and insertion of classical models of human pilot dynamics within the flight control loops of V/STOL aircraft. The pilots were designed and configured for use in integrated control system research and design. The models of human behavior that were considered are: McRuer-Krendel (a single variable transfer function model); and Optimal Control Model (a multi-variable approach based on optimal control and stochastic estimation theory). These models attempt to predict human control response characteristics when confronted with compensatory tracking and state regulation tasks. An overview, mathematical description, and discussion of predictive limitations of the pilot models is presented. Design strategies and closed loop insertion configurations are introduced and considered for various flight control scenarios. Models of aircraft dynamics (both transfer function and state space based) are developed and discussed for their use in pilot design and application. Pilot design and insertion are illustrated for various flight control objectives. Results of pilot insertion within the control loops of two V/STOL research aricraft (Sikorski Black Hawk UH-60A, McDonnell Douglas Harrier II AV-8B) are presented and compared against actual pilot flight data. Conclusions are reached on the ability of the pilot models to adequately predict human behavior when confronted with similar control objectives.

Individual differences in bodily freezing predict emotional biases in decision making

PubMed Central

Ly, Verena; Huys, Quentin J. M.; Stins, John F.; Roelofs, Karin; Cools, Roshan

2014-01-01

Instrumental decision making has long been argued to be vulnerable to emotional responses. Literature on multiple decision making systems suggests that this emotional biasing might reflect effects of a system that regulates innately specified, evolutionarily preprogrammed responses. To test this hypothesis directly, we investigated whether effects of emotional faces on instrumental action can be predicted by effects of emotional faces on bodily freezing, an innately specified response to aversive relative to appetitive cues. We tested 43 women using a novel emotional decision making task combined with posturography, which involves a force platform to detect small oscillations of the body to accurately quantify postural control in upright stance. On the platform, participants learned whole body approach-avoidance actions based on monetary feedback, while being primed by emotional faces (angry/happy). Our data evidence an emotional biasing of instrumental action. Thus, angry relative to happy faces slowed instrumental approach relative to avoidance responses. Critically, individual differences in this emotional biasing effect were predicted by individual differences in bodily freezing. This result suggests that emotional biasing of instrumental action involves interaction with a system that controls innately specified responses. Furthermore, our findings help bridge (animal and human) decision making and emotion research to advance our mechanistic understanding of decision making anomalies in daily encounters as well as in a wide range of psychopathology. PMID:25071491

Response repetition biases in human perceptual decisions are explained by activity decay in competitive attractor models

PubMed Central

Bonaiuto, James J; de Berker, Archy; Bestmann, Sven

2016-01-01

Animals and humans have a tendency to repeat recent choices, a phenomenon known as choice hysteresis. The mechanism for this choice bias remains unclear. Using an established, biophysically informed model of a competitive attractor network for decision making, we found that decaying tail activity from the previous trial caused choice hysteresis, especially during difficult trials, and accurately predicted human perceptual choices. In the model, choice variability could be directionally altered through amplification or dampening of post-trial activity decay through simulated depolarizing or hyperpolarizing network stimulation. An analogous intervention using transcranial direct current stimulation (tDCS) over left dorsolateral prefrontal cortex (dlPFC) yielded a close match between model predictions and experimental results: net soma depolarizing currents increased choice hysteresis, while hyperpolarizing currents suppressed it. Residual activity in competitive attractor networks within dlPFC may thus give rise to biases in perceptual choices, which can be directionally controlled through non-invasive brain stimulation. DOI: http://dx.doi.org/10.7554/eLife.20047.001 PMID:28005007

Performances of the PIPER scalable child human body model in accident reconstruction

PubMed Central

Giordano, Chiara; Kleiven, Svein

2017-01-01

Human body models (HBMs) have the potential to provide significant insights into the pediatric response to impact. This study describes a scalable/posable approach to perform child accident reconstructions using the Position and Personalize Advanced Human Body Models for Injury Prediction (PIPER) scalable child HBM of different ages and in different positions obtained by the PIPER tool. Overall, the PIPER scalable child HBM managed reasonably well to predict the injury severity and location of the children involved in real-life crash scenarios documented in the medical records. The developed methodology and workflow is essential for future work to determine child injury tolerances based on the full Child Advanced Safety Project for European Roads (CASPER) accident reconstruction database. With the workflow presented in this study, the open-source PIPER scalable HBM combined with the PIPER tool is also foreseen to have implications for improved safety designs for a better protection of children in traffic accidents. PMID:29135997

Sexual selection on male vocal fundamental frequency in humans and other anthropoids.

PubMed

Puts, David A; Hill, Alexander K; Bailey, Drew H; Walker, Robert S; Rendall, Drew; Wheatley, John R; Welling, Lisa L M; Dawood, Khytam; Cárdenas, Rodrigo; Burriss, Robert P; Jablonski, Nina G; Shriver, Mark D; Weiss, Daniel; Lameira, Adriano R; Apicella, Coren L; Owren, Michael J; Barelli, Claudia; Glenn, Mary E; Ramos-Fernandez, Gabriel

2016-04-27

In many primates, including humans, the vocalizations of males and females differ dramatically, with male vocalizations and vocal anatomy often seeming to exaggerate apparent body size. These traits may be favoured by sexual selection because low-frequency male vocalizations intimidate rivals and/or attract females, but this hypothesis has not been systematically tested across primates, nor is it clear why competitors and potential mates should attend to vocalization frequencies. Here we show across anthropoids that sexual dimorphism in fundamental frequency (F0) increased during evolutionary transitions towards polygyny, and decreased during transitions towards monogamy. Surprisingly, humans exhibit greater F0 sexual dimorphism than any other ape. We also show that low-F0 vocalizations predict perceptions of men's dominance and attractiveness, and predict hormone profiles (low cortisol and high testosterone) related to immune function. These results suggest that low male F0 signals condition to competitors and mates, and evolved in male anthropoids in response to the intensity of mating competition. © 2016 The Author(s).

Measuring Anxious Responses to Predictable and Unpredictable Threat in Children and Adolescents

ERIC Educational Resources Information Center

Schmitz, Anja; Merikangas, Kathleen; Swendsen, Haruka; Cui, Lihong; Heaton, Leann; Grillon, Christian

2011-01-01

Research has highlighted the need for new methods to assess emotions in children on multiple levels to gain better insight into the complex processes of emotional development. The startle reflex is a unique translational tool that has been used to study physiological processes during fear and anxiety in rodents and in human participants. However,…

A Comparison Between the Effects of Hexamethonium and Atropine in Combination and of Vagotomy with Gastrojejunostomy on Human Gastric Secretion

PubMed Central

McArthur, J.; Tankel, H. I.; Kay, A. W.

1960-01-01

This study records the gastric secretory response, using the Kay augmented histamine test, and compares “medical” vagotomy with atropine and hexamethonium with “surgical” vagotomy. The results suggest that it may be of value in predicting the effect of vagotomy with gastrojejunostomy. PMID:13773727

The Role of Oxysterols in a Computational Steroidogenesis Model of Human H295R Cells to Improve Predictability of Biochemical Responses to Endocrine Disruptors

EPA Science Inventory

Steroids, which have an important role in a wide range of physiological processes, are synthesized primarily in the gonads and adrenal glands through a series of enzyme mediated reactions. The activity of steroidogenic enzymes can be altered by a variety of endocrine disruptors (...

FUNCTIONAL SUBCLONE PROFILING FOR PREDICTION OF TREATMENT-INDUCED INTRA-TUMOR POPULATION SHIFTS AND DISCOVERY OF RATIONAL DRUG COMBINATIONS IN HUMAN GLIOBLASTOMA

PubMed Central

Reinartz, Roman; Wang, Shanshan; Kebir, Sied; Silver, Daniel J.; Wieland, Anja; Zheng, Tong; Küpper, Marius; Rauschenbach, Laurèl; Fimmers, Rolf; Shepherd, Timothy M.; Trageser, Daniel; Till, Andreas; Schäfer, Niklas; Glas, Martin; Hillmer, Axel M.; Cichon, Sven; Smith, Amy A.; Pietsch, Torsten; Liu, Ying; Reynolds, Brent A.; Yachnis, Anthony; Pincus, David W.; Simon, Matthias; Brüstle, Oliver; Steindler, Dennis A.; Scheffler, Björn

2016-01-01

Purpose Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors. Experimental Design Here, we used 33 single cell-derived subclones generated from five clinical glioblastoma specimens for exploring intra- and inter-individual spectra of drug resistance profiles in vitro. In a personalized setting, we explored whether differences in pharmacological sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors. Results Subclones from individual tumors exhibited a remarkable heterogeneity of drug resistance to a library of potential anti-glioblastoma compounds. A more comprehensive intra-tumoral analysis revealed that stable genetic and phenotypic characteristics of co-existing subclones could be correlated with distinct drug sensitivity profiles. The data obtained from differential drug response analysis could be employed to predict clonal population shifts within the naïve parental tumor in vitro and in orthotopic xenografts. Furthermore, the value of pharmacological profiles could be shown for establishing rational strategies for individualized secondary lines of treatment. Conclusions Our data provide a previously unrecognized strategy for revealing functional consequences of intra-tumor heterogeneity by enabling predictive modeling of treatment-related subclone dynamics in human glioblastoma. PMID:27521447

How Nature-Based Tourism Might Increase Prey Vulnerability to Predators.

PubMed

Geffroy, Benjamin; Samia, Diogo S M; Bessa, Eduardo; Blumstein, Daniel T

2015-12-01

Tourism can be deleterious for wildlife because it triggers behavioral changes in individuals with cascading effects on populations and communities. Among these behavioral changes, animals around humans often reduce their fearfulness and antipredator responses towards humans. A straightforward prediction is that habituation to humans associated with tourism would negatively influence reaction to predators. This could happen indirectly, where human presence decreases the number of natural predators and thus prey become less wary, or directly, where human-habituated individuals become bolder and thus more vulnerable to predation. Building on ideas from the study of traits associated with domestication and urbanization, we develop a framework to understand how behavioral changes associated with nature-based tourism can impact individual fitness, and thus the demographic trajectory of a population. Copyright © 2015 Elsevier Ltd. All rights reserved.