Strategies for Leading Academics to Rethink Humanities and Social Sciences Curricula in the Context of Discipline Standards

ERIC Educational Resources Information Center

Thomas, Theda; Wallace, Joy; Allen, Pamela; Clark, Jennifer; Jones, Adrian; Lawrence, Jill; Cole, Bronwyn; Sheridan Burns, Lynette

2017-01-01

The introduction of discipline standards in Australia has required a comprehensive rethinking of humanities and social science curricula from first year through to graduation. This paper proposes a model to facilitate academics' engagement with discipline standards and their implication for first-year curricula. The model supports…

Building sector feedbacks lead to increased energy demands

NASA Astrophysics Data System (ADS)

Hartin, C.; Link, R. P.; Patel, P.; Horowitz, R.; Clarke, L.; Mundra, A.

2017-12-01

Typically in human-earth system modeling studies, feedbacks between the earth and human systems are analyzed by passing information between independent models, leading to data errors and poor reproducibility. In this study we explore the two-way feedbacks between the human and earth systems in the building sector of GCAM, an integrated assessment model and, its fully-integrated climate component, Hector. While there is a general agreement in the literature that increasing temperatures will increase cooling energy demands and decrease heating energy demands, there has been no fully-coupled analysis of this dynamic that would, for example, account for the feedbacks on hydrofluorocarbons from increased cooling demands. Using a statistical relationship between global mean temperature change and heating and cooling degree days, we find that the feedbacks on hydrofluorocarbons lead to an increase in global mean temperature of between 0.16 to 0.27 °C in 2100. Demands for electricity increase by about 10% in Africa, while demands decrease in Canada by about 3.0% when taking into account these feedbacks. While the feedbacks between building energy demand and global mean temperature are modest by themselves, this study prompts future research on coupled human-earth system feedbacks, in particular in regards to land, water, and other energy infrastructure.

Mathematical concepts for modeling human behavior in complex man-machine systems

NASA Technical Reports Server (NTRS)

Johannsen, G.; Rouse, W. B.

1979-01-01

Many human behavior (e.g., manual control) models have been found to be inadequate for describing processes in certain real complex man-machine systems. An attempt is made to find a way to overcome this problem by examining the range of applicability of existing mathematical models with respect to the hierarchy of human activities in real complex tasks. Automobile driving is chosen as a baseline scenario, and a hierarchy of human activities is derived by analyzing this task in general terms. A structural description leads to a block diagram and a time-sharing computer analogy.

Space Radiation Effects on Human Cells: Modeling DNA Breakage, DNA Damage Foci Distribution, Chromosomal Aberrations and Tissue Effects

NASA Technical Reports Server (NTRS)

Ponomarev, A. L.; Huff, J. L.; Cucinotta, F. A.

2011-01-01

Future long-tem space travel will face challenges from radiation concerns as the space environment poses health risk to humans in space from radiations with high biological efficiency and adverse post-flight long-term effects. Solar particles events may dramatically affect the crew performance, while Galactic Cosmic Rays will induce a chronic exposure to high-linear-energy-transfer (LET) particles. These types of radiation, not present on the ground level, can increase the probability of a fatal cancer later in astronaut life. No feasible shielding is possible from radiation in space, especially for the heavy ion component, as suggested solutions will require a dramatic increase in the mass of the mission. Our research group focuses on fundamental research and strategic analysis leading to better shielding design and to better understanding of the biological mechanisms of radiation damage. We present our recent effort to model DNA damage and tissue damage using computational models based on the physics of heavy ion radiation, DNA structure and DNA damage and repair in human cells. Our particular area of expertise include the clustered DNA damage from high-LET radiation, the visualization of DSBs (DNA double strand breaks) via DNA damage foci, image analysis and the statistics of the foci for different experimental situations, chromosomal aberration formation through DSB misrepair, the kinetics of DSB repair leading to a model-derived spectrum of chromosomal aberrations, and, finally, the simulation of human tissue and the pattern of apoptotic cell damage. This compendium of theoretical and experimental data sheds light on the complex nature of radiation interacting with human DNA, cells and tissues, which can lead to mutagenesis and carcinogenesis later in human life after the space mission.

The Genetic Basis for Variation in Sensitivity to Lead Toxicity in Drosophila melanogaster.

PubMed

Zhou, Shanshan; Morozova, Tatiana V; Hussain, Yasmeen N; Luoma, Sarah E; McCoy, Lenovia; Yamamoto, Akihiko; Mackay, Trudy F C; Anholt, Robert R H

2016-07-01

Lead toxicity presents a worldwide health problem, especially due to its adverse effects on cognitive development in children. However, identifying genes that give rise to individual variation in susceptibility to lead toxicity is challenging in human populations. Our goal was to use Drosophila melanogaster to identify evolutionarily conserved candidate genes associated with individual variation in susceptibility to lead exposure. To identify candidate genes associated with variation in susceptibility to lead toxicity, we measured effects of lead exposure on development time, viability and adult activity in the Drosophila melanogaster Genetic Reference Panel (DGRP) and performed genome-wide association analyses to identify candidate genes. We used mutants to assess functional causality of candidate genes and constructed a genetic network associated with variation in sensitivity to lead exposure, on which we could superimpose human orthologs. We found substantial heritabilities for all three traits and identified candidate genes associated with variation in susceptibility to lead exposure for each phenotype. The genetic architectures that determine variation in sensitivity to lead exposure are highly polygenic. Gene ontology and network analyses showed enrichment of genes associated with early development and function of the nervous system. Drosophila melanogaster presents an advantageous model to study the genetic underpinnings of variation in susceptibility to lead toxicity. Evolutionary conservation of cellular pathways that respond to toxic exposure allows predictions regarding orthologous genes and pathways across phyla. Thus, studies in the D. melanogaster model system can identify candidate susceptibility genes to guide subsequent studies in human populations. Zhou S, Morozova TV, Hussain YN, Luoma SE, McCoy L, Yamamoto A, Mackay TF, Anholt RR. 2016. The genetic basis for variation in sensitivity to lead toxicity in Drosophila melanogaster. Environ Health Perspect 124:1062-1070; http://dx.doi.org/10.1289/ehp.1510513.

An integrated modeling framework for exploring flow regime and water quality changes with increasing biofuel crop production in the U.S. Corn Belt

NASA Astrophysics Data System (ADS)

Yaeger, Mary A.; Housh, Mashor; Cai, Ximing; Sivapalan, Murugesu

2014-12-01

To better address the dynamic interactions between human and hydrologic systems, we develop an integrated modeling framework that employs a System of Systems optimization model to emulate human development decisions which are then incorporated into a watershed model to estimate the resulting hydrologic impacts. The two models are run interactively to simulate the coevolution of coupled human-nature systems, such that reciprocal feedbacks between hydrologic processes and human decisions (i.e., human impacts on critical low flows and hydrologic impacts on human decisions on land and water use) can be assessed. The framework is applied to a Midwestern U.S. agricultural watershed, in the context of proposed biofuels development. This operation is illustrated by projecting three possible future coevolution trajectories, two of which use dedicated biofuel crops to reduce annual watershed nitrate export while meeting ethanol production targets. Imposition of a primary external driver (biofuel mandate) combined with different secondary drivers (water quality targets) results in highly nonlinear and multiscale responses of both the human and hydrologic systems, including multiple tradeoffs, impacting the future coevolution of the system in complex, heterogeneous ways. The strength of the hydrologic response is sensitive to the magnitude of the secondary driver; 45% nitrate reduction target leads to noticeable impacts at the outlet, while a 30% reduction leads to noticeable impacts that are mainly local. The local responses are conditioned by previous human-hydrologic modifications and their spatial relationship to the new biofuel development, highlighting the importance of past coevolutionary history in predicting future trajectories of change.

Inquiry-Based Investigation on the Internet: Sound and the Human Ear

ERIC Educational Resources Information Center

Quinlan, Kevin; Sterling, Donna R.

2006-01-01

In this online exploration of sound energy and the human ear, students carry out an inquiry-based activity, which leads them to websites featuring a diagram of a human ear, an interactive demonstration of the Doppler effect, a model of longitudinal waves, and an animation of human hearing. In the activity, students formulate, justify, and evaluate…

Human cognition and mobility in aging: a model for berry fruit interventions

USDA-ARS?s Scientific Manuscript database

Changes in motor function in aging, in both animals and humans, include decrements in balance, strength, and coordination, even in the absence of specific movement disorders such as Parkinson’s disease. In humans, these alterations can increase fall risk, often leading to injury and premature nursin...

Human-arm-and-hand-dynamic model with variability analyses for a stylus-based haptic interface.

PubMed

Fu, Michael J; Cavuşoğlu, M Cenk

2012-12-01

Haptic interface research benefits from accurate human arm models for control and system design. The literature contains many human arm dynamic models but lacks detailed variability analyses. Without accurate measurements, variability is modeled in a very conservative manner, leading to less than optimal controller and system designs. This paper not only presents models for human arm dynamics but also develops inter- and intrasubject variability models for a stylus-based haptic device. Data from 15 human subjects (nine male, six female, ages 20-32) were collected using a Phantom Premium 1.5a haptic device for system identification. In this paper, grip-force-dependent models were identified for 1-3-N grip forces in the three spatial axes. Also, variability due to human subjects and grip-force variation were modeled as both structured and unstructured uncertainties. For both forms of variability, the maximum variation, 95 %, and 67 % confidence interval limits were examined. All models were in the frequency domain with force as input and position as output. The identified models enable precise controllers targeted to a subset of possible human operator dynamics.

A numerical investigation on the effect of RF coil feed variability on global and local electromagnetic field exposure in human body models at 64 MHz.

PubMed

Lucano, Elena; Liberti, Micaela; Lloyd, Tom; Apollonio, Francesca; Wedan, Steve; Kainz, Wolfgang; Angelone, Leonardo M

2018-02-01

This study aims to investigate how the positions of the feeding sources of the transmit radiofrequency (RF) coil, field orientation direction with respect to the patient, and patient dimensions affect the global and local electromagnetic exposure in human body models. Three RF coil models were implemented, namely a specific two-source (S2) feed and two multisource feed configurations: generic 32-source (G32) and hybrid 16-source (H16). Thirty-two feeding conditions were studied for the S2, whereas two were studied for the G32 and H16. The study was performed using five human body models. Additionally, for two of the body models, the case of a partially implanted lead was evaluated. The results showed an overall variation due to coil feeding conditions of the whole-body specific absorption rate (SAR) of less than 20%, but deviations up to 98% of the magnitude of the electric field tangential to a possible lead path. For the analysis with the partially implanted lead, a variation of local SAR at the tip of the lead of up to 60% was observed with respect to feed position and field orientation direction. The results of this study suggest that specific information about feed position and field orientation direction must be considered for an accurate evaluation of patient exposure. Magn Reson Med 79:1135-1144, 2018. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

The Analysis of the Contribution of Human Factors to the In-Flight Loss of Control Accidents

NASA Technical Reports Server (NTRS)

Ancel, Ersin; Shih, Ann T.

2012-01-01

In-flight loss of control (LOC) is currently the leading cause of fatal accidents based on various commercial aircraft accident statistics. As the Next Generation Air Transportation System (NextGen) emerges, new contributing factors leading to LOC are anticipated. The NASA Aviation Safety Program (AvSP), along with other aviation agencies and communities are actively developing safety products to mitigate the LOC risk. This paper discusses the approach used to construct a generic integrated LOC accident framework (LOCAF) model based on a detailed review of LOC accidents over the past two decades. The LOCAF model is comprised of causal factors from the domain of human factors, aircraft system component failures, and atmospheric environment. The multiple interdependent causal factors are expressed in an Object-Oriented Bayesian belief network. In addition to predicting the likelihood of LOC accident occurrence, the system-level integrated LOCAF model is able to evaluate the impact of new safety technology products developed in AvSP. This provides valuable information to decision makers in strategizing NASA's aviation safety technology portfolio. The focus of this paper is on the analysis of human causal factors in the model, including the contributions from flight crew and maintenance workers. The Human Factors Analysis and Classification System (HFACS) taxonomy was used to develop human related causal factors. The preliminary results from the baseline LOCAF model are also presented.

Organizational intellectual capital and the role of the nurse manager: A proposed conceptual model.

PubMed

Gilbert, Jason H; Von Ah, Diane; Broome, Marion E

Nurse managers must leverage both the human capital and social capital of the teams they lead in order to produce quality outcomes. Little is known about the relationship between human capital and social capital and how these concepts may work together to produce organizational outcomes through leadership of nurses. The purpose of this article was to explore the concepts of human capital and social capital as they relate to nursing leadership in health care organizations. Specific aims included (a) to synthesize the literature related to human capital and social capital in leadership, (b) to refine the conceptual definitions of human capital and social capital with associated conceptual antecedents and consequences, and (c) to propose a synthesized conceptual model guiding further empirical research of social capital and human capital in nursing leadership. A systematic integrative review of leadership literature using criteria informed by Whittemore and Knafl (2005) was completed. CINAHL Plus with Full Text, Academic Search Premier, Business Source Premier, Health Business FullTEXT, MEDLINE, and PsychINFO databases were searched for the years 1995 to 2016 using terms "human capital," "social capital," and "management." Analysis of conceptual definitions, theoretical and conceptual models, antecedents and consequences, propositions or hypotheses, and empirical support for 37 articles fitting review criteria resulted in the synthesis of the proposed Gilbert Conceptual Model of Organizational Intellectual Capital. The Gilbert Conceptual Model of Organizational Intellectual Capital advances the propositions of human capital theory and social capital theory and is the first model to conceptualize the direct and moderating effects that nurse leaders have on the human capital and social capital of the teams they lead. This model provides a framework for further empirical study and may have implications for practice, organizational policy, and education related to nursing leadership. Copyright © 2017 Elsevier Inc. All rights reserved.

Molecular Docking, Pharmacophore, and 3D-QSAR Approach: Can Adenine Derivatives Exhibit Significant Inhibitor Towards Ebola Virus?

PubMed Central

Rai, Amit; Aboumanei, Mohamed H.; Verma, Suraj P.; Kumar, Sachidanand; Raj, Vinit

2017-01-01

Introduction: Ebola Virus Disease (EVD) is caused by Ebola virus, which is often accompanied by fatal hemorrhagic fever upon infection in humans. This virus has caused the majority of deaths in human. There are no proper vaccinations and medications available for EVD. It is pivoting the attraction of scientist to develop the potent vaccination or novel lead to inhibit Ebola virus. Methods & Materials: In the present study, we developed 3D-QSAR and the pharmacophoric model from the previous reported potent compounds for the Ebola virus. Results & Discussion: Results & Discussion: The pharmacophoric model AAAP.116 was generated with better survival value and selectivity. Moreover, the 3D-QSAR model also showed the best r2 value 0.99 using PLS factor. Thereby, we found the higher F value, which demonstrated the statistical significance of both the models. Furthermore, homological modeling and molecular docking study were performed to analyze the affinity of the potent lead. This showed the best binding energy and bond formation with targeted protein. Conclusion: Finally, all the results of this study concluded that 3D-QSAR and Pharmacophore models may be helpful to search potent lead for EVD treatment in future. PMID:29387271

Human pluripotent stem cells in modeling human disorders: the case of fragile X syndrome.

PubMed

Vershkov, Dan; Benvenisty, Nissim

2017-01-01

Human pluripotent stem cells (PSCs) generated from affected blastocysts or from patient-derived somatic cells are an emerging platform for disease modeling and drug discovery. Fragile X syndrome (FXS), the leading cause of inherited intellectual disability, was one of the first disorders modeled in both embryonic stem cells and induced PCSs and can serve as an exemplary case for the utilization of human PSCs in the study of human diseases. Over the past decade, FXS-PSCs have been used to address the fundamental questions regarding the pathophysiology of FXS. In this review we summarize the methodologies for generation of FXS-PSCs, discuss their advantages and disadvantages compared with existing modeling systems and describe their utilization in the study of FXS pathogenesis and in the development of targeted treatment.

How human drivers control their vehicle

NASA Astrophysics Data System (ADS)

Wagner, P.

2006-08-01

The data presented here show that human drivers apply a discrete noisy control mechanism to drive their vehicle. A car-following model built on these observations, together with some physical limitations (crash-freeness, acceleration), lead to non-Gaussian probability distributions in the speed difference and distance which are in good agreement with empirical data. All model parameters have a clear physical meaning and can be measured. Despite its apparent complexity, this model is simple to understand and might serve as a starting point to develop even quantitatively correct models.

Today's and yesterday's of pathophysiology: biochemistry of metabolic syndrome and animal models.

PubMed

Aydin, Suleyman; Aksoy, Aziz; Aydin, Suna; Kalayci, Mehmet; Yilmaz, Musa; Kuloglu, Tuncay; Citil, Cihan; Catak, Zekiye

2014-01-01

During the past 20 y, there has been much interest in sugars and especially fructose in relation to human health. Over the past decade, considerable scientific debate and controversy have arisen about the potential health effects of sucrose, high-fructose corn syrup (HFCS), and fructose itself. HFCS increasingly has been used as a sweetener in thousands of food products and soft drinks, leading to the development of obesity, diabetes, dyslipidemia, and metabolic syndrome (MetS) in both rodents and humans, which is associated with an increase in body weight. There is a need for detailed research on the mechanism underlying MetS that could lead to a remedy. This review will first systematically present a definition of MetS, its history, prevalence, and comparative diagnostic criteria. We will then consider fructose and its effects on human health, the diet-induced obesity model (various fat contents), the hypercholesterolemic model, the diabetes model, the hypertensive model, the MetS or insulin resistance model, and biomarkers related to MetS, in light of contemporary data using multiple databases (PubMed, MEDLINE, and OVID). Copyright © 2014 Elsevier Inc. All rights reserved.

Genome Editing in Rats Using TALE Nucleases.

PubMed

Tesson, Laurent; Remy, Séverine; Ménoret, Séverine; Usal, Claire; Thinard, Reynald; Savignard, Chloé; De Cian, Anne; Giovannangeli, Carine; Concordet, Jean-Paul; Anegon, Ignacio

2016-01-01

The rat is an important animal model to understand gene function and model human diseases. Since recent years, the development of gene-specific nucleases has become important for generating new rat models of human diseases, to analyze the role of genes and to generate human antibodies. Transcription activator-like (TALE) nucleases efficiently create gene-specific knockout rats and lead to the possibility of gene targeting by homology-directed recombination (HDR) and generating knock-in rats. We describe a detailed protocol for generating knockout and knock-in rats via microinjection of TALE nucleases into fertilized eggs. This technology is an efficient, cost- and time-effective method for creating new rat models.

A prototypic mathematical model of the human hair cycle.

PubMed

Al-Nuaimi, Yusur; Goodfellow, Marc; Paus, Ralf; Baier, Gerold

2012-10-07

The human hair cycle is a complex, dynamic organ-transformation process during which the hair follicle repetitively progresses from a growth phase (anagen) to a rapid apoptosis-driven involution (catagen) and finally a relative quiescent phase (telogen) before returning to anagen. At present no theory satisfactorily explains the origin of the hair cycle rhythm. Based on experimental evidence we propose a prototypic model that focuses on the dynamics of hair matrix keratinocytes. We argue that a plausible feedback-control structure between two key compartments (matrix keratinocytes and dermal papilla) leads to dynamic instabilities in the population dynamics resulting in rhythmic hair growth. The underlying oscillation consists of an autonomous switching between two quasi-steady states. Additional features of the model, namely bistability and excitability, lead to new hypotheses about the impact of interventions on hair growth. We show how in silico testing may facilitate testing of candidate hair growth modulatory agents in human HF organ culture or in clinical trials. Copyright © 2012 Elsevier Ltd. All rights reserved.

Dynamic Human Body Modeling Using a Single RGB Camera.

PubMed

Zhu, Haiyu; Yu, Yao; Zhou, Yu; Du, Sidan

2016-03-18

In this paper, we present a novel automatic pipeline to build personalized parametric models of dynamic people using a single RGB camera. Compared to previous approaches that use monocular RGB images, our system can model a 3D human body automatically and incrementally, taking advantage of human motion. Based on coarse 2D and 3D poses estimated from image sequences, we first perform a kinematic classification of human body parts to refine the poses and obtain reconstructed body parts. Next, a personalized parametric human model is generated by driving a general template to fit the body parts and calculating the non-rigid deformation. Experimental results show that our shape estimation method achieves comparable accuracy with reconstructed models using depth cameras, yet requires neither user interaction nor any dedicated devices, leading to the feasibility of using this method on widely available smart phones.

Dynamic Human Body Modeling Using a Single RGB Camera

PubMed Central

Zhu, Haiyu; Yu, Yao; Zhou, Yu; Du, Sidan

2016-01-01

In this paper, we present a novel automatic pipeline to build personalized parametric models of dynamic people using a single RGB camera. Compared to previous approaches that use monocular RGB images, our system can model a 3D human body automatically and incrementally, taking advantage of human motion. Based on coarse 2D and 3D poses estimated from image sequences, we first perform a kinematic classification of human body parts to refine the poses and obtain reconstructed body parts. Next, a personalized parametric human model is generated by driving a general template to fit the body parts and calculating the non-rigid deformation. Experimental results show that our shape estimation method achieves comparable accuracy with reconstructed models using depth cameras, yet requires neither user interaction nor any dedicated devices, leading to the feasibility of using this method on widely available smart phones. PMID:26999159

Testing the Human Capital Development Model: The Case of Apprenticeships in Turkey

ERIC Educational Resources Information Center

Akpinar, Taner; Gün, Servet

2016-01-01

Human capital theory was developed to study how individual agents make rational choices or how they invest in human capital to maximize their welfare. One of the leading founders of this perspective, Becker, argues that schooling, on-the-job training, medical care, migration and searching for information about prices and incomes are different…

Human pluripotent stem cell models of Fragile X syndrome.

PubMed

Bhattacharyya, Anita; Zhao, Xinyu

2016-06-01

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism. The causal mutation in FXS is a trinucleotide CGG repeat expansion in the FMR1 gene that leads to human specific epigenetic silencing and loss of Fragile X Mental Retardation Protein (FMRP) expression. Human pluripotent stem cells (PSCs), including human embryonic stem cells (ESCs) and particularly induced PSCs (iPSCs), offer a model system to reveal cellular and molecular events underlying human neuronal development and function in FXS. Human FXS PSCs have been established and have provided insight into the epigenetic silencing of the FMR1 gene as well as aspects of neuronal development. Copyright © 2015 Elsevier Inc. All rights reserved.

The Genetic Basis for Variation in Sensitivity to Lead Toxicity in Drosophila melanogaster

PubMed Central

Zhou, Shanshan; Morozova, Tatiana V.; Hussain, Yasmeen N.; Luoma, Sarah E.; McCoy, Lenovia; Yamamoto, Akihiko; Mackay, Trudy F.C.; Anholt, Robert R.H.

2016-01-01

Background: Lead toxicity presents a worldwide health problem, especially due to its adverse effects on cognitive development in children. However, identifying genes that give rise to individual variation in susceptibility to lead toxicity is challenging in human populations. Objectives: Our goal was to use Drosophila melanogaster to identify evolutionarily conserved candidate genes associated with individual variation in susceptibility to lead exposure. Methods: To identify candidate genes associated with variation in susceptibility to lead toxicity, we measured effects of lead exposure on development time, viability and adult activity in the Drosophila melanogaster Genetic Reference Panel (DGRP) and performed genome-wide association analyses to identify candidate genes. We used mutants to assess functional causality of candidate genes and constructed a genetic network associated with variation in sensitivity to lead exposure, on which we could superimpose human orthologs. Results: We found substantial heritabilities for all three traits and identified candidate genes associated with variation in susceptibility to lead exposure for each phenotype. The genetic architectures that determine variation in sensitivity to lead exposure are highly polygenic. Gene ontology and network analyses showed enrichment of genes associated with early development and function of the nervous system. Conclusions: Drosophila melanogaster presents an advantageous model to study the genetic underpinnings of variation in susceptibility to lead toxicity. Evolutionary conservation of cellular pathways that respond to toxic exposure allows predictions regarding orthologous genes and pathways across phyla. Thus, studies in the D. melanogaster model system can identify candidate susceptibility genes to guide subsequent studies in human populations. Citation: Zhou S, Morozova TV, Hussain YN, Luoma SE, McCoy L, Yamamoto A, Mackay TF, Anholt RR. 2016. The genetic basis for variation in sensitivity to lead toxicity in Drosophila melanogaster. Environ Health Perspect 124:1062–1070; http://dx.doi.org/10.1289/ehp.1510513 PMID:26859824

A comparison of some organizational characteristics of the mouse central retina and the human macula.

PubMed

Volland, Stefanie; Esteve-Rudd, Julian; Hoo, Juyea; Yee, Claudine; Williams, David S

2015-01-01

Mouse models have greatly assisted our understanding of retinal degenerations. However, the mouse retina does not have a macula, leading to the question of whether the mouse is a relevant model for macular degeneration. In the present study, a quantitative comparison between the organization of the central mouse retina and the human macula was made, focusing on some structural characteristics that have been suggested to be important in predisposing the macula to stresses leading to degeneration: photoreceptor density, phagocytic load on the RPE, and the relative thinness of Bruch's membrane. Light and electron microscopy measurements from retinas of two strains of mice, together with published data on human retinas, were used for calculations and subsequent comparisons. As in the human retina, the central region of the mouse retina possesses a higher photoreceptor cell density and a thinner Bruch's membrane than in the periphery; however, the magnitudes of these periphery to center gradients are larger in the human. Of potentially greater relevance is the actual photoreceptor cell density, which is much greater in the mouse central retina than in the human macula, underlying a higher phagocytic load for the mouse RPE. Moreover, at eccentricities that correspond to the peripheral half of the human macula, the rod to cone ratio is similar between mouse and human. Hence, with respect to photoreceptor density and phagocytic load of the RPE, the central mouse retina models at least the more peripheral part of the macula, where macular degeneration is often first evident.

Modeling Niemann Pick type C1 using human embryonic and induced pluripotent stem cells.

PubMed

Ordoñez, M Paulina; Steele, John W

2017-02-01

Data generated in Niemann Pick type C1 (NPC1) human embryonic and human induced pluripotent stem cell derived neurons complement on-going studies in animal models and provide the first example, in disease-relevant human cells, of processes that underlie preferential neuronal defects in a NPC1. Our work and that of other investigators in human neurons derived from stem cells highlight the importance of performing rigorous mechanistic studies in relevant cell types to guide drug discovery and therapeutic development, alongside of existing animal models. Through the use of human stem cell-derived models of disease, we can identify and discover or repurpose drugs that revert early events that lead to neuronal failure in NPC1. Together with the study of disease pathogenesis and efficacy of therapies in animal models, these strategies will fulfill the promise of stem cell technology in the development of new treatments for human diseases. This article is part of a Special Issue entitled SI: Exploiting human neurons. Copyright © 2016 Elsevier B.V. All rights reserved.

Modeling human influenza infection in the laboratory

PubMed Central

Radigan, Kathryn A; Misharin, Alexander V; Chi, Monica; Budinger, GR Scott

2015-01-01

Influenza is the leading cause of death from an infectious cause. Because of its clinical importance, many investigators use animal models to understand the biologic mechanisms of influenza A virus replication, the immune response to the virus, and the efficacy of novel therapies. This review will focus on the biosafety, biosecurity, and ethical concerns that must be considered in pursuing influenza research, in addition to focusing on the two animal models – mice and ferrets – most frequently used by researchers as models of human influenza infection. PMID:26357484

New directions in the toxicokinetics of human lead exposure

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

Mushak, P.

An important determinant of body lead (Pb) burden and Pb toxicity in exposed humans is Pb metabolism, or more correctly, Pb toxicokinetics. It affects the former through the quantitative processes of uptake, distribution and retention/excretion and the latter via delivery of toxic doses to cellular/molecular sites of action. Pb toxicokinetics has useful application in understanding Pb's behavior in populations. Several of these applications have been studied and results are presented for the toxicokinetic basis of dose-neurotoxic effect relationships in selected longitudinal studies and the use of toxicokinetic modeling for estimation of body lead burden in early populations. Three well-known, ongoingmore » longitudinal studies of developmental neurotoxicity--in Boston, Cincinnati, and Port Pirie, Australia--involve cohorts who differ markedly as to their pre- and postnatal lead exposure profiles. Toxicokinetic examination of these exposure differences helps to explain the temporal variability seen in blood Pb-toxic effect relationships and supports a causal role for lead. Toxicokinetic models of Pb uptake and in-vivo behavior are increasingly being considered for estimating Pb-B levels in lieu of direct measurement. A linear biokinetic model, using reliable input data for natural/prehistoric levels of Pb in sources, was applied to estimation of prehistoric/preindustrial children's blood lead. A range of 0.06 to 0.12 microgram/dl was estimated for two lead intakes. These estimates are still two orders of magnitude (85 to 165-fold) lower than the newly issued CDC toxicity guideline for children of 10 micrograms/dl. Lastly, the toxicokinetics of lead in bone, particularly its resorption with metabolic stimuli, is of concern, particularly for baby boom women who are either of childbearing age or approaching menopause and who had greatly elevated environmental lead exposures in the 1940s to 1970s. 115 refs.« less

Engineering a humanized bone organ model in mice to study bone metastases.

PubMed

Martine, Laure C; Holzapfel, Boris M; McGovern, Jacqui A; Wagner, Ferdinand; Quent, Verena M; Hesami, Parisa; Wunner, Felix M; Vaquette, Cedryck; De-Juan-Pardo, Elena M; Brown, Toby D; Nowlan, Bianca; Wu, Dan Jing; Hutmacher, Cosmo Orlando; Moi, Davide; Oussenko, Tatiana; Piccinini, Elia; Zandstra, Peter W; Mazzieri, Roberta; Lévesque, Jean-Pierre; Dalton, Paul D; Taubenberger, Anna V; Hutmacher, Dietmar W

2017-04-01

Current in vivo models for investigating human primary bone tumors and cancer metastasis to the bone rely on the injection of human cancer cells into the mouse skeleton. This approach does not mimic species-specific mechanisms occurring in human diseases and may preclude successful clinical translation. We have developed a protocol to engineer humanized bone within immunodeficient hosts, which can be adapted to study the interactions between human cancer cells and a humanized bone microenvironment in vivo. A researcher trained in the principles of tissue engineering will be able to execute the protocol and yield study results within 4-6 months. Additive biomanufactured scaffolds seeded and cultured with human bone-forming cells are implanted ectopically in combination with osteogenic factors into mice to generate a physiological bone 'organ', which is partially humanized. The model comprises human bone cells and secreted extracellular matrix (ECM); however, other components of the engineered tissue, such as the vasculature, are of murine origin. The model can be further humanized through the engraftment of human hematopoietic stem cells (HSCs) that can lead to human hematopoiesis within the murine host. The humanized organ bone model has been well characterized and validated and allows dissection of some of the mechanisms of the bone metastatic processes in prostate and breast cancer.

Redistribution spurs growth by using a portfolio effect on risky human capital.

PubMed

Lorenz, Jan; Paetzel, Fabian; Schweitzer, Frank

2013-01-01

We demonstrate by mathematical analysis and systematic computer simulations that redistribution can lead to sustainable growth in a society. In accordance with economic models of risky human capital, we assume that dynamics of human capital is modeled as a multiplicative stochastic process which, in the long run, leads to the destruction of individual human capital. When agents are linked by fully redistributive taxation the situation might turn to individual growth in the long run. We consider that a government collects a proportion of income and reduces it by a fraction as costs for administration (efficiency losses). The remaining public good is equally redistributed to all agents. Sustainable growth is induced by redistribution despite the losses from the random growth process and despite administrative costs. Growth results from a portfolio effect. The findings are verified for three different tax schemes: proportional tax, taking proportionally more from the rich, and proportionally more from the poor. We discuss which of these tax schemes performs better with respect to maximize growth under a fixed rate of administrative costs, and the governmental income. This leads us to general conclusions about governmental decisions, the relation to public good games with free riding, and the function of taxation in a risk-taking society.

Redistribution Spurs Growth by Using a Portfolio Effect on Risky Human Capital

PubMed Central

Lorenz, Jan; Paetzel, Fabian; Schweitzer, Frank

2013-01-01

We demonstrate by mathematical analysis and systematic computer simulations that redistribution can lead to sustainable growth in a society. In accordance with economic models of risky human capital, we assume that dynamics of human capital is modeled as a multiplicative stochastic process which, in the long run, leads to the destruction of individual human capital. When agents are linked by fully redistributive taxation the situation might turn to individual growth in the long run. We consider that a government collects a proportion of income and reduces it by a fraction as costs for administration (efficiency losses). The remaining public good is equally redistributed to all agents. Sustainable growth is induced by redistribution despite the losses from the random growth process and despite administrative costs. Growth results from a portfolio effect. The findings are verified for three different tax schemes: proportional tax, taking proportionally more from the rich, and proportionally more from the poor. We discuss which of these tax schemes performs better with respect to maximize growth under a fixed rate of administrative costs, and the governmental income. This leads us to general conclusions about governmental decisions, the relation to public good games with free riding, and the function of taxation in a risk-taking society. PMID:23390505

Application of the epidemiological model in studying human error in aviation

NASA Technical Reports Server (NTRS)

Cheaney, E. S.; Billings, C. E.

1981-01-01

An epidemiological model is described in conjunction with the analytical process through which aviation occurrence reports are composed into the events and factors pertinent to it. The model represents a process in which disease, emanating from environmental conditions, manifests itself in symptoms that may lead to fatal illness, recoverable illness, or no illness depending on individual circumstances of patient vulnerability, preventive actions, and intervention. In the aviation system the analogy of the disease process is the predilection for error of human participants. This arises from factors in the operating or physical environment and results in errors of commission or omission that, again depending on the individual circumstances, may lead to accidents, system perturbations, or harmless corrections. A discussion of the previous investigations, each of which manifests the application of the epidemiological method, exemplifies its use and effectiveness.

Lead.

PubMed

Bellinger, David C

2004-04-01

Children differ from adults in the relative importance of lead sources and pathways, lead metabolism, and the toxicities expressed. The central nervous system effects of lead on children seem not to be reversible. Periods of enhanced vulnerability within childhood have not consistently been identified. The period of greatest vulnerability might be endpoint specific, perhaps accounting for the failure to identify a coherent "behavioral signature" for lead toxicity. The bases for the substantial individual variability in vulnerability to lead are uncertain, although they might include genetic polymorphisms and contextual factors. The current Centers for Disease Control and Prevention screening guideline of 10 micro g/dL is a risk management tool and should not be interpreted as a threshold for toxicity. No threshold has been identified, and some data are consistent with effects well below 10. Historically, most studies have concentrated on neurocognitive effects of lead, but higher exposures have recently been associated with morbidities such as antisocial behavior and delinquency. Studies of lead toxicity in experimental animal models are critical to the interpretation of nonexperimental human studies, particularly in addressing the likelihood that associations observed in the latter studies can be attributed to residual confounding. Animal models are also helpful in investigating the behavioral and neurobiological mechanisms of the functional deficits observed in lead-exposed humans. Studies of adults who have been exposed to lead are of limited use in understanding childhood lead toxicity because developmental and acquired lead exposure differ in terms of the maturity of the organs affected, the presumed mechanisms of toxicity, and the forms in which toxicities are expressed.

Real-Time Monitoring and Prediction of the Pilot Vehicle System (PVS) Closed-Loop Stability

NASA Astrophysics Data System (ADS)

Mandal, Tanmay Kumar

Understanding human control behavior is an important step for improving the safety of future aircraft. Considerable resources are invested during the design phase of an aircraft to ensure that the aircraft has desirable handling qualities. However, human pilots exhibit a wide range of control behaviors that are a function of external stimulus, aircraft dynamics, and human psychological properties (such as workload, stress factor, confidence, and sense of urgency factor). This variability is difficult to address comprehensively during the design phase and may lead to undesirable pilot-aircraft interaction, such as pilot-induced oscillations (PIO). This creates the need to keep track of human pilot performance in real-time to monitor the pilot vehicle system (PVS) stability. This work focused on studying human pilot behavior for the longitudinal axis of a remotely controlled research aircraft and using human-in-the-loop (HuIL) simulations to obtain information about the human controlled system (HCS) stability. The work in this dissertation is divided into two main parts: PIO analysis and human control model parameters estimation. To replicate different flight conditions, this study included time delay and elevator rate limiting phenomena, typical of actuator dynamics during the experiments. To study human control behavior, this study employed the McRuer model for single-input single-output manual compensatory tasks. McRuer model is a lead-lag controller with time delay which has been shown to adequately model manual compensatory tasks. This dissertation presents a novel technique to estimate McRuer model parameters in real-time and associated validation using HuIL simulations to correctly predict HCS stability. The McRuer model parameters were estimated in real-time using a Kalman filter approach. The estimated parameters were then used to analyze the stability of the closed-loop HCS and verify them against the experimental data. Therefore, the main contribution of this dissertation is the design of an unscented Kalman filter-based algorithm to estimate McRuer model parameters in real time, and a framework to validate this algorithm for single-input single-output manual compensatory tasks to predict instabilities.

Specialists without spirit: limitations of the mechanistic biomedical model.

PubMed

Hewa, S; Hetherington, R W

1995-06-01

This paper examines the origin and the development of the mechanistic model of the human body and health in terms of Max Weber's theory of rationalization. It is argued that the development of Western scientific medicine is a part of the broad process of rationalization that began in sixteenth century Europe as a result of the Reformation. The development of the mechanistic view of the human body in Western medicine is consistent with the ideas of calculability, predictability, and control-the major tenets of the process of rationalization as described by Weber. In recent years, however, the limitations of the mechanistic model have been the topic of many discussions. George Engel, a leading advocate of general systems theory, is one of the leading proponents of a new medical model which includes the general quality of life, clean environment, and psychological, or spiritual stability of life. The paper concludes with consideration of the potential of Engel's proposed new model in the context of the current state of rationalization in modern industrialized society.

Generation of a three-dimensional ultrastructural model of human respiratory cilia.

PubMed

Burgoyne, Thomas; Dixon, Mellisa; Luther, Pradeep; Hogg, Claire; Shoemark, Amelia

2012-12-01

The ultrastructures of cilia and flagella are highly similar and well conserved through evolution. Consequently, Chlamydomonas is commonly used as a model organism for the study of human respiratory cilia. Since detailed models of Chlamydomonas axonemes were generated using cryoelectron tomography, disparities among some of the ultrastructural features have become apparent when compared with human cilia. Extrapolating information on human disease from the Chlamydomonas model may lead to discrepancies in translational research. This study aimed to establish the first three-dimensional ultrastructural model of human cilia. Tomograms of transverse sections (n = 6) and longitudinal sections (n = 9) of human nasal respiratory cilia were generated from three healthy volunteers. Key features of the cilium were resolved using subatomic averaging, and were measured. For validation of the method, a model of the well characterized structure of Chlamydomonas reinhardtii was simultaneously generated. Data were combined to create a fully quantified three-dimensional reconstruction of human nasal respiratory cilia. We highlight key differences in the axonemal sheath, microtubular doublets, radial spokes, and dynein arms between the two structures. We show a decreased axial periodicity of the radial spokes, inner dynein arms, and central pair protrusions in the human model. We propose that this first human model will provide a basis for research into the function and structure of human respiratory cilia in health and in disease.

Bridging Animal and Human Models

PubMed Central

Barkley-Levenson, Amanda M.; Crabbe, John C.

2012-01-01

Genetics play an important role in the development and course of alcohol abuse, and understanding genetic contributions to this disorder may lead to improved preventative and therapeutic strategies in the future. Studies both in humans and in animal models are necessary to fully understand the neurobiology of alcoholism from the molecular to the cognitive level. By dissecting the complex facets of alcoholism into discrete, well-defined phenotypes that are measurable in both human populations and animal models of the disease, researchers will be better able to translate findings across species and integrate the knowledge obtained from various disciplines. Some of the key areas of alcoholism research where consilience between human and animal studies is possible are alcohol withdrawal severity, sensitivity to rewards, impulsivity, and dysregulated alcohol consumption. PMID:23134048

Neurotoxicity of lead, methylmercury, and PCBs in relation to the Great Lakes.

PubMed Central

Rice, D C

1995-01-01

There is ample evidence identifying lead, methylmercury, and polychlorinated biphenyls (PCBs) as neurotoxic agents. A large body of data on the neurotoxicity of lead, based on both epidemiologic studies in children and animal models of developmental exposure, reveals that body burdens of lead typical of people in industrialized environments produce behavioral impairment. Methylmercury was identified as a neurotoxicant in both adults and the developing organism based on episodes of human poisoning: these effects have been replicated and extended in animals. High-dose PCB exposure was recognized as a developmental toxicant as a result of several episodes of contamination of cooking oil. The threshold for PCB neurotoxicity in humans is less clear, although research in animals suggests that relatively low-level exposure produces behavioral impairment and other toxic effects. Tissue levels in fish below which human health would not be adversely affected were estimated for methylmercury and PCBs based on calculated reference doses (RfDs) and estimated fish intake. Present levels in fish tissue in the Great Lakes exceed these levels for both neurotoxicants. Great Lakes fish and water do not pose a particular hazard for increased lead intake. However, the fact that the present human body burden is in a range at which functional deficits are probable suggests that efforts should be made to eliminate point sources of lead contamination in the Great Lakes basin. PMID:8635443

Modelling drivers and distribution of lead and zinc concentrations in soils of an urban catchment (Sydney estuary, Australia).

PubMed

Johnson, L E; Bishop, T F A; Birch, G F

2017-11-15

The human population is increasing globally and land use is changing to accommodate for this growth. Soils within urban areas require closer attention as the higher population density increases the chance of human exposure to urban contaminants. One such example of an urban area undergoing an increase in population density is Sydney, Australia. The city also possesses a notable history of intense industrial activity. By integrating multiple soil surveys and covariates into a linear mixed model, it was possible to determine the main drivers and map the distribution of lead and zinc concentrations within the Sydney estuary catchment. The main drivers as derived from the model included elevation, distance to main roads, main road type, soil landscape, population density (lead only) and land use (zinc only). Lead concentrations predicted using the model exceeded the established guideline value of 300mgkg -1 over a large portion of the study area with concentrations exceeding 1000mgkg -1 in the south of the catchment. Predicted zinc did not exceed the established guideline value of 7400mgkg -1 ; however concentrations were higher to the south and west of the study area. Unlike many other studies we considered the prediction uncertainty when assessing the contamination risk. Although the predictions indicate contamination over a large area, the broadness of the prediction intervals suggests that in many of these areas we cannot be sure that the site is contaminated. More samples are required to determine the contaminant distribution with greater precision, especially in residential areas where contamination was highest. Managing sources and addressing areas of elevated lead and zinc concentrations in urban areas has the potential to reduce the impact of past human activities and improve the urban environment of the future. Copyright © 2017 Elsevier B.V. All rights reserved.

Long-term human exposure to lead from different media and intake pathways.

PubMed

Pizzol, Massimo; Thomsen, Marianne; Andersen, Mikael Skou

2010-10-15

Lead (Pb) is well known as an environmental pollutant: it can accumulate in various media, so actual lead exposure reflects both historical and present contaminations. Two main challenges then emerge: obtaining updated information to gain an overall picture of the sources of exposure, and predicting the resulting internal body exposure levels and effects that occur under long-term exposure conditions. In this paper, a modeling approach is used to meet these challenges with reference to Danish exposure conditions. Levels of lead content in various media have been coupled with data for lead intake and absorption in the human body, for both children and adults. An age-dependent biokinetic model allows then for determination of the blood lead levels resulting from chronic exposure. The study shows that the actual intake of lead is up to 27% of the Provisional Tolerable Daily Intake (PTDI) for children and around 8% for adults. It is confirmed that the critical route of exposure is via ingestion, accounting for 99% of total lead intake, while inhalation contributes only to 1% of total lead intake. The resulting lead levels in the blood after 2 years of exposure to actual contamination conditions have been estimated as up to 2.2μg/dl in children and almost 1μg/dl in adults. Impacts from lead can occur even at such levels. The role of historical and present sources to lead in the environment is discussed, and, for specific child and adult exposure scenarios, external-internal concentration relationships for the direct linkage between lead in environmental media and resulting concentrations of lead in blood are then presented. Copyright © 2010 Elsevier B.V. All rights reserved.

Trehalose upregulates progranulin expression in human and mouse models of GRN haploinsufficiency: a novel therapeutic lead to treat frontotemporal dementia.

PubMed

Holler, Christopher J; Taylor, Georgia; McEachin, Zachary T; Deng, Qiudong; Watkins, William J; Hudson, Kathryn; Easley, Charles A; Hu, William T; Hales, Chadwick M; Rossoll, Wilfried; Bassell, Gary J; Kukar, Thomas

2016-06-24

Progranulin (PGRN) is a secreted growth factor important for neuronal survival and may do so, in part, by regulating lysosome homeostasis. Mutations in the PGRN gene (GRN) are a common cause of frontotemporal lobar degeneration (FTLD) and lead to disease through PGRN haploinsufficiency. Additionally, complete loss of PGRN in humans leads to neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Importantly, Grn-/- mouse models recapitulate pathogenic lysosomal features of NCL. Further, GRN variants that decrease PGRN expression increase the risk of developing Alzheimer's disease (AD) and Parkinson's disease (PD). Together these findings demonstrate that insufficient PGRN predisposes neurons to degeneration. Therefore, compounds that increase PGRN levels are potential therapeutics for multiple neurodegenerative diseases. Here, we performed a cell-based screen of a library of known autophagy-lysosome modulators and identified multiple novel activators of a human GRN promoter reporter including several common mTOR inhibitors and an mTOR-independent activator of autophagy, trehalose. Secondary cellular screens identified trehalose, a natural disaccharide, as the most promising lead compound because it increased endogenous PGRN in all cell lines tested and has multiple reported neuroprotective properties. Trehalose dose-dependently increased GRN mRNA as well as intracellular and secreted PGRN in both mouse and human cell lines and this effect was independent of the transcription factor EB (TFEB). Moreover, trehalose rescued PGRN deficiency in human fibroblasts and neurons derived from induced pluripotent stem cells (iPSCs) generated from GRN mutation carriers. Finally, oral administration of trehalose to Grn haploinsufficient mice significantly increased PGRN expression in the brain. This work reports several novel autophagy-lysosome modulators that enhance PGRN expression and identifies trehalose as a promising therapeutic for raising PGRN levels to treat multiple neurodegenerative diseases.

Curve Estimation of Number of People Killed in Traffic Accidents in Turkey

NASA Astrophysics Data System (ADS)

Berkhan Akalin, Kadir; Karacasu, Murat; Altin, Arzu Yavuz; Ergül, Bariş

2016-10-01

One or more than one vehicle in motion on the highway involving death, injury and loss events which have resulted are called accidents. As a result of increasing population and traffic density, traffic accidents continue to increase and this leads to both human losses and harm to the economy. In addition, also leads to social problems. As a result of increasing population and traffic density, traffic accidents continue to increase and this leads to both human losses and harm to the economy. In addition to this, it also leads to social problems. As a result of traffic accidents, millions of people die year by year. A great majority of these accidents occur in developing countries. One of the most important tasks of transportation engineers is to reduce traffic accidents by creating a specific system. For that reason, statistical information about traffic accidents which occur in the past years should be organized by versed people. Factors affecting the traffic accidents are analyzed in various ways. In this study, modelling the number of people killed in traffic accidents in Turkey is determined. The dead people were modelled using curve fitting method with the number of people killed in traffic accidents in Turkey dataset between 1990 and 2014. It was also predicted the number of dead people by using various models for the future. It is decided that linear model is suitable for the estimates.

Functional Analysis of Human NF1 in Drosophila

DTIC Science & Technology

2008-12-01

also have learning problem. Such learning phenotypes have been recapitulated in animal models, including in mouse and Drosophila mutants. This proposal...by examining the phenotypes of mutated human genes expressed in Drosophila NF1 null mutants. We also propose that Gsα/NF1 activated AC pathway...in both Drosophila and mouse NF1 models. Our previous work has shown that defective cAMP signaling leads to the learning phenotype in Drosophila Nf1

Calling in Sick: Impacts of Fever on Intra-Urban Human Mobility

DTIC Science & Technology

2016-07-13

Disease manifestations can significantly alter behavior in human and non-human animal hosts [1], leading to important consequences for the ecology of both...due to illness is a case in point. Such effects have potentially broad significance throughout epidemiology, ecology , and evolution. Hypothesized...goals and the nested relationships among our models [35]. 6 Ethics approval The procedures for enrollment of participants, dengue diagnosis

Comparing the Hematopoetic Syndrome Time Course in the NHP Animal Model to Radiation Accident Cases From the Database Search.

PubMed

Graessle, Dieter H; Dörr, Harald; Bennett, Alexander; Shapiro, Alla; Farese, Ann M; MacVittie, Thomas J; Meineke, Viktor

2015-11-01

Since controlled clinical studies on drug administration for the acute radiation syndrome are lacking, clinical data of human radiation accident victims as well as experimental animal models are the main sources of information. This leads to the question of how to compare and link clinical observations collected after human radiation accidents with experimental observations in non-human primate (NHP) models. Using the example of granulocyte counts in the peripheral blood following radiation exposure, approaches for adaptation between NHP and patient databases on data comparison and transformation are introduced. As a substitute for studying the effects of administration of granulocyte-colony stimulating factor (G-CSF) in human clinical trials, the method of mathematical modeling is suggested using the example of G-CSF administration to NHP after total body irradiation.

A Comparison of Some Organizational Characteristics of the Mouse Central Retina and the Human Macula

PubMed Central

Hoo, Juyea; Yee, Claudine; Williams, David S.

2015-01-01

Mouse models have greatly assisted our understanding of retinal degenerations. However, the mouse retina does not have a macula, leading to the question of whether the mouse is a relevant model for macular degeneration. In the present study, a quantitative comparison between the organization of the central mouse retina and the human macula was made, focusing on some structural characteristics that have been suggested to be important in predisposing the macula to stresses leading to degeneration: photoreceptor density, phagocytic load on the RPE, and the relative thinness of Bruch’s membrane. Light and electron microscopy measurements from retinas of two strains of mice, together with published data on human retinas, were used for calculations and subsequent comparisons. As in the human retina, the central region of the mouse retina possesses a higher photoreceptor cell density and a thinner Bruch’s membrane than in the periphery; however, the magnitudes of these periphery to center gradients are larger in the human. Of potentially greater relevance is the actual photoreceptor cell density, which is much greater in the mouse central retina than in the human macula, underlying a higher phagocytic load for the mouse RPE. Moreover, at eccentricities that correspond to the peripheral half of the human macula, the rod to cone ratio is similar between mouse and human. Hence, with respect to photoreceptor density and phagocytic load of the RPE, the central mouse retina models at least the more peripheral part of the macula, where macular degeneration is often first evident. PMID:25923208

From Network Analysis to Functional Metabolic Modeling of the Human Gut Microbiota.

PubMed

Bauer, Eugen; Thiele, Ines

2018-01-01

An important hallmark of the human gut microbiota is its species diversity and complexity. Various diseases have been associated with a decreased diversity leading to reduced metabolic functionalities. Common approaches to investigate the human microbiota include high-throughput sequencing with subsequent correlative analyses. However, to understand the ecology of the human gut microbiota and consequently design novel treatments for diseases, it is important to represent the different interactions between microbes with their associated metabolites. Computational systems biology approaches can give further mechanistic insights by constructing data- or knowledge-driven networks that represent microbe interactions. In this minireview, we will discuss current approaches in systems biology to analyze the human gut microbiota, with a particular focus on constraint-based modeling. We will discuss various community modeling techniques with their advantages and differences, as well as their application to predict the metabolic mechanisms of intestinal microbial communities. Finally, we will discuss future perspectives and current challenges of simulating realistic and comprehensive models of the human gut microbiota.

TALEN-based generation of a cynomolgus monkey disease model for human microcephaly

PubMed Central

Ke, Qiong; Li, Weiqiang; Lai, Xingqiang; Chen, Hong; Huang, Lihua; Kang, Zhuang; Li, Kai; Ren, Jie; Lin, Xiaofeng; Zheng, Haiqing; Huang, Weijun; Ma, Yunhan; Xu, Dongdong; Chen, Zheng; Song, Xinming; Lin, Xinyi; Zhuang, Min; Wang, Tao; Zhuang, Fengfeng; Xi, Jianzhong; Mao, Frank Fuxiang; Xia, Huimin; Lahn, Bruce T; Zhou, Qi; Yang, Shihua; Xiang, Andy Peng

2016-01-01

Gene editing in non-human primates may lead to valuable models for exploring the etiologies and therapeutic strategies of genetically based neurological disorders in humans. However, a monkey model of neurological disorders that closely mimics pathological and behavioral deficits in humans has not yet been successfully generated. Microcephalin 1 (MCPH1) is implicated in the evolution of the human brain, and MCPH1 mutation causes microcephaly accompanied by mental retardation. Here we generated a cynomolgus monkey (Macaca fascicularis) carrying biallelic MCPH1 mutations using transcription activator-like effector nucleases. The monkey recapitulated most of the important clinical features observed in patients, including marked reductions in head circumference, premature chromosome condensation (PCC), hypoplasia of the corpus callosum and upper limb spasticity. Moreover, overexpression of MCPH1 in mutated dermal fibroblasts rescued the PCC syndrome. This monkey model may help us elucidate the role of MCPH1 in the pathogenesis of human microcephaly and better understand the function of this protein in the evolution of primate brain size. PMID:27502025

Understanding Kidney Disease: Toward the Integration of Regulatory Networks Across Species

PubMed Central

Ju, Wenjun; Brosius, Frank C.

2010-01-01

Animal models have long been useful in investigating both normal and abnormal human physiology. Systems biology provides a relatively new set of approaches to identify similarities and differences between animal models and humans that may lead to a more comprehensive understanding of human kidney pathophysiology. In this review, we briefly describe how genome-wide analyses of mouse models have helped elucidate features of human kidney diseases, discuss strategies to achieve effective network integration, and summarize currently available web-based tools that may facilitate integration of data across species. The rapid progress in systems biology and orthology, as well as the advent of web-based tools to facilitate these processes, now make it possible to take advantage of knowledge from distant animal species in targeted identification of regulatory networks that may have clinical relevance for human kidney diseases. PMID:21044762

Exposure to the environmental endocrine disruptor TCDD and human reproductive dysfunction: Translating lessons from murine models.

PubMed

Bruner-Tran, Kaylon L; Gnecco, Juan; Ding, Tianbing; Glore, Dana R; Pensabene, Virginia; Osteen, Kevin G

2017-03-01

Humans and other animals are exposed to a wide array of man-made toxicants, many of which act as endocrine disruptors that exhibit differential effects across the lifespan. In humans, while the impact of adult exposure is known for some compounds, the potential consequences of developmental exposure to endocrine disrupting chemicals (EDCs) is more difficult to ascertain. Animal studies have revealed that exposure to EDCs prior to puberty can lead to adult reproductive disease and dysfunction. Specifically, in adult female mice with an early life exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), we demonstrated a transgenerational occurrence of several reproductive diseases that have been linked to endometriosis in women. Herein, we review the evidence for TCDD-associated development of adult reproductive disease as well as known epigenetic alterations associated with TCDD and/or endometriosis. We will also introduce new "Organ-on-Chip" models which, combined with our established murine model, are expected to further enhance our ability to examine alterations in gene-environment interactions that lead to heritable disease. Copyright © 2016 Elsevier Inc. All rights reserved.

Exposure to the Environmental Endocrine Disruptor TCDD and Human Reproductive Dysfunction: Translating Lessons from Murine Models

PubMed Central

Bruner-Tran, Kaylon L.; Gnecco, Juan; Ding, Tianbing; Glore, Dana R.; Pensabene, Virginia; Osteen, Kevin G.

2016-01-01

Humans and other animals are exposed to a wide array of man-made toxicants, many of which act as endocrine disruptors that exhibit differential effects across the lifespan. In humans, while the impact of adult exposure is known for some compounds, the potential consequences of developmental exposure to endocrine disrupting chemicals (EDCs) is more difficult to ascertain. Animal studies have revealed that exposure to EDCs prior to puberty can lead to adult reproductive disease and dysfunction. Specifically, in adult female mice with an early life exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), we demonstrated a transgenerational occurrence of several reproductive diseases that have been linked to endometriosis in women. Herein, we review the evidence for TCDD-associated development of adult reproductive disease as well as known epigenetic alterations associated with TCDD and/or endometriosis. We will also introduce new “Organ-on-Chip” models which, combined with our established murine model, are expected to further enhance our ability to examine alterations in gene-environment interactions that lead to heritable disease. PMID:27423904

Stability in skipping gaits

NASA Astrophysics Data System (ADS)

Andrada, Emanuel; Müller, Roy; Blickhan, Reinhard

2016-11-01

As an alternative to walking and running, humans are able to skip. However, adult humans avoid it. This fact seems to be related to the higher energetic costs associated with skipping. Still, children, some birds, lemurs and lizards use skipping gaits during daily locomotion. We combined experimental data on humans with numerical simulations to test whether stability and robustness motivate this choice. Parameters for modelling were obtained from 10 male subjects. They locomoted using unilateral skipping along a 12 m runway. We used a bipedal spring loaded inverted pendulum to model and to describe the dynamics of skipping. The subjects displayed higher peak ground reaction forces and leg stiffness in the first landing leg (trailing leg) compared to the second landing leg (leading leg). In numerical simulations, we found that skipping is stable across an amazing speed range from skipping on the spot to fast running speeds. Higher leg stiffness in the trailing leg permits longer strides at same system energy. However, this strategy is at the same time less robust to sudden drop perturbations than skipping with a stiffer leading leg. A slightly higher stiffness in the leading leg is most robust, but might be costlier.

Preventable Medical Errors Driven Modeling of Medical Best Practice Guidance Systems.

PubMed

Ou, Andrew Y-Z; Jiang, Yu; Wu, Po-Liang; Sha, Lui; Berlin, Richard B

2017-01-01

In a medical environment such as Intensive Care Unit, there are many possible reasons to cause errors, and one important reason is the effect of human intellectual tasks. When designing an interactive healthcare system such as medical Cyber-Physical-Human Systems (CPHSystems), it is important to consider whether the system design can mitigate the errors caused by these tasks or not. In this paper, we first introduce five categories of generic intellectual tasks of humans, where tasks among each category may lead to potential medical errors. Then, we present an integrated modeling framework to model a medical CPHSystem and use UPPAAL as the foundation to integrate and verify the whole medical CPHSystem design models. With a verified and comprehensive model capturing the human intellectual tasks effects, we can design a more accurate and acceptable system. We use a cardiac arrest resuscitation guidance and navigation system (CAR-GNSystem) for such medical CPHSystem modeling. Experimental results show that the CPHSystem models help determine system design flaws and can mitigate the potential medical errors caused by the human intellectual tasks.

A Multiscale Survival Process for Modeling Human Activity Patterns.

PubMed

Zhang, Tianyang; Cui, Peng; Song, Chaoming; Zhu, Wenwu; Yang, Shiqiang

2016-01-01

Human activity plays a central role in understanding large-scale social dynamics. It is well documented that individual activity pattern follows bursty dynamics characterized by heavy-tailed interevent time distributions. Here we study a large-scale online chatting dataset consisting of 5,549,570 users, finding that individual activity pattern varies with timescales whereas existing models only approximate empirical observations within a limited timescale. We propose a novel approach that models the intensity rate of an individual triggering an activity. We demonstrate that the model precisely captures corresponding human dynamics across multiple timescales over five orders of magnitudes. Our model also allows extracting the population heterogeneity of activity patterns, characterized by a set of individual-specific ingredients. Integrating our approach with social interactions leads to a wide range of implications.

Mouse Models for Down Syndrome-Associated Developmental Cognitive Disabilities

PubMed Central

Liu, Chunhong; Belichenko, Pavel V.; Zhang, Li; Fu, Dawei; Kleschevnikov, Alexander M.; Baldini, Antonio; Antonarakis, Stylianos E.; Mobley, William C.; Yu, Y. Eugene

2011-01-01

Down syndrome (DS) is mainly caused by the presence of an extra copy of human chromosome 21 (Hsa21) and is a leading genetic cause for developmental cognitive disabilities in humans. The mouse is a premier model organism for DS because the regions on Hsa21 are syntenically conserved with three regions in the mouse genome, which are located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. With the advance of chromosomal manipulation technologies, new mouse mutants have been generated to mimic DS at both the genotypic and phenotypic levels. Further mouse-based molecular genetic studies in the future may lead to the unraveling of the mechanisms underlying DS-associated developmental cognitive disabilities, which would lay the groundwork for developing effective treatments for this phenotypic manifestation. In this review, we will discuss recent progress and future challenges in modeling DS-associated developmental cognitive disability in mice with an emphasis on hippocampus-related phenotypes. PMID:21865664

Fast hierarchical knowledge-based approach for human face detection in color images

NASA Astrophysics Data System (ADS)

Jiang, Jun; Gong, Jie; Zhang, Guilin; Hu, Ruolan

2001-09-01

This paper presents a fast hierarchical knowledge-based approach for automatically detecting multi-scale upright faces in still color images. The approach consists of three levels. At the highest level, skin-like regions are determinated by skin model, which is based on the color attributes hue and saturation in HSV color space, as well color attributes red and green in normalized color space. In level 2, a new eye model is devised to select human face candidates in segmented skin-like regions. An important feature of the eye model is that it is independent of the scale of human face. So it is possible for finding human faces in different scale with scanning image only once, and it leads to reduction the computation time of face detection greatly. In level 3, a human face mosaic image model, which is consistent with physical structure features of human face well, is applied to judge whether there are face detects in human face candidate regions. This model includes edge and gray rules. Experiment results show that the approach has high robustness and fast speed. It has wide application perspective at human-computer interactions and visual telephone etc.

Human Stem Cell-Derived Cardiomyocytes: An Alternative Model to Evaluate Environmental Chemical Cardiac Safety and Development of Predictive Adverse Outcome Pathways

EPA Science Inventory

Biomonitoring over the last 14 years has shown human exposure to environmental chemicals has increased ~10-fold (1). In addition, mortality and morbidity related cardiovascular disease continues to be the leading national and global public health issue (2, 3). The association bet...

Children Perseverate to a Human's Actions but Not to a Robot's Actions

ERIC Educational Resources Information Center

Moriguchi, Yusuke; Kanda, Takayuki; Ishiguro, Hiroshi; Itakura, Shoji

2010-01-01

Previous research has shown that young children commit perseverative errors from their observation of another person's actions. The present study examined how social observation would lead children to perseverative tendencies, using a robot. In Experiment 1, preschoolers watched either a human model or a robot sorting cards according to one…

Minnows as a Classroom Model for Human Environmental Health

ERIC Educational Resources Information Center

Weber, Daniel N.; Hesselbach, Renee; Kane, Andrew S.; Petering, David H.; Petering, Louise; Berg, Craig A.

2013-01-01

Understanding human environmental health is difficult for high school students, as is the process of scientific investigation. This module provides a framework to address both concerns through an inquiry-based approach using a hypothesis-driven set of experiments that draws upon a real-life concern, environmental exposures to lead (Pb2+). Students…

The short-lived African turquoise killifish: an emerging experimental model for ageing

PubMed Central

Kim, Yumi; Nam, Hong Gil; Valenzano, Dario Riccardo

2016-01-01

ABSTRACT Human ageing is a fundamental biological process that leads to functional decay, increased risk for various diseases and, ultimately, death. Some of the basic biological mechanisms underlying human ageing are shared with other organisms; thus, animal models have been invaluable in providing key mechanistic and molecular insights into the common bases of biological ageing. In this Review, we briefly summarise the major applications of the most commonly used model organisms adopted in ageing research and highlight their relevance in understanding human ageing. We compare the strengths and limitations of different model organisms and discuss in detail an emerging ageing model, the short-lived African turquoise killifish. We review the recent progress made in using the turquoise killifish to study the biology of ageing and discuss potential future applications of this promising animal model. PMID:26839399

Spina Bifida: Pathogenesis, Mechanisms, and Genes in Mice and Humans

PubMed Central

Abou Chaar, Mohamad K.; Ahmad-Annuar, Azlina

2017-01-01

Spina bifida is among the phenotypes of the larger condition known as neural tube defects (NTDs). It is the most common central nervous system malformation compatible with life and the second leading cause of birth defects after congenital heart defects. In this review paper, we define spina bifida and discuss the phenotypes seen in humans as described by both surgeons and embryologists in order to compare and ultimately contrast it to the leading animal model, the mouse. Our understanding of spina bifida is currently limited to the observations we make in mouse models, which reflect complete or targeted knockouts of genes, which perturb the whole gene(s) without taking into account the issue of haploinsufficiency, which is most prominent in the human spina bifida condition. We thus conclude that the need to study spina bifida in all its forms, both aperta and occulta, is more indicative of the spina bifida in surviving humans and that the measure of deterioration arising from caudal neural tube defects, more commonly known as spina bifida, must be determined by the level of the lesion both in mouse and in man. PMID:28286691

Molecular design and structure--activity relationships leading to the potent, selective, and orally active thrombin active site inhibitor BMS-189664.

PubMed

Das, Jagabandhu; Kimball, S David; Hall, Steven E; Han, Wen Ching; Iwanowicz, Edwin; Lin, James; Moquin, Robert V; Reid, Joyce A; Sack, John S; Malley, Mary F; Chang, Chiehying Y; Chong, Saeho; Wang-Iverson, David B; Roberts, Daniel G M; Seiler, Steven M; Schumacher, William A; Ogletree, Martin L

2002-01-07

A series of structurally novel small molecule inhibitors of human alpha-thrombin was prepared to elucidate their structure-activity relationships (SARs), selectivity and activity in vivo. BMS-189664 (3) is identified as a potent, selective, and orally active reversible inhibitor of human alpha-thrombin which is efficacious in vivo in a mouse lethality model, and at inhibiting both arterial and venous thrombosis in cynomolgus monkey models.

MODELING APPROACHES FOR ESTIMATING THE DOSIMETRY OF INHALED TOXICANTS IN CHILDREN

EPA Science Inventory

Risk assessment of inhaled toxicants has typically focused upon adults, with modeling used to extrapolate dosimetry and risks from laboratory animals to humans. However, behavioral factors such as time spent playing outdoors can lead to more exposure to inhaled toxicants in chil...

The road traffic crashes as a neglected public health concern; an observational study from Iranian population.

PubMed

Bakhtiyari, Mahmood; Delpisheh, Ali; Monfared, Ayad Bahadori; Kazemi-Galougahi, Mohammad Hassan; Mehmandar, Mohammad Reza; Riahi, Mohammad; Salehi, Masoud; Mansournia, Mohammad Ali

2015-01-01

Traffic crashes are multifactorial events caused by human factors, technical issues, and environmental conditions. The present study aimed to determine the role of human factors in traffic crashes in Iran using the proportional odds regression model. The database of all traffic crashes in Iran in 2010 (n = 592, 168) registered through the "COM.114" police forms was investigated. Human risk factors leading to traffic crashes were determined and the odds ratio (OR) of each risk factor was estimated using an ordinal regression model and adjusted for potential confounding factors such as age, gender, and lighting status within and outside of cities. The drivers' mean age ± standard deviation was 34.1 ± 14.0 years. The most prevalent risk factors leading to death within cities were disregarding traffic rules and regulations (45%), driver rushing (31%), and alcohol consumption (12.3%). Using the proportional odds regression model, alcohol consumption was the most significant human risk factor in traffic crashes within cities (OR = 6.5, 95% confidence interval [CI], 4.88-8.65) and outside of cities (OR = 1.73, 95% CI, 1.22-3.29). Public health strategies and preventive policies should be focused on more common human risk factors such as disregarding traffic rules and regulations, drivers' rushing, and alcohol consumption due to their greater population attributable fraction and more intuitive impacts on society.

Leadership in moving human groups.

PubMed

Boos, Margarete; Pritz, Johannes; Lange, Simon; Belz, Michael

2014-04-01

How is movement of individuals coordinated as a group? This is a fundamental question of social behaviour, encompassing phenomena such as bird flocking, fish schooling, and the innumerable activities in human groups that require people to synchronise their actions. We have developed an experimental paradigm, the HoneyComb computer-based multi-client game, to empirically investigate human movement coordination and leadership. Using economic games as a model, we set monetary incentives to motivate players on a virtual playfield to reach goals via players' movements. We asked whether (I) humans coordinate their movements when information is limited to an individual group member's observation of adjacent group member motion, (II) whether an informed group minority can lead an uninformed group majority to the minority's goal, and if so, (III) how this minority exerts its influence. We showed that in a human group--on the basis of movement alone--a minority can successfully lead a majority. Minorities lead successfully when (a) their members choose similar initial steps towards their goal field and (b) they are among the first in the whole group to make a move. Using our approach, we empirically demonstrate that the rules of swarming behaviour apply to humans. Even complex human behaviour, such as leadership and directed group movement, follow simple rules that are based on visual perception of local movement.

Effect of Age-Related Human Lens Sutures Growth on Its Fluid Dynamics.

PubMed

Wu, Ho-Ting D; Howse, Louisa A; Vaghefi, Ehsan

2017-12-01

Age-related nuclear cataract is the opacification of the clear ocular lens due to oxidative damage as we age, and is the leading cause of blindness in the world. A lack of antioxidant supply to the core of ever-growing ocular lens could contribute to the cause of this condition. In this project, a computational model was developed to study the sutural fluid inflow of the aging human lens. Three different SOLIDWORKS computational fluid dynamics models of the human lens (7 years old; 28 years old; 46 years old) were created, based on available literature data. The fluid dynamics of the lens sutures were modelled using the Stokes flow equations, combined with realistic physiological boundary conditions and embedded in COMSOL Multiphysics. The flow rate, volume, and flow rate per volume of fluid entering the aging lens were examined, and all increased over the 40 years modelled. However, while the volume of the lens grew by ∼300% and the flow rate increased by ∼400%, the flow rate per volume increased only by very moderate ∼38%. Here, sutural information from humans of 7 to 46 years of age was obtained. In this modelled age range, an increase of flow rate per volume was observed, albeit at very slow rate. We hypothesize that with even further increasing age (60+ years old), the lens volume growth would outpace its flow rate increases, which would eventually lead to malnutrition of the lens nucleus and onset of cataracts.

A lethal murine infection model for dengue virus 3 in AG129 mice deficient in type I and II interferon receptors leads to systemic disease.

PubMed

Sarathy, Vanessa V; White, Mellodee; Li, Li; Gorder, Summer R; Pyles, Richard B; Campbell, Gerald A; Milligan, Gregg N; Bourne, Nigel; Barrett, Alan D T

2015-01-15

The mosquito-borne disease dengue (DEN) is caused by four serologically and genetically related viruses, termed DENV-1 to DENV-4. Infection with one DENV usually leads to acute illness and results in lifelong homotypic immunity, but individuals remain susceptible to infection by the other three DENVs. The lack of a small-animal model that mimics systemic DEN disease without neurovirulence has been an obstacle, but DENV-2 models that resemble human disease have been recently developed in AG129 mice (deficient in interferon alpha/beta and interferon gamma receptor signaling). However, comparable DENV-1, -3, and -4 models have not been developed. We utilized a non-mouse-adapted DENV-3 Thai human isolate to develop a lethal infection model in AG129 mice. Intraperitoneal inoculation of six to eight-week-old animals with strain C0360/94 led to rapid, fatal disease. Lethal C0360/94 infection resulted in physical signs of illness, high viral loads in the spleen, liver, and large intestine, histological changes in the liver and spleen tissues, and increased serum cytokine levels. Importantly, the animals developed vascular leakage, thrombocytopenia, and leukopenia. Overall, we have developed a lethal DENV-3 murine infection model, with no evidence of neurotropic disease based on a non-mouse-adapted human isolate, which can be used to investigate DEN pathogenesis and to evaluate candidate vaccines and antivirals. This suggests that murine models utilizing non-mouse-adapted isolates can be obtained for all four DENVs. Dengue (DEN) is a mosquito-borne disease caused by four DENV serotypes (DENV-1, -2, -3, and -4) that have no treatments or vaccines. Primary infection with one DENV usually leads to acute illness followed by lifelong homotypic immunity, but susceptibility to infection by the other three DENVs remains. Therefore, a vaccine needs to protect from all four DENVs simultaneously. To date a suitable animal model to mimic systemic human illness exists only for DENV-2 in immunocompromised mice using passaged viruses; however, models are still needed for the remaining serotypes. This study describes establishment of a lethal systemic DENV-3 infection model with a human isolate in immunocompromised mice and is the first report of lethal infection by a nonadapted clinical DENV isolate without evidence of neurological disease. Our DENV-3 model provides a relevant platform to test DEN vaccines and antivirals. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

A Novel Field-Circuit FEM Modeling and Channel Gain Estimation for Galvanic Coupling Real IBC Measurements.

PubMed

Gao, Yue-Ming; Wu, Zhu-Mei; Pun, Sio-Hang; Mak, Peng-Un; Vai, Mang-I; Du, Min

2016-04-02

Existing research on human channel modeling of galvanic coupling intra-body communication (IBC) is primarily focused on the human body itself. Although galvanic coupling IBC is less disturbed by external influences during signal transmission, there are inevitable factors in real measurement scenarios such as the parasitic impedance of electrodes, impedance matching of the transceiver, etc. which might lead to deviations between the human model and the in vivo measurements. This paper proposes a field-circuit finite element method (FEM) model of galvanic coupling IBC in a real measurement environment to estimate the human channel gain. First an anisotropic concentric cylinder model of the electric field intra-body communication for human limbs was developed based on the galvanic method. Then the electric field model was combined with several impedance elements, which were equivalent in terms of parasitic impedance of the electrodes, input and output impedance of the transceiver, establishing a field-circuit FEM model. The results indicated that a circuit module equivalent to external factors can be added to the field-circuit model, which makes this model more complete, and the estimations based on the proposed field-circuit are in better agreement with the corresponding measurement results.

On modeling human reliability in space flights - Redundancy and recovery operations

NASA Astrophysics Data System (ADS)

Aarset, M.; Wright, J. F.

The reliability of humans is of paramount importance to the safety of space flight systems. This paper describes why 'back-up' operators might not be the best solution, and in some cases, might even degrade system reliability. The problem associated with human redundancy calls for special treatment in reliability analyses. The concept of Standby Redundancy is adopted, and psychological and mathematical models are introduced to improve the way such problems can be estimated and handled. In the past, human reliability has practically been neglected in most reliability analyses, and, when included, the humans have been modeled as a component and treated numerically the way technical components are. This approach is not wrong in itself, but it may lead to systematic errors if too simple analogies from the technical domain are used in the modeling of human behavior. In this paper redundancy in a man-machine system will be addressed. It will be shown how simplification from the technical domain, when applied to human components of a system, may give non-conservative estimates of system reliability.

Cardiac Ca2+ signalling in zebrafish: Translation of findings to man.

PubMed

van Opbergen, Chantal J M; van der Voorn, Stephanie M; Vos, Marc A; de Boer, Teun P; van Veen, Toon A B

2018-05-07

Sudden cardiac death is a leading cause of death worldwide, mainly caused by highly disturbed electrical activation patterns in the heart. Currently, murine models are the most popular model to study underlying molecular mechanisms of inherited or acquired cardiac electrical abnormalities, although the numerous electrophysiological discrepancies between mouse and human raise the question whether mice are the optimal model to study cardiac rhythm disorders. Recently it has been uncovered that the zebrafish cardiac electrophysiology seems surprisingly similar to the human heart, mainly because the zebrafish AP contains a clear plateau phase and ECG characteristics show alignment with the human ECG. Although, before using zebrafish as a model to study cardiac arrhythmogenesis, however, it is very important to gain a better insight into the electrophysiological characteristics of the zebrafish heart. In this review we outline the electrophysiological machinery of the zebrafish cardiomyocytes, with a special focus on the intracellular Ca 2+ dynamics and excitation-contraction coupling. We debate the potential of zebrafish as a model to study human cardiovascular diseases and postulate steps to employ zebrafish into a more 'humanized' model. Copyright © 2018 Elsevier Ltd. All rights reserved.

Interaction between synaptic inhibition and glial-potassium dynamics leads to diverse seizure transition modes in biophysical models of human focal seizures.

PubMed

Y Ho, E C; Truccolo, Wilson

2016-10-01

How focal seizures initiate and evolve in human neocortex remains a fundamental problem in neuroscience. Here, we use biophysical neuronal network models of neocortical patches to study how the interaction between inhibition and extracellular potassium ([K (+)] o ) dynamics may contribute to different types of focal seizures. Three main types of propagated focal seizures observed in recent intracortical microelectrode recordings in humans were modelled: seizures characterized by sustained (∼30-60 Hz) gamma local field potential (LFP) oscillations; seizures where the onset in the propagated site consisted of LFP spikes that later evolved into rhythmic (∼2-3 Hz) spike-wave complexes (SWCs); and seizures where a brief stage of low-amplitude fast-oscillation (∼10-20 Hz) LFPs preceded the SWC activity. Our findings are fourfold: (1) The interaction between elevated [K (+)] o (due to abnormal potassium buffering by glial cells) and the strength of synaptic inhibition plays a predominant role in shaping these three types of seizures. (2) Strengthening of inhibition leads to the onset of sustained narrowband gamma seizures. (3) Transition into SWC seizures is obtained either by the weakening of inhibitory synapses, or by a transient strengthening followed by an inhibitory breakdown (e.g. GABA depletion). This reduction or breakdown of inhibition among fast-spiking (FS) inhibitory interneurons increases their spiking activity and leads them eventually into depolarization block. Ictal spike-wave discharges in the model are then sustained solely by pyramidal neurons. (4) FS cell dynamics are also critical for seizures where the evolution into SWC activity is preceded by low-amplitude fast oscillations. Different levels of elevated [K (+)] o were important for transitions into and maintenance of sustained gamma oscillations and SWC discharges. Overall, our modelling study predicts that the interaction between inhibitory interneurons and [K (+)] o glial buffering under abnormal conditions may explain different types of ictal transitions and dynamics during propagated seizures in human focal epilepsy.

The contributions of human factors on human error in Malaysia aviation maintenance industries

NASA Astrophysics Data System (ADS)

Padil, H.; Said, M. N.; Azizan, A.

2018-05-01

Aviation maintenance is a multitasking activity in which individuals perform varied tasks under constant pressure to meet deadlines as well as challenging work conditions. These situational characteristics combined with human factors can lead to various types of human related errors. The primary objective of this research is to develop a structural relationship model that incorporates human factors, organizational factors, and their impact on human errors in aviation maintenance. Towards that end, a questionnaire was developed which was administered to Malaysian aviation maintenance professionals. Structural Equation Modelling (SEM) approach was used in this study utilizing AMOS software. Results showed that there were a significant relationship of human factors on human errors and were tested in the model. Human factors had a partial effect on organizational factors while organizational factors had a direct and positive impact on human errors. It was also revealed that organizational factors contributed to human errors when coupled with human factors construct. This study has contributed to the advancement of knowledge on human factors effecting safety and has provided guidelines for improving human factors performance relating to aviation maintenance activities and could be used as a reference for improving safety performance in the Malaysian aviation maintenance companies.

Translating dosages from animal models to human clinical trials--revisiting body surface area scaling.

PubMed

Blanchard, Otis L; Smoliga, James M

2015-05-01

Body surface area (BSA) scaling has been used for prescribing individualized dosages of various drugs and has also been recommended by the U.S. Food and Drug Administration as one method for using data from animal model species to establish safe starting dosages for first-in-human clinical trials. Although BSA conversion equations have been used in certain clinical applications for decades, recent recommendations to use BSA to derive interspecies equivalents for therapeutic dosages of drug and natural products are inappropriate. A thorough review of the literature reveals that BSA conversions are based on antiquated science and have little justification in current translational medicine compared to more advanced allometric and physiologically based pharmacokinetic modeling. Misunderstood and misinterpreted use of BSA conversions may have disastrous consequences, including underdosing leading to abandonment of potentially efficacious investigational drugs, and unexpected deadly adverse events. We aim to demonstrate that recent recommendations for BSA are not appropriate for animal-to-human dosage conversions and use pharmacokinetic data from resveratrol studies to demonstrate how confusion between the "human equivalent dose" and "pharmacologically active dose" can lead to inappropriate dose recommendations. To optimize drug development, future recommendations for interspecies scaling must be scientifically justified using physiologic, pharmacokinetic, and toxicology data rather than simple BSA conversion. © FASEB.

Syndromes of the global water crisis - exploring the emergent dynamics through socio-hydrological modeling

NASA Astrophysics Data System (ADS)

Kuil, Linda; Levy, Morgan; Pavao-Zuckerman, Mitch; Penny, Gopal; Scott, Christopher; Srinivasan, Veena; Thompson, Sally; Troy, Tara

2014-05-01

There is a great variety of human water systems at the global scale due to the types and timing of water supply/availability, and the high diversity in water use, management, and abstraction methods. Importantly, this is largely driven by differences in welfare, social values, institutional frameworks, and cultural traditions of communities. The observed trend of a growing world population in combination with changing habits that generally increase our water consumption per capita implies that an increasing number of communities will face water scarcity. Over the years much research has been done in order to increase our understanding of human water systems and their associated water problems, using both top-down and bottom-up approaches. Despite these efforts, the challenge has remained to generalize findings beyond the areas of interests and to establish a common framework in order to compare and learn from different cases as a basis for finding solutions. In a recent analysis of multiple interdisciplinary subnational water resources case studies, it was shown that a suite of distinct resources utilization patterns leading to a water crisis can be identified, namely: 1) groundwater depletion, 2) ecological destruction, 3) drought-driven conflicts, 4) unmet subsistence needs, 5) resource capture by elite and 6) water reallocation to nature (Srinivasan et al., 2012). The effects of these syndromes on long-lasting human wellbeing can be grouped in the following outcomes: unsustainability, vulnerability, chronic scarcity and adaptation. The aim of this group collaboration is to build on this work through the development of a socio-hydrological model that is capable of reproducing the above syndromes and outcomes, ultimately giving insight in the different pathways leading to the syndromes. The resulting model will be distinct compared to existing model frameworks for two reasons. First of all, feedback loops between the hydrological, the environmental and the human agency components of the model are central to the model structure, thereby accounting for the co-evolutionary nature of human-water systems. Second, the model is designed to be general and integrative aimed at the simulation of emergent qualitative dynamics of the human-water system. The explicit inclusion of feedbacks and the aim of the model to capture the general dynamics as opposed to case-specific trajectories will allow us to deepen our fundamental understanding of the causal pathways leading to water crises across multiple locations. All authors contributed equally to this work. Srinivasan, V., Lambin, E.F., Gorelick, S.M., Thompson, B.H., Rozelle, S., 2012. The nature and causes of the global water crisis: Syndromes from a meta-analysis of coupled human-water studies. Water Resources Research 48(10), doi:10.1029/2011WR011087

The use of human tumour cell lines in the discovery of new cancer chemotherapeutic drugs.

PubMed

Baguley, Bruce C; Marshall, Elaine S

2008-02-01

Human tumour cell lines have played a major role in anticancer drug discovery, but cell lines may model only some aspects of tumour behaviour in cancer patients. Growing evidence supports a theory that stem cells with self-renewing properties sustain tumours. This review considers the extent to which a deeper understanding of the origin and properties of tumour cell lines might lead to new strategies for anticancer drug discovery. Recent literature on normal and tumour stem cells is reviewed and placed in the context of a discussion on the derivation and properties of tumour cell lines. Early-passage cell lines may model the more rapidly proliferating cells in human tumours and, thus, retain some of the properties of tumour stem cells. The effects of anticancer drugs on cell lines should be considered not only with regards to the induction of apoptosis, but also to the induction of senescence or other pathways that lead to host immune and inflammatory responses.

Can Inhibitors of Snake Venom Phospholipases A₂ Lead to New Insights into Anti-Inflammatory Therapy in Humans? A Theoretical Study.

PubMed

Sales, Thaís A; Marcussi, Silvana; da Cunha, Elaine F F; Kuca, Kamil; Ramalho, Teodorico C

2017-10-25

Human phospholipase A₂ ( h PLA₂) of the IIA group (HGIIA) catalyzes the hydrolysis of membrane phospholipids, producing arachidonic acid and originating potent inflammatory mediators. Therefore, molecules that can inhibit this enzyme are a source of potential anti-inflammatory drugs, with different action mechanisms of known anti-inflammatory agents. For the study and development of new anti-inflammatory drugs with this action mechanism, snake venom PLA₂ ( sv PLA₂) can be employed, since the sv PLA₂ has high similarity with the human PLA₂ HGIIA. Despite the high similarity between these secretory PLA₂s , it is still not clear if these toxins can really be employed as an experimental model to predict the interactions that occur with the human PLA₂ HGIIA and its inhibitors. Thus, the present study aims to compare and evaluate, by means of theoretical calculations, docking and molecular dynamics simulations, as well as experimental studies, the interactions of human PLA₂ HGIIA and two sv PLA₂s , Bothrops toxin II and Crotoxin B (BthTX-II and CB, respectively). Our theoretical findings corroborate experimental data and point out that the human PLA₂ HGIIA and sv PLA₂ BthTX-II lead to similar interactions with the studied compounds. From our results, the sv PLA₂ BthTX-II can be used as an experimental model for the development of anti-inflammatory drugs for therapy in humans.

Water Buffalo (Bubalus bubalis) as a spontaneous animal model of Vitiligo.

PubMed

Singh, Vijay Pal; Motiani, Rajender K; Singh, Archana; Malik, Garima; Aggarwal, Rangoli; Pratap, Kunal; Wani, Mohan R; Gokhale, Suresh B; Natarajan, Vivek T; Gokhale, Rajesh S

2016-07-01

Vitiligo is a multifactorial acquired depigmenting disorder. Recent insights into the molecular mechanisms driving the gradual destruction of melanocytes in vitiligo will likely lead to the discovery of novel therapies, which need to be evaluated in animal models that closely recapitulate the pathogenesis of human vitiligo. In humans, vitiligo is characterized by a spontaneous loss of functional melanocytes from the epidermis, but most animal models of vitiligo are either inducible or genetically programmed. Here, we report that acquired depigmentation in water buffalo recapitulates molecular, histological, immunohistochemical, and ultrastructural changes observed in human vitiligo and hence could be used as a model to study vitiligo pathogenesis and facilitate the discovery and evaluation of therapeutic interventions for vitiligo. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Assessing risk with increasingly stringent public health goals: the case of water lead and blood lead in children.

PubMed

Triantafyllidou, Simoni; Gallagher, Daniel; Edwards, Marc

2014-03-01

Previous predictions of children's blood lead levels (BLLs) through biokinetic models conclude that lead in tap water is not a primary health risk for a typical child under scenarios representative of chronic exposure, when applying a 10 μg/dL BLL of concern. Use of the US Environmental Protection Agency Integrated Exposure Uptake Biokinetic (IEUBK) model and of the International Commission on Radiological Protection (ICRP) biokinetic model to simulate children's exposure to water lead at home and at school was re-examined by expanding the scope of previous modeling efforts to consider new public health goals and improved methodology. Specifically, explicit consideration of the more sensitive population groups (e.g., young children and, particularly, formula-fed infants), the variability in BLLs amongst exposed individuals within those groups (e.g., more sensitive children at the upper tail of the BLL distribution), more conservative BLL reference values (e.g., 5 and 2 μg/dL versus 10 μg/dL) and concerns of acute exposure revealed situations where relatively low water lead levels were predicted to pose a human health concern.

A New Algorithm to Diagnose Atrial Ectopic Origin from Multi Lead ECG Systems - Insights from 3D Virtual Human Atria and Torso

PubMed Central

Alday, Erick A. Perez; Colman, Michael A.; Langley, Philip; Butters, Timothy D.; Higham, Jonathan; Workman, Antony J.; Hancox, Jules C.; Zhang, Henggui

2015-01-01

Rapid atrial arrhythmias such as atrial fibrillation (AF) predispose to ventricular arrhythmias, sudden cardiac death and stroke. Identifying the origin of atrial ectopic activity from the electrocardiogram (ECG) can help to diagnose the early onset of AF in a cost-effective manner. The complex and rapid atrial electrical activity during AF makes it difficult to obtain detailed information on atrial activation using the standard 12-lead ECG alone. Compared to conventional 12-lead ECG, more detailed ECG lead configurations may provide further information about spatio-temporal dynamics of the body surface potential (BSP) during atrial excitation. We apply a recently developed 3D human atrial model to simulate electrical activity during normal sinus rhythm and ectopic pacing. The atrial model is placed into a newly developed torso model which considers the presence of the lungs, liver and spinal cord. A boundary element method is used to compute the BSP resulting from atrial excitation. Elements of the torso mesh corresponding to the locations of the placement of the electrodes in the standard 12-lead and a more detailed 64-lead ECG configuration were selected. The ectopic focal activity was simulated at various origins across all the different regions of the atria. Simulated BSP maps during normal atrial excitation (i.e. sinoatrial node excitation) were compared to those observed experimentally (obtained from the 64-lead ECG system), showing a strong agreement between the evolution in time of the simulated and experimental data in the P-wave morphology of the ECG and dipole evolution. An algorithm to obtain the location of the stimulus from a 64-lead ECG system was developed. The algorithm presented had a success rate of 93%, meaning that it correctly identified the origin of atrial focus in 75/80 simulations, and involved a general approach relevant to any multi-lead ECG system. This represents a significant improvement over previously developed algorithms. PMID:25611350

The NOTCH3 score: a pre-clinical CADASIL biomarker in a novel human genomic NOTCH3 transgenic mouse model with early progressive vascular NOTCH3 accumulation.

PubMed

Rutten, Julie W; Klever, Roselin R; Hegeman, Ingrid M; Poole, Dana S; Dauwerse, Hans G; Broos, Ludo A M; Breukel, Cor; Aartsma-Rus, Annemieke M; Verbeek, J Sjef; van der Weerd, Louise; van Duinen, Sjoerd G; van den Maagdenberg, Arn M J M; Lesnik Oberstein, Saskia A J

2015-12-29

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a hereditary small vessel disease caused by mutations in the NOTCH3 gene, leading to toxic NOTCH3 protein accumulation in the small- to medium sized arterioles. The accumulation is systemic but most pronounced in the brain vasculature where it leads to clinical symptoms of recurrent stroke and dementia. There is no therapy for CADASIL, and therapeutic development is hampered by a lack of feasible clinical outcome measures and biomarkers, both in mouse models and in CADASIL patients. To facilitate pre-clinical therapeutic interventions for CADASIL, we aimed to develop a novel, translational CADASIL mouse model. We generated transgenic mice in which we overexpressed the full length human NOTCH3 gene from a genomic construct with the archetypal c.544C > T, p.Arg182Cys mutation. The four mutant strains we generated have respective human NOTCH3 RNA expression levels of 100, 150, 200 and 350 % relative to endogenous mouse Notch3 RNA expression. Immunohistochemistry on brain sections shows characteristic vascular human NOTCH3 accumulation in all four mutant strains, with human NOTCH3 RNA expression levels correlating with age at onset and progression of NOTCH3 accumulation. This finding was the basis for developing the 'NOTCH3 score', a quantitative measure for the NOTCH3 accumulation load. This score proved to be a robust and sensitive method to assess the progression of NOTCH3 accumulation, and a feasible biomarker for pre-clinical therapeutic testing. This novel, translational CADASIL mouse model is a suitable model for pre-clinical testing of therapeutic strategies aimed at delaying or reversing NOTCH3 accumulation, using the NOTCH3 score as a biomarker.

Sclerostin and Dickkopf-1 as therapeutic targets in bone diseases.

PubMed

Ke, Hua Zhu; Richards, William G; Li, Xiaodong; Ominsky, Michael S

2012-10-01

The processes of bone growth, modeling, and remodeling determine the structure, mass, and biomechanical properties of the skeleton. Dysregulated bone resorption or bone formation may lead to metabolic bone diseases. The Wnt pathway plays an important role in bone formation and regeneration, and expression of two Wnt pathway inhibitors, sclerostin and Dickkopf-1 (DKK1), appears to be associated with changes in bone mass. Inactivation of sclerostin leads to substantially increased bone mass in humans and in genetically manipulated animals. Studies in various animal models of bone disease have shown that inhibition of sclerostin using a monoclonal antibody (Scl-Ab) increases bone formation, density, and strength. Additional studies show that Scl-Ab improves bone healing in models of bone repair. Inhibition of DKK1 by monoclonal antibody (DKK1-Ab) stimulates bone formation in younger animals and to a lesser extent in adult animals and enhances fracture healing. Thus, sclerostin and DKK1 are emerging as the leading new targets for anabolic therapies to treat bone diseases such as osteoporosis and for bone repair. Clinical trials are ongoing to evaluate the effects of Scl-Ab and DKK1-Ab in humans for the treatment of bone loss and for bone repair.

The relevance of human stem cell-derived organoid models for epithelial translational medicine

PubMed Central

Hynds, Robert E.; Giangreco, Adam

2014-01-01

Epithelial organ remodeling is a major contributing factor to worldwide death and disease, costing healthcare systems billions of dollars every year. Despite this, most fundamental epithelial organ research fails to produce new therapies and mortality rates for epithelial organ diseases remain unacceptably high. In large part, this failure in translating basic epithelial research into clinical therapy is due to a lack of relevance in existing preclinical models. To correct this, new models are required that improve preclinical target identification, pharmacological lead validation, and compound optimization. In this review, we discuss the relevance of human stem cell-derived, three-dimensional organoid models for addressing each of these challenges. We highlight the advantages of stem cell-derived organoid models over existing culture systems, discuss recent advances in epithelial tissue-specific organoids, and present a paradigm for using organoid models in human translational medicine. PMID:23203919

The short-lived African turquoise killifish: an emerging experimental model for ageing.

PubMed

Kim, Yumi; Nam, Hong Gil; Valenzano, Dario Riccardo

2016-02-01

Human ageing is a fundamental biological process that leads to functional decay, increased risk for various diseases and, ultimately, death. Some of the basic biological mechanisms underlying human ageing are shared with other organisms; thus, animal models have been invaluable in providing key mechanistic and molecular insights into the common bases of biological ageing. In this Review, we briefly summarise the major applications of the most commonly used model organisms adopted in ageing research and highlight their relevance in understanding human ageing. We compare the strengths and limitations of different model organisms and discuss in detail an emerging ageing model, the short-lived African turquoise killifish. We review the recent progress made in using the turquoise killifish to study the biology of ageing and discuss potential future applications of this promising animal model. © 2016. Published by The Company of Biologists Ltd.

A Cellular High-Throughput Screening Approach for Therapeutic trans-Cleaving Ribozymes and RNAi against Arbitrary mRNA Disease Targets

PubMed Central

Yau, Edwin H.; Butler, Mark C.; Sullivan, Jack M.

2016-01-01

Major bottlenecks in development of therapeutic post transcriptional gene silencing (PTGS) agents (e.g. ribozymes, RNA interference, antisense) include the challenge of mapping rare accessible regions of the mRNA target that are open for annealing and cleavage, testing and optimization of agents in human cells to identify lead agents, testing for cellular toxicity, and preclinical evaluation in appropriate animal models of disease. Methods for rapid and reliable cellular testing of PTGS agents are needed to identify potent lead candidates for optimization. Our goal was to develop a means of rapid assessment of many RNA agents to identify a lead candidate for a given mRNA associated with a disease state. We developed a rapid human cell-based screening platform to test efficacy of hammerhead ribozyme (hhRz) or RNA interference (RNAi) constructs, using a model retinal degeneration target, human rod opsin (RHO) mRNA. The focus is on RNA Drug Discovery for diverse retinal degeneration targets. To validate the approach, candidate hhRzs were tested against NUH↓ cleavage sites (N=G,C,A,U; H=C,A,U) within the target mRNA of secreted alkaline phosphatase (SEAP), a model gene expression reporter, based upon in silico predictions of mRNA accessibility. HhRzs were embedded in a larger stable adenoviral VAI RNA scaffold for high cellular expression, cytoplasmic trafficking, and stability. Most hhRz expression plasmids exerted statistically significant knockdown of extracellular SEAP enzyme activity when readily assayed by a fluorescence enzyme assay intended for high throughput screening (HTS). Kinetics of PTGS knockdown of cellular targets is measureable in live cells with the SEAP reporter. The validated SEAP HTS platform was transposed to identify lead PTGS agents against a model hereditary retinal degeneration target, RHO mRNA. Two approaches were used to physically fuse the model retinal gene target mRNA to the SEAP reporter mRNA. The most expedient way to evaluate a large set of potential VAI-hhRz expression plasmids against diverse NUH↓ cleavage sites uses cultured human HEK293S cells stably expressing a dicistronic Target-IRES-SEAP target fusion mRNA. Broad utility of this rational RNA drug discovery approach is feasible for any ophthalmological disease-relevant mRNA targets and any disease mRNA targets in general. The approach will permit rank ordering of PTGS agents based on potency to identify a lead therapeutic compound for further optimization. PMID:27233447

A vascular biology network model focused on inflammatory processes to investigate atherogenesis and plaque instability

PubMed Central

2014-01-01

Background Numerous inflammation-related pathways have been shown to play important roles in atherogenesis. Rapid and efficient assessment of the relative influence of each of those pathways is a challenge in the era of “omics” data generation. The aim of the present work was to develop a network model of inflammation-related molecular pathways underlying vascular disease to assess the degree of translatability of preclinical molecular data to the human clinical setting. Methods We constructed and evaluated the Vascular Inflammatory Processes Network (V-IPN), a model representing a collection of vascular processes modulated by inflammatory stimuli that lead to the development of atherosclerosis. Results Utilizing the V-IPN as a platform for biological discovery, we have identified key vascular processes and mechanisms captured by gene expression profiling data from four independent datasets from human endothelial cells (ECs) and human and murine intact vessels. Primary ECs in culture from multiple donors revealed a richer mapping of mechanisms identified by the V-IPN compared to an immortalized EC line. Furthermore, an evaluation of gene expression datasets from aortas of old ApoE-/- mice (78 weeks) and human coronary arteries with advanced atherosclerotic lesions identified significant commonalities in the two species, as well as several mechanisms specific to human arteries that are consistent with the development of unstable atherosclerotic plaques. Conclusions We have generated a new biological network model of atherogenic processes that demonstrates the power of network analysis to advance integrative, systems biology-based knowledge of cross-species translatability, plaque development and potential mechanisms leading to plaque instability. PMID:24965703

Molecular Mechanisms of External Genitalia Development

PubMed Central

Blaschko, Sarah D.; Cunha, Gerald R.; Baskin, Laurence S.

2012-01-01

External genitalia development occurs through a combination of hormone independent, hormone dependent, and endocrine pathways. Perturbation of these pathways can lead to abnormal external genitalia development. We review human and animal mechanisms of normal and abnormal external genitalia development, and we evaluate abnormal mechanisms that lead to hypospadias. We also discuss recent laboratory findings that further our understanding of animal models of hypospadias. PMID:22790208

Measurement of soil lead bioavailability and influence of soil types and properties: A review.

PubMed

Yan, Kaihong; Dong, Zhaomin; Wijayawardena, M A Ayanka; Liu, Yanju; Naidu, Ravi; Semple, Kirk

2017-10-01

Lead (Pb) is a widespread heavy metal which is harmful to human health, especially to young children. To provide a human health risk assessment that is more relevant to real conditions, Pb bioavailability in soils is increasingly employed in the assessment procedure. Both in vivo and in vitro measurements for lead bioavailability are available. In vivo models are time- consuming and expensive, while in vitro models are rapid, economic, reproducible, and reliable while involving more uncertainties. Uncertainties in various measurements create difficulties in accurately predicting Pb bioavailability, resulting in the unnecessary remediation of sites. In this critical review, we utilised available data from in vivo and in vitro studies to identify the key parameters influencing the in vitro measurements, and presented uncertainties existing in Pb bioavailability measurements. Soil type, properties and metal content are reported to influence lead bioavailability; however, the differences in methods for assessing bioavailability and the differences in Pb source limit one's ability to conduct statistical analyses on influences of soil factors on Pb bioavailability. The information provided in the review is fundamentally useful for the measurement of bioavailability and risk assessment practices. Copyright © 2017 Elsevier Ltd. All rights reserved.

Existential and Phenomenological Foundations of Currere: Self-Report in Curriculum Inquiry.

ERIC Educational Resources Information Center

Grumet, Madeleine R.

Traditional models for curriculum theory describe human development as a sum of its parts, organized in a hierarchy leading to operational competencies. The reconceptualist Currere model, originated by William Penar, develops horizontally with energy and learning moving outward and inward rather than upward in a linear trajectory. Educational…

Linking Agricultural Crop Management and Air Quality Models for Regional to National-Scale Nitrogen Assessments

EPA Science Inventory

While nitrogen (N) is an essential element for life, human population growth and demands for energy, transportation and food can lead to excess nitrogen in the environment. A modeling framework is described and implemented to promote a more integrated, process-based and system le...

From animal models to human disease: a genetic approach for personalized medicine in ALS.

PubMed

Picher-Martel, Vincent; Valdmanis, Paul N; Gould, Peter V; Julien, Jean-Pierre; Dupré, Nicolas

2016-07-11

Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disease in adults. Classical ALS is characterized by the death of upper and lower motor neurons leading to progressive paralysis. Approximately 10 % of ALS patients have familial form of the disease. Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others. Multiple animal models were generated to mimic the disease and to test future treatments. However, no animal model fully replicates the spectrum of phenotypes in the human disease and it is difficult to assess how a therapeutic effect in disease models can predict efficacy in humans. Importantly, the genetic and phenotypic heterogeneity of ALS leads to a variety of responses to similar treatment regimens. From this has emerged the concept of personalized medicine (PM), which is a medical scheme that combines study of genetic, environmental and clinical diagnostic testing, including biomarkers, to individualized patient care. In this perspective, we used subgroups of specific ALS-linked gene mutations to go through existing animal models and to provide a comprehensive profile of the differences and similarities between animal models of disease and human disease. Finally, we reviewed application of biomarkers and gene therapies relevant in personalized medicine approach. For instance, this includes viral delivering of antisense oligonucleotide and small interfering RNA in SOD1, TDP-43 and C9orf72 mice models. Promising gene therapies raised possibilities for treating differently the major mutations in familial ALS cases.

A quantitative measure of the electrical activity of human rod photoreceptors using electroretinography.

PubMed

Hood, D C; Birch, D G

1990-10-01

An electrical potential recorded from the cornea, the a-wave of the ERG, is evaluated as a measure of human photoreceptor activity by comparing its behavior to a model derived from in vitro recordings from rod photoreceptors. The leading edge of the ERG exhibits both the linear and nonlinear behavior predicted by this model. The capability for recording the electrical activity of human photoreceptors in vivo opens new avenues for assessing normal and abnormal receptor activity in humans. Furthermore, the quantitative model of the receptor response can be used to isolate the inner retinal contribution, Granit's PII, to the gross ERG. Based on this analysis, the practice of using the trough-to-peak amplitude of the b-wave as a proxy for the amplitude of the inner nuclear layer activity is evaluated.

Molecular pathways leading to loss of skeletal muscle mass in cancer cachexia--can findings from animal models be translated to humans?

PubMed

Mueller, Tara C; Bachmann, Jeannine; Prokopchuk, Olga; Friess, Helmut; Martignoni, Marc E

2016-02-08

Cachexia is a multi-factorial, systemic syndrome that especially affects patients with cancer of the gastrointestinal tract, and leads to reduced treatment response, survival and quality of life. The most important clinical feature of cachexia is the excessive wasting of skeletal muscle mass. Currently, an effective treatment is still lacking and the search for therapeutic targets continues. Even though a substantial number of animal studies have contributed to a better understanding of the underlying mechanisms of the loss of skeletal muscle mass, subsequent clinical trials of potential new drugs have not yet yielded any effective treatment for cancer cachexia. Therefore, we questioned to which degree findings from animal studies can be translated to humans in clinical practice and research. A substantial amount of animal studies on the molecular mechanisms of muscle wasting in cancer cachexia has been conducted in recent years. This extensive review of the literature showed that most of their observations could not be consistently reproduced in studies on human skeletal muscle samples. However, studies on human material are scarce and limited in patient numbers and homogeneity. Therefore, their results have to be interpreted critically. More research is needed on human tissue samples to clarify the signaling pathways that lead to skeletal muscle loss, and to confirm pre-selected drug targets from animal models in clinical trials. In addition, improved diagnostic tools and standardized clinical criteria for cancer cachexia are needed to conduct standardized, randomized controlled trials of potential drug candidates in the future.

Animal and Human Tissue Models of Vertical Listeria monocytogenes Transmission and Implications for Other Pregnancy-Associated Infections.

PubMed

Lowe, David E; Robbins, Jennifer R; Bakardjiev, Anna I

2018-06-01

Intrauterine infections lead to serious complications for mother and fetus, including preterm birth, maternal and fetal death, and neurological sequelae in the surviving offspring. Improving maternal and child heath is a global priority. Yet, the development of strategies to prevent and treat pregnancy-related diseases has lagged behind progress made in other medical fields. One of the challenges is finding tractable model systems that replicate the human maternal-fetal interface. Animal models offer the ability to study pathogenesis and host defenses in vivo However, the anatomy of the maternal-fetal interface is highly divergent across species. While many tools are available to study host responses in the pregnant mouse model, other animals have placentas that are more similar to that of humans. Here we describe new developments in animal and human tissue models to investigate the pathogenesis of listeriosis at the maternal-fetal interface. We highlight gaps in existing knowledge and make recommendations on how they can be filled. Copyright © 2018 American Society for Microbiology.

Children's Lead Exposure: A Multimedia Modeling Analysis to Guide Public Health Decision-Making.

PubMed

Zartarian, Valerie; Xue, Jianping; Tornero-Velez, Rogelio; Brown, James

2017-09-12

Drinking water and other sources for lead are the subject of public health concerns around the Flint, Michigan, drinking water and East Chicago, Indiana, lead in soil crises. In 2015, the U.S. Environmental Protection Agency (EPA)'s National Drinking Water Advisory Council (NDWAC) recommended establishment of a "health-based, household action level" for lead in drinking water based on children's exposure. The primary objective was to develop a coupled exposure-dose modeling approach that can be used to determine what drinking water lead concentrations keep children's blood lead levels (BLLs) below specified values, considering exposures from water, soil, dust, food, and air. Related objectives were to evaluate the coupled model estimates using real-world blood lead data, to quantify relative contributions by the various media, and to identify key model inputs. A modeling approach using the EPA's Stochastic Human Exposure and Dose Simulation (SHEDS)-Multimedia and Integrated Exposure Uptake and Biokinetic (IEUBK) models was developed using available data. This analysis for the U.S. population of young children probabilistically simulated multimedia exposures and estimated relative contributions of media to BLLs across all population percentiles for several age groups. Modeled BLLs compared well with nationally representative BLLs (0-23% relative error). Analyses revealed relative importance of soil and dust ingestion exposure pathways and associated Pb intake rates; water ingestion was also a main pathway, especially for infants. This methodology advances scientific understanding of the relationship between lead concentrations in drinking water and BLLs in children. It can guide national health-based benchmarks for lead and related community public health decisions. https://doi.org/10.1289/EHP1605.

Children’s Lead Exposure: A Multimedia Modeling Analysis to Guide Public Health Decision-Making

PubMed Central

Xue, Jianping; Tornero-Velez, Rogelio; Brown, James

2017-01-01

Background: Drinking water and other sources for lead are the subject of public health concerns around the Flint, Michigan, drinking water and East Chicago, Indiana, lead in soil crises. In 2015, the U.S. Environmental Protection Agency (EPA)’s National Drinking Water Advisory Council (NDWAC) recommended establishment of a “health-based, household action level” for lead in drinking water based on children’s exposure. Objectives: The primary objective was to develop a coupled exposure–dose modeling approach that can be used to determine what drinking water lead concentrations keep children’s blood lead levels (BLLs) below specified values, considering exposures from water, soil, dust, food, and air. Related objectives were to evaluate the coupled model estimates using real-world blood lead data, to quantify relative contributions by the various media, and to identify key model inputs. Methods: A modeling approach using the EPA’s Stochastic Human Exposure and Dose Simulation (SHEDS)-Multimedia and Integrated Exposure Uptake and Biokinetic (IEUBK) models was developed using available data. This analysis for the U.S. population of young children probabilistically simulated multimedia exposures and estimated relative contributions of media to BLLs across all population percentiles for several age groups. Results: Modeled BLLs compared well with nationally representative BLLs (0–23% relative error). Analyses revealed relative importance of soil and dust ingestion exposure pathways and associated Pb intake rates; water ingestion was also a main pathway, especially for infants. Conclusions: This methodology advances scientific understanding of the relationship between lead concentrations in drinking water and BLLs in children. It can guide national health-based benchmarks for lead and related community public health decisions. https://doi.org/10.1289/EHP1605 PMID:28934096

Chimeric animal models in human stem cell biology.

PubMed

Glover, Joel C; Boulland, Jean-Luc; Halasi, Gabor; Kasumacic, Nedim

2009-01-01

The clinical use of stem cells for regenerative medicine is critically dependent on preclinical studies in animal models. In this review we examine some of the key issues and challenges in the use of animal models to study human stem cell biology-experimental standardization, body size, immunological barriers, cell survival factors, fusion of host and donor cells, and in vivo imaging and tracking. We focus particular attention on the various imaging modalities that can be used to track cells in living animals, comparing their strengths and weaknesses and describing technical developments that are likely to lead to new opportunities for the dynamic assessment of stem cell behavior in vivo. We then provide an overview of some of the most commonly used animal models, their advantages and disadvantages, and examples of their use for xenotypic transplantation of human stem cells, with separate reviews of models involving rodents, ungulates, nonhuman primates, and the chicken embryo. As the use of human somatic, embryonic, and induced pluripotent stem cells increases, so too will the range of applications for these animal models. It is likely that increasingly sophisticated uses of human/animal chimeric models will be developed through advances in genetic manipulation, cell delivery, and in vivo imaging.

A predictive model of nuclear power plant crew decision-making and performance in a dynamic simulation environment

NASA Astrophysics Data System (ADS)

Coyne, Kevin Anthony

The safe operation of complex systems such as nuclear power plants requires close coordination between the human operators and plant systems. In order to maintain an adequate level of safety following an accident or other off-normal event, the operators often are called upon to perform complex tasks during dynamic situations with incomplete information. The safety of such complex systems can be greatly improved if the conditions that could lead operators to make poor decisions and commit erroneous actions during these situations can be predicted and mitigated. The primary goal of this research project was the development and validation of a cognitive model capable of simulating nuclear plant operator decision-making during accident conditions. Dynamic probabilistic risk assessment methods can improve the prediction of human error events by providing rich contextual information and an explicit consideration of feedback arising from man-machine interactions. The Accident Dynamics Simulator paired with the Information, Decision, and Action in a Crew context cognitive model (ADS-IDAC) shows promise for predicting situational contexts that might lead to human error events, particularly knowledge driven errors of commission. ADS-IDAC generates a discrete dynamic event tree (DDET) by applying simple branching rules that reflect variations in crew responses to plant events and system status changes. Branches can be generated to simulate slow or fast procedure execution speed, skipping of procedure steps, reliance on memorized information, activation of mental beliefs, variations in control inputs, and equipment failures. Complex operator mental models of plant behavior that guide crew actions can be represented within the ADS-IDAC mental belief framework and used to identify situational contexts that may lead to human error events. This research increased the capabilities of ADS-IDAC in several key areas. The ADS-IDAC computer code was improved to support additional branching events and provide a better representation of the IDAC cognitive model. An operator decision-making engine capable of responding to dynamic changes in situational context was implemented. The IDAC human performance model was fully integrated with a detailed nuclear plant model in order to realistically simulate plant accident scenarios. Finally, the improved ADS-IDAC model was calibrated, validated, and updated using actual nuclear plant crew performance data. This research led to the following general conclusions: (1) A relatively small number of branching rules are capable of efficiently capturing a wide spectrum of crew-to-crew variabilities. (2) Compared to traditional static risk assessment methods, ADS-IDAC can provide a more realistic and integrated assessment of human error events by directly determining the effect of operator behaviors on plant thermal hydraulic parameters. (3) The ADS-IDAC approach provides an efficient framework for capturing actual operator performance data such as timing of operator actions, mental models, and decision-making activities.

Epigenetics: relevance and implications for public health.

PubMed

Rozek, Laura S; Dolinoy, Dana C; Sartor, Maureen A; Omenn, Gilbert S

2014-01-01

Improved understanding of the multilayer regulation of the human genome has led to a greater appreciation of environmental, nutritional, and epigenetic risk factors for human disease. Chromatin remodeling, histone tail modifications, and DNA methylation are dynamic epigenetic changes responsive to external stimuli. Careful interpretation can provide insights for actionable public health through collaboration between population and basic scientists and through integration of multiple data sources. We review key findings in environmental epigenetics both in human population studies and in animal models, and discuss the implications of these results for risk assessment and public health protection. To ultimately succeed in identifying epigenetic mechanisms leading to complex phenotypes and disease, researchers must integrate the various animal models, human clinical approaches, and human population approaches while paying attention to life-stage sensitivity, to generate effective prescriptions for human health evaluation and disease prevention.

The association of the blood lead level and serum lipid concentrations may be modified by the genetic combination of the metallothionein 2A polymorphisms rs10636 GC and rs28366003 AA.

PubMed

Yang, Chen-Cheng; Chuang, Chih-Shien; Lin, Chia-I; Wang, Chao-Ling; Huang, Yung-Cheng; Chuang, Hung-Yi

Lead in blood can stimulate lipid oxidation in phosphatidylcholine and increase peroxidation in lipids. Metallothionein (MT) is a cysteine-rich protein that can influence the detoxification of heavy metals and scavenge oxidative stress for free radicals. One of the most expressive functional genes in humans is the MT2A gene. This study aims to determine if the association of the blood lead level and lipid biomarkers was influenced by MT2A polymorphisms. We recruited 677 participants after informed consent was obtained. All the samples collected were analyzed for lipid biomarkers and blood lead levels and were genotyped for MT2A polymorphisms by reverse transcription polymerase chain reaction. A short questionnaire collected the medical history and alcohol and cigarette consumption information. The data were used for descriptive analyses and linear regression models. The investigation revealed that lead elevated concentration increased low-density lipoprotein cholesterol and decreased high-density lipoprotein cholesterol (HDL-C) by multiple linear models. The carriers of the rs10636 GC-rs28366003 AA genetic combination may be less susceptive to lead elevated concentration on HDL-C than other types. In conclusion, the association of the blood lead level and HDL-C may be modified by the MT2A genetic combination: the rs10636 GC-rs28366003 AA genotype could play a protective role in lead elevated concentration on HDL-C in humans. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Antinociceptive effect of intrathecal microencapsulated human pheochromocytoma cell in a rat model of bone cancer pain.

PubMed

Li, Xiao; Li, Guoqi; Wu, Shaoling; Zhang, Baiyu; Wan, Qing; Yu, Ding; Zhou, Ruijun; Ma, Chao

2014-07-08

Human pheochromocytoma cells, which are demonstrated to contain and release met-enkephalin and norepinephrine, may be a promising resource for cell therapy in cancer-induced intractable pain. Intrathecal injection of alginate-poly (l) lysine-alginate (APA) microencapsulated human pheochromocytoma cells leads to antinociceptive effect in a rat model of bone cancer pain, and this effect was blocked by opioid antagonist naloxone and alpha 2-adrenergic antagonist rauwolscine. Neurochemical changes of cerebrospinal fluid are in accordance with the analgesic responses. Taken together, these data support that human pheochromocytoma cell implant-induced antinociception was mediated by met-enkephalin and norepinephrine secreted from the cell implants and acting at spinal receptors. Spinal implantation of microencapsulated human pheochromocytoma cells may provide an alternative approach for the therapy of chronic intractable pain.

Human scalp permeability to the chemical warfare agent VX.

PubMed

Rolland, P; Bolzinger, M-A; Cruz, C; Briançon, S; Josse, D

2011-12-01

The use of chemical warfare agents such as VX in terrorism act might lead to contamination of the civilian population. Human scalp decontamination may require appropriate products and procedures. Due to ethical reasons, skin decontamination studies usually involve in vitro skin models, but human scalp skin samples are uncommon and expensive. The purpose of this study was to characterize the in vitro permeability to VX of human scalp, and to compare it with (a) human abdominal skin, and (b) pig skin from two different anatomic sites: ear and skull roof, in order to design a relevant model. Based on the VX skin permeation kinetics and distribution, we demonstrated that (a) human scalp was significantly more permeable to VX than abdominal skin and (b) pig-ear skin was the most relevant model to predict the in vitro human scalp permeability. Our results indicated that the follicular pathway significantly contributed to the skin absorption of VX through human scalp. In addition, the hair follicles and the stratum corneum significantly contributed to the formation of a skin reservoir for VX. Copyright © 2011 Elsevier Ltd. All rights reserved.

Modeling aspects of human memory for scientific study.

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

Caudell, Thomas P.; Watson, Patrick; McDaniel, Mark A.

Working with leading experts in the field of cognitive neuroscience and computational intelligence, SNL has developed a computational architecture that represents neurocognitive mechanisms associated with how humans remember experiences in their past. The architecture represents how knowledge is organized and updated through information from individual experiences (episodes) via the cortical-hippocampal declarative memory system. We compared the simulated behavioral characteristics with those of humans measured under well established experimental standards, controlling for unmodeled aspects of human processing, such as perception. We used this knowledge to create robust simulations of & human memory behaviors that should help move the scientific community closermore » to understanding how humans remember information. These behaviors were experimentally validated against actual human subjects, which was published. An important outcome of the validation process will be the joining of specific experimental testing procedures from the field of neuroscience with computational representations from the field of cognitive modeling and simulation.« less

A simple physiologically based pharmacokinetic model evaluating the effect of anti-nicotine antibodies on nicotine disposition in the brains of rats and humans

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

Saylor, Kyle, E-mail: saylor@vt.edu; Zhang, Chenmi

Physiologically based pharmacokinetic (PBPK) modeling was applied to investigate the effects of anti-nicotine antibodies on nicotine disposition in the brains of rats and humans. Successful construction of both rat and human models was achieved by fitting model outputs to published nicotine concentration time course data in the blood and in the brain. Key parameters presumed to have the most effect on the ability of these antibodies to prevent nicotine from entering the brain were selected for investigation using the human model. These parameters, which included antibody affinity for nicotine, antibody cross-reactivity with cotinine, and antibody concentration, were broken down intomore » different, clinically-derived in silico treatment levels and fed into the human PBPK model. Model predictions suggested that all three parameters, in addition to smoking status, have a sizable impact on anti-nicotine antibodies' ability to prevent nicotine from entering the brain and that the antibodies elicited by current human vaccines do not have sufficient binding characteristics to reduce brain nicotine concentrations. If the antibody binding characteristics achieved in animal studies can similarly be achieved in human studies, however, nicotine vaccine efficacy in terms of brain nicotine concentration reduction is predicted to meet threshold values for alleviating nicotine dependence. - Highlights: • Modelling of nicotine disposition in the presence of anti-nicotine antibodies • Key vaccine efficacy factors are evaluated in silico in rats and in humans. • Model predicts insufficient antibody binding in past human nicotine vaccines. • Improving immunogenicity and antibody specificity may lead to vaccine success.« less

Adaptive neuroplastic responses in early and late hemispherectomized monkeys.

PubMed

Burke, Mark W; Kupers, Ron; Ptito, Maurice

2012-01-01

Behavioural recovery in children who undergo medically required hemispherectomy showcase the remarkable ability of the cerebral cortex to adapt and reorganize following insult early in life. Case study data suggest that lesions sustained early in childhood lead to better recovery compared to those that occur later in life. In these children, it is possible that neural reorganization had begun prior to surgery but was masked by the dysfunctional hemisphere. The degree of neural reorganization has been difficult to study systematically in human infants. Here we present a 20-year culmination of data on our nonhuman primate model (Chlorocebus sabeus) of early-life hemispherectomy in which behavioral recovery is interpreted in light of plastic processes that lead to the anatomical reorganization of the early-damaged brain. The model presented here suggests that significant functional recovery occurs after the removal of one hemisphere in monkeys with no preexisting neurological dysfunctions. Human and primate studies suggest a critical role for subcortical and brainstem structures as well as corticospinal tracts in the neuroanatomical reorganization which result in the remarkable behavioral recovery following hemispherectomy. The non-human primate model presented here offers a unique opportunity for studying the behavioral and functional neuroanatomical reorganization that underlies developmental plasticity.

Learning a Continuous-Time Streaming Video QoE Model.

PubMed

Ghadiyaram, Deepti; Pan, Janice; Bovik, Alan C

2018-05-01

Over-the-top adaptive video streaming services are frequently impacted by fluctuating network conditions that can lead to rebuffering events (stalling events) and sudden bitrate changes. These events visually impact video consumers' quality of experience (QoE) and can lead to consumer churn. The development of models that can accurately predict viewers' instantaneous subjective QoE under such volatile network conditions could potentially enable the more efficient design of quality-control protocols for media-driven services, such as YouTube, Amazon, Netflix, and so on. However, most existing models only predict a single overall QoE score on a given video and are based on simple global video features, without accounting for relevant aspects of human perception and behavior. We have created a QoE evaluator, called the time-varying QoE Indexer, that accounts for interactions between stalling events, analyzes the spatial and temporal content of a video, predicts the perceptual video quality, models the state of the client-side data buffer, and consequently predicts continuous-time quality scores that agree quite well with human opinion scores. The new QoE predictor also embeds the impact of relevant human cognitive factors, such as memory and recency, and their complex interactions with the video content being viewed. We evaluated the proposed model on three different video databases and attained standout QoE prediction performance.

Animal and human models to understand ageing.

PubMed

Lees, Hayley; Walters, Hannah; Cox, Lynne S

2016-11-01

Human ageing is the gradual decline in organ and tissue function with increasing chronological time, leading eventually to loss of function and death. To study the processes involved over research-relevant timescales requires the use of accessible model systems that share significant similarities with humans. In this review, we assess the usefulness of various models, including unicellular yeasts, invertebrate worms and flies, mice and primates including humans, and highlight the benefits and possible drawbacks of each model system in its ability to illuminate human ageing mechanisms. We describe the strong evolutionary conservation of molecular pathways that govern cell responses to extracellular and intracellular signals and which are strongly implicated in ageing. Such pathways centre around insulin-like growth factor signalling and integration of stress and nutritional signals through mTOR kinase. The process of cellular senescence is evaluated as a possible underlying cause for many of the frailties and diseases of human ageing. Also considered is ageing arising from systemic changes that cannot be modelled in lower organisms and instead require studies either in small mammals or in primates. We also touch briefly on novel therapeutic options arising from a better understanding of the biology of ageing. Copyright © 2016. Published by Elsevier Ireland Ltd.

integrated Earth System Model

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

Jones, Andew; Di Vittorio, Alan; Collins, William

The integrated Earth system model (iESM) has been developed as a new tool for projecting the joint human/climate system. The iESM is based upon coupling an integrated assessment model (IAM) and an Earth system model (ESM) into a common modeling infrastructure. IAMs are the primary tool for describing the human-Earth system, including the sources of global greenhouse gases (GHGs) and short-lived species (SLS), land use and land cover change (LULCC), and other resource-related drivers of anthropogenic climate change. ESMs are the primary scientific tools for examining the physical, chemical, and biogeochemical impacts of human-induced changes to the climate system. Themore » iESM project integrates the economic and human-dimension modeling of an IAM and a fully coupled ESM within a single simulation system while maintaining the separability of each model if needed. Both IAM and ESM codes are developed and used by large communities and have been extensively applied in recent national and international climate assessments. By introducing heretofore-omitted feedbacks between natural and societal drivers, we can improve scientific understanding of the human-Earth system dynamics. Potential applications include studies of the interactions and feedbacks leading to the timing, scale, and geographic distribution of emissions trajectories and other human influences, corresponding climate effects, and the subsequent impacts of a changing climate on human and natural systems.« less

Developmental exposure to lead (Pb) alters the expression of the human tau gene and its products in a transgenic animal model

PubMed Central

Dash, M.; Eid, A.; Subaiea, G.; Chang, J.; Deeb, R.; Masoud, A.; Renehan, W.E.; Adem, A.; Zawia, N.H.

2016-01-01

Tauopathies are a class of neurodegenerative diseases associated with the pathological aggregationof the tau protein in the human brain. The best known of these illnesses is Alzheimer's disease (AD); a disease where the microtubule associated protein tau (MAPT) becomes hyperphosphorylated (lowering its binding affinity to microtubules) and aggregates within neurons in the form of neurofibrillary tangles (NFTs). In this paper we examine whether environmental factors play a significant role in tau pathogenesis. Our studies were conducted in a double mutant mouse model that expressed the human tau gene and lacked the gene for murine tau. The human tau mouse model was tested for the transgene's ability to respond to an environmental toxicant. Pups were developmentally exposed to lead (Pb) from postnatal day (PND) 1-20 with 0.2% Pb acetate. Mice were then sacrificed at PND 20, 30, 40 and 60. Protein and mRNA levels for tau and CDK5 as well as tau phosphorylation at Ser396 were determined. In addition, the potential role of miRNA in tau expression was investigated by measuring levels of miR-34c, a miRNA that targets the mRNA for human tau, at PND20 and 50. The expression of the human tau transgene was altered by developmental exposure to Pb. This exposure also altered the expression of miR-34c. Our findings are the first of their kind to test the responsiveness of the human tau gene to an environmental toxicant and to examine an epigenetic mechanism that may be involved in the regulation of this gene's expression. PMID:27293183

Building-associated neurological damage modeled in human cells: a mechanism of neurotoxic effects by exposure to mycotoxins in the indoor environment.

PubMed

Karunasena, Enusha; Larrañaga, Michael D; Simoni, Jan S; Douglas, David R; Straus, David C

2010-12-01

Damage to human neurological system cells resulting from exposure to mycotoxins confirms a previously controversial public health threat for occupants of water-damaged buildings. Leading scientific organizations disagree about the ability of inhaled mycotoxins in the indoor environment to cause adverse human health effects. Damage to the neurological system can result from exposure to trichothecene mycotoxins in the indoor environment. This study demonstrates that neurological system cell damage can occur from satratoxin H exposure to neurological cells at exposure levels that can be found in water-damaged buildings contaminated with fungal growth. The constant activation of inflammatory and apoptotic pathways at low levels of exposure in human brain capillary endothelial cells, astrocytes, and neural progenitor cells may amplify devastation to neurological tissues and lead to neurological system cell damage from indirect events triggered by the presence of trichothecenes.

The cultural parameters of lead poisoning: A medical anthropologist's view of intervention in environmental lead exposure

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

Trotter, R.T. II

1990-11-01

This article identifies four culturally shaped sources of lead exposure in human societies: modern and historic technological sources; food habits; culturally defined health beliefs; and beauty practices. Examples of these potential sources of lead poisoning are presented from current cultures. They include the use of lead-glazed cooking pottery in Mexican-American households; folk medical use of lead in Hispanic, Arabic, South Asian, Chinese, and Hmong communities; as well as the use of lead as a cosmetic in the Near East, Southeast Asia, and South Asia. Four interacting cultural conditions that create barriers to the reduction of lead exposure and lead poisoningmore » are identified and discussed. These are knowledge deficiencies, communication resistance, cultural reinterpretations, and incongruity of explanatory models.« less

A Drosophila Model for Amyotrophic Lateral Sclerosis Reveals Motor Neuron Damage by Human SOD1*♦

PubMed Central

Watson, Melanie R.; Lagow, Robert D.; Xu, Kexiang; Zhang, Bing; Bonini, Nancy M.

2008-01-01

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that leads to loss of motor function and early death. About 5% of cases are inherited, with the majority of identified linkages in the gene encoding copper, zinc-superoxide dismutase (SOD1). Strong evidence indicates that the SOD1 mutations confer dominant toxicity on the protein. To provide new insight into mechanisms of ALS, we have generated and characterized a model for familial ALS in Drosophila with transgenic expression of human SOD1. Expression of wild type or disease-linked (A4V, G85R) mutants of human SOD1 selectively in motor neurons induced progressive climbing deficits. These effects were accompanied by defective neural circuit electrophysiology, focal accumulation of human SOD1 protein in motor neurons, and a stress response in surrounding glia. However, toxicity was not associated with oligomerization of SOD1 and did not lead to neuronal loss. These studies uncover cell-autonomous injury by SOD1 to motor neurons in vivo, as well as non-autonomous effects on glia, and provide the foundation for new insight into injury and protection of motor neurons in ALS. PMID:18596033

Demodulation processes in auditory perception

NASA Astrophysics Data System (ADS)

Feth, Lawrence L.

1994-08-01

The long range goal of this project is the understanding of human auditory processing of information conveyed by complex, time-varying signals such as speech, music or important environmental sounds. Our work is guided by the assumption that human auditory communication is a 'modulation - demodulation' process. That is, we assume that sound sources produce a complex stream of sound pressure waves with information encoded as variations ( modulations) of the signal amplitude and frequency. The listeners task then is one of demodulation. Much of past. psychoacoustics work has been based in what we characterize as 'spectrum picture processing.' Complex sounds are Fourier analyzed to produce an amplitude-by-frequency 'picture' and the perception process is modeled as if the listener were analyzing the spectral picture. This approach leads to studies such as 'profile analysis' and the power-spectrum model of masking. Our approach leads us to investigate time-varying, complex sounds. We refer to them as dynamic signals and we have developed auditory signal processing models to help guide our experimental work.

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.

Human pluripotent stem cell models of autism spectrum disorder: emerging frontiers, opportunities, and challenges towards neuronal networks in a dish.

PubMed

Aigner, Stefan; Heckel, Tobias; Zhang, Jitao D; Andreae, Laura C; Jagasia, Ravi

2014-03-01

Autism spectrum disorder (ASD) is characterized by deficits in language development and social cognition and the manifestation of repetitive and restrictive behaviors. Despite recent major advances, our understanding of the pathophysiological mechanisms leading to ASD is limited. Although most ASD cases have unknown genetic underpinnings, animal and human cellular models of several rare, genetically defined syndromic forms of ASD have provided evidence for shared pathophysiological mechanisms that may extend to idiopathic cases. Here, we review our current knowledge of the genetic basis and molecular etiology of ASD and highlight how human pluripotent stem cell-based disease models have the potential to advance our understanding of molecular dysfunction. We summarize landmark studies in which neuronal cell populations generated from human embryonic stem cells and patient-derived induced pluripotent stem cells have served to model disease mechanisms, and we discuss recent technological advances that may ultimately allow in vitro modeling of specific human neuronal circuitry dysfunction in ASD. We propose that these advances now offer an unprecedented opportunity to help better understand ASD pathophysiology. This should ultimately enable the development of cellular models for ASD, allowing drug screening and the identification of molecular biomarkers for patient stratification.

Social Psychological Dynamics of Enhanced HIV Risk Reduction among Peer Interventionists

ERIC Educational Resources Information Center

Dickson-Gomez, Julia; Weeks, Margaret R.; Convey, Mark; Li, Jianghong

2011-01-01

The authors present a model of interactive social psychological and relational feedback processes leading to human immunodeficiency virus (HIV) risk reduction behavior change among active drug users trained as Peer Health Advocates (PHAs). The model is supported by data from qualitative interviews with PHAs and members of their drug-using networks…

General ecological models for human subsistence, health and poverty.

PubMed

Ngonghala, Calistus N; De Leo, Giulio A; Pascual, Mercedes M; Keenan, Donald C; Dobson, Andrew P; Bonds, Matthew H

2017-08-01

The world's rural poor rely heavily on their immediate natural environment for subsistence and suffer high rates of morbidity and mortality from infectious diseases. We present a general framework for modelling subsistence and health of the rural poor by coupling simple dynamic models of population ecology with those for economic growth. The models show that feedbacks between the biological and economic systems can lead to a state of persistent poverty. Analyses of a wide range of specific systems under alternative assumptions show the existence of three possible regimes corresponding to a globally stable development equilibrium, a globally stable poverty equilibrium and bistability. Bistability consistently emerges as a property of generalized disease-economic systems for about a fifth of the feasible parameter space. The overall proportion of parameters leading to poverty is larger than that resulting in healthy/wealthy development. All the systems are found to be most sensitive to human disease parameters. The framework highlights feedbacks, processes and parameters that are important to measure in studies of rural poverty to identify effective pathways towards sustainable development.

A mechanistic model on the role of “radially-running” collagen fibers on dissection properties of human ascending thoracic aorta

PubMed Central

Pal, Siladitya; Tsamis, Alkiviadis; Pasta, Salvatore; D'Amore, Antonio; Gleason, Thomas G.; Vorp, David A.; Maiti, Spandan

2014-01-01

Aortic dissection (AoD) is a common condition that often leads to life-threatening cardiovaular emergency. From a biomechanics viewpoint, AoD involves failure of load-bearing microstructural components of the aortic wall, mainly elastin and collagen fibers. Delamination strength of the aortic wall depends on the load-bearing capacity and local micro-architecture of these fibers, which may vary with age, disease and aortic location. Therefore, quantifying the role of fiber micro-architecture on the delamination strength of the aortic wall may lead to improved understanding of AoD. We present an experimentally-driven modeling paradigm towards this goal. Specifically, we utilize collagen fiber microarchitecture, obtained in a parallel study from multi-photon microopy, in a predictive mechanistic framework to characterize the delamination strength. We then validate our model against peel test experiments on human aortic strips and utilize the model to predict the delamination strength of separate aortic strips and compare with experimental findings. We observe that the number density and failure energy of the radially-running collagen fibers control the peel strength. Furthermore, our model suggests that the lower delamination strength previously found for the circumferential direction in human aorta is related to a lower number density of radially-running collagen fibers in that direction. Our model sets the stage for an expanded future study that could predict AoD propagation in patient-specific aortic geometries and better understand factors that may influence propensity for occurrence. PMID:24484644

Irrational beliefs, biases and gambling: exploring the role of animal models in elucidating vulnerabilities for the development of pathological gambling.

PubMed

Cocker, P J; Winstanley, C A

2015-02-15

Gambling is a heterogeneous and complex disorder. Multiple factors may lead to problem gambling, yet one of the most important appears to be the increased presence of cognitive biases or distortions. These biases are thought to precipitate gambling as they can lead to dysfunctional decision making under risk or ambiguity. Modelling these cognitive perturbations in animals can improve our understanding of their neurobiological bases, and potentially stimulate novel treatment options. The first aim of this review is to give a broad overview of some of the cognitive biases that are most commonly associated with gambling. Secondly, we will discuss several animal models that we have developed in which rodent decision-making appears hallmarked by the same cognitive inconsistencies as human choice. In particular, we will discuss two tasks that capture elements of risk and loss averse decision making, and another in which rats appear susceptible to the 'near-miss' effect. To date, findings from both human and non-human studies suggest that these different biases are neuropharmacologically and neurostructurally dissociable, and that dopamine plays a key role in their expression. Lastly, we will briefly discuss areas in both human and animal research where limitations within the field may be hampering a more complete understanding of pathological gambling as a disorder. Copyright © 2014 Elsevier B.V. All rights reserved.

Convergence of Human Genetics and Animal Studies: Gene Therapy for X-Linked Retinoschisis

PubMed Central

Bush, Ronald A.; Wei, Lisa L.; Sieving, Paul A.

2015-01-01

Retinoschisis is an X-linked recessive genetic disease that leads to vision loss in males. X-linked retinoschisis (XLRS) typically affects young males; however, progressive vision loss continues throughout life. Although discovered in 1898 by Haas in two brothers, the underlying biology leading to blindness has become apparent only in the last 15 years with the advancement of human genetic analyses, generation of XLRS animal models, and the development of ocular monitoring methods such as the electroretinogram and optical coherence tomography. It is now recognized that retinoschisis results from cyst formations within the retinal layers that interrupt normal visual neurosignaling and compromise structural integrity. Mutations in the human retinoschisin gene have been correlated with disease severity of the human XLRS phenotype. Introduction of a normal human retinoschisin cDNA into retinoschisin knockout mice restores retinal structure and improves neural function, providing proof-of-concept that gene replacement therapy is a plausible treatment for XLRS. PMID:26101206

Local air gap thickness and contact area models for realistic simulation of human thermo-physiological response

NASA Astrophysics Data System (ADS)

Psikuta, Agnes; Mert, Emel; Annaheim, Simon; Rossi, René M.

2018-02-01

To evaluate the quality of new energy-saving and performance-supporting building and urban settings, the thermal sensation and comfort models are often used. The accuracy of these models is related to accurate prediction of the human thermo-physiological response that, in turn, is highly sensitive to the local effect of clothing. This study aimed at the development of an empirical regression model of the air gap thickness and the contact area in clothing to accurately simulate human thermal and perceptual response. The statistical model predicted reliably both parameters for 14 body regions based on the clothing ease allowances. The effect of the standard error in air gap prediction on the thermo-physiological response was lower than the differences between healthy humans. It was demonstrated that currently used assumptions and methods for determination of the air gap thickness can produce a substantial error for all global, mean, and local physiological parameters, and hence, lead to false estimation of the resultant physiological state of the human body, thermal sensation, and comfort. Thus, this model may help researchers to strive for improvement of human thermal comfort, health, productivity, safety, and overall sense of well-being with simultaneous reduction of energy consumption and costs in built environment.

An alternative perspective on assistive technology: the Person-Environment-Tool (PET) model.

PubMed

Jarl, Gustav; Lundqvist, Lars-Olov

2018-04-20

The medical and social models of disability are based on a dichotomy that categorizes people as able-bodied or disabled. In contrast, the biopsychosocial model, which forms the basis for the International Classification of Functioning, Disability and Health (ICF), suggests a universalistic perspective on human functioning, encompassing all human beings. In this article we argue that the artificial separation of function-enhancing technology into assistive technology (AT) and mainstream technology might be one of the barriers to a universalistic view of human functioning. Thus, an alternative view of AT is needed. The aim of this article was to construct a conceptual model to demonstrate how all human activities and participation depend on factors related to the person, environment, and tools, emphasizing a universalistic perspective on human functioning. In the Person-Environment-Tool (PET) model, a person's activity and participation are described as a function of factors related to the person, environment, and tool, drawing on various ICF components. Importantly, the PET model makes no distinction between people of different ability levels, between environmental modifications intended for people of different ability levels, or between different function-enhancing technologies (AT and mainstream technology). A fictive patient case is used to illustrate how the universalistic view of the PET model lead to a different approach in rehabilitation. The PET model supports a universalistic view of technology use, environmental adaptations, and variations in human functioning.

Past and Future of Astronomy and SETI Cast in Maths

NASA Astrophysics Data System (ADS)

Maccone, C.

Assume that the history of Astronomy and SETI is the leading proof of the evolution of human knowledge on Earth over the last 3000 years. Then, human knowledge has increased a lot, although not at a uniform pace. A mathematical description of how much human knowledge has increased, however, is difficult to achieve. In this paper, we cast a mathematical model of the evolution of human knowledge over the last three thousand years that seems to reflect reasonably well both what is known from the past and might be extrapolated into the future. Our model is based on two seminal books by Sagan and Finney and Jones. Our model is based on the use of two cubic curves, representing the evolution of Astronomy and of SETI, respectively. We conclude by extrapolating these curves into the future and reach the conclusion that the "Star Trek" age of humankind might possibly begin by the end of this century.

Characterization of human septic sera induced gene expression modulation in human myocytes

PubMed Central

Hussein, Shaimaa; Michael, Paul; Brabant, Danielle; Omri, Abdelwahab; Narain, Ravin; Passi, Kalpdrum; Ramana, Chilakamarti V.; Parrillo, Joseph E.; Kumar, Anand; Parissenti, Amadeo; Kumar, Aseem

2009-01-01

To gain a better understanding of the gene expression changes that occurs during sepsis, we have performed a cDNA microarray study utilizing a tissue culture model that mimics human sepsis. This study utilized an in vitro model of cultured human fetal cardiac myocytes treated with 10% sera from septic patients or 10% sera from healthy volunteers. A 1700 cDNA expression microarray was used to compare the transcription profile from human cardiac myocytes treated with septic sera vs normal sera. Septic sera treatment of myocytes resulted in the down-regulation of 178 genes and the up-regulation of 4 genes. Our data indicate that septic sera induced cell cycle, metabolic, transcription factor and apoptotic gene expression changes in human myocytes. Identification and characterization of gene expression changes that occur during sepsis may lead to the development of novel therapeutics and diagnostics. PMID:19684886

HIV and drug abuse mediate astrocyte senescence in a β-catenin-dependent manner leading to neuronal toxicity.

PubMed

Yu, Chunjiang; Narasipura, Srinivas D; Richards, Maureen H; Hu, Xiu-Ti; Yamamoto, Bryan; Al-Harthi, Lena

2017-10-01

Emerging evidence suggests that cell senescence plays an important role in aging-associated diseases including neurodegenerative diseases. HIV leads to a spectrum of neurologic diseases collectively termed HIV-associated neurocognitive disorders (HAND). Drug abuse, particularly methamphetamine (meth), is a frequently abused psychostimulant among HIV+ individuals and its abuse exacerbates HAND. The mechanism by which HIV and meth lead to brain cell dysregulation is not entirely clear. In this study, we evaluated the impact of HIV and meth on astrocyte senescence using in vitro and several animal models. Astrocytes constitute up to 50% of brain cells and play a pivotal role in marinating brain homeostasis. We show here that HIV and meth induce significant senescence of primary human fetal astrocytes, as evaluated by induction of senescence markers (β-galactosidase and p16 INK 4A ), senescence-associated morphologic changes, and cell cycle arrest. HIV- and meth-mediated astrocyte senescence was also demonstrated in three small animal models (humanized mouse model of HIV/NSG-huPBMCs, HIV-transgenic rats, and in a meth administration rat model). Senescent astrocytes in turn mediated neuronal toxicity. Further, we show that β-catenin, a pro-survival/proliferation transcriptional co-activator, is downregulated by HIV and meth in human astrocytes and this downregulation promotes astrocyte senescence while induction of β-catenin blocks HIV- and meth-mediated astrocyte senescence. These studies, for the first time, demonstrate that HIV and meth induce astrocyte senescence and implicate the β-catenin pathway as potential therapeutic target to overcome astrocyte senescence. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

A mouse model for fucosidosis recapitulates storage pathology and neurological features of the milder form of the human disease

PubMed Central

Wolf, Heike; Stroobants, Stijn; D'Hooge, Rudi; Hermans-Borgmeyer, Irm; Lüllmann-Rauch, Renate; Dierks, Thomas; Lübke, Torben

2016-01-01

ABSTRACT Fucosidosis is a rare lysosomal storage disorder caused by the inherited deficiency of the lysosomal hydrolase α-L-fucosidase, which leads to an impaired degradation of fucosylated glycoconjugates. Here, we report the generation of a fucosidosis mouse model, in which the gene for lysosomal α-L-fucosidase (Fuca1) was disrupted by gene targeting. Homozygous knockout mice completely lack α-L-fucosidase activity in all tested organs leading to highly elevated amounts of the core-fucosylated glycoasparagine Fuc(α1,6)-GlcNAc(β1-N)-Asn and, to a lesser extent, other fucosylated glycoasparagines, which all were also partially excreted in urine. Lysosomal storage pathology was observed in many visceral organs, such as in the liver, kidney, spleen and bladder, as well as in the central nervous system (CNS). On the cellular level, storage was characterized by membrane-limited cytoplasmic vacuoles primarily containing water-soluble storage material. In the CNS, cellular alterations included enlargement of the lysosomal compartment in various cell types, accumulation of secondary storage material and neuroinflammation, as well as a progressive loss of Purkinje cells combined with astrogliosis leading to psychomotor and memory deficits. Our results demonstrate that this new fucosidosis mouse model resembles the human disease and thus will help to unravel underlying pathological processes. Moreover, this model could be utilized to establish diagnostic and therapeutic strategies for fucosidosis. PMID:27491075

Walking in circles: a modelling approach

PubMed Central

Maus, Horst-Moritz; Seyfarth, Andre

2014-01-01

Blindfolded or disoriented people have the tendency to walk in circles rather than on a straight line even if they wanted to. Here, we use a minimalistic walking model to examine this phenomenon. The bipedal spring-loaded inverted pendulum exhibits asymptotically stable gaits with centre of mass (CoM) dynamics and ground reaction forces similar to human walking in the sagittal plane. We extend this model into three dimensions, and show that stable walking patterns persist if the leg is aligned with respect to the body (here: CoM velocity) instead of a world reference frame. Further, we demonstrate that asymmetric leg configurations, which are common in humans, will typically lead to walking in circles. The diameter of these circles depends strongly on parameter configuration, but is in line with empirical data from human walkers. Simulation results suggest that walking radius and especially direction of rotation are highly dependent on leg configuration and walking velocity, which explains inconsistent veering behaviour in repeated trials in human data. Finally, we discuss the relation between findings in the model and implications for human walking. PMID:25056215

Brain Injury Differences in Frontal Impact Crash Using Different Simulation Strategies

PubMed Central

Ma, Chunsheng; Shen, Ming; Li, Peiyu; Zhang, Jinhuan

2015-01-01

In the real world crashes, brain injury is one of the leading causes of deaths. Using isolated human head finite element (FE) model to study the brain injury patterns and metrics has been a simplified methodology widely adopted, since it costs significantly lower computation resources than a whole human body model does. However, the degree of precision of this simplification remains questionable. This study compared these two kinds of methods: (1) using a whole human body model carried on the sled model and (2) using an isolated head model with prescribed head motions, to study the brain injury. The distribution of the von Mises stress (VMS), maximum principal strain (MPS), and cumulative strain damage measure (CSDM) was used to compare the two methods. The results showed that the VMS of brain mainly concentrated at the lower cerebrum and occipitotemporal region close to the cerebellum. The isolated head modelling strategy predicted higher levels of MPS and CSDM 5%, while the difference is small in CSDM 10% comparison. It suggests that isolated head model may not equivalently reflect the strain levels below the 10% compared to the whole human body model. PMID:26495029

Leading the Higher Education IT Organization: Six Building Blocks of Success

ERIC Educational Resources Information Center

Laster, Stephen J.

2011-01-01

Many of the worries for IT leaders are new--and much broader. The traditional teaching, learning, and research models of the past will not be and cannot be the models for the future. These models break down as costs (human and financial) continue to grow faster than they can be funded, as digital natives change forever the nature of being "in…

Three Scenarios on the Technology Education Base.

ERIC Educational Resources Information Center

Lauda, Donald

1983-01-01

Outlines a K-12 scope and sequence model for technology education that has as its integrating thread the concept that technology is fundamental to human survival and that its study leads to an understanding of culture. (SK)

3D Miniaturization of Human Organs for Drug Discovery.

PubMed

Park, Joseph; Wetzel, Isaac; Dréau, Didier; Cho, Hansang

2018-01-01

"Engineered human organs" hold promises for predicting the effectiveness and accuracy of drug responses while reducing cost, time, and failure rates in clinical trials. Multiorgan human models utilize many aspects of currently available technologies including self-organized spherical 3D human organoids, microfabricated 3D human organ chips, and 3D bioprinted human organ constructs to mimic key structural and functional properties of human organs. They enable precise control of multicellular activities, extracellular matrix (ECM) compositions, spatial distributions of cells, architectural organizations of ECM, and environmental cues. Thus, engineered human organs can provide the microstructures and biological functions of target organs and advantageously substitute multiscaled drug-testing platforms including the current in vitro molecular assays, cell platforms, and in vivo models. This review provides an overview of advanced innovative designs based on the three main technologies used for organ construction leading to single and multiorgan systems useable for drug development. Current technological challenges and future perspectives are also discussed. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Language competition in a population of migrating agents.

PubMed

Lipowska, Dorota; Lipowski, Adam

2017-05-01

Influencing various aspects of human activity, migration is associated also with language formation. To examine the mutual interaction of these processes, we study a Naming Game with migrating agents. The dynamics of the model leads to formation of low-mobility clusters, which turns out to break the symmetry of the model: although the Naming Game remains symmetric, low-mobility languages are favored. High-mobility languages are gradually eliminated from the system, and the dynamics of language formation considerably slows down. Our model is too simple to explain in detail language competition of migrating human communities, but it certainly shows that languages of settlers are favored over nomadic ones.

Lessons from the Murine Models of West Nile Virus Infection.

PubMed

McGruder, Brenna; Saxena, Vandana; Wang, Tian

2016-01-01

West Nile virus (WNV), a mosquito-borne, single positive-stranded RNA virus, has been the leading cause of arboviral encephalitis in the U.S. and other parts of the world over the past decade. Up to 50 % of WNV convalescent patients were reported to have long-term neurological sequelae or chronic kidney diseases. However, there are neither antiviral drugs nor vaccines available for humans. The underlying mechanism of the long-term sequelae is not clearly understood either. Animal models have been an effective tool to investigate viral pathogenesis and host immunity in humans. Here, we will review several commonly used murine models of WNV infection.

Language competition in a population of migrating agents

NASA Astrophysics Data System (ADS)

Lipowska, Dorota; Lipowski, Adam

2017-05-01

Influencing various aspects of human activity, migration is associated also with language formation. To examine the mutual interaction of these processes, we study a Naming Game with migrating agents. The dynamics of the model leads to formation of low-mobility clusters, which turns out to break the symmetry of the model: although the Naming Game remains symmetric, low-mobility languages are favored. High-mobility languages are gradually eliminated from the system, and the dynamics of language formation considerably slows down. Our model is too simple to explain in detail language competition of migrating human communities, but it certainly shows that languages of settlers are favored over nomadic ones.

Integrated earth system dynamic modeling for life cycle impact assessment of ecosystem services.

PubMed

Arbault, Damien; Rivière, Mylène; Rugani, Benedetto; Benetto, Enrico; Tiruta-Barna, Ligia

2014-02-15

Despite the increasing awareness of our dependence on Ecosystem Services (ES), Life Cycle Impact Assessment (LCIA) does not explicitly and fully assess the damages caused by human activities on ES generation. Recent improvements in LCIA focus on specific cause-effect chains, mainly related to land use changes, leading to Characterization Factors (CFs) at the midpoint assessment level. However, despite the complexity and temporal dynamics of ES, current LCIA approaches consider the environmental mechanisms underneath ES to be independent from each other and devoid of dynamic character, leading to constant CFs whose representativeness is debatable. This paper takes a step forward and is aimed at demonstrating the feasibility of using an integrated earth system dynamic modeling perspective to retrieve time- and scenario-dependent CFs that consider the complex interlinkages between natural processes delivering ES. The GUMBO (Global Unified Metamodel of the Biosphere) model is used to quantify changes in ES production in physical terms - leading to midpoint CFs - and changes in human welfare indicators, which are considered here as endpoint CFs. The interpretation of the obtained results highlights the key methodological challenges to be solved to consider this approach as a robust alternative to the mainstream rationale currently adopted in LCIA. Further research should focus on increasing the granularity of environmental interventions in the modeling tools to match current standards in LCA and on adapting the conceptual approach to a spatially-explicit integrated model. Copyright © 2013 Elsevier B.V. All rights reserved.

Addressing socioeconomic and political challenges posed by climate change

NASA Astrophysics Data System (ADS)

Fernando, Harindra Joseph; Klaic, Zvjezdana Bencetic

2011-08-01

NATO Advanced Research Workshop: Climate Change, Human Health and National Security; Dubrovnik, Croatia, 28-30 April 2011; Climate change has been identified as one of the most serious threats to humanity. It not only causes sea level rise, drought, crop failure, vector-borne diseases, extreme events, degradation of water and air quality, heat waves, and other phenomena, but it is also a threat multiplier wherein concatenation of multiple events may lead to frequent human catastrophes and intranational and international conflicts. In particular, urban areas may bear the brunt of climate change because of the amplification of climate effects that cascade down from global to urban scales, but current modeling and downscaling capabilities are unable to predict these effects with confidence. These were the main conclusions of a NATO Advanced Research Workshop (ARW) sponsored by the NATO Science for Peace and Security program. Thirty-two invitees from 17 counties, including leading modelers; natural, political, and social scientists; engineers; politicians; military experts; urban planners; industry analysts; epidemiologists; and health care professionals, parsed the topic on a common platform.

Effects of Disturbance on Populations of Marine Mammals

DTIC Science & Technology

2015-09-30

will respond to alternative scenarios of human activities, from those that produce sound to climate change to changes in human density and...develop transferable models of the population-level effects of anthropogenic and natural disturbances on marine mammals. Disturbances can affect the...physiology or behavior of animals, which in turn may lead to changes in demographic rates and viability. Population-level effects of disturbance

Human Learning of Elemental Category Structures: Revising the Classic Result of Shepard, Hovland, and Jenkins (1961)

ERIC Educational Resources Information Center

Kurtz, Kenneth J.; Levering, Kimery R.; Stanton, Roger D.; Romero, Joshua; Morris, Steven N.

2013-01-01

The findings of Shepard, Hovland, and Jenkins (1961) on the relative ease of learning 6 elemental types of 2-way classifications have been deeply influential 2 times over: 1st, as a rebuke to pure stimulus generalization accounts, and again as the leading benchmark for evaluating formal models of human category learning. The litmus test for models…

Stem Cells: A Renaissance in Human Biology Research.

PubMed

Wu, Jun; Izpisua Belmonte, Juan Carlos

2016-06-16

The understanding of human biology and how it relates to that of other species represents an ancient quest. Limited access to human material, particularly during early development, has restricted researchers to only scratching the surface of this inherently challenging subject. Recent technological innovations, such as single cell "omics" and human stem cell derivation, have now greatly accelerated our ability to gain insights into uniquely human biology. The opportunities afforded to delve molecularly into scarce material and to model human embryogenesis and pathophysiological processes are leading to new insights of human development and are changing our understanding of disease and choice of therapy options. Copyright © 2016 Elsevier Inc. All rights reserved.

Cultivation of Staphylococcus epidermidis in the Human Spaceflight Environment Leads to Alterations in the Frequency and Spectrum of Spontaneous Rifampicin-Resistance Mutations in the rpoB Gene

PubMed Central

Fajardo-Cavazos, Patricia; Nicholson, Wayne L.

2016-01-01

Bacteria of the genus Staphylococcus are persistent inhabitants of human spaceflight habitats and represent potential opportunistic pathogens. The effect of the human spaceflight environment on the growth and the frequency of mutations to antibiotic resistance in the model organism Staphylococcus epidermidis strain ATCC12228 was investigated. Six cultures of the test organism were cultivated in biological research in canisters–Petri dish fixation units for 122 h on orbit in the International Space Station (ISS) as part of the SpaceX-3 resupply mission. Asynchronous ground controls (GCs) consisted of identical sets of cultures cultivated for 122 h in the ISS Environmental Simulator at Kennedy Space Center. S. epidermidis exhibited significantly lower viable counts but significantly higher frequencies of mutation to rifampicin (Rif) resistance in space vs. GC cultures. The spectrum of mutations in the rpoB gene leading to RifR was altered in S. epidermidis isolates cultivated in the ISS compared to GCs. The results suggest that the human spaceflight environment induces unique physiologic stresses on growing bacterial cells leading to changes in mutagenic potential. PMID:27446039

Cultivation of Staphylococcus epidermidis in the Human Spaceflight Environment Leads to Alterations in the Frequency and Spectrum of Spontaneous Rifampicin-Resistance Mutations in the rpoB Gene.

PubMed

Fajardo-Cavazos, Patricia; Nicholson, Wayne L

2016-01-01

Bacteria of the genus Staphylococcus are persistent inhabitants of human spaceflight habitats and represent potential opportunistic pathogens. The effect of the human spaceflight environment on the growth and the frequency of mutations to antibiotic resistance in the model organism Staphylococcus epidermidis strain ATCC12228 was investigated. Six cultures of the test organism were cultivated in biological research in canisters-Petri dish fixation units for 122 h on orbit in the International Space Station (ISS) as part of the SpaceX-3 resupply mission. Asynchronous ground controls (GCs) consisted of identical sets of cultures cultivated for 122 h in the ISS Environmental Simulator at Kennedy Space Center. S. epidermidis exhibited significantly lower viable counts but significantly higher frequencies of mutation to rifampicin (Rif) resistance in space vs. GC cultures. The spectrum of mutations in the rpoB gene leading to Rif(R) was altered in S. epidermidis isolates cultivated in the ISS compared to GCs. The results suggest that the human spaceflight environment induces unique physiologic stresses on growing bacterial cells leading to changes in mutagenic potential.

Predicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea-pig model

PubMed Central

Yao, X; Anderson, D L; Ross, S A; Lang, D G; Desai, B Z; Cooper, D C; Wheelan, P; McIntyre, M S; Bergquist, M L; MacKenzie, K I; Becherer, J D; Hashim, M A

2008-01-01

Background and purpose: Drug-induced prolongation of the QT interval can lead to torsade de pointes, a life-threatening ventricular arrhythmia. Finding appropriate assays from among the plethora of options available to predict reliably this serious adverse effect in humans remains a challenging issue for the discovery and development of drugs. The purpose of the present study was to develop and verify a reliable and relatively simple approach for assessing, during preclinical development, the propensity of drugs to prolong the QT interval in humans. Experimental approach: Sixteen marketed drugs from various pharmacological classes with a known incidence—or lack thereof—of QT prolongation in humans were examined in hERG (human ether a-go-go-related gene) patch-clamp assay and an anaesthetized guinea-pig assay for QT prolongation using specific protocols. Drug concentrations in perfusates from hERG assays and plasma samples from guinea-pigs were determined using liquid chromatography-mass spectrometry. Key results: Various pharmacological agents that inhibit hERG currents prolong the QT interval in anaesthetized guinea-pigs in a manner similar to that seen in humans and at comparable drug exposures. Several compounds not associated with QT prolongation in humans failed to prolong the QT interval in this model. Conclusions and implications: Analysis of hERG inhibitory potency in conjunction with drug exposures and QT interval measurements in anaesthetized guinea-pigs can reliably predict, during preclinical drug development, the risk of human QT prolongation. A strategy is proposed for mitigating the risk of QT prolongation of new chemical entities during early lead optimization. PMID:18587422

How can we deal with ANN in flood forecasting? As a simulation model or updating kernel!

NASA Astrophysics Data System (ADS)

Hassan Saddagh, Mohammad; Javad Abedini, Mohammad

2010-05-01

Flood forecasting and early warning, as a non-structural measure for flood control, is often considered to be the most effective and suitable alternative to mitigate the damage and human loss caused by flood. Forecast results which are output of hydrologic, hydraulic and/or black box models should secure accuracy of flood values and timing, especially for long lead time. The application of the artificial neural network (ANN) in flood forecasting has received extensive attentions in recent years due to its capability to capture the dynamics inherent in complex processes including flood. However, results obtained from executing plain ANN as simulation model demonstrate dramatic reduction in performance indices as lead time increases. This paper is intended to monitor the performance indices as it relates to flood forecasting and early warning using two different methodologies. While the first method employs a multilayer neural network trained using back-propagation scheme to forecast output hydrograph of a hypothetical river for various forecast lead time up to 6.0 hr, the second method uses 1D hydrodynamic MIKE11 model as forecasting model and multilayer neural network as updating kernel to monitor and assess the performance indices compared to ANN alone in light of increase in lead time. Results presented in both graphical and tabular format indicate superiority of MIKE11 coupled with ANN as updating kernel compared to ANN as simulation model alone. While plain ANN produces more accurate results for short lead time, the errors increase expeditiously for longer lead time. The second methodology provides more accurate and reliable results for longer forecast lead time.

Experimental primates and non-human primate (NHP) models of human diseases in China: current status and progress.

PubMed

Zhang, Xiao-Liang; Pang, Wei; Hu, Xin-Tian; Li, Jia-Li; Yao, Yong-Gang; Zheng, Yong-Tang

2014-11-18

Non-human primates (NHPs) are phylogenetically close to humans, with many similarities in terms of physiology, anatomy, immunology, as well as neurology, all of which make them excellent experimental models for biomedical research. Compared with developed countries in America and Europe, China has relatively rich primate resources and has continually aimed to develop NHPs resources. Currently, China is a leading producer and a major supplier of NHPs on the international market. However, there are some deficiencies in feeding and management that have hampered China's growth in NHP research and materials. Nonetheless, China has recently established a number of primate animal models for human diseases and achieved marked scientific progress on infectious diseases, cardiovascular diseases, endocrine diseases, reproductive diseases, neurological diseases, and ophthalmic diseases, etc. Advances in these fields via NHP models will undoubtedly further promote the development of China's life sciences and pharmaceutical industry, and enhance China's position as a leader in NHP research. This review covers the current status of NHPs in China and other areas, highlighting the latest developments in disease models using NHPs, as well as outlining basic problems and proposing effective countermeasures to better utilize NHP resources and further foster NHP research in China.

Use of Statechart Assertions for Modeling Human-in-the-Loop Security Analysis and Decision-Making Processes

DTIC Science & Technology

2012-06-01

THIS PAGE INTENTIONALLY LEFT BLANK xv LIST OF ACRONYMS AND ABBREVIATIONS BPM Business Process Model BPMN Business Process Modeling Notation C&A...checking leads to an improvement in the quality and success of enterprise software development. Business Process Modeling Notation ( BPMN ) is an...emerging standard that allows business processes to be captured in a standardized format. BPMN lacks formal semantics which leaves many of its features

Development of an errorable car-following driver model

NASA Astrophysics Data System (ADS)

Yang, H.-H.; Peng, H.

2010-06-01

An errorable car-following driver model is presented in this paper. An errorable driver model is one that emulates human driver's functions and can generate both nominal (error-free), as well as devious (with error) behaviours. This model was developed for evaluation and design of active safety systems. The car-following data used for developing and validating the model were obtained from a large-scale naturalistic driving database. The stochastic car-following behaviour was first analysed and modelled as a random process. Three error-inducing behaviours were then introduced. First, human perceptual limitation was studied and implemented. Distraction due to non-driving tasks was then identified based on the statistical analysis of the driving data. Finally, time delay of human drivers was estimated through a recursive least-square identification process. By including these three error-inducing behaviours, rear-end collisions with the lead vehicle could occur. The simulated crash rate was found to be similar but somewhat higher than that reported in traffic statistics.

Of Mice and Men: Comparative Analysis of Neuro-Inflammatory Mechanisms in Human and Mouse Using Cause-and-Effect Models.

PubMed

Kodamullil, Alpha Tom; Iyappan, Anandhi; Karki, Reagon; Madan, Sumit; Younesi, Erfan; Hofmann-Apitius, Martin

2017-01-01

Perturbance in inflammatory pathways have been identified as one of the major factors which leads to neurodegenerative diseases (NDD). Owing to the limited access of human brain tissues and the immense complexity of the brain, animal models, specifically mouse models, play a key role in advancing the NDD field. However, many of these mouse models fail to reproduce the clinical manifestations and end points of the disease. NDD drugs, which passed the efficacy test in mice, were repeatedly not successful in clinical trials. There are numerous studies which are supporting and opposing the applicability of mouse models in neuroinflammation and NDD. In this paper, we assessed to what extend a mouse can mimic the cellular and molecular interactions in humans at a mechanism level. Based on our mechanistic modeling approach, we investigate the failure of a neuroinflammation targeted drug in the late phases of clinical trials based on the comparative analyses between the two species.

The Bayesian reader: explaining word recognition as an optimal Bayesian decision process.

PubMed

Norris, Dennis

2006-04-01

This article presents a theory of visual word recognition that assumes that, in the tasks of word identification, lexical decision, and semantic categorization, human readers behave as optimal Bayesian decision makers. This leads to the development of a computational model of word recognition, the Bayesian reader. The Bayesian reader successfully simulates some of the most significant data on human reading. The model accounts for the nature of the function relating word frequency to reaction time and identification threshold, the effects of neighborhood density and its interaction with frequency, and the variation in the pattern of neighborhood density effects seen in different experimental tasks. Both the general behavior of the model and the way the model predicts different patterns of results in different tasks follow entirely from the assumption that human readers approximate optimal Bayesian decision makers. ((c) 2006 APA, all rights reserved).

Using Latent Class Modeling to Detect Bimodality in Spacing Effect Data

ERIC Educational Resources Information Center

Verkoeijen, Peter P. J. L.; Bouwmeester, Samantha

2008-01-01

A recently proposed theory of the spacing effect [Raaijmakers, J. G. W. (2003). Spacing and repetition effects in human memory: application of the SAM model. "Cognitive Science," 27, 431-452.] suggests that the spacing effect is conditional on study-phase retrieval leading to two groups of students showing different magnitudes of the spacing…

Human population reduction is not a quick fix for environmental problems.

PubMed

Bradshaw, Corey J A; Brook, Barry W

2014-11-18

The inexorable demographic momentum of the global human population is rapidly eroding Earth's life-support system. There are consequently more frequent calls to address environmental problems by advocating further reductions in human fertility. To examine how quickly this could lead to a smaller human population, we used scenario-based matrix modeling to project the global population to the year 2100. Assuming a continuation of current trends in mortality reduction, even a rapid transition to a worldwide one-child policy leads to a population similar to today's by 2100. Even a catastrophic mass mortality event of 2 billion deaths over a hypothetical 5-y window in the mid-21(st) century would still yield around 8.5 billion people by 2100. In the absence of catastrophe or large fertility reductions (to fewer than two children per female worldwide), the greatest threats to ecosystems--as measured by regional projections within the 35 global Biodiversity Hotspots--indicate that Africa and South Asia will experience the greatest human pressures on future ecosystems. Humanity's large demographic momentum means that there are no easy policy levers to change the size of the human population substantially over coming decades, short of extreme and rapid reductions in female fertility; it will take centuries, and the long-term target remains unclear. However, some reduction could be achieved by midcentury and lead to hundreds of millions fewer people to feed. More immediate results for sustainability would emerge from policies and technologies that reverse rising consumption of natural resources.

Assessment of mechanical properties of human head tissues for trauma modelling.

PubMed

Lozano-Mínguez, Estívaliz; Palomar, Marta; Infante-García, Diego; Rupérez, María José; Giner, Eugenio

2018-05-01

Many discrepancies are found in the literature regarding the damage and constitutive models for head tissues as well as the values of the constants involved in the constitutive equations. Their proper definition is required for consistent numerical model performance when predicting human head behaviour, and hence skull fracture and brain damage. The objective of this research is to perform a critical review of constitutive models and damage indicators describing human head tissue response under impact loading. A 3D finite element human head model has been generated by using computed tomography images, which has been validated through the comparison to experimental data in the literature. The threshold values of the skull and the scalp that lead to fracture have been analysed. We conclude that (1) compact bone properties are critical in skull fracture, (2) the elastic constants of the cerebrospinal fluid affect the intracranial pressure distribution, and (3) the consideration of brain tissue as a nearly incompressible solid with a high (but not complete) water content offers pressure responses consistent with the experimental data. Copyright © 2018 John Wiley & Sons, Ltd.

Scaling Pharmacodynamics from In Vitro and Preclinical Animal Studies to Humans

PubMed Central

Mager, Donald E.; Woo, Sukyung; Jusko, William J.

2013-01-01

Summary An important feature of mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) models is the identification of drug- and system-specific factors that determine the intensity and time-course of pharmacological effects. This provides an opportunity to integrate information obtained from in vitro bioassays and preclinical pharmacological studies in animals to anticipate the clinical and adverse responses to drugs in humans. The fact that contemporary PK/PD modeling continues to evolve and seeks to emulate systems level properties should provide enhanced capabilities to scale-up pharmacodynamic data. Critical steps in drug discovery and development, such as lead compound and first in human dose selection, may become more efficient with the implementation and further refinement of translational PK/PD modeling. In this review, we highlight fundamental principles in pharmacodynamics and the basic expectations for in vitro bioassays and traditional allometric scaling in PK/PD modeling. Discussion of PK/PD modeling efforts for recombinant human erythropoietin is also included as a case study showing the potential for advanced systems analysis to facilitate extrapolations and improve understanding of inter-species differences in drug responses. PMID:19252333

Tissue and Animal Models of Sudden Cardiac Death

PubMed Central

Sallam, Karim; Li, Yingxin; Sager, Philip T.; Houser, Steven R.; Wu, Joseph C.

2015-01-01

Sudden Cardiac Death (SCD) is a common cause of death in patients with structural heart disease, genetic mutations or acquired disorders affecting cardiac ion channels. A wide range of platforms exist to model and study disorders associated with SCD. Human clinical studies are cumbersome and are thwarted by the extent of investigation that can be performed on human subjects. Animal models are limited by their degree of homology to human cardiac electrophysiology including ion channel expression. Most commonly used cellular models are cellular transfection models, which are able to mimic the expression of a single ion channel offering incomplete insight into changes of the action potential profile. Induced pluripotent stem cell derived Cardiomyocytes (iPSC-CMs) resemble, but are not identical, to adult human cardiomyocytes, and provide a new platform for studying arrhythmic disorders leading to SCD. A variety of platforms exist to phenotype cellular models including conventional and automated patch clamp, multi-electrode array, and computational modeling. iPSC-CMs have been used to study Long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy and other hereditary cardiac disorders. Although iPSC-CMs are distinct from adult cardiomyocytes, they provide a robust platform to advance the science and clinical care of SCD. PMID:26044252

Objective Model Selection for Identifying the Human Feedforward Response in Manual Control.

PubMed

Drop, Frank M; Pool, Daan M; van Paassen, Marinus Rene M; Mulder, Max; Bulthoff, Heinrich H

2018-01-01

Realistic manual control tasks typically involve predictable target signals and random disturbances. The human controller (HC) is hypothesized to use a feedforward control strategy for target-following, in addition to feedback control for disturbance-rejection. Little is known about human feedforward control, partly because common system identification methods have difficulty in identifying whether, and (if so) how, the HC applies a feedforward strategy. In this paper, an identification procedure is presented that aims at an objective model selection for identifying the human feedforward response, using linear time-invariant autoregressive with exogenous input models. A new model selection criterion is proposed to decide on the model order (number of parameters) and the presence of feedforward in addition to feedback. For a range of typical control tasks, it is shown by means of Monte Carlo computer simulations that the classical Bayesian information criterion (BIC) leads to selecting models that contain a feedforward path from data generated by a pure feedback model: "false-positive" feedforward detection. To eliminate these false-positives, the modified BIC includes an additional penalty on model complexity. The appropriate weighting is found through computer simulations with a hypothesized HC model prior to performing a tracking experiment. Experimental human-in-the-loop data will be considered in future work. With appropriate weighting, the method correctly identifies the HC dynamics in a wide range of control tasks, without false-positive results.

A Mechanistic Model of Human Recall of Social Network Structure and Relationship Affect.

PubMed

Omodei, Elisa; Brashears, Matthew E; Arenas, Alex

2017-12-07

The social brain hypothesis argues that the need to deal with social challenges was key to our evolution of high intelligence. Research with non-human primates as well as experimental and fMRI studies in humans produce results consistent with this claim, leading to an estimate that human primary groups should consist of roughly 150 individuals. Gaps between this prediction and empirical observations can be partially accounted for using "compression heuristics", or schemata that simplify the encoding and recall of social information. However, little is known about the specific algorithmic processes used by humans to store and recall social information. We describe a mechanistic model of human network recall and demonstrate its sufficiency for capturing human recall behavior observed in experimental contexts. We find that human recall is predicated on accurate recall of a small number of high degree network nodes and the application of heuristics for both structural and affective information. This provides new insight into human memory, social network evolution, and demonstrates a novel approach to uncovering human cognitive operations.

X‐linked retinoschisis: an update

PubMed Central

Sikkink, Stephen K; Biswas, Susmito; Parry, Neil R A; Stanga, Paulo E; Trump, Dorothy

2007-01-01

X‐linked retinoschisis is the leading cause of macular degeneration in males and leads to splitting within the inner retinal layers leading to visual deterioration. Many missense and protein truncating mutations have now been identified in the causative retinoschisis gene (RS1) which encodes a 224 amino acid secreting retinal protein, retinoschisin. Retinoschisin octamerises is implicated in cell–cell interactions and cell adhesion perhaps by interacting with β2 laminin. Mutations cause loss of retinoschisin function by one of the three mechanisms: by interfering with protein secretion, by preventing its octamerisation or by reducing function in the secreted octamerised protein. The development of retinoschisis mouse models have provided a model system that closely resembles the human disease. Recent reports of RS1 gene transfer to these models and the sustained restoration of some retinal function and morphology suggest gene replacement may be a possible future therapy for patients. PMID:17172462

The Evolution of the Human Genome

PubMed Central

Simonti, Corinne N.; Capra, John A.

2015-01-01

Human genomes hold a record of the evolutionary forces that have shaped our species. Advances in DNA sequencing, functional genomics, and population genetic modeling have deepened our understanding of human demographic history, natural selection, and many other long-studied topics. These advances have also revealed many previously underappreciated factors that influence the evolution of the human genome, including functional modifications to DNA and histones, conserved 3D topological chromatin domains, structural variation, and heterogeneous mutation patterns along the genome. Using evolutionary theory as a lens to study these phenomena will lead to significant breakthroughs in understanding what makes us human and why we get sick. PMID:26338498

A communication channel model of the software process

NASA Technical Reports Server (NTRS)

Tausworthe, R. C.

1988-01-01

Reported here is beginning research into a noisy communication channel analogy of software development process productivity, in order to establish quantifiable behavior and theoretical bounds. The analogy leads to a fundamental mathematical relationship between human productivity and the amount of information supplied by the developers, the capacity of the human channel for processing and transmitting information, the software product yield (object size), the work effort, requirements efficiency, tool and process efficiency, and programming environment advantage. Also derived is an upper bound to productivity that shows that software reuse is the only means than can lead to unbounded productivity growth; practical considerations of size and cost of reusable components may reduce this to a finite bound.

A communication channel model of the software process

NASA Technical Reports Server (NTRS)

Tausworthe, Robert C.

1988-01-01

Beginning research into a noisy communication channel analogy of software development process productivity, in order to establish quantifiable behavior and theoretical bounds is discussed. The analogy leads to a fundamental mathematical relationship between human productivity and the amount of information supplied by the developers, the capacity of the human channel for processing and transmitting information, the software product yield (object size) the work effort, requirements efficiency, tool and process efficiency, and programming environment advantage. An upper bound to productivity is derived that shows that software reuse is the only means that can lead to unbounded productivity growth; practical considerations of size and cost of reusable components may reduce this to a finite bound.

Socio-Hydrology: Conceptual and Methodological Challenges in the Bidirectional Coupling of Human and Water Systems

NASA Astrophysics Data System (ADS)

Scott, C. A.

2014-12-01

This presentation reviews conceptual advances in the emerging field of socio-hydrology that focuses on coupled human and water systems. An important current challenge is how to better couple the bidirectional influences between human and water systems, which lead to emergent dynamics. The interactions among (1) the structure and dynamics of systems with (2) human values and norms lead to (3) outcomes, which in turn influence subsequent interactions. Human influences on hydrological systems are relatively well understood, chiefly resulting from developments in the field of water resources. The ecosystem-service concept of cultural value has expanded understanding of decision-making beyond economic rationality criteria. Hydrological impacts on social processes are less well developed conceptually, but this is changing with growing attention to vulnerability, adaptation, and resilience, particularly in the face of climate change. Methodological limitations, especially in characterizing the range of human responses to hydrological events and drivers, still pose challenges to modeling bidirectional human-water influences. Evidence from multiple case studies, synthesized in more broadly generic syndromes, helps surmount these methodological limitations and offers the potential to improve characterization and quantification of socio-hydrological systems.

Cognitive Model of Trust Dynamics Predicts Human Behavior within and between Two Games of Strategic Interaction with Computerized Confederate Agents

PubMed Central

Collins, Michael G.; Juvina, Ion; Gluck, Kevin A.

2016-01-01

When playing games of strategic interaction, such as iterated Prisoner's Dilemma and iterated Chicken Game, people exhibit specific within-game learning (e.g., learning a game's optimal outcome) as well as transfer of learning between games (e.g., a game's optimal outcome occurring at a higher proportion when played after another game). The reciprocal trust players develop during the first game is thought to mediate transfer of learning effects. Recently, a computational cognitive model using a novel trust mechanism has been shown to account for human behavior in both games, including the transfer between games. We present the results of a study in which we evaluate the model's a priori predictions of human learning and transfer in 16 different conditions. The model's predictive validity is compared against five model variants that lacked a trust mechanism. The results suggest that a trust mechanism is necessary to explain human behavior across multiple conditions, even when a human plays against a non-human agent. The addition of a trust mechanism to the other learning mechanisms within the cognitive architecture, such as sequence learning, instance-based learning, and utility learning, leads to better prediction of the empirical data. It is argued that computational cognitive modeling is a useful tool for studying trust development, calibration, and repair. PMID:26903892

A human neurodevelopmental model for Williams syndrome.

PubMed

Chailangkarn, Thanathom; Trujillo, Cleber A; Freitas, Beatriz C; Hrvoj-Mihic, Branka; Herai, Roberto H; Yu, Diana X; Brown, Timothy T; Marchetto, Maria C; Bardy, Cedric; McHenry, Lauren; Stefanacci, Lisa; Järvinen, Anna; Searcy, Yvonne M; DeWitt, Michelle; Wong, Wenny; Lai, Philip; Ard, M Colin; Hanson, Kari L; Romero, Sarah; Jacobs, Bob; Dale, Anders M; Dai, Li; Korenberg, Julie R; Gage, Fred H; Bellugi, Ursula; Halgren, Eric; Semendeferi, Katerina; Muotri, Alysson R

2016-08-18

Williams syndrome is a genetic neurodevelopmental disorder characterized by an uncommon hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. Nearly all clinically diagnosed individuals with Williams syndrome lack precisely the same set of genes, with breakpoints in chromosome band 7q11.23 (refs 1-5). The contribution of specific genes to the neuroanatomical and functional alterations, leading to behavioural pathologies in humans, remains largely unexplored. Here we investigate neural progenitor cells and cortical neurons derived from Williams syndrome and typically developing induced pluripotent stem cells. Neural progenitor cells in Williams syndrome have an increased doubling time and apoptosis compared with typically developing neural progenitor cells. Using an individual with atypical Williams syndrome, we narrowed this cellular phenotype to a single gene candidate, frizzled 9 (FZD9). At the neuronal stage, layer V/VI cortical neurons derived from Williams syndrome were characterized by longer total dendrites, increased numbers of spines and synapses, aberrant calcium oscillation and altered network connectivity. Morphometric alterations observed in neurons from Williams syndrome were validated after Golgi staining of post-mortem layer V/VI cortical neurons. This model of human induced pluripotent stem cells fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain.

A human neurodevelopmental model for Williams syndrome

PubMed Central

Chailangkarn, Thanathom; Trujillo, Cleber A.; Freitas, Beatriz C.; Hrvoj-Mihic, Branka; Herai, Roberto H.; Yu, Diana X.; Brown, Timothy T.; Marchetto, Maria C. N.; Bardy, Cedric; McHenry, Lauren; Stefanacci, Lisa; Järvinen, Anna; Searcy, Yvonne M.; DeWitt, Michelle; Wong, Wenny; Lai, Philip; Ard, M. Colin; Hanson, Kari L.; Romero, Sarah; Jacobs, Bob; Dale, Anders M.; Dai, Li; Korenberg, Julie R.; Gage, Fred H.; Bellugi, Ursula; Halgren, Eric; Semendeferi, Katerina; Muotri, Alysson R.

2016-01-01

Summary Williams syndrome (WS) is a genetic neurodevelopmental disorder characterized by an uncommon hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. Nearly all clinically diagnosed individuals with WS lack precisely the same set of genes, with breakpoints in chromosome band 7q11.231–5. The contribution of specific genes to the neuroanatomical and functional alterations, leading to behavioral pathologies in humans, remains largely unexplored. Here, we investigate neural progenitor cells (NPCs) and cortical neurons derived from WS and typically developing (TD) induced pluripotent stem cells (iPSCs). WS NPCs have an increased doubling time and apoptosis compared to TD NPCs. Using an atypical WS subject6, 7, we narrowed this cellular phenotype to a single gene candidate, FZD9. At the neuronal stage, WS-derived layers V/VI cortical neurons were characterized by longer total dendrites, increased numbers of spines and synapses, aberrant calcium oscillation and altered network connectivity. Morphometric alterations observed in WS neurons were validated after Golgi staining of postmortem layers V/VI cortical neurons. This human iPSC model8 fills in the current knowledge gap in WS cellular biology and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain. PMID:27509850

Engineered cell and tissue models of pulmonary fibrosis.

PubMed

Sundarakrishnan, Aswin; Chen, Ying; Black, Lauren D; Aldridge, Bree B; Kaplan, David L

2018-04-01

Pulmonary fibrosis includes several lung disorders characterized by scar formation and Idiopathic Pulmonary Fibrosis (IPF) is a particularly severe form of pulmonary fibrosis of unknown etiology with a mean life expectancy of 3years' post-diagnosis. Treatments for IPF are limited to two FDA approved drugs, pirfenidone and nintedanib. Most lead candidate drugs that are identified in pre-clinical animal studies fail in human clinical trials. Thus, there is a need for advanced humanized in vitro models of the lung to improve candidate treatments prior to moving to human clinical trials. The development of 3D tissue models has created systems capable of emulating human lung structure, function, and cell and matrix interactions. The specific models accomplish these features and preliminary studies conducted using some of these systems have shown potential for in vitro anti-fibrotic drug testing. Further characterization and improvements will enable these tissue models to extend their utility for in vitro drug testing, to help identify signaling pathways and mechanisms for new drug targets, and potentially reduce animal models as standard pre-clinical models of study. In the current review, we contrast different in vitro models based on increasing dimensionality (2D, 2.5D and 3D), with added focus on contemporary 3D pulmonary models of fibrosis. Copyright © 2017. Published by Elsevier B.V.

Evasion of cell senescence in SHH medulloblastoma.

PubMed

Tamayo-Orrego, Lukas; Swikert, Shannon M; Charron, Frédéric

2016-08-17

The mechanisms leading to brain tumor formation are poorly understood. Using Ptch1 +/- mice as a medulloblastoma model, sequential mutations were found to shape tumor evolution. Initially, medulloblastoma preneoplastic lesions display loss of heterozygosity of the Ptch1 wild-type allele, an event associated with cell senescence in preneoplasia. Subsequently, p53 mutations lead to senescence evasion and progression from preneoplasia to medulloblastoma. These findings are consistent with a model where high levels of Hedgehog signaling caused by the loss of the tumor suppressor Ptch1 lead to oncogene-induced senescence and drive p53 mutations. Thus, cell senescence is an important characteristic of a subset of SHH medulloblastoma and might explain the acquisition of somatic TP53 mutations in human medulloblastoma. This mode of medulloblastoma formation contrasts with the one characterizing Li-Fraumeni patients with medulloblastoma, where TP53 germ-line mutations cause chromothriptic genomic instability and lead to mutations in Hedgehog signaling genes, which drive medulloblastoma growth. Here we discuss in detail these 2 alternative mechanisms leading to medulloblastoma tumorigenesis.

Evasion of cell senescence in SHH medulloblastoma

PubMed Central

Tamayo-Orrego, Lukas; Swikert, Shannon M.; Charron, Frédéric

2016-01-01

ABSTRACT The mechanisms leading to brain tumor formation are poorly understood. Using Ptch1+/− mice as a medulloblastoma model, sequential mutations were found to shape tumor evolution. Initially, medulloblastoma preneoplastic lesions display loss of heterozygosity of the Ptch1 wild-type allele, an event associated with cell senescence in preneoplasia. Subsequently, p53 mutations lead to senescence evasion and progression from preneoplasia to medulloblastoma. These findings are consistent with a model where high levels of Hedgehog signaling caused by the loss of the tumor suppressor Ptch1 lead to oncogene-induced senescence and drive p53 mutations. Thus, cell senescence is an important characteristic of a subset of SHH medulloblastoma and might explain the acquisition of somatic TP53 mutations in human medulloblastoma. This mode of medulloblastoma formation contrasts with the one characterizing Li-Fraumeni patients with medulloblastoma, where TP53 germ-line mutations cause chromothriptic genomic instability and lead to mutations in Hedgehog signaling genes, which drive medulloblastoma growth. Here we discuss in detail these 2 alternative mechanisms leading to medulloblastoma tumorigenesis. PMID:27229128

Systemic Mesenchymal Stromal Cell Transplantation Prevents Functional Bone Loss in a Mouse Model of Age-Related Osteoporosis.

PubMed

Kiernan, Jeffrey; Hu, Sally; Grynpas, Marc D; Davies, John E; Stanford, William L

2016-05-01

Age-related osteoporosis is driven by defects in the tissue-resident mesenchymal stromal cells (MSCs), a heterogeneous population of musculoskeletal progenitors that includes skeletal stem cells. MSC decline leads to reduced bone formation, causing loss of bone volume and the breakdown of bony microarchitecture crucial to trabecular strength. Furthermore, the low-turnover state precipitated by MSC loss leads to low-quality bone that is unable to perform remodeling-mediated maintenance--replacing old damaged bone with new healthy tissue. Using minimally expanded exogenous MSCs injected systemically into a mouse model of human age-related osteoporosis, we show long-term engraftment and markedly increased bone formation. This led to improved bone quality and turnover and, importantly, sustained microarchitectural competence. These data establish proof of concept that MSC transplantation may be used to prevent or treat human age-related osteoporosis. This study shows that a single dose of minimally expanded mesenchymal stromal cells (MSCs) injected systemically into a mouse model of human age-related osteoporosis display long-term engraftment and prevent the decline in bone formation, bone quality, and microarchitectural competence. This work adds to a growing body of evidence suggesting that the decline of MSCs associated with age-related osteoporosis is a major transformative event in the progression of the disease. Furthermore, it establishes proof of concept that MSC transplantation may be a viable therapeutic strategy to treat or prevent human age-related osteoporosis. ©AlphaMed Press.

Systemic Mesenchymal Stromal Cell Transplantation Prevents Functional Bone Loss in a Mouse Model of Age-Related Osteoporosis

PubMed Central

Kiernan, Jeffrey; Hu, Sally; Grynpas, Marc D.

2016-01-01

Age-related osteoporosis is driven by defects in the tissue-resident mesenchymal stromal cells (MSCs), a heterogeneous population of musculoskeletal progenitors that includes skeletal stem cells. MSC decline leads to reduced bone formation, causing loss of bone volume and the breakdown of bony microarchitecture crucial to trabecular strength. Furthermore, the low-turnover state precipitated by MSC loss leads to low-quality bone that is unable to perform remodeling-mediated maintenance—replacing old damaged bone with new healthy tissue. Using minimally expanded exogenous MSCs injected systemically into a mouse model of human age-related osteoporosis, we show long-term engraftment and markedly increased bone formation. This led to improved bone quality and turnover and, importantly, sustained microarchitectural competence. These data establish proof of concept that MSC transplantation may be used to prevent or treat human age-related osteoporosis. Significance This study shows that a single dose of minimally expanded mesenchymal stromal cells (MSCs) injected systemically into a mouse model of human age-related osteoporosis display long-term engraftment and prevent the decline in bone formation, bone quality, and microarchitectural competence. This work adds to a growing body of evidence suggesting that the decline of MSCs associated with age-related osteoporosis is a major transformative event in the progression of the disease. Furthermore, it establishes proof of concept that MSC transplantation may be a viable therapeutic strategy to treat or prevent human age-related osteoporosis. PMID:26987353

The use of analytical models in human-computer interface design

NASA Technical Reports Server (NTRS)

Gugerty, Leo

1993-01-01

Recently, a large number of human-computer interface (HCI) researchers have investigated building analytical models of the user, which are often implemented as computer models. These models simulate the cognitive processes and task knowledge of the user in ways that allow a researcher or designer to estimate various aspects of an interface's usability, such as when user errors are likely to occur. This information can lead to design improvements. Analytical models can supplement design guidelines by providing designers rigorous ways of analyzing the information-processing requirements of specific tasks (i.e., task analysis). These models offer the potential of improving early designs and replacing some of the early phases of usability testing, thus reducing the cost of interface design. This paper describes some of the many analytical models that are currently being developed and evaluates the usefulness of analytical models for human-computer interface design. This paper will focus on computational, analytical models, such as the GOMS model, rather than less formal, verbal models, because the more exact predictions and task descriptions of computational models may be useful to designers. The paper also discusses some of the practical requirements for using analytical models in complex design organizations such as NASA.

Swatting flies: modelling wound healing and inflammation in Drosophila

PubMed Central

Razzell, William; Wood, Will; Martin, Paul

2011-01-01

Aberrant wound healing can lead to a variety of human pathologies, from non-healing chronic wounds that can become dangerously infected, to exuberant fibrotic healing in which repair is accompanied by excessive inflammation. To guide therapeutic intervention, we need a better understanding of the fundamental mechanisms driving tissue repair; this will require complementary wound-healing studies in several model organisms. Drosophila has been used to model genetic aspects of numerous human pathologies, and is being used increasingly to gain insight into the molecular and genetic aspects of tissue repair and inflammation, which have classically been modelled in mice or cultured cells. This review discusses the advantages and disadvantages of Drosophila as a wound-healing model, as well as some exciting new research opportunities that will be enabled by its use. PMID:21810906

Early-life stress origins of gastrointestinal disease: animal models, intestinal pathophysiology, and translational implications

PubMed Central

Pohl, Calvin S.; Medland, Julia E.

2015-01-01

Early-life stress and adversity are major risk factors in the onset and severity of gastrointestinal (GI) disease in humans later in life. The mechanisms by which early-life stress leads to increased GI disease susceptibility in adult life remain poorly understood. Animal models of early-life stress have provided a foundation from which to gain a more fundamental understanding of this important GI disease paradigm. This review focuses on animal models of early-life stress-induced GI disease, with a specific emphasis on translational aspects of each model to specific human GI disease states. Early postnatal development of major GI systems and the consequences of stress on their development are discussed in detail. Relevant translational differences between species and models are highlighted. PMID:26451004

The importance of shared mental models and shared situation awareness for transforming robots from tools to teammates

NASA Astrophysics Data System (ADS)

Ososky, Scott; Schuster, David; Jentsch, Florian; Fiore, Stephen; Shumaker, Randall; Lebiere, Christian; Kurup, Unmesh; Oh, Jean; Stentz, Anthony

2012-06-01

Current ground robots are largely employed via tele-operation and provide their operators with useful tools to extend reach, improve sensing, and avoid dangers. To move from robots that are useful as tools to truly synergistic human-robot teaming, however, will require not only greater technical capabilities among robots, but also a better understanding of the ways in which the principles of teamwork can be applied from exclusively human teams to mixed teams of humans and robots. In this respect, a core characteristic that enables successful human teams to coordinate shared tasks is their ability to create, maintain, and act on a shared understanding of the world and the roles of the team and its members in it. The team performance literature clearly points towards two important cornerstones for shared understanding of team members: mental models and situation awareness. These constructs have been investigated as products of teams as well; amongst teams, they are shared mental models and shared situation awareness. Consequently, we are studying how these two constructs can be measured and instantiated in human-robot teams. In this paper, we report results from three related efforts that are investigating process and performance outcomes for human robot teams. Our investigations include: (a) how human mental models of tasks and teams change whether a teammate is human, a service animal, or an advanced automated system; (b) how computer modeling can lead to mental models being instantiated and used in robots; (c) how we can simulate the interactions between human and future robotic teammates on the basis of changes in shared mental models and situation assessment.

Integrating Household Risk Mitigation Behavior in Flood Risk Analysis: An Agent-Based Model Approach.

PubMed

Haer, Toon; Botzen, W J Wouter; de Moel, Hans; Aerts, Jeroen C J H

2017-10-01

Recent studies showed that climate change and socioeconomic trends are expected to increase flood risks in many regions. However, in these studies, human behavior is commonly assumed to be constant, which neglects interaction and feedback loops between human and environmental systems. This neglect of human adaptation leads to a misrepresentation of flood risk. This article presents an agent-based model that incorporates human decision making in flood risk analysis. In particular, household investments in loss-reducing measures are examined under three economic decision models: (1) expected utility theory, which is the traditional economic model of rational agents; (2) prospect theory, which takes account of bounded rationality; and (3) a prospect theory model, which accounts for changing risk perceptions and social interactions through a process of Bayesian updating. We show that neglecting human behavior in flood risk assessment studies can result in a considerable misestimation of future flood risk, which is in our case study an overestimation of a factor two. Furthermore, we show how behavior models can support flood risk analysis under different behavioral assumptions, illustrating the need to include the dynamic adaptive human behavior of, for instance, households, insurers, and governments. The method presented here provides a solid basis for exploring human behavior and the resulting flood risk with respect to low-probability/high-impact risks. © 2016 The Authors Risk Analysis published by Wiley Periodicals, Inc. on behalf of Society for Risk Analysis.

West Nile Virus Infection in the Central Nervous System

PubMed Central

Winkelmann, Evandro R.; Luo, Huanle; Wang, Tian

2016-01-01

West Nile virus (WNV), a neurotropic single-stranded flavivirus has been the leading cause of arboviral encephalitis worldwide.  Up to 50% of WNV convalescent patients in the United States were reported to have long-term neurological sequelae.  Neither antiviral drugs nor vaccines are available for humans.  Animal models have been used to investigate WNV pathogenesis and host immune response in humans.  In this review, we will discuss recent findings from studies in animal models of WNV infection, and provide new insights on WNV pathogenesis and WNV-induced host immunity in the central nervous system. PMID:26918172

Modeling study of radiation effects on thrombocytopoietic and granulocytopoietic systems in human

NASA Astrophysics Data System (ADS)

Smirnova, Olga

Biophysical models describing the dynamics of thrombocytopoiesis and granulocytopoiesis in nonirradiated and irradiated human are developed. These models, being based on conventional biological theories, are implemented as the systems of nonlinear differential equations whose variables and constant parameters have clear biological meaning. Thorough analytical and nu-merical analysis of the proposed models is performed. It is revealed that the models in hand are capable of describing the dynamical regimes which are typical for these hematological lines in the norm and in the case of hematological disorders, such as cyclic thrombocytopenia and cyclic neutropenia. The models reproduce, on quantitative level, the dynamics of thrombocytopoiesis and granulocytopoiesis in acutely irradiated human. Modeling assessment for the critical dose rate of chronic irradiation, which leads to the complete extinction of the most radiosensitive hematological line (thrombocytopoiesis), agrees with the real dose rates of lethal irradiation for human. The models are applied for simulating the dynamics of thrombocytopoietic and granulocytopoietic systems in astronauts exposed to space radiation during long-term missions such as voyages to Mars. The dose rate equivalents for the Galactic Cosmic Rays (GCR) and for Solar Particles Event (SPE) are taken as the variable parameters of the models. It is found that effects of GCR on the hematological lines under consideration are negligible. It is also revealed that SPE causes damped oscillations of "effective" radiosensitivity of the thrombocy-topoiesis and granulocytopoiesis that, in turn, defines the strength of response of these systems to the subsequent SPE. Specifically, the preceding SPE can induce either radiosensitization or radioprotection effects on these hematological lines, depending on the time interval between SPEs. All this testifies to the efficiency of employment of the developed models in investigation and prediction of effects of space radiation on the thrombocytopoiesis and granulocytopoiesis, whose damages can lead to development of hemorrhages and infections, respectively. The devel-oped biophysical models of these vital body systems provide a better understanding of the risks to health from the Solar Particles Events and enable one to evaluate the need of operational applications of countermeasures for astronauts in the long-term space missions.

Ground-based research with heavy ions for space radiation protection

NASA Astrophysics Data System (ADS)

Durante, M.; Kronenberg, A.

Human exposure to ionizing radiation is one of the acknowledged potential showstoppers for long duration manned interplanetary missions. Human exploratory missions cannot be safely performed without a substantial reduction of the uncertainties associated with different space radiation health risks, and the development of effective countermeasures. Most of our knowledge of the biological effects of heavy charged particles comes from accelerator-based experiments. During the 35th COSPAR meeting, recent ground-based experiments with high-energy iron ions were discussed, and these results are briefly summarised in this paper. High-quality accelerator-based research with heavy ions will continue to be the main source of knowledge of space radiation health effects and will lead to reductions of the uncertainties in predictions of human health risks. Efforts in materials science, nutrition and pharmaceutical sciences and their rigorous evaluation with biological model systems in ground-based accelerator experiments will lead to the development of safe and effective countermeasures to permit human exploration of the Solar System.

Quantitative Modeling of Human-Environment Interactions in Preindustrial Time

NASA Astrophysics Data System (ADS)

Sommer, Philipp S.; Kaplan, Jed O.

2017-04-01

Quantifying human-environment interactions and anthropogenic influences on the environment prior to the Industrial revolution is essential for understanding the current state of the earth system. This is particularly true for the terrestrial biosphere, but marine ecosystems and even climate were likely modified by human activities centuries to millennia ago. Direct observations are however very sparse in space and time, especially as one considers prehistory. Numerical models are therefore essential to produce a continuous picture of human-environment interactions in the past. Agent-based approaches, while widely applied to quantifying human influence on the environment in localized studies, are unsuitable for global spatial domains and Holocene timescales because of computational demands and large parameter uncertainty. Here we outline a new paradigm for the quantitative modeling of human-environment interactions in preindustrial time that is adapted to the global Holocene. Rather than attempting to simulate agency directly, the model is informed by a suite of characteristics describing those things about society that cannot be predicted on the basis of environment, e.g., diet, presence of agriculture, or range of animals exploited. These categorical data are combined with the properties of the physical environment in coupled human-environment model. The model is, at its core, a dynamic global vegetation model with a module for simulating crop growth that is adapted for preindustrial agriculture. This allows us to simulate yield and calories for feeding both humans and their domesticated animals. We couple this basic caloric availability with a simple demographic model to calculate potential population, and, constrained by labor requirements and land limitations, we create scenarios of land use and land cover on a moderate-resolution grid. We further implement a feedback loop where anthropogenic activities lead to changes in the properties of the physical environment, e.g., through soil erosion.

Do we have to choose between feeding the human population and conserving nature? Modelling the global dependence of people on ecosystem services.

PubMed

Cazalis, Victor; Loreau, Michel; Henderson, Kirsten

2018-09-01

The ability of the human population to continue growing depends strongly on the ecosystem services provided by nature. Nature, however, is becoming more and more degraded as the number of individuals increases, which could potentially threaten the future well-being of the human population. We use a dynamic model to conceptualise links between the global proportion of natural habitats and human demography, through four categories of ecosystem services (provisioning, regulating, cultural recreational and informational) to investigate the common future of nature and humanity in terms of size and well-being. Our model shows that there is generally a trade-off between the quality of life and human population size and identifies four short-term scenarios, corresponding to three long-term steady states of the model. First, human population could experience declines if nature becomes too degraded and regulating services diminish; second the majority of the population could be in a famine state, where the population continues to grow with minimal food provision. Between these scenarios, a desirable future scenario emerges from the model. It occurs if humans convert enough land to feed all the population, while maintaining biodiversity and ecosystem services. Finally, we find a fourth scenario, which combines famine and a decline in the population because of an overexploitation of land leading to a decrease in food production. Human demography is embedded in natural dynamics; the two factors should be considered together if we are to identify a desirable future for both nature and humans. Copyright © 2018 Elsevier B.V. All rights reserved.

Stem cell-derived organoids to model gastrointestinal facets of cystic fibrosis

PubMed Central

Hohwieler, Meike; Perkhofer, Lukas; Liebau, Stefan; Seufferlein, Thomas; Müller, Martin

2016-01-01

Cystic fibrosis (CF) is one of the most frequently occurring inherited human diseases caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) which lead to ample defects in anion transport and epithelial fluid secretion. Existing models lack both access to early stages of CF development and a coeval focus on the gastrointestinal CF phenotypes, which become increasingly important due increased life span of the affected individuals. Here, we provide a comprehensive overview of gastrointestinal facets of CF and the opportunity to model these in various systems in an attempt to understand and treat CF. A particular focus is given on forward-leading organoid cultures, which may circumvent current limitations of existing models and thereby provide a platform for drug testing and understanding of disease pathophysiology in gastrointestinal organs. PMID:28815024

Effects of habitat characteristics on the growth of carrier population leading to increased spread of typhoid fever: a model.

PubMed

Shukla, J B; Goyal, Ashish; Singh, Shikha; Chandra, Peeyush

2014-06-01

In this paper, a non-linear model is proposed and analyzed to study the effects of habitat characteristics favoring logistically growing carrier population leading to increased spread of typhoid fever. It is assumed that the cumulative density of habitat characteristics and the density of carrier population are governed by logistic models; the growth rate of the former increases as the density of human population increases. The model is analyzed by stability theory of differential equations and computer simulation. The analysis shows that as the density of the infective carrier population increases due to habitat characteristics, the spread of typhoid fever increases in comparison with the case without such factors. Copyright © 2013 Ministry of Health, Saudi Arabia. Published by Elsevier Ltd. All rights reserved.

The planum temporale as a computational hub.

PubMed

Griffiths, Timothy D; Warren, Jason D

2002-07-01

It is increasingly recognized that the human planum temporale is not a dedicated language processor, but is in fact engaged in the analysis of many types of complex sound. We propose a model of the human planum temporale as a computational engine for the segregation and matching of spectrotemporal patterns. The model is based on segregating the components of the acoustic world and matching these components with learned spectrotemporal representations. Spectrotemporal information derived from such a 'computational hub' would be gated to higher-order cortical areas for further processing, leading to object recognition and the perception of auditory space. We review the evidence for the model and specific predictions that follow from it.

Carrying capacity for species richness as context for conservation: a case study of North American birds

Treesearch

Andrew J. Hansen; Linda Bowers Phillips; Curtis H. Flather; Jim Robinson-Cox

2011-01-01

We evaluated the leading hypotheses on biophysical factors affecting species richness for Breeding Bird Survey routes from areas with little influence of human activities.We then derived a best model based on information theory, and used this model to extrapolate SK across North America based on the biophysical predictor variables. The predictor variables included the...

Using a Model of Analysts' Judgments to Augment an Item Calibration Process

ERIC Educational Resources Information Center

Hauser, Carl; Thum, Yeow Meng; He, Wei; Ma, Lingling

2015-01-01

When conducting item reviews, analysts evaluate an array of statistical and graphical information to assess the fit of a field test (FT) item to an item response theory model. The process can be tedious, particularly when the number of human reviews (HR) to be completed is large. Furthermore, such a process leads to decisions that are susceptible…

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

Probabilistic Modeling and Visualization of the Flexibility in Morphable Models

NASA Astrophysics Data System (ADS)

Lüthi, M.; Albrecht, T.; Vetter, T.

Statistical shape models, and in particular morphable models, have gained widespread use in computer vision, computer graphics and medical imaging. Researchers have started to build models of almost any anatomical structure in the human body. While these models provide a useful prior for many image analysis task, relatively little information about the shape represented by the morphable model is exploited. We propose a method for computing and visualizing the remaining flexibility, when a part of the shape is fixed. Our method, which is based on Probabilistic PCA, not only leads to an approach for reconstructing the full shape from partial information, but also allows us to investigate and visualize the uncertainty of a reconstruction. To show the feasibility of our approach we performed experiments on a statistical model of the human face and the femur bone. The visualization of the remaining flexibility allows for greater insight into the statistical properties of the shape.

The vicious cycle of vitamin a deficiency: A review.

PubMed

Wiseman, Elina Manusevich; Bar-El Dadon, Shimrit; Reifen, Ram

2017-11-22

Vitamin A deficiency (VAD) is a serious and widespread public health problem and the leading cause of preventable blindness in young children. It is also associated with increased rates of death from severe infections, especially in developing countries. Over the past 35 years, researchers have examined the numerous activities of vitamin A in different tissues of the human body. VAD can lead to a series of ocular symptoms, anemia, and weak resistance to infection, which can increase the severity of infectious diseases and the risk of death. Cell development, vision, growth, and normal metabolism are among the vital processes that are insufficiently supported in the presence of VAD. VAD leads to impaired tissue function especially during the developmental periods of infancy, childhood, pregnancy, and lactation. We describe a multidirectional model of VAD that demonstrates how VAD can have progressive, negative effects on vital processes of the human body throughout the life cycle. This model starts with impaired intake and its link to decreased absorption and digestion and includes outcomes such as malnutrition, inflammation, and improper growth processes, including possible mechanisms. Together, these clinical and biochemical manifestations contribute to the vicious cycle of VAD.

Relative influences of climate change and human activity on the onshore distribution of polar bears

USGS Publications Warehouse

Wilson, Ryan R.; Regehr, Eric V.; St. Martin, Michelle; Atwood, Todd C.; Peacock, Elizabeth; Miller, Susanne; Divoky, George J.

2017-01-01

Climate change is altering habitat for many species, leading to shifts in distributions that can increase levels of human-wildlife conflict. To develop effective strategies for minimizing human-wildlife conflict, we must understand the relative influences that climate change and other factors have on wildlife distributions. Polar bears (Ursus maritimus) are increasingly using land during summer and autumn due to sea ice loss, leading to higher incidents of conflict and concerns for human safety. We sought to understand the relative influence of sea ice conditions, onshore habitat characteristics, and human-provisioned food attractants on the distribution and abundance of polar bears while on shore. We also wanted to determine how mitigation measures might reduce human-polar bear conflict associated with an anthropogenic food source. We built a Bayesian hierarchical model based on 14 years of aerial survey data to estimate the weekly number and distribution of polar bears on the coast of northern Alaska in autumn. We then used the model to predict how effective two management options for handling subsistence-harvested whale remains in the community of Kaktovik, Alaska might be. The distribution of bears on shore was most strongly influenced by the presence of whale carcasses and to a lesser extent sea ice and onshore habitat conditions. The numbers of bears on shore were related to sea ice conditions. The two management strategies for handling the whale carcasses reduced the estimated number of bears near Kaktovik by > 75%. By considering multiple factors associated with the onshore distribution and abundance of polar bears we discerned what role human activities played in where bears occur and how successful efforts to manage the whale carcasses might be for reducing human-polar bear conflict.

Lead suppresses chimeric human transferrin gene expression in transgenic mouse liver.

PubMed

Adrian, G S; Rivera, E V; Adrian, E K; Lu, Y; Buchanan, J; Herbert, D C; Weaker, F J; Walter, C A; Bowman, B H

1993-01-01

The major iron-transport protein in serum is transferrin (TF) which also has the capacity to transport other metals. This report presents evidence that synthesis of human TF can be regulated by the metal lead. Transgenic mice carrying chimeric human TF-chloramphenicol acetyl transferase (CAT) genes received lead or sodium salts by intraperitoneal injections or in drinking water. Transgene expression in liver was suppressed 31 to 50% by the lead treatment. Lead regulates human TF transgenes at the mRNA level since liver CAT enzyme activity, CAT protein, and TF-CAT mRNA levels were all suppressed. The dosages of lead did not alter synthesis of the other liver proteins, mouse TF and albumin, as measured by Northern blot analysis of total liver RNA and rocket immunoelectrophoresis of mouse sera. Moderate levels of lead exposure were sufficient to evoke the human TF transgene response; blood lead levels in mice that received lead acetate in drinking water ranged from 30 micrograms/dl to 56 micrograms/dl. In addition to suppressing expression of TF-CAT genes in transgenic mice, lead also suppressed synthesis of TF protein in cultured human hepatoma HepG2 cells. The regulation of human TF apparently differs from the regulation of mouse TF which is unresponsive to lead exposure.

Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia

PubMed Central

Kharas, Michael G; Lengner, Christopher J; Al-Shahrour, Fatima; Bullinger, Lars; Ball, Brian; Zaidi, Samir; Morgan, Kelly; Tam, Winnie; Paktinat, Mahnaz; Okabe, Rachel; Gozo, Maricel; Einhorn, William; Lane, Steven W; Scholl, Claudia; Fröhling, Stefan; Fleming, Mark; Ebert, Benjamin L; Gilliland, D Gary; Jaenisch, Rudolf; Daley, George Q

2011-01-01

RNA-binding proteins of the Musashi (Msi) family are expressed in stem cell compartments and in aggressive tumors, but they have not yet been widely explored in the blood. Here we demonstrate that Msi2 is the predominant form expressed in hematopoietic stem cells (HSCs), and its knockdown leads to reduced engraftment and depletion of HSCs in vivo. Overexpression of human MSI2 in a mouse model increases HSC cell cycle progression and cooperates with the chronic myeloid leukemia–associated BCR-ABL1 oncoprotein to induce an aggressive leukemia. MSI2 is overexpressed in human myeloid leukemia cell lines, and its depletion leads to decreased proliferation and increased apoptosis. Expression levels in human myeloid leukemia directly correlate with decreased survival in patients with the disease, thereby defining MSI2 expression as a new prognostic marker and as a new target for therapy in acute myeloid leukemia (AML). PMID:20616797

Describing the Neuron Axons Network of the Human Brain by Continuous Flow Models

NASA Astrophysics Data System (ADS)

Hizanidis, J.; Katsaloulis, P.; Verganelakis, D. A.; Provata, A.

2014-12-01

The multifractal spectrum Dq (Rényi dimensions) is used for the analysis and comparison between the Neuron Axons Network (NAN) of healthy and pathological human brains because it conveys information about the statistics in many scales, from the very rare to the most frequent network configurations. Comparison of the Fractional Anisotropy Magnetic Resonance Images between healthy and pathological brains is performed with and without noise reduction. Modelling the complex structure of the NAN in the human brain is undertaken using the dynamics of the Lorenz model in the chaotic regime. The Lorenz multifractal spectra capture well the human brain characteristics in the large negative q's which represent the rare network configurations. In order to achieve a closer approximation in the positive part of the spectrum (q > 0) two independent modifications are considered: a) redistribution of the dense parts of the Lorenz model's phase space into their neighbouring areas and b) inclusion of additive uniform noise in the Lorenz model. Both modifications, independently, drive the Lorenz spectrum closer to the human NAN one in the positive q region without destroying the already good correspondence of the negative spectra. The modelling process shows that the unmodified Lorenz model in its full chaotic regime has a phase space distribution with high fluctuations in its dense parts, while the fluctuations in the human brain NAN are smoother. The induced modifications (phase space redistribution or additive noise) moderate the fluctuations only in the positive part of the Lorenz spectrum leading to a faithful representation of the human brain axons network in all scales.

Development and validation of a novel, simple, and accurate spectrophotometric method for the determination of lead in human serum.

PubMed

Shayesteh, Tavakol Heidari; Khajavi, Farzad; Khosroshahi, Abolfazl Ghafuri; Mahjub, Reza

2016-01-01

The determination of blood lead levels is the most useful indicator of the determination of the amount of lead that is absorbed by the human body. Various methods, like atomic absorption spectroscopy (AAS), have already been used for the detection of lead in biological fluid, but most of these methods are based on complicated, expensive, and highly instructed instruments. In this study, a simple and accurate spectroscopic method for the determination of lead has been developed and applied for the investigation of lead concentration in biological samples. In this study, a silica gel column was used to extract lead and eliminate interfering agents in human serum samples. The column was washed with deionized water. The pH was adjusted to the value of 8.2 using phosphate buffer, and then tartrate and cyanide solutions were added as masking agents. The lead content was extracted into the organic phase containing dithizone as a complexion reagent and the dithizone-Pb(II) complex was formed and approved by visible spectrophotometry at 538 nm. The recovery was found to be 84.6 %. In order to validate the method, a calibration curve involving the use of various concentration levels was calculated and proven to be linear in the range of 0.01-1.5 μg/ml, with an R (2) regression coefficient of 0.9968 by statistical analysis of linear model validation. The largest error % values were found to be -5.80 and +11.6 % for intra-day and inter-day measurements, respectively. The largest RSD % values were calculated to be 6.54 and 12.32 % for intra-day and inter-day measurements, respectively. Further, the limit of detection (LOD) was calculated to be 0.002 μg/ml. The developed method was applied to determine the lead content in the human serum of voluntary miners, and it has been proven that there is no statistically significant difference between the data provided from this novel method and the data obtained from previously studied AAS.

New generation humanized mice for virus research: Comparative aspects and future prospects

PubMed Central

Akkina, Ramesh

2014-01-01

Work with human specific viruses will greatly benefit from the use of an in vivo system that provides human target cells and tissues in a physiological setting. In this regard humanized mice (hu-Mice) have played an important role in our understanding of viral pathogenesis and testing of therapeutic strategies. Limitations with earlier versions of hu-Mice that lacked a functioning human immune system are currently being overcome. The new generation hu-Mouse models are capable of multilineage human hematopoiesis and generate T cells, B cells, macrophages and dendritic cells required for an adaptive human immune response. Now any human specific pathogen that can infect humanized mice can be studied in the context of ongoing infection and immune responses. Two leading humanized mouse models are currently employed: the hu-HSC model is created by transplantation of human hematopoietic stem cells (HSC), whereas the BLT mouse model is prepared by transplantation of human fetal liver, thymus and HSC. A number of human specific viruses such as HIV-1, dengue, EBV and HCV are being studied intensively in these systems. Both models permit infection by mucosal routes with viruses such as HIV-1 thus allowing transmission prevention studies. Cellular and humoral immune responses are seen in both the models. While there is efficient antigen specific IgM production, IgG responses are suboptimal due to inefficient immunoglobulin class switching. With the maturation of T cells occurring in the autologous human thymus, BLT mice permit human HLA restricted T cell responses in contrast to hu-HSC mice. However, the strength of the immune responses needs further improvement in both models to reach the levels seen in humans. The scope of hu-Mice use is further broadened by transplantation of additional tissues like human liver thus permitting immunopathogenesis studies on hepatotropic viruses such as HCV. Numerous studies that encompass antivirals, gene therapy, viral evolution, and the generation of human monoclonal antibodies have been conducted with promising results in these mice. For further improvement of the new hu-Mouse models, ongoing work is focused on generating new strains of immunodeficient mice transgenic for human HLA molecules to strengthen immune responses and human cytokines and growth factors to improve human cell reconstitution and their homeostatic maintenance. PMID:23217612

Human Subject Research Protocol: Computer-Aided Human Centric Cyber Situation Awareness: Understanding Cognitive Processes of Cyber Analysts

DTIC Science & Technology

2013-11-01

by existing cyber-attack detection tools far exceeds the analysts’ cognitive capabilities. Grounded in perceptual and cognitive theory , many visual...Processes Inspired by the sense-making theory discussed earlier, we model the analytical reasoning process of cyber analysts using three key...analyst are called “working hypotheses”); each hypothesis could trigger further actions to confirm or disconfirm it. New actions will lead to new

Port d’Entrée for Respiratory Infections – Does the Influenza A Virus Pave the Way for Bacteria?

PubMed Central

Siemens, Nikolai; Oehmcke-Hecht, Sonja; Mettenleiter, Thomas C.; Kreikemeyer, Bernd; Valentin-Weigand, Peter; Hammerschmidt, Sven

2017-01-01

Bacterial and viral co-infections of the respiratory tract are life-threatening and present a global burden to the global community. Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes are frequent colonizers of the upper respiratory tract. Imbalances through acquisition of seasonal viruses, e.g., Influenza A virus, can lead to bacterial dissemination to the lower respiratory tract, which in turn can result in severe pneumonia. In this review, we summarize the current knowledge about bacterial and viral co-infections of the respiratory tract and focus on potential experimental models suitable for mimicking this disease. Transmission of IAV and pneumonia is mainly modeled by mouse infection. Few studies utilizing ferrets, rats, guinea pigs, rabbits, and non-human primates are also available. The knowledge gained from these studies led to important discoveries and advances in understanding these infectious diseases. Nevertheless, mouse and other infection models have limitations, especially in translation of the discoveries to humans. Here, we suggest the use of human engineered lung tissue, human ex vivo lung tissue, and porcine models to study respiratory co-infections, which might contribute to a greater translation of the results to humans and improve both, animal and human health. PMID:29312268

Animal models of pancreatitis: Can it be translated to human pain study?

PubMed Central

Zhao, Jing-Bo; Liao, Dong-Hua; Nissen, Thomas Dahl

2013-01-01

Chronic pancreatitis affects many individuals around the world, and the study of the underlying mechanisms leading to better treatment possibilities are important tasks. Therefore, animal models are needed to illustrate the basic study of pancreatitis. Recently, animal models of acute and chronic pancreatitis have been thoroughly reviewed, but few reviews address the important aspect on the translation of animal studies to human studies. It is well known that pancreatitis is associated with epigastric pain, but the understanding regarding to mechanisms and appropriate treatment of this pain is still unclear. Using animal models to study pancreatitis associated visceral pain is difficult, however, these types of models are a unique way to reveal the mechanisms behind pancreatitis associated visceral pain. In this review, the animal models of acute, chronic and un-common pancreatitis are briefly outlined and animal models related to pancreatitis associated visceral pain are also addressed. PMID:24259952

The Use of Animal Models for Stroke Research: A Review

PubMed Central

Casals, Juliana B; Pieri, Naira CG; Feitosa, Matheus LT; Ercolin, Anna CM; Roballo, Kelly CS; Barreto, Rodrigo SN; Bressan, Fabiana F; Martins, Daniele S; Miglino, Maria A; Ambrósio, Carlos E

2011-01-01

Stroke has been identified as the second leading cause of death worldwide. Stroke is a focal neurologic deficit caused by a change in cerebral circulation. The use of animal models in recent years has improved our understanding of the physiopathology of this disease. Rats and mice are the most commonly used stroke models, but the demand for larger models, such as rabbits and even nonhuman primates, is increasing so as to better understand the disease and its treatment. Although the basic mechanisms of stroke are nearly identical among mammals, we here discuss the differences between the human encephalon and various animals. In addition, we compare common surgical techniques used to induce animal models of stroke. A more complete anatomic knowledge of the cerebral vessels of various model species is needed to develop more reliable models for objective results that improve knowledge of the pathology of stroke in both human and veterinary medicine. PMID:22330245

Tadalafil modulates aromatase activity and androgen receptor expression in a human osteoblastic cell in vitro model.

PubMed

Aversa, A; Fittipaldi, S; Bimonte, V M; Wannenes, F; Papa, V; Francomano, D; Greco, E A; Lenzi, A; Migliaccio, S

2016-02-01

Phosphodiesterase type-5 inhibitor (PDE5i) tadalafil administration in men with erectile dysfunction is associated with increased testosterone/estradiol ratio, leading to hypothesize a potential increased effect of androgen action on target tissues. We aimed to characterize, in a cellular model system in vitro, the potential modulation of aromatase and sex steroid hormone receptors upon exposure to tadalafil (TAD). Human osteoblast-like cells SAOS-2 were chosen as an in vitro model system since osteoblasts are target of steroid hormones. Cells were tested for viability upon TAD exposure, which increased cell proliferation. Then, cells were treated with/without TAD for several times to evaluate potential modulation in PDE5, aromatase (ARO), androgen (AR) and estrogen (ER) receptor expression. Osteoblasts express significant levels of both PDE5 mRNA and protein. Exposure of cells to increasing concentrations of TAD (10(-8)-10(-7) M) decreased PDE5 mRNA and protein expression. Also, TAD inhibited ARO mRNA and protein expression leading to an increase in testosterone levels in the supernatants. Interestingly, TAD increased total AR mRNA and protein expression and decreased ERα, with an increased ratio of AR/ER, suggesting preferential androgenic vs estrogenic pathway activation. Our results demonstrate for the first time that TAD decreases ARO expression and increases AR protein expression in human SAOS-2, strongly suggesting a new control of steroid hormones pathway by PDE5i. These findings might represent the first evidence of translational actions of PDE5i on AR, which leads to hypothesize a growing relevance of this molecule in men with prostate cancer long-term treated with TAD for sexual rehabilitation.

Modeling lead concentration in drinking water of residential plumbing pipes and hot water tanks.

PubMed

Chowdhury, Shakhawat; Kabir, Fayzul; Mazumder, Mohammad Abu Jafar; Zahir, Md Hasan

2018-09-01

Drinking water is a potential source of exposure to lead (Pb), which can pose risk to humans. The regulatory agencies often monitor Pb in water treatment plants (WTP) and/or water distribution systems (WDS). However, people are exposed to tap water inside the house while water may stay in the plumbing premise for several hours prior to reaching the tap. Depending on stagnation period and plumbing premise, concentrations of Pb in tap water can be significantly higher than the WDS leading to higher intake of Pb than the values from WDS or WTP. In this study, concentrations of Pb and water quality parameters were investigated in WDS, plumbing pipe (PP) and hot water tanks (HWT) for 7months. The samples were collected and analyzed on bi-weekly basis for 7 times a day. Several linear, non-linear and neural network models were developed for predicting Pb in PP and HWT. The models were validated using the additional data, which were not used for model development. The concentrations of Pb in PP and HWT were 1-1.17 and 1-1.21 times the Pb in WDS respectively. Concentrations of Pb were higher in summer than winter. The models showed moderate to excellent performance (R 2 =0.85-0.99) in predicting Pb in PP and HWT. The correlation coefficients (r) with the validation data were in the ranges of 0.76-0.90 and 0.97-0.99 for PP and HWT respectively. The models can be used for predicting Pb in tap water, which can assist to better protect the humans. Copyright © 2018. Published by Elsevier B.V.

Sustained synchronized neuronal network activity in a human astrocyte co-culture system

PubMed Central

Kuijlaars, Jacobine; Oyelami, Tutu; Diels, Annick; Rohrbacher, Jutta; Versweyveld, Sofie; Meneghello, Giulia; Tuefferd, Marianne; Verstraelen, Peter; Detrez, Jan R.; Verschuuren, Marlies; De Vos, Winnok H.; Meert, Theo; Peeters, Pieter J.; Cik, Miroslav; Nuydens, Rony; Brône, Bert; Verheyen, An

2016-01-01

Impaired neuronal network function is a hallmark of neurodevelopmental and neurodegenerative disorders such as autism, schizophrenia, and Alzheimer’s disease and is typically studied using genetically modified cellular and animal models. Weak predictive capacity and poor translational value of these models urge for better human derived in vitro models. The implementation of human induced pluripotent stem cells (hiPSCs) allows studying pathologies in differentiated disease-relevant and patient-derived neuronal cells. However, the differentiation process and growth conditions of hiPSC-derived neurons are non-trivial. In order to study neuronal network formation and (mal)function in a fully humanized system, we have established an in vitro co-culture model of hiPSC-derived cortical neurons and human primary astrocytes that recapitulates neuronal network synchronization and connectivity within three to four weeks after final plating. Live cell calcium imaging, electrophysiology and high content image analyses revealed an increased maturation of network functionality and synchronicity over time for co-cultures compared to neuronal monocultures. The cells express GABAergic and glutamatergic markers and respond to inhibitors of both neurotransmitter pathways in a functional assay. The combination of this co-culture model with quantitative imaging of network morphofunction is amenable to high throughput screening for lead discovery and drug optimization for neurological diseases. PMID:27819315

Experimental primates and non-human primate (NHP) models of human diseases in China: current status and progress

PubMed Central

ZHANG, Xiao-Liang; PANG, Wei; HU, Xin-Tian; LI, Jia-Li; YAO, Yong-Gang; ZHENG, Yong-Tang

2014-01-01

Non-human primates (NHPs) are phylogenetically close to humans, with many similarities in terms of physiology, anatomy, immunology, as well as neurology, all of which make them excellent experimental models for biomedical research. Compared with developed countries in America and Europe, China has relatively rich primate resources and has continually aimed to develop NHPs resources. Currently, China is a leading producer and a major supplier of NHPs on the international market. However, there are some deficiencies in feeding and management that have hampered China’s growth in NHP research and materials. Nonetheless, China has recently established a number of primate animal models for human diseases and achieved marked scientific progress on infectious diseases, cardiovascular diseases, endocrine diseases, reproductive diseases, neurological diseases, and ophthalmic diseases, etc. Advances in these fields via NHP models will undoubtedly further promote the development of China’s life sciences and pharmaceutical industry, and enhance China’s position as a leader in NHP research. This review covers the current status of NHPs in China and other areas, highlighting the latest developments in disease models using NHPs, as well as outlining basic problems and proposing effective countermeasures to better utilize NHP resources and further foster NHP research in China. PMID:25465081

Developments in deep brain stimulation using time dependent magnetic fields

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

Crowther, L.J.; Nlebedim, I.C.; Jiles, D.C.

2012-03-07

The effect of head model complexity upon the strength of field in different brain regions for transcranial magnetic stimulation (TMS) has been investigated. Experimental measurements were used to verify the validity of magnetic field calculations and induced electric field calculations for three 3D human head models of varying complexity. Results show the inability for simplified head models to accurately determine the site of high fields that lead to neuronal stimulation and highlight the necessity for realistic head modeling for TMS applications.

Developments in deep brain stimulation using time dependent magnetic fields

NASA Astrophysics Data System (ADS)

Crowther, L. J.; Nlebedim, I. C.; Jiles, D. C.

2012-04-01

The effect of head model complexity upon the strength of field in different brain regions for transcranial magnetic stimulation (TMS) has been investigated. Experimental measurements were used to verify the validity of magnetic field calculations and induced electric field calculations for three 3D human head models of varying complexity. Results show the inability for simplified head models to accurately determine the site of high fields that lead to neuronal stimulation and highlight the necessity for realistic head modeling for TMS applications.

GAA repeat expansion mutation mouse models of Friedreich ataxia exhibit oxidative stress leading to progressive neuronal and cardiac pathology.

PubMed

Al-Mahdawi, Sahar; Pinto, Ricardo Mouro; Varshney, Dhaval; Lawrence, Lorraine; Lowrie, Margaret B; Hughes, Sian; Webster, Zoe; Blake, Julian; Cooper, J Mark; King, Rosalind; Pook, Mark A

2006-11-01

Friedreich ataxia (FRDA) is a neurodegenerative disorder caused by an unstable GAA repeat expansion mutation within intron 1 of the FXN gene. However, the origins of the GAA repeat expansion, its unstable dynamics within different cells and tissues, and its effects on frataxin expression are not yet completely understood. Therefore, we have chosen to generate representative FRDA mouse models by using the human FXN GAA repeat expansion itself as the genetically modified mutation. We have previously reported the establishment of two lines of human FXN YAC transgenic mice that contain unstable GAA repeat expansions within the appropriate genomic context. We now describe the generation of FRDA mouse models by crossbreeding of both lines of human FXN YAC transgenic mice with heterozygous Fxn knockout mice. The resultant FRDA mice that express only human-derived frataxin show comparatively reduced levels of frataxin mRNA and protein expression, decreased aconitase activity, and oxidative stress, leading to progressive neurodegenerative and cardiac pathological phenotypes. Coordination deficits are present, as measured by accelerating rotarod analysis, together with a progressive decrease in locomotor activity and increase in weight. Large vacuoles are detected within neurons of the dorsal root ganglia (DRG), predominantly within the lumbar regions in 6-month-old mice, but spreading to the cervical regions after 1 year of age. Secondary demyelination of large axons is also detected within the lumbar roots of older mice. Lipofuscin deposition is increased in both DRG neurons and cardiomyocytes, and iron deposition is detected in cardiomyocytes after 1 year of age. These mice represent the first GAA repeat expansion-based FRDA mouse models that exhibit progressive FRDA-like pathology and thus will be of use in testing potential therapeutic strategies, particularly GAA repeat-based strategies.

Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma.

PubMed

Johnson, Laura A; Scholler, John; Ohkuri, Takayuki; Kosaka, Akemi; Patel, Prachi R; McGettigan, Shannon E; Nace, Arben K; Dentchev, Tzvete; Thekkat, Pramod; Loew, Andreas; Boesteanu, Alina C; Cogdill, Alexandria P; Chen, Taylor; Fraietta, Joseph A; Kloss, Christopher C; Posey, Avery D; Engels, Boris; Singh, Reshma; Ezell, Tucker; Idamakanti, Neeraja; Ramones, Melissa H; Li, Na; Zhou, Li; Plesa, Gabriela; Seykora, John T; Okada, Hideho; June, Carl H; Brogdon, Jennifer L; Maus, Marcela V

2015-02-18

Chimeric antigen receptors (CARs) are synthetic molecules designed to redirect T cells to specific antigens. CAR-modified T cells can mediate long-term durable remissions in B cell malignancies, but expanding this platform to solid tumors requires the discovery of surface targets with limited expression in normal tissues. The variant III mutation of the epidermal growth factor receptor (EGFRvIII) results from an in-frame deletion of a portion of the extracellular domain, creating a neoepitope. We chose a vector backbone encoding a second-generation CAR based on efficacy of a murine scFv-based CAR in a xenograft model of glioblastoma. Next, we generated a panel of humanized scFvs and tested their specificity and function as soluble proteins and in the form of CAR-transduced T cells; a low-affinity scFv was selected on the basis of its specificity for EGFRvIII over wild-type EGFR. The lead candidate scFv was tested in vitro for its ability to direct CAR-transduced T cells to specifically lyse, proliferate, and secrete cytokines in response to antigen-bearing targets. We further evaluated the specificity of the lead CAR candidate in vitro against EGFR-expressing keratinocytes and in vivo in a model of mice grafted with normal human skin. EGFRvIII-directed CAR T cells were also able to control tumor growth in xenogeneic subcutaneous and orthotopic models of human EGFRvIII(+) glioblastoma. On the basis of these results, we have designed a phase 1 clinical study of CAR T cells transduced with humanized scFv directed to EGFRvIII in patients with either residual or recurrent glioblastoma (NCT02209376). Copyright © 2015, American Association for the Advancement of Science.

Multilevel depth and image fusion for human activity detection.

PubMed

Ni, Bingbing; Pei, Yong; Moulin, Pierre; Yan, Shuicheng

2013-10-01

Recognizing complex human activities usually requires the detection and modeling of individual visual features and the interactions between them. Current methods only rely on the visual features extracted from 2-D images, and therefore often lead to unreliable salient visual feature detection and inaccurate modeling of the interaction context between individual features. In this paper, we show that these problems can be addressed by combining data from a conventional camera and a depth sensor (e.g., Microsoft Kinect). We propose a novel complex activity recognition and localization framework that effectively fuses information from both grayscale and depth image channels at multiple levels of the video processing pipeline. In the individual visual feature detection level, depth-based filters are applied to the detected human/object rectangles to remove false detections. In the next level of interaction modeling, 3-D spatial and temporal contexts among human subjects or objects are extracted by integrating information from both grayscale and depth images. Depth information is also utilized to distinguish different types of indoor scenes. Finally, a latent structural model is developed to integrate the information from multiple levels of video processing for an activity detection. Extensive experiments on two activity recognition benchmarks (one with depth information) and a challenging grayscale + depth human activity database that contains complex interactions between human-human, human-object, and human-surroundings demonstrate the effectiveness of the proposed multilevel grayscale + depth fusion scheme. Higher recognition and localization accuracies are obtained relative to the previous methods.

Human impact on wildfires varies between regions and with vegetation productivity

NASA Astrophysics Data System (ADS)

Lasslop, Gitta; Kloster, Silvia

2017-11-01

We assess the influence of humans on burned area simulated with a dynamic global vegetation model. The human impact in the model is based on population density and cropland fraction, which were identified as important drivers of burned area in analyses of global datasets, and are commonly used in global models. After an evaluation of the sensitivity to these two variables we extend the model by including an additional effect of the cropland fraction on the fire duration. The general pattern of human influence is similar in both model versions: the strongest human impact is found in regions with intermediate productivity, where fire occurrence is not limited by fuel load or climatic conditions. Human effects in the model increases burned area in the tropics, while in temperate regions burned area is reduced. While the population density is similar on average for the tropical and temperate regions, the cropland fraction is higher in temperate regions, and leads to a strong suppression of fire. The model shows a low human impact in the boreal region, where both population density and cropland fraction is very low and the climatic conditions, as well as the vegetation productivity limit fire. Previous studies attributed a decrease in fire activity found in global charcoal datasets to human activity. This is confirmed by our simulations, which only show a decrease in burned area when the human influence on fire is accounted for, and not with only natural effects on fires. We assess how the vegetation-fire feedback influences the results, by comparing simulations with dynamic vegetation biogeography to simulations with prescribed vegetation. The vegetation-fire feedback increases the human impact on burned area by 10% for present day conditions. These results emphasize that projections of burned area need to account for the interactions between fire, climate, vegetation and humans.

An optimal state estimation model of sensory integration in human postural balance

NASA Astrophysics Data System (ADS)

Kuo, Arthur D.

2005-09-01

We propose a model for human postural balance, combining state feedback control with optimal state estimation. State estimation uses an internal model of body and sensor dynamics to process sensor information and determine body orientation. Three sensory modalities are modeled: joint proprioception, vestibular organs in the inner ear, and vision. These are mated with a two degree-of-freedom model of body dynamics in the sagittal plane. Linear quadratic optimal control is used to design state feedback and estimation gains. Nine free parameters define the control objective and the signal-to-noise ratios of the sensors. The model predicts statistical properties of human sway in terms of covariance of ankle and hip motion. These predictions are compared with normal human responses to alterations in sensory conditions. With a single parameter set, the model successfully reproduces the general nature of postural motion as a function of sensory environment. Parameter variations reveal that the model is highly robust under normal sensory conditions, but not when two or more sensors are inaccurate. This behavior is similar to that of normal human subjects. We propose that age-related sensory changes may be modeled with decreased signal-to-noise ratios, and compare the model's behavior with degraded sensors against experimental measurements from older adults. We also examine removal of the model's vestibular sense, which leads to instability similar to that observed in bilateral vestibular loss subjects. The model may be useful for predicting which sensors are most critical for balance, and how much they can deteriorate before posture becomes unstable.

Modeling the within-host dynamics of cholera: bacterial-viral interaction.

PubMed

Wang, Xueying; Wang, Jin

2017-08-01

Novel deterministic and stochastic models are proposed in this paper for the within-host dynamics of cholera, with a focus on the bacterial-viral interaction. The deterministic model is a system of differential equations describing the interaction among the two types of vibrios and the viruses. The stochastic model is a system of Markov jump processes that is derived based on the dynamics of the deterministic model. The multitype branching process approximation is applied to estimate the extinction probability of bacteria and viruses within a human host during the early stage of the bacterial-viral infection. Accordingly, a closed-form expression is derived for the disease extinction probability, and analytic estimates are validated with numerical simulations. The local and global dynamics of the bacterial-viral interaction are analysed using the deterministic model, and the result indicates that there is a sharp disease threshold characterized by the basic reproduction number [Formula: see text]: if [Formula: see text], vibrios ingested from the environment into human body will not cause cholera infection; if [Formula: see text], vibrios will grow with increased toxicity and persist within the host, leading to human cholera. In contrast, the stochastic model indicates, more realistically, that there is always a positive probability of disease extinction within the human host.

Damage and Loss Estimation for Natural Gas Networks: The Case of Istanbul

NASA Astrophysics Data System (ADS)

Çaktı, Eser; Hancılar, Ufuk; Şeşetyan, Karin; Bıyıkoǧlu, Hikmet; Şafak, Erdal

2017-04-01

Natural gas networks are one of the major lifeline systems to support human, urban and industrial activities. The continuity of gas supply is critical for almost all functions of modern life. Under natural phenomena such as earthquakes and landslides the damages to the system elements may lead to explosions and fires compromising human life and damaging physical environment. Furthermore, the disruption in the gas supply puts human activities at risk and also results in economical losses. This study is concerned with the performance of one of the largest natural gas distribution systems in the world. Physical damages to Istanbul's natural gas network are estimated under the most recent probabilistic earthquake hazard models available, as well as under simulated ground motions from physics based models. Several vulnerability functions are used in modelling damages to system elements. A first-order assessment of monetary losses to Istanbul's natural gas distribution network is also attempted.

The effect of model uncertainty on cooperation in sensorimotor interactions

PubMed Central

Grau-Moya, J.; Hez, E.; Pezzulo, G.; Braun, D. A.

2013-01-01

Decision-makers have been shown to rely on probabilistic models for perception and action. However, these models can be incorrect or partially wrong in which case the decision-maker has to cope with model uncertainty. Model uncertainty has recently also been shown to be an important determinant of sensorimotor behaviour in humans that can lead to risk-sensitive deviations from Bayes optimal behaviour towards worst-case or best-case outcomes. Here, we investigate the effect of model uncertainty on cooperation in sensorimotor interactions similar to the stag-hunt game, where players develop models about the other player and decide between a pay-off-dominant cooperative solution and a risk-dominant, non-cooperative solution. In simulations, we show that players who allow for optimistic deviations from their opponent model are much more likely to converge to cooperative outcomes. We also implemented this agent model in a virtual reality environment, and let human subjects play against a virtual player. In this game, subjects' pay-offs were experienced as forces opposing their movements. During the experiment, we manipulated the risk sensitivity of the computer player and observed human responses. We found not only that humans adaptively changed their level of cooperation depending on the risk sensitivity of the computer player but also that their initial play exhibited characteristic risk-sensitive biases. Our results suggest that model uncertainty is an important determinant of cooperation in two-player sensorimotor interactions. PMID:23945266

Combined impact of lead, cadmium, polychlorinated biphenyls and non-chemical risk factors on blood pressure in NHANES

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

Peters, Junenette L., E-mail: petersj@bu.edu; Patricia Fabian, M., E-mail: pfabian@bu.edu; Levy, Jonathan I., E-mail: jonlevy@bu.edu

High blood pressure is associated with exposure to multiple chemical and non-chemical risk factors, but epidemiological analyses to date have not assessed the combined effects of both chemical and non-chemical stressors on human populations in the context of cumulative risk assessment. We developed a novel modeling approach to evaluate the combined impact of lead, cadmium, polychlorinated biphenyls (PCBs), and multiple non-chemical risk factors on four blood pressure measures using data for adults aged ≥20 years from the National Health and Nutrition Examination Survey (1999–2008). We developed predictive models for chemical and other stressors. Structural equation models were applied to accountmore » for complex associations among predictors of stressors as well as blood pressure. Models showed that blood lead, serum PCBs, and established non-chemical stressors were significantly associated with blood pressure. Lead was the chemical stressor most predictive of diastolic blood pressure and mean arterial pressure, while PCBs had a greater influence on systolic blood pressure and pulse pressure, and blood cadmium was not a significant predictor of blood pressure. The simultaneously fit exposure models explained 34%, 43% and 52% of the variance for lead, cadmium and PCBs, respectively. The structural equation models were developed using predictors available from public data streams (e.g., U.S. Census), which would allow the models to be applied to any U.S. population exposed to these multiple stressors in order to identify high risk subpopulations, direct intervention strategies, and inform public policy. - Highlights: • We evaluated joint impact of chemical and non-chemical stressors on blood pressure. • We built predictive models for lead, cadmium and polychlorinated biphenyls (PCBs). • Our approach allows joint evaluation of predictors from population-specific data. • Lead, PCBs and established non-chemical stressors were related to blood pressure. • Framework allows cumulative risk assessment in specific geographic settings.« less

Lead exposures in the human environment. Final report

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

Elias, R.W.

Humans consume lead by inhaling air, drinking beverages, eating food and ingesting dust. The natural source of this lead is primarily soil. Anthropogenic sources are lead in gasoline, fossil fuels and industrial products and processes. Lead is ubiquitous in the human environment, and pinpointing the primary sources of lead in any particular environmental component is difficult. Nevertheless, our purpose is to describe the total exposure of humans to environmental lead and to determine the sources of lead contributing to this exposure. The total exposure is the total amount of lead consumed by ingestion and inhalation. Excluding lead exposure from choicemore » or circumstance, a baseline level of potential human exposure can be defined for a normal individual eating a typical diet and living in a non-urban community remote from industrial sources of lead in a house without lead-based paints. Beyond this level, additive exposure factors can be determined for other environments (e.g. urban, occupational and smelter communities) and for certain habits and activities (e.g. pica, smoking, drinking and hobbies), with variation for age, sex or socioeconomic status.« less

Chemically induced skin carcinogenesis: Updates in experimental models (Review)

PubMed Central

NEAGU, MONICA; CARUNTU, CONSTANTIN; CONSTANTIN, CAROLINA; BODA, DANIEL; ZURAC, SABINA; SPANDIDOS, DEMETRIOS A.; TSATSAKIS, ARISTIDIS M.

2016-01-01

Skin cancer is one of the most common malignancies affecting humans worldwide, and its incidence is rapidly increasing. The study of skin carcinogenesis is of major interest for both scientific research and clinical practice and the use of in vivo systems may facilitate the investigation of early alterations in the skin and of the mechanisms involved, and may also lead to the development of novel therapeutic strategies for skin cancer. This review outlines several aspects regarding the skin toxicity testing domain in mouse models of chemically induced skin carcinogenesis. There are important strain differences in view of the histological type, development and clinical evolution of the skin tumor, differences reported decades ago and confirmed by our hands-on experience. Using mouse models in preclinical testing is important due to the fact that, at the molecular level, common mechanisms with human cutaneous tumorigenesis are depicted. These animal models resemble human skin cancer development, in that genetic changes caused by carcinogens and pro-inflammatory cytokines, and simultaneous inflammation sustained by pro-inflammatory cytokines and chemokines favor tumor progression. Drugs and environmental conditions can be tested using these animal models. keeping in mind the differences between human and rodent skin physiology. PMID:26986013

Research on biophysical evaluation of the human vestibular system

NASA Technical Reports Server (NTRS)

Young, L. R.

1974-01-01

The human vestibular function was studied by the combined approach of advanced measurement and mathematical modelling. Fundamental measurements of some physical properties of endolymph and perilymph, combined with nystagmus measurements and fluid mechanical analysis of semicircular canal function furthered the theory of canal mechanical response to angular acceleration, caloric stimulation and relating linear acceleration. The effects of adaptation seen at low frequency angular stimulation were studied and modelled to remove some shortcomings of the torsion pendulum models. Otolith function was also studied experimentally and analytically, leading to a new set of models for subjective orientation. Applications to special problems of space, including the case of rotating spacecraft were investigated and the interaction of visual and vestibular cues and their relation to proprioceptive information was explored relative to postural control.

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.

Maternal hypothyroidism: An overview of current experimental models.

PubMed

Ghanbari, Mahboubeh; Ghasemi, Asghar

2017-10-15

Maternal hypothyroidism (MH) is the most common cause of transient congenital hypothyroidism. Different animal models are used for assessing developmental effects of MH in offspring. The severity and status of hypothyroidism in animal models must be a reflection of the actual conditions in humans. To obtain comparable results with different clinical conditions, which lead to MH in humans, several factors have been suggested for researchers to consider before designing the experimental models. Regarding development of fetal body systems during pregnancy, interference at different times provides different results and the appropriate time for induction of hypothyroidism should be selected based on accurate time of development of the system under assessment. Other factors that should be taken into consideration include, physiological and biochemical differences between humans and other species, thyroid hormone-independent effects of anti-thyroid drugs, circadian rhythms in TSH secretion, sex differences, physical and psychological stress. This review addresses essential guidelines for selecting and managing the optimal animal model for MH as well as discussing the pros and cons of currently used models. Copyright © 2017 Elsevier Inc. All rights reserved.

The effects of gut microbiota on CNS function in humans

PubMed Central

Tillisch, Kirsten

2014-01-01

The role of the gastrointestinal microbiota in human brain development and function is an area of increasing interest and research. Preclinical models suggest a role for the microbiota in broad aspects of human health, including mood, cognition, and chronic pain. Early human studies suggest that altering the microbiota with beneficial bacteria, or probiotics, can lead to changes in brain function, as well as subjective reports of mood. As the mechanisms of bidirectional communication between the brain and microbiota are better understood, it is expected that these pathways will be harnessed to provide novel methods to enhance health and treat disease. PMID:24838095

Feedforward object-vision models only tolerate small image variations compared to human

PubMed Central

Ghodrati, Masoud; Farzmahdi, Amirhossein; Rajaei, Karim; Ebrahimpour, Reza; Khaligh-Razavi, Seyed-Mahdi

2014-01-01

Invariant object recognition is a remarkable ability of primates' visual system that its underlying mechanism has constantly been under intense investigations. Computational modeling is a valuable tool toward understanding the processes involved in invariant object recognition. Although recent computational models have shown outstanding performances on challenging image databases, they fail to perform well in image categorization under more complex image variations. Studies have shown that making sparse representation of objects by extracting more informative visual features through a feedforward sweep can lead to higher recognition performances. Here, however, we show that when the complexity of image variations is high, even this approach results in poor performance compared to humans. To assess the performance of models and humans in invariant object recognition tasks, we built a parametrically controlled image database consisting of several object categories varied in different dimensions and levels, rendered from 3D planes. Comparing the performance of several object recognition models with human observers shows that only in low-level image variations the models perform similar to humans in categorization tasks. Furthermore, the results of our behavioral experiments demonstrate that, even under difficult experimental conditions (i.e., briefly presented masked stimuli with complex image variations), human observers performed outstandingly well, suggesting that the models are still far from resembling humans in invariant object recognition. Taken together, we suggest that learning sparse informative visual features, although desirable, is not a complete solution for future progresses in object-vision modeling. We show that this approach is not of significant help in solving the computational crux of object recognition (i.e., invariant object recognition) when the identity-preserving image variations become more complex. PMID:25100986

Geochemistry Of Lead In Contaminated Soils: Effects Of Soil Physico-Chemical Properties

NASA Astrophysics Data System (ADS)

Saminathan, S.; Sarkar, D.; Datta, R.; Andra, S. P.

2006-05-01

Lead (Pb) is an environmental contaminant with proven human health effects. When assessing human health risks associated with Pb, one of the most common exposure pathways typically evaluated is soil ingestion by children. However, bioaccessibility of Pb primarily depends on the solubility and hence, the geochemical form of Pb, which in turn is a function of site specific soil chemistry. Certain fractions of ingested soil-Pb may not dissociate during digestion in the gastro-intestinal tract, and hence, may not be available for transport across the intestinal membrane. Therefore, this study is being currently performed to assess the geochemical forms and bioaccessibility of Pb in soils with varying physico-chemical properties. In order to elucidate the level of Pb that can be ingested and assimilated by humans, an in-vitro model that simulates the physiological conditions of the human digestive system has been developed and is being used in this study. Four different types of soils from the Immokalee (an acid sandy soil with minimal Pb retention potential), Millhopper (a sandy loam with high Fe/Al content), Pahokee (a muck soil with more than 80% soil organic matter), and Tobosa series (an alkaline soil with high clay content) were artificially contaminated with Pb as lead nitrate at the rate equivalent to 0, 400, 800, and 1200 mg/kg dry soil. Analysis of soils by a sequential extraction method at time zero (immediately after spiking) showed that Immokalee and Millhopper soils had the highest amount of Pb in exchangeable form, whereas Pahokee and Tobosa soils had higher percentages of carbonate-bound and Fe/Al-bound Pb. The results of in-vitro experiment at time zero showed that majority of Pb was dissolved in the acidic stomach environment in Immokalee, Millhopper, and Tobosa, whereas it was in the intestinal phase in Pahokee soils. Because the soil system is not in equilibrium at time zero, the effect of soil properties on Pb geochemistry is not clear as yet. The subsequent analysis of soils (after 6 and 8 months months) is expected to better demonstrate the influence of soil properties on human bioaccessibility of Pb in contaminated soils. Furthermore, the geochemical forms of Pb will be correlated with bioaccessible Pb to identify those soil-Pb species with higher solubility in the human gastrointestinal system. Key words: Lead, Geochemical species, Bioaccessibility, In-vitro model, Health risk

Research the Gait Characteristics of Human Walking Based on a Robot Model and Experiment

NASA Astrophysics Data System (ADS)

He, H. J.; Zhang, D. N.; Yin, Z. W.; Shi, J. H.

2017-02-01

In order to research the gait characteristics of human walking in different walking ways, a robot model with a single degree of freedom is put up in this paper. The system control models of the robot are established through Matlab/Simulink toolbox. The gait characteristics of straight, uphill, turning, up the stairs, down the stairs up and down areanalyzed by the system control models. To verify the correctness of the theoretical analysis, an experiment was carried out. The comparison between theoretical results and experimental results shows that theoretical results are better agreement with the experimental ones. Analyze the reasons leading to amplitude error and phase error and give the improved methods. The robot model and experimental ways can provide foundation to further research the various gait characteristics of the exoskeleton robot.

Early-life stress origins of gastrointestinal disease: animal models, intestinal pathophysiology, and translational implications.

PubMed

Pohl, Calvin S; Medland, Julia E; Moeser, Adam J

2015-12-15

Early-life stress and adversity are major risk factors in the onset and severity of gastrointestinal (GI) disease in humans later in life. The mechanisms by which early-life stress leads to increased GI disease susceptibility in adult life remain poorly understood. Animal models of early-life stress have provided a foundation from which to gain a more fundamental understanding of this important GI disease paradigm. This review focuses on animal models of early-life stress-induced GI disease, with a specific emphasis on translational aspects of each model to specific human GI disease states. Early postnatal development of major GI systems and the consequences of stress on their development are discussed in detail. Relevant translational differences between species and models are highlighted. Copyright © 2015 the American Physiological Society.

ANALYSIS OF HOUSEHOLD WATER USE BEHAVIOR FOR USE AS IAQ MODEL PARAMETERS

EPA Science Inventory

Chemicals brought into the home through the domestic water supply, result in human exposure via the three principal routes: ingestion, inhalation, and dermal contact. Disinfection byproducts resulting from the treatment of municipal water supplies lead to the formation of a mix...

Dark matter as a cancer hazard

NASA Astrophysics Data System (ADS)

Chashchina, Olga; Silagadze, Zurab

2016-07-01

We comment on the paper ;Dark matter collisions with the human body; by K. Freese and C. Savage (2012) [1] and describe a dark matter model for which the results of the previous paper do not quite apply. Within this mirror dark matter model, potentially hazardous objects, mirror micrometeorites, can exist and may lead to diseases triggered by multiple mutations, such as cancer, though with very low probability.

Human pluripotent stem cells as tools for neurodegenerative and neurodevelopmental disease modeling and drug discovery.

PubMed

Corti, Stefania; Faravelli, Irene; Cardano, Marina; Conti, Luciano

2015-06-01

Although intensive efforts have been made, effective treatments for neurodegenerative and neurodevelopmental diseases have not been yet discovered. Possible reasons for this include the lack of appropriate disease models of human neurons and a limited understanding of the etiological and neurobiological mechanisms. Recent advances in pluripotent stem cell (PSC) research have now opened the path to the generation of induced pluripotent stem cells (iPSCs) starting from somatic cells, thus offering an unlimited source of patient-specific disease-relevant neuronal cells. In this review, the authors focus on the use of human PSC-derived cells in modeling neurological disorders and discovering of new drugs and provide their expert perspectives on the field. The advent of human iPSC-based disease models has fuelled renewed enthusiasm and enormous expectations for insights of disease mechanisms and identification of more disease-relevant and novel molecular targets. Human PSCs offer a unique tool that is being profitably exploited for high-throughput screening (HTS) platforms. This process can lead to the identification and optimization of molecules/drugs and thus move forward new pharmacological therapies for a wide range of neurodegenerative and neurodevelopmental conditions. It is predicted that improvements in the production of mature neuronal subtypes, from patient-specific human-induced pluripotent stem cells and their adaptation to culture, to HTS platforms will allow the increased exploitation of human pluripotent stem cells in drug discovery programs.

Genome-scale modeling of human metabolism - a systems biology approach.

PubMed

Mardinoglu, Adil; Gatto, Francesco; Nielsen, Jens

2013-09-01

Altered metabolism is linked to the appearance of various human diseases and a better understanding of disease-associated metabolic changes may lead to the identification of novel prognostic biomarkers and the development of new therapies. Genome-scale metabolic models (GEMs) have been employed for studying human metabolism in a systematic manner, as well as for understanding complex human diseases. In the past decade, such metabolic models - one of the fundamental aspects of systems biology - have started contributing to the understanding of the mechanistic relationship between genotype and phenotype. In this review, we focus on the construction of the Human Metabolic Reaction database, the generation of healthy cell type- and cancer-specific GEMs using different procedures, and the potential applications of these developments in the study of human metabolism and in the identification of metabolic changes associated with various disorders. We further examine how in silico genome-scale reconstructions can be employed to simulate metabolic flux distributions and how high-throughput omics data can be analyzed in a context-dependent fashion. Insights yielded from this mechanistic modeling approach can be used for identifying new therapeutic agents and drug targets as well as for the discovery of novel biomarkers. Finally, recent advancements in genome-scale modeling and the future challenge of developing a model of whole-body metabolism are presented. The emergent contribution of GEMs to personalized and translational medicine is also discussed. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A Circuit Model of Real Time Human Body Hydration.

PubMed

Asogwa, Clement Ogugua; Teshome, Assefa K; Collins, Stephen F; Lai, Daniel T H

2016-06-01

Changes in human body hydration leading to excess fluid losses or overload affects the body fluid's ability to provide the necessary support for healthy living. We propose a time-dependent circuit model of real-time human body hydration, which models the human body tissue as a signal transmission medium. The circuit model predicts the attenuation of a propagating electrical signal. Hydration rates are modeled by a time constant τ, which characterizes the individual specific metabolic function of the body part measured. We define a surrogate human body anthropometric parameter θ by the muscle-fat ratio and comparing it with the body mass index (BMI), we find theoretically, the rate of hydration varying from 1.73 dB/min, for high θ and low τ to 0.05 dB/min for low θ and high τ. We compare these theoretical values with empirical measurements and show that real-time changes in human body hydration can be observed by measuring signal attenuation. We took empirical measurements using a vector network analyzer and obtained different hydration rates for various BMI, ranging from 0.6 dB/min for 22.7 [Formula: see text] down to 0.04 dB/min for 41.2 [Formula: see text]. We conclude that the galvanic coupling circuit model can predict changes in the volume of the body fluid, which are essential in diagnosing and monitoring treatment of body fluid disorder. Individuals with high BMI would have higher time-dependent biological characteristic, lower metabolic rate, and lower rate of hydration.

Subtoxic Concentrations of Hepatotoxic Drugs Lead to Kupffer Cell Activation in a Human In Vitro Liver Model: An Approach to Study DILI

PubMed Central

Kegel, Victoria; Pfeiffer, Elisa; Burkhardt, Britta; Liu, Jia L.; Zeilinger, Katrin; Nüssler, Andreas K.; Seehofer, Daniel; Damm, Georg

2015-01-01

Drug induced liver injury (DILI) is an idiosyncratic adverse drug reaction leading to severe liver damage. Kupffer cells (KC) sense hepatic tissue stress/damage and therefore could be a tool for the estimation of consequent effects associated with DILI. Aim of the present study was to establish a human in vitro liver model for the investigation of immune-mediated signaling in the pathogenesis of DILI. Hepatocytes and KC were isolated from human liver specimens. The isolated KC yield was 1.2 ± 0.9 × 106 cells/g liver tissue with a purity of >80%. KC activation was investigated by the measurement of reactive oxygen intermediates (ROI, DCF assay) and cell activity (XTT assay). The initial KC activation levels showed broad donor variability. Additional activation of KC using supernatants of hepatocytes treated with hepatotoxic drugs increased KC activity and led to donor-dependent changes in the formation of ROI compared to KC incubated with supernatants from untreated hepatocytes. Additionally, a compound- and donor-dependent increase in proinflammatory cytokines or in anti-inflammatory cytokines was detected. In conclusion, KC related immune signaling in hepatotoxicity was successfully determined in a newly established in vitro liver model. KC were able to detect hepatocyte stress/damage and to transmit a donor- and compound-dependent immune response via cytokine production. PMID:26491234

Metabolically Competent Human Skin Models: Activation and Genotoxicity of Benzo[a]pyrene

PubMed Central

Henkler, Frank

2013-01-01

The polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene (BP) is metabolized into a complex pattern of BP derivatives, among which the ultimate carcinogen (+)-anti-BP-7,8-diol-9,10-epoxide (BPDE) is formed to certain extents. Skin is frequently in contact with PAHs and data on the metabolic capacity of skin tissue toward these compounds are inconclusive. We compared BP metabolism in excised human skin, commercially available in vitro 3D skin models and primary 2D skin cell cultures, and analyzed the metabolically catalyzed occurrence of seven different BP follow-up products by means of liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). All models investigated were competent to metabolize BP, and the metabolic profiles generated by ex vivo human skin and skin models were remarkably similar. Furthermore, the genotoxicity of BP and its derivatives was monitored in these models via comet assays. In a full-thickness skin, equivalent BP-mediated genotoxic stress was generated via keratinocytes. Cultured primary keratinocytes revealed a level of genotoxicity comparable with that of direct exposure to 50–100nM of BPDE. Our data demonstrate that the metabolic capacity of human skin ex vivo, as well as organotypic human 3D skin models toward BP, is sufficient to cause significant genotoxic stress and thus cutaneous bioactivation may potentially contribute to mutations that ultimately lead to skin cancer. PMID:23148024

Modeling of Blood Lead Levels in Astronauts Exposed to Lead from Microgravity-Accelerated Bone Loss

NASA Technical Reports Server (NTRS)

Garcia, H.; James, J.; Tsuji, J.

2014-01-01

Human exposure to lead has been associated with toxicity to multiple organ systems. Studies of various population groups with relatively low blood lead concentrations (<10 µg/dL) have indicated associations of blood lead level with lower cognitive test scores in children, later onset of puberty in girls, and increased blood pressure and cardiovascular mortality rates in adults. Cognitive effects are considered by regulatory agencies to be the most sensitive endpoint at low doses. Although 95% of the body burden of lead is stored in the bones, the adverse effects of lead correlate with the concentration of lead in the blood better than with that in the bones. NASA has found that prolonged exposure to microgravity during spaceflight results in a significant loss of bone minerals, the extent of which varies from individual to individual and from bone to bone, but generally averages about 0.5% per month. During such bone loss, lead that had been stored in bones would be released along with calcium. The effects on the concentration of lead in the blood (PbB) of various concentrations of lead in drinking water (PbW) and of lead released from bones due to accelerated osteoporosis in microgravity, as well as changes in exposure to environmental lead before, during, and after spaceflight were evaluated using a physiologically based pharmacokinetic (PBPK) model that incorporated exposure to environmental lead both on earth and in flight and included temporarily increased rates of osteoporosis during spaceflight.

Fractional calculus in biomechanics: a 3D viscoelastic model using regularized fractional derivative kernels with application to the human calcaneal fat pad.

PubMed

Freed, A D; Diethelm, K

2006-11-01

A viscoelastic model of the K-BKZ (Kaye, Technical Report 134, College of Aeronautics, Cranfield 1962; Bernstein et al., Trans Soc Rheol 7: 391-410, 1963) type is developed for isotropic biological tissues and applied to the fat pad of the human heel. To facilitate this pursuit, a class of elastic solids is introduced through a novel strain-energy function whose elements possess strong ellipticity, and therefore lead to stable material models. This elastic potential - via the K-BKZ hypothesis - also produces the tensorial structure of the viscoelastic model. Candidate sets of functions are proposed for the elastic and viscoelastic material functions present in the model, including two functions whose origins lie in the fractional calculus. The Akaike information criterion is used to perform multi-model inference, enabling an objective selection to be made as to the best material function from within a candidate set.

Retrospective revaluation in sequential decision making: a tale of two systems.

PubMed

Gershman, Samuel J; Markman, Arthur B; Otto, A Ross

2014-02-01

Recent computational theories of decision making in humans and animals have portrayed 2 systems locked in a battle for control of behavior. One system--variously termed model-free or habitual--favors actions that have previously led to reward, whereas a second--called the model-based or goal-directed system--favors actions that causally lead to reward according to the agent's internal model of the environment. Some evidence suggests that control can be shifted between these systems using neural or behavioral manipulations, but other evidence suggests that the systems are more intertwined than a competitive account would imply. In 4 behavioral experiments, using a retrospective revaluation design and a cognitive load manipulation, we show that human decisions are more consistent with a cooperative architecture in which the model-free system controls behavior, whereas the model-based system trains the model-free system by replaying and simulating experience.

Animal Models of Bone Metastasis

PubMed Central

Simmons, J. K.; Hildreth, B. E.; Supsavhad, W.; Elshafae, S. M.; Hassan, B. B.; Dirksen, W. P.; Toribio, R. E.; Rosol, T. J.

2015-01-01

Bone is one of the most common sites of cancer metastasis in humans and is a significant source of morbidity and mortality. Bone metastases are considered incurable and result in pain, pathologic fracture, and decreased quality of life. Animal models of skeletal metastases are essential to improve the understanding of the molecular pathways of cancer metastasis and growth in bone and to develop new therapies to inhibit and prevent bone metastases. The ideal animal model should be clinically relevant, reproducible, and representative of human disease. Currently, an ideal model does not exist; however, understanding the strengths and weaknesses of the available models will lead to proper study design and successful cancer research. This review provides an overview of the current in vivo animal models used in the study of skeletal metastases or local tumor invasion into bone and focuses on mammary and prostate cancer, lymphoma, multiple myeloma, head and neck squamous cell carcinoma, and miscellaneous tumors that metastasize to bone. PMID:26021553

Aggression, Social Stress, and the Immune System in Humans and Animal Models.

PubMed

Takahashi, Aki; Flanigan, Meghan E; McEwen, Bruce S; Russo, Scott J

2018-01-01

Social stress can lead to the development of psychological problems ranging from exaggerated anxiety and depression to antisocial and violence-related behaviors. Increasing evidence suggests that the immune system is involved in responses to social stress in adulthood. For example, human studies show that individuals with high aggression traits display heightened inflammatory cytokine levels and dysregulated immune responses such as slower wound healing. Similar findings have been observed in patients with depression, and comorbidity of depression and aggression was correlated with stronger immune dysregulation. Therefore, dysregulation of the immune system may be one of the mediators of social stress that produces aggression and/or depression. Similar to humans, aggressive animals also show increased levels of several proinflammatory cytokines, however, unlike humans these animals are more protected from infectious organisms and have faster wound healing than animals with low aggression. On the other hand, subordinate animals that receive repeated social defeat stress have been shown to develop escalated and dysregulated immune responses such as glucocorticoid insensitivity in monocytes. In this review we synthesize the current evidence in humans, non-human primates, and rodents to show a role for the immune system in responses to social stress leading to psychiatric problems such as aggression or depression. We argue that while depression and aggression represent two fundamentally different behavioral and physiological responses to social stress, it is possible that some overlapped, as well as distinct, pattern of immune signaling may underlie both of them. We also argue the necessity of studying animal models of maladaptive aggression induced by social stress (i.e., social isolation) for understanding neuro-immune mechanism of aggression, which may be relevant to human aggression.

Murine but not human basophil undergoes cell-specific proteolysis of a major endoplasmic reticulum chaperone.

PubMed

Liu, Bei; Staron, Matthew; Li, Zihai

2012-01-01

Basophil has been implicated in anti-parasite defense, allergy and in polarizing T(H)2 response. Mouse model has been commonly used to study basophil function although the difference between human and mouse basophils is underappreciated. As an essential chaperone for multiple Toll-like receptors and integrins in the endoplasmic reticulum, gp96 also participates in general protein homeostasis and in the ER unfolded protein response to ensure cell survival during stress. The roles of gp96 in basophil development are unknown. We genetically delete gp96 in mice and examined the expression of gp96 in basophils by Western blot and flow cytometry. We compared the expression pattern of gp96 between human and mouse basophils. We found that gp96 was dispensable for murine basophil development. Moreover, gp96 was cleaved by serine protease(s) in murine but not human basophils leading to accumulation of a nun-functional N-terminal ∼50 kDa fragment and striking induction of the unfolded protein response. The alteration of gp96 was unique to basophils and was not observed in any other cell types including mast cells. We also demonstrated that the ectopic expression of a mouse-specific tryptase mMCP11 does not lead to gp96 cleavage in human basophils. Our study revealed a remarkable biochemical event of gp96 silencing in murine but not human basophils, highlighting the need for caution in using mouse models to infer the function of basophils in human immune response. Our study also reveals a novel mechanism of shutting down gp96 post-translationally in regulating its function.

Aggression, Social Stress, and the Immune System in Humans and Animal Models

PubMed Central

Takahashi, Aki; Flanigan, Meghan E.; McEwen, Bruce S.; Russo, Scott J.

2018-01-01

Social stress can lead to the development of psychological problems ranging from exaggerated anxiety and depression to antisocial and violence-related behaviors. Increasing evidence suggests that the immune system is involved in responses to social stress in adulthood. For example, human studies show that individuals with high aggression traits display heightened inflammatory cytokine levels and dysregulated immune responses such as slower wound healing. Similar findings have been observed in patients with depression, and comorbidity of depression and aggression was correlated with stronger immune dysregulation. Therefore, dysregulation of the immune system may be one of the mediators of social stress that produces aggression and/or depression. Similar to humans, aggressive animals also show increased levels of several proinflammatory cytokines, however, unlike humans these animals are more protected from infectious organisms and have faster wound healing than animals with low aggression. On the other hand, subordinate animals that receive repeated social defeat stress have been shown to develop escalated and dysregulated immune responses such as glucocorticoid insensitivity in monocytes. In this review we synthesize the current evidence in humans, non-human primates, and rodents to show a role for the immune system in responses to social stress leading to psychiatric problems such as aggression or depression. We argue that while depression and aggression represent two fundamentally different behavioral and physiological responses to social stress, it is possible that some overlapped, as well as distinct, pattern of immune signaling may underlie both of them. We also argue the necessity of studying animal models of maladaptive aggression induced by social stress (i.e., social isolation) for understanding neuro-immune mechanism of aggression, which may be relevant to human aggression. PMID:29623033

Ecosocial consequences and policy implications of disease management in East African agropastoral systems.

PubMed

Gutierrez, Andrew Paul; Gilioli, Gianni; Baumgärtner, Johann

2009-08-04

International research and development efforts in Africa have brought ecological and social change, but analyzing the consequences of this change and developing policy to manage it for sustainable development has been difficult. This has been largely due to a lack of conceptual and analytical models to access the interacting dynamics of the different components of ecosocial systems. Here, we examine the ecological and social changes resulting from an ongoing suppression of trypanosomiasis disease in cattle in an agropastoral community in southwest Ethiopia to illustrate how such problems may be addressed. The analysis combines physiologically based demographic models of pasture, cattle, and pastoralists and a bioeconomic model that includes the demographic models as dynamic constraints in the economic objective function that maximizes the utility of individual consumption under different level of disease risk in cattle. Field data and model analysis show that suppression of trypanosomiasis leads to increased cattle and human populations and to increased agricultural development. However, in the absence of sound management, these changes will lead to a decline in pasture quality and increase the risk from tick-borne diseases in cattle and malaria in humans that would threaten system sustainability and resilience. The analysis of these conflicting outcomes of trypanosomiasis suppression is used to illustrate the need for and utility of conceptual bioeconomic models to serve as a basis for developing policy for sustainable agropastoral resource management in sub-Saharan Africa.

Modeled Microgravity Disrupts Collagen I/Integrin Signaling During Osteoblastic Differentiation of Human Mesenchymal Stem Cells

NASA Technical Reports Server (NTRS)

Meyers, Valerie E.; Zayzafoon, Majd; Gonda, Steven R.; Gathings, William E.; McDonald, Jay M.

2004-01-01

Spaceflight leads to reduced bone mineral density in weight bearing bones that is primarily attributed to a reduction in bone formation. We have previously demonstrated severely reduced osteoblastogenesis of human mesenchymal stem cells (hMSC) following seven days culture in modeled microgravity. One potential mechanism for reduced osteoblastic differentiation is disruption of type I collagen-integrin interactions and reduced integrin signaling. Integrins are heterodimeric transmembrane receptors that bind extracellular matrix proteins and produce signals essential for proper cellular function, survival, and differentiation. Therefore, we investigated the effects of modeled microgravity on integrin expression and function in hMSC. We demonstrate that seven days of culture in modeled microgravity leads to reduced expression of the extracellular matrix protein, type I collagen (Col I). Conversely, modeled microgravity consistently increases Col I-specific alpha2 and beta1 integrin protein expression. Despite this increase in integrin sub-unit expression, autophosphorylation of adhesion-dependent kinases, focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2), is significantly reduced. Activation of Akt is unaffected by the reduction in FAK activation. However, reduced downstream signaling via the Ras-MAPK pathway is evidenced by a reduction in Ras and ERK activation. Taken together, our findings indicate that modeled microgravity decreases integrin/MAPK signaling, which likely contributes to the observed reduction in osteoblastogenesis.

Technical approaches for mouse models of human disease.

PubMed

Justice, Monica J; Siracusa, Linda D; Stewart, A Francis

2011-05-01

The mouse is the leading organism for disease research. A rich resource of genetic variation occurs naturally in inbred and special strains owing to spontaneous mutations. However, one can also obtain desired gene mutations by using the following processes: targeted mutations that eliminate function in the whole organism or in a specific tissue; forward genetic screens using chemicals or transposons; or the introduction of exogenous transgenes as DNAs, bacterial artificial chromosomes (BACs) or reporter constructs. The mouse is the only mammal that provides such a rich resource of genetic diversity coupled with the potential for extensive genome manipulation, and is therefore a powerful application for modeling human disease. This poster review outlines the major genome manipulations available in the mouse that are used to understand human disease: natural variation, reverse genetics, forward genetics, transgenics and transposons. Each of these applications will be essential for understanding the diversity that is being discovered within the human population.

Returners and explorers dichotomy in human mobility

PubMed Central

Pappalardo, Luca; Simini, Filippo; Rinzivillo, Salvatore; Pedreschi, Dino; Giannotti, Fosca; Barabási, Albert-László

2015-01-01

The availability of massive digital traces of human whereabouts has offered a series of novel insights on the quantitative patterns characterizing human mobility. In particular, numerous recent studies have lead to an unexpected consensus: the considerable variability in the characteristic travelled distance of individuals coexists with a high degree of predictability of their future locations. Here we shed light on this surprising coexistence by systematically investigating the impact of recurrent mobility on the characteristic distance travelled by individuals. Using both mobile phone and GPS data, we discover the existence of two distinct classes of individuals: returners and explorers. As existing models of human mobility cannot explain the existence of these two classes, we develop more realistic models able to capture the empirical findings. Finally, we show that returners and explorers play a distinct quantifiable role in spreading phenomena and that a correlation exists between their mobility patterns and social interactions. PMID:26349016

Closing the loop: integrating human impacts on water resources to advanced land surface models

NASA Astrophysics Data System (ADS)

Zaitchik, B. F.; Nie, W.; Rodell, M.; Kumar, S.; Li, B.

2016-12-01

Advanced Land Surface Models (LSMs), including those used in the North American Land Data Assimilation System (NLDAS), offer a physically consistent and spatially and temporally complete analysis of the distributed water balance. These models are constrained both by physically-based process representation and by observations ingested as meteorological forcing or as data assimilation updates. As such, they have become important tools for hydrological monitoring and long-term climate analysis. The representation of water management, however, is extremely limited in these models. Recent advances have brought prognostic irrigation routines into models used in NLDAS, while assimilation of Gravity Recovery and Climate Experiment (GRACE) derived estimates of terrestrial water storage anomaly has made it possible to nudge models towards observed states in water storage below the root zone. But with few exceptions these LSMs do not account for the source of irrigation water, leading to a disconnect between the simulated water balance and the observed human impact on water resources. This inconsistency is unacceptable for long-term studies of climate change and human impact on water resources in North America. Here we define the modeling challenge, review instances of models that have begun to account for water withdrawals (e.g., CLM), and present ongoing efforts to improve representation of human impacts on water storage across models through integration of irrigation routines, water withdrawal information, and GRACE Data Assimilation in NLDAS LSMs.

Agent based simulation on the process of human flesh search-From perspective of knowledge and emotion

NASA Astrophysics Data System (ADS)

Zhu, Hou; Hu, Bin

2017-03-01

Human flesh search as a new net crowed behavior, on the one hand can help us to find some special information, on the other hand may lead to privacy leaking and offending human right. In order to study the mechanism of human flesh search, this paper proposes a simulation model based on agent-based model and complex networks. The computational experiments show some useful results. Discovered information quantity and involved personal ratio are highly correlated, and most of net citizens will take part in the human flesh search or will not take part in the human flesh search. Knowledge quantity does not influence involved personal ratio, but influences whether HFS can find out the target human. When the knowledge concentrates on hub nodes, the discovered information quantity is either perfect or almost zero. Emotion of net citizens influences both discovered information quantity and involved personal ratio. Concretely, when net citizens are calm to face the search topic, it will be hardly to find out the target; But when net citizens are agitated, the target will be found out easily.

Multiple scales modelling approaches to social interaction in crowd dynamics and crisis management. Comment on "Human behaviours in evacuation crowd dynamics: From modelling to "big data" toward crisis management" by Nicola Bellomo et al.

NASA Astrophysics Data System (ADS)

Trucu, Dumitru

2016-09-01

In this comprehensive review concerning the modelling of human behaviours in crowd dynamics [3], the authors explore a wide range of mathematical approaches spanning over multiple scales that are suitable to describe emerging crowd behaviours in extreme situations. Focused on deciphering the key aspects leading to emerging crowd patterns evolutions in challenging times such as those requiring an evacuation on a complex venue, the authors address this complex dynamics at both microscale (individual level), mesoscale (probability distributions of interacting individuals), and macroscale (population level), ultimately aiming to gain valuable understanding and knowledge that would inform decision making in managing crisis situations.

An expanding toolkit for preclinical pre-erythrocytic malaria vaccine development: bridging traditional mouse malaria models and human trials

PubMed Central

Steel, Ryan WJ; Kappe, Stefan HI; Sack, Brandon K

2016-01-01

Malaria remains a significant public health burden with 214 million new infections and over 400,000 deaths in 2015. Elucidating relevant Plasmodium parasite biology can lead to the identification of novel ways to control and ultimately eliminate the parasite within geographic areas. Particularly, the development of an effective vaccine that targets the clinically silent pre-erythrocytic stages of infection would significantly augment existing malaria elimination tools by preventing both the onset of blood-stage infection/disease as well as spread of the parasite through mosquito transmission. In this Perspective, we discuss the role of small animal models in pre-erythrocytic stage vaccine development, highlighting how human liver-chimeric and human immune system mice are emerging as valuable components of these efforts. PMID:27855488

An expanding toolkit for preclinical pre-erythrocytic malaria vaccine development: bridging traditional mouse malaria models and human trials.

PubMed

Steel, Ryan Wj; Kappe, Stefan Hi; Sack, Brandon K

2016-12-01

Malaria remains a significant public health burden with 214 million new infections and over 400,000 deaths in 2015. Elucidating relevant Plasmodium parasite biology can lead to the identification of novel ways to control and ultimately eliminate the parasite within geographic areas. Particularly, the development of an effective vaccine that targets the clinically silent pre-erythrocytic stages of infection would significantly augment existing malaria elimination tools by preventing both the onset of blood-stage infection/disease as well as spread of the parasite through mosquito transmission. In this Perspective, we discuss the role of small animal models in pre-erythrocytic stage vaccine development, highlighting how human liver-chimeric and human immune system mice are emerging as valuable components of these efforts.

Children perseverate to a human's actions but not to a robot's actions.

PubMed

Moriguchi, Yusuke; Kanda, Takayuki; Ishiguro, Hiroshi; Itakura, Shoji

2010-01-01

Previous research has shown that young children commit perseverative errors from their observation of another person's actions. The present study examined how social observation would lead children to perseverative tendencies, using a robot. In Experiment 1, preschoolers watched either a human model or a robot sorting cards according to one dimension (e.g. shape), after which they were asked to sort according to a different dimension (e.g. colour). The results showed that children's behaviours in the task were significantly influenced by the human model's actions but not by the robot's actions. Experiment 2 excluded the possibility that children's behaviours were not affected by the robot's actions because they did not observe its actions. We concluded that children's perseverative errors from social observation resulted, in part, from their socio-cognitive ability.

Chromosomal instability mediated by non-B DNA: cruciform conformation and not DNA sequence is responsible for recurrent translocation in humans.

PubMed

Inagaki, Hidehito; Ohye, Tamae; Kogo, Hiroshi; Kato, Takema; Bolor, Hasbaira; Taniguchi, Mariko; Shaikh, Tamim H; Emanuel, Beverly S; Kurahashi, Hiroki

2009-02-01

Chromosomal aberrations have been thought to be random events. However, recent findings introduce a new paradigm in which certain DNA segments have the potential to adopt unusual conformations that lead to genomic instability and nonrandom chromosomal rearrangement. One of the best-studied examples is the palindromic AT-rich repeat (PATRR), which induces recurrent constitutional translocations in humans. Here, we established a plasmid-based model that promotes frequent intermolecular rearrangements between two PATRRs in HEK293 cells. In this model system, the proportion of PATRR plasmid that extrudes a cruciform structure correlates to the levels of rearrangement. Our data suggest that PATRR-mediated translocations are attributable to unusual DNA conformations that confer a common pathway for chromosomal rearrangements in humans.

NASA Specialized Center for Research and Training (NSCORT) in space environmental health

NASA Technical Reports Server (NTRS)

Clarkson, Thomas W.; Utell, Mark J.; Morgenthaler, George W.; Eberhardt, Ralph; Rabin, Robert

1992-01-01

Activities of the Center for Space Environmental Health (CSEH), one of several NSCORTs supported by NASA in order to advance knowledge in environmental health in space habitats, are reviewed. Research in environmental health will define the standards or requirements needed to protect human health. This information will affect mission plans and the design of space habitats. This reseach will study unique contaminant stresses and lead to risk models for human health and performance.

Roles for the endocannabinoid system in ethanol-motivated behavior

PubMed Central

Henderson-Redmond, Angela N; Guindon, Josée; Morgan, Daniel J

2015-01-01

Alcohol use disorder represents a significant human health problem that leads to substantial loss of human life and financial cost to society. Currently available treatment options do not adequately address this human health problem, and thus, additional therapies are desperately needed. The endocannabinoid system has been shown, using animal models, to modulate ethanol-motivated behavior, and it has also been demonstrated that chronic ethanol exposure can have potentially long-lasting effects on the endocannabinoid system. For example, chronic exposure to ethanol, in either cell culture or preclinical rodent models, causes an increase in endocannabinoid levels that results in down-regulation of the cannabinoid receptor 1 (CB1) and uncoupling of this receptor from downstream G protein signaling pathways. Using positron emission tomography (PET), similar down-regulation of CB1 has been noted in multiple regions of the brain in human alcoholic patients. In rodents, treatment with the CB1 inverse agonist SR141716A (Rimonabant), or genetic deletion of CB1 leads to a reduction in voluntary ethanol drinking, ethanol-stimulated dopamine release in the nucleus accumbens, operant self-administration of ethanol, sensitization to the locomotor effects of ethanol, and reinstatement/relapse of ethanol-motivated behavior. Although the clinical utility of Rimonabant or other antagonists/inverse agonists for CB1 is limited due to negative neuropsychiatric side effects, negative allosteric modulators of CB1 and inhibitors of endocannabinoid catabolism represent therapeutic targets worthy of additional examination. PMID:26123153

Hebbian Plasticity in CPG Controllers Facilitates Self-Synchronization for Human-Robot Handshaking.

PubMed

Jouaiti, Melanie; Caron, Lancelot; Hénaff, Patrick

2018-01-01

It is well-known that human social interactions generate synchrony phenomena which are often unconscious. If the interaction between individuals is based on rhythmic movements, synchronized and coordinated movements will emerge from the social synchrony. This paper proposes a plausible model of plastic neural controllers that allows the emergence of synchronized movements in physical and rhythmical interactions. The controller is designed with central pattern generators (CPG) based on rhythmic Rowat-Selverston neurons endowed with neuronal and synaptic Hebbian plasticity. To demonstrate the interest of the proposed model, the case of handshaking is considered because it is a very common, both physically and socially, but also, a very complex act in the point of view of robotics, neuroscience and psychology. Plastic CPGs controllers are implemented in the joints of a simulated robotic arm that has to learn the frequency and amplitude of an external force applied to its effector, thus reproducing the act of handshaking with a human. Results show that the neural and synaptic Hebbian plasticity are working together leading to a natural and autonomous synchronization between the arm and the external force even if the frequency is changing during the movement. Moreover, a power consumption analysis shows that, by offering emergence of synchronized and coordinated movements, the plasticity mechanisms lead to a significant decrease in the energy spend by the robot actuators thus generating a more adaptive and natural human/robot handshake.

Challenges in Modelling Hypoglycaemia-Associated Autonomic Failure: A Review of Human and Animal Studies

PubMed Central

Zhou, Xin-Fu

2016-01-01

Recurrent insulin-induced hypoglycaemia is a major limitation to insulin treatment in diabetes patients leading to a condition called hypoglycaemia-associated autonomic failure (HAAF). HAAF is characterised by reduced sympathoadrenal response to subsequent hypoglycaemia thereby predisposing the patients to severe hypoglycaemia that can lead to coma or even death. Despite several attempts being made, the mechanism of HAAF is yet to be clearly established. In order for the mechanism of HAAF to be elucidated, establishing a human/animal model of the phenomenon is the foremost requirement. Several research groups have attempted to reproduce the phenomenon in diabetic and nondiabetic humans and rodents and reported variable results. The success of the phenomenon is marked by a significant reduction in plasma adrenaline response to subsequent hypoglycaemic episode relative to that of the antecedent hypoglycaemic episode. A number of factors such as the insulin dosage, route of administration, fasting conditions, blood sampling methods and analyses, depth, duration, and number of antecedent hypoglycaemic episodes can impact the successful reproduction of the phenomenon and thus have to be carefully considered while developing the protocol. In this review, we have outlined the protocols followed by different research groups to reproduce the phenomenon in diabetic and nondiabetic humans and rodents including our own observations in rats and discussed the factors that have to be given careful consideration in reproducing the phenomenon successfully. PMID:27843452

QSAR modeling based on structure-information for properties of interest in human health.

PubMed

Hall, L H; Hall, L M

2005-01-01

The development of QSAR models based on topological structure description is presented for problems in human health. These models are based on the structure-information approach to quantitative biological modeling and prediction, in contrast to the mechanism-based approach. The structure-information approach is outlined, starting with basic structure information developed from the chemical graph (connection table). Information explicit in the connection table (element identity and skeletal connections) leads to significant (implicit) structure information that is useful for establishing sound models of a wide range of properties of interest in drug design. Valence state definition leads to relationships for valence state electronegativity and atom/group molar volume. Based on these important aspects of molecules, together with skeletal branching patterns, both the electrotopological state (E-state) and molecular connectivity (chi indices) structure descriptors are developed and described. A summary of four QSAR models indicates the wide range of applicability of these structure descriptors and the predictive quality of QSAR models based on them: aqueous solubility (5535 chemically diverse compounds, 938 in external validation), percent oral absorption (%OA, 417 therapeutic drugs, 195 drugs in external validation testing), AMES mutagenicity (2963 compounds including 290 therapeutic drugs, 400 in external validation), fish toxicity (92 substituted phenols, anilines and substituted aromatics). These models are established independent of explicit three-dimensional (3-D) structure information and are directly interpretable in terms of the implicit structure information useful to the drug design process.

MEASUREMENT OF PHTHALATE LEVELS IN HUMAN MILK IN THE US EPA MAMA STUDY

EPA Science Inventory

Phthalates are plasticizers used to impart flexibility in products including PVC, plastic toys, and medical devices. These products are widely used by the general population. Phthalates act as anti-androgens and in utero or perinatal exposure in laboratory animal models leads to ...

Modeling the Air-Vegetation-Soil Exchange of Reactive Nitrogen

EPA Science Inventory

Nitrogen is an essential building block of all proteins and thus an essential nutrient for all life. However, in excess reactive nitrogen can lead to poor air or water quality, loss of biodiversity, and impact respiratory and cardiac health. Human activity has perturbed this cycl...

Anatomical Data for Analyzing Human Motion.

ERIC Educational Resources Information Center

Plagenhoef, Stanley; And Others

1983-01-01

Anatomical data obtained from cadavers and from water displacement studies with living subjects were used to determine the weight, center of gravity, and radius of gyration for 16 body segments. A lead model was used to study movement patterns of the trunk section of the body. (Authors/PP)

The Future is Now: OpenTERRAworks - Interoperable 2D/3D Landscape Design Software for Integrated Environmental Modeling

EPA Science Inventory

Human activities involving significant terrain alteration (e.g., earthworks operations associated with mines, urban development, landslides) can lead to broad-ranging changes in the surrounding terrestrial and aquatic environments. Potential aesthetic impacts can be associated wi...

LARGE SCALE DISASTER ANALYSIS AND MANAGEMENT: SYSTEM LEVEL STUDY ON AN INTEGRATED MODEL

EPA Science Inventory

The increasing intensity and scale of human activity across the globe leading to severe depletion and deterioration of the Earth's natural resources has meant that sustainability has emerged as a new paradigm of analysis and management. Sustainability, conceptually defined by the...

MATREX Leads the Way in Implementing New DOD VV&A Documentation Standards

DTIC Science & Technology

2007-05-24

Acquisition Operations & Support B C Sustainment FRP Decision Review FOC LRIP/IOT& ECritical Design Review Pre-Systems Acquisition Concept...Communications Human Performance Model • C3GRID – Command & Control, Computer GRID • CES – Communications Effects Server • CMS2 – Comprehensive

Quantitative Adverse Outcome Pathway for Neurodevelopmental Effects of Thyroid Peroxidase-Induced Thyroid Hormone Synthesis Inhibition

EPA Science Inventory

Adequate levels of thyroid hormones (TH) are needed for proper brain development and deficiencies lead to adverse neurological outcomes in humans and in animal models. Environmental chemicals have been shown to disrupt TH levels, yet the relationship between developmental exposur...

Cues that Trigger Social Transmission of Disinhibition in Young Children

ERIC Educational Resources Information Center

Moriguchi, Yusuke; Minato, Takashi; Ishiguro, Hiroshi; Shinohara, Ikuko; Itakura, Shoji

2010-01-01

Previous studies have shown that observing a human model's actions, but not a robot's actions, could induce young children's perseverative behaviors and suggested that children's sociocognitive abilities can lead to perseverative errors ("social transmission of disinhibition"). This study investigated how the social transmission of disinhibition…

Fruit stones from industrial waste for the removal of lead ions from polluted water.

PubMed

Rashed, M N

2006-08-01

Lead, one of the earliest metals recognized and used by humans, has a long history of beneficial use. However, it is now recognized as toxic and as posing a widespread threat to humans and wildlife. Treatment of lead from polluted water and wastewater has received a great deal of attention. Adsorption is one of the most common technologies for the treatment of lead-polluted water. This technique was evaluated here, with the goal of identifying innovative, low-cost adsorbent. This study presents experiments undertaken to determine the suitable conditions for the use of peach and apricot stones, produced from food industries as solid waste, as adsorbents for the removal of lead from aqueous solution. Chemical stability of adsorbents, effect of pH, adsorbents dose, adsorption time and equilibrium concentration were studied. The results reveal that adsorption of lead ions onto peach stone was stronger than onto apricot stone up to 3.36% at 3 h adsorption time. Suitable equilibrium time for the adsorption was 3-5 h (% Pb adsorption 93% for apricot and 97.64% for peach). The effective adsorption range for pH in the range was 7-8. Application of Langmuir and Freundlich isotherm models show high adsorption maximum and binding energies for using these adsorbents for the removal of lead ions from contaminated water and wastewater.

A stochastic dynamic model for human error analysis in nuclear power plants

NASA Astrophysics Data System (ADS)

Delgado-Loperena, Dharma

Nuclear disasters like Three Mile Island and Chernobyl indicate that human performance is a critical safety issue, sending a clear message about the need to include environmental press and competence aspects in research. This investigation was undertaken to serve as a roadmap for studying human behavior through the formulation of a general solution equation. The theoretical model integrates models from two heretofore-disassociated disciplines (behavior specialists and technical specialists), that historically have independently studied the nature of error and human behavior; including concepts derived from fractal and chaos theory; and suggests re-evaluation of base theory regarding human error. The results of this research were based on comprehensive analysis of patterns of error, with the omnipresent underlying structure of chaotic systems. The study of patterns lead to a dynamic formulation, serving for any other formula used to study human error consequences. The search for literature regarding error yielded insight for the need to include concepts rooted in chaos theory and strange attractors---heretofore unconsidered by mainstream researchers who investigated human error in nuclear power plants or those who employed the ecological model in their work. The study of patterns obtained from the rupture of a steam generator tube (SGTR) event simulation, provided a direct application to aspects of control room operations in nuclear power plant operations. In doing so, the conceptual foundation based in the understanding of the patterns of human error analysis can be gleaned, resulting in reduced and prevent undesirable events.

Apparent threshold of lead's effect on child intelligence

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

Rabinowitz, M.B.; Wang, J.D.; Soong, W.T.

1992-05-01

The developing human brain is perhaps the most sensitive of the many targets of lead toxicity. This particular sensitivity is a driving factor in setting health and environmental standards for lead. A recent compilation of studies of the association between lead and IQ has shown a consistent dose-response pattern across the range of reported exposures. In surveying the neurotoxicity of lead in humans and animals, there has been speculation of the existence of a threshold for these effects which may become apparent at lower lead levels. In that context we examined our data of tooth lead and IQ scores tomore » determine whether there was any apparent threshold for this effect. This cohort's lead levels are among the lowest documented and provide the opportunity to extend downward the range of interest. Family factors are the strongest predictors of a child's intelligence, in particular the parent's intelligence. We therefore followed the model of Perino and Ernhart (1974) by examining whether at various levels of lead there is a disruption of the usual association between family and child intelligence. As noted by Bellinger and Needleman (1983), a difference in the correlations between parental and child intelligence in two groups, high and low lead, may be an artifact of other relationships among the predictor variables. Accordingly, they recommend a more appropriate test that would search for differences in the IQ deficits according to lead level, where the IQ deficit is the difference between a child's observed IQ and the IQ predicted from all available information about the child aside from lead. This is especially appropriate when the lead exposure correlates with the family's educational background. We examined our data this way. 12 refs., 1 fig., 2 tabs.« less

Finding the rhythm of sudden cardiac death: new opportunities using induced pluripotent stem cell-derived cardiomyocytes.

PubMed

Sallam, Karim; Li, Yingxin; Sager, Philip T; Houser, Steven R; Wu, Joseph C

2015-06-05

Sudden cardiac death is a common cause of death in patients with structural heart disease, genetic mutations, or acquired disorders affecting cardiac ion channels. A wide range of platforms exist to model and study disorders associated with sudden cardiac death. Human clinical studies are cumbersome and are thwarted by the extent of investigation that can be performed on human subjects. Animal models are limited by their degree of homology to human cardiac electrophysiology, including ion channel expression. Most commonly used cellular models are cellular transfection models, which are able to mimic the expression of a single-ion channel offering incomplete insight into changes of the action potential profile. Induced pluripotent stem cell-derived cardiomyocytes resemble, but are not identical, adult human cardiomyocytes and provide a new platform for studying arrhythmic disorders leading to sudden cardiac death. A variety of platforms exist to phenotype cellular models, including conventional and automated patch clamp, multielectrode array, and computational modeling. Induced pluripotent stem cell-derived cardiomyocytes have been used to study long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy, and other hereditary cardiac disorders. Although induced pluripotent stem cell-derived cardiomyocytes are distinct from adult cardiomyocytes, they provide a robust platform to advance the science and clinical care of sudden cardiac death. © 2015 American Heart Association, Inc.

HETEROTYPIC INTERACTIONS ENABLED BY POLARIZED NEUTROPHIL MICRODOMAINS MEDIATE THROMBO-INFLAMMATORY INJURY

PubMed Central

Hidalgo, Andrés; Chang, Jungshan; Jang, Jung-Eun; Peired, Anna J.; Chiang, Elaine Y.; Frenette, Paul S.

2009-01-01

Selectins and their ligands mediate leukocyte rolling allowing interactions with chemokines that lead to integrin activation and arrest. Here, we demonstrate that E-selectin is critical to induce a secondary wave of activating signals transduced specifically by E-selectin ligand-1, that induces polarized, activated αMβ2 integrin clusters at the leading edge of crawling neutrophils, allowing the capture of circulating erythrocytes or platelets. In a humanized model of sickle cell disease (SCD), the capture of erythrocytes by αMβ2 microdomains leads to acute lethal vascular occlusions. In a model of transfusion-related acute lung injury, polarized neutrophils capture circulating platelets, resulting in the generation of oxidative species that produces vascular damage and lung injury. Inactivation of E-selectin or αMβ2 prevented tissue injury in both inflammatory models, suggesting broad implications of this paradigm in thrombo-inflammatory diseases. These results indicate that endothelial selectins can influence neutrophil behavior beyond its canonical rolling step through delayed, organ-damaging, polarized activation. PMID:19305412

Ethical issues when modelling brain disorders innon-human primates.

PubMed

Neuhaus, Carolyn P

2018-05-01

Non-human animal models of human diseases advance our knowledge of the genetic underpinnings of disease and lead to the development of novel therapies for humans. While mice are the most common model organisms, their usefulness is limited. Larger animals may provide more accurate and valuable disease models, but it has, until recently, been challenging to create large animal disease models. Genome editors, such as Clustered Randomised Interspersed Palindromic Repeat (CRISPR), meet some of these challenges and bring routine genome engineering of larger animals and non-human primates (NHPs) well within reach. There is growing interest in creating NHP models of brain disorders such as autism, depression and Alzheimer's, which are very difficult to model or study in other organisms, including humans. New treatments are desperately needed for this set of disorders. This paper is novel in asking: Insofar as NHPs are being considered for use as model organisms for brain disorders, can this be done ethically? The paper concludes that it cannot. Notwithstanding ongoing debate about NHPs' moral status, (1) animal welfare concerns, (2) the availability of alternative methods of studying brain disorders and (3) unmet expectations of benefit justify a stop on the creation of NHP model organisms to study brain disorders. The lure of using new genetic technologies combined with the promise of novel therapeutics presents a formidable challenge to those who call for slow, careful, and only necessary research involving NHPs. But researchers should not create macaques with social deficits or capuchin monkeys with memory deficits just because they can. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Saccharomyces cerevisiae show low levels of traversal across human endothelial barrier in vitro.

PubMed

Pérez-Torrado, Roberto; Querol, Amparo

2017-01-01

Background :   Saccharomyces cerevisiae is generally considered safe, and is involved in the production of many types of foods and dietary supplements. However, some isolates, which are genetically related to strains used in brewing and baking, have shown virulent traits, being able to produce infections in humans, mainly in immunodeficient patients. This can lead to systemic infections in humans. Methods : In this work, we studied S. cerevisiae isolates in an in vitro human endothelial barrier model, comparing their behaviour with that of several strains of the related pathogens Candida glabrata and Candida albicans . Results : The results showed that this food related yeast is able to cross the endothelial barrier in vitro . However, in contrast to C. glabrata and C. albicans , S. cerevisiae showed very low levels of traversal. Conclusions : We conclude that using an in vitro human endothelial barrier model with S. cerevisiae can be useful to evaluate the safety of S. cerevisiae strains isolated from foods.

Phenotypic outcomes in Mouse and Human Foxc1 dependent Dandy-Walker cerebellar malformation suggest shared mechanisms.

PubMed

Haldipur, Parthiv; Dang, Derek; Aldinger, Kimberly A; Janson, Olivia K; Guimiot, Fabien; Adle-Biasette, Homa; Dobyns, William B; Siebert, Joseph R; Russo, Rosa; Millen, Kathleen J

2017-01-16

FOXC1 loss contributes to Dandy-Walker malformation (DWM), a common human cerebellar malformation. Previously, we found that complete Foxc1 loss leads to aberrations in proliferation, neuronal differentiation and migration in the embryonic mouse cerebellum (Haldipur et al., 2014). We now demonstrate that hypomorphic Foxc1 mutant mice have granule and Purkinje cell abnormalities causing subsequent disruptions in postnatal cerebellar foliation and lamination. Particularly striking is the presence of a partially formed posterior lobule which echoes the posterior vermis DW 'tail sign' observed in human imaging studies. Lineage tracing experiments in Foxc1 mutant mouse cerebella indicate that aberrant migration of granule cell progenitors destined to form the posterior-most lobule causes this unique phenotype. Analyses of rare human del chr 6p25 fetal cerebella demonstrate extensive phenotypic overlap with our Foxc1 mutant mouse models, validating our DWM models and demonstrating that many key mechanisms controlling cerebellar development are likely conserved between mouse and human.

Next Generation Respiratory Viral Vaccine System: Advanced and Emerging Bioengineered Human Lung Epithelia Model (HLEM) Organoid Technology

NASA Technical Reports Server (NTRS)

Goodwin, Thomas J.; Schneider, Sandra L.; MacIntosh, Victor; Gibbons, Thomas F.

2010-01-01

Acute respiratory infections, including pneumonia and influenza, are the S t" leading cause of United States and worldwide deaths. Newly emerging pathogens signaled the need for an advanced generation of vaccine technology.. Human bronchial-tracheal epithelial tissue was bioengineered to detect, identify, host and study the pathogenesis of acute respiratory viral disease. The 3-dimensional (3D) human lung epithelio-mesechymal tissue-like assemblies (HLEM TLAs) share characteristics with human respiratory epithelium: tight junctions, desmosomes, microvilli, functional markers villin, keratins and production of tissue mucin. Respiratory Syntial Virus (RSV) studies demonstrate viral growth kinetics and membrane bound glycoproteins up to day 20 post infection in the human lung-orgainoid infected cell system. Peak replication of RSV occurred on day 10 at 7 log10 particles forming units per ml/day. HLEM is an advanced virus vaccine model and biosentinel system for emergent viral infectious diseases to support DoD global surveillance and military readiness.

Physiologically Based Pharmacokinetic Modeling in Lead Optimization. 1. Evaluation and Adaptation of GastroPlus To Predict Bioavailability of Medchem Series.

PubMed

Daga, Pankaj R; Bolger, Michael B; Haworth, Ian S; Clark, Robert D; Martin, Eric J

2018-03-05

When medicinal chemists need to improve bioavailability (%F) within a chemical series during lead optimization, they synthesize new series members with systematically modified properties mainly by following experience and general rules of thumb. More quantitative models that predict %F of proposed compounds from chemical structure alone have proven elusive. Global empirical %F quantitative structure-property (QSPR) models perform poorly, and projects have too little data to train local %F QSPR models. Mechanistic oral absorption and physiologically based pharmacokinetic (PBPK) models simulate the dissolution, absorption, systemic distribution, and clearance of a drug in preclinical species and humans. Attempts to build global PBPK models based purely on calculated inputs have not achieved the <2-fold average error needed to guide lead optimization. In this work, local GastroPlus PBPK models are instead customized for individual medchem series. The key innovation was building a local QSPR for a numerically fitted effective intrinsic clearance (CL loc ). All inputs are subsequently computed from structure alone, so the models can be applied in advance of synthesis. Training CL loc on the first 15-18 rat %F measurements gave adequate predictions, with clear improvements up to about 30 measurements, and incremental improvements beyond that.

Genetic and flow anomalies in congenital heart disease.

PubMed

Rugonyi, Sandra

2016-01-01

Congenital heart defects are the most common malformations in humans, affecting approximately 1% of newborn babies. While genetic causes of congenital heart disease have been studied, only less than 20% of human cases are clearly linked to genetic anomalies. The cause for the majority of the cases remains unknown. Heart formation is a finely orchestrated developmental process and slight disruptions of it can lead to severe malformations. Dysregulation of developmental processes leading to heart malformations are caused by genetic anomalies but also environmental factors including blood flow. Intra-cardiac blood flow dynamics plays a significant role regulating heart development and perturbations of blood flow lead to congenital heart defects in animal models. Defects that result from hemodynamic alterations, however, recapitulate those observed in human babies, even those due to genetic anomalies and toxic teratogen exposure. Because important cardiac developmental events, such as valve formation and septation, occur under blood flow conditions while the heart is pumping, blood flow regulation of cardiac formation might be a critical factor determining cardiac phenotype. The contribution of flow to cardiac phenotype, however, is frequently ignored. More research is needed to determine how blood flow influences cardiac development and the extent to which flow may determine cardiac phenotype.

Climate Induced Spillover and Implications for U.S. Security.

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

Tidwell, Vincent C.; Naugle, Asmeret Bier; Backus, George A.

Developing nations incur a greater risk to climate change than the developed world due to poorly managed human/natural resources, unreliable infrastructure and brittle governing/economic institutions. These vulnerabilities often give rise to a climate induced “domino effect” of reduced natural resource production-leading to economic hardship, social unrest, and humanitarian crises. Integral to this cascading set of events is increased human migration, leading to the “spillover” of impacts to adjoining areas with even broader impact on global markets and security. Given the complexity of factors influencing human migration and the resultant spill-over effect, quantitative tools are needed to aid policy analysis. Towardmore » this need, a series of migration models were developed along with a system dynamics model of the spillover effect. The migration decision models were structured according to two interacting paths, one that captured long-term “chronic” impacts related to protracted deteriorating quality of life and a second focused on short-term “acute” impacts of disaster and/or conflict. Chronic migration dynamics were modeled for two different cases; one that looked only at emigration but at a national level for the entire world; and a second that looked at both emigration and immigration but focused on a single nation. Model parameterization for each of the migration models was accomplished through regression analysis using decadal data spanning the period 1960-2010. A similar approach was taken with acute migration dynamics except regression analysis utilized annual data sets limited to a shorter time horizon (2001-2013). The system dynamics spillover model was organized around two broad modules, one simulating the decision dynamics of migration and a second module that treats the changing environmental conditions that influence the migration decision. The environmental module informs the migration decision, endogenously simulating interactions/changes in the economy, labor, population, conflict, water, and food. A regional model focused on Mali in western Africa was used as a test case to demonstrate the efficacy of the model.« less

Human population reduction is not a quick fix for environmental problems

PubMed Central

Bradshaw, Corey J. A.; Brook, Barry W.

2014-01-01

The inexorable demographic momentum of the global human population is rapidly eroding Earth’s life-support system. There are consequently more frequent calls to address environmental problems by advocating further reductions in human fertility. To examine how quickly this could lead to a smaller human population, we used scenario-based matrix modeling to project the global population to the year 2100. Assuming a continuation of current trends in mortality reduction, even a rapid transition to a worldwide one-child policy leads to a population similar to today’s by 2100. Even a catastrophic mass mortality event of 2 billion deaths over a hypothetical 5-y window in the mid-21st century would still yield around 8.5 billion people by 2100. In the absence of catastrophe or large fertility reductions (to fewer than two children per female worldwide), the greatest threats to ecosystems—as measured by regional projections within the 35 global Biodiversity Hotspots—indicate that Africa and South Asia will experience the greatest human pressures on future ecosystems. Humanity’s large demographic momentum means that there are no easy policy levers to change the size of the human population substantially over coming decades, short of extreme and rapid reductions in female fertility; it will take centuries, and the long-term target remains unclear. However, some reduction could be achieved by midcentury and lead to hundreds of millions fewer people to feed. More immediate results for sustainability would emerge from policies and technologies that reverse rising consumption of natural resources. PMID:25349398

Substantial differences between human and ovine mesenchymal stem cells in response to osteogenic media: how to explain and how to manage?

PubMed

Kalaszczynska, Ilona; Ruminski, Slawomir; Platek, Anna E; Bissenik, Igor; Zakrzewski, Piotr; Noszczyk, Maria; Lewandowska-Szumiel, Malgorzata

2013-10-01

It is expected that use of adult multipotential mesenchymal stem cells (MSCs) for bone tissue engineering (TE) will lead to improvement of TE products. Prior to clinical application, biocompatibility of bone TE products need to be tested in vitro and in vivo. In orthopedic research, sheep are a well-accepted model due to similarities with humans and are assumed to be predictive of human outcomes. In this study we uncover differences between human and ovine bone marrow-derived MSCs (BMSCs) and adipose tissue-derived MSCs (ADSCs) in response to osteogenic media. Osteogenic differentiation of BMSCs and ADSCs was monitored by alkaline phosphatase (ALP) activity and calcium deposition. Mineralization of ovine BMSC was achieved in medium containing NaH2PO4 as a source of phosphate ions (Pi), but not in medium containing β-glycerophosphate (β-GP), which is most often used. In a detailed study we found no induction of ALP activity in ovine BMSCs and ADSCs upon osteogenic stimulation, which makes β-GP an unsuitable source of phosphate ions for ovine cells. Moreover, mineralization of human ADSCs was more efficient in osteogenic medium containing NaH2PO4. These results indicate major differences between ovine and human MSCs and suggest that standard in vitro osteogenic differentiation techniques may not be suitable for all types of cells used in cell-based therapies. Since mineralization is a widely accepted marker of the osteogenic differentiation and maturation of cells in culture, it may lead to potentially misleading results and should be taken into account at the stage of planning and interpreting preclinical observations performed in animal models. We also present a cell culture protocol for ovine ADSCs, which do not express ALP activity and do not mineralize under routine pro-osteogenic conditions in vitro. We plan to apply it in preclinical experiments of bone tissue-engineered products performed in an ovine model.

Substantial Differences Between Human and Ovine Mesenchymal Stem Cells in Response to Osteogenic Media: How to Explain and How to Manage?

PubMed Central

Kalaszczynska, Ilona; Ruminski, Slawomir; Platek, Anna E.; Bissenik, Igor; Zakrzewski, Piotr; Noszczyk, Maria

2013-01-01

Abstract It is expected that use of adult multipotential mesenchymal stem cells (MSCs) for bone tissue engineering (TE) will lead to improvement of TE products. Prior to clinical application, biocompatibility of bone TE products need to be tested in vitro and in vivo. In orthopedic research, sheep are a well-accepted model due to similarities with humans and are assumed to be predictive of human outcomes. In this study we uncover differences between human and ovine bone marrow–derived MSCs (BMSCs) and adipose tissue–derived MSCs (ADSCs) in response to osteogenic media. Osteogenic differentiation of BMSCs and ADSCs was monitored by alkaline phosphatase (ALP) activity and calcium deposition. Mineralization of ovine BMSC was achieved in medium containing NaH2PO4 as a source of phosphate ions (Pi), but not in medium containing β-glycerophosphate (β-GP), which is most often used. In a detailed study we found no induction of ALP activity in ovine BMSCs and ADSCs upon osteogenic stimulation, which makes β-GP an unsuitable source of phosphate ions for ovine cells. Moreover, mineralization of human ADSCs was more efficient in osteogenic medium containing NaH2PO4. These results indicate major differences between ovine and human MSCs and suggest that standard in vitro osteogenic differentiation techniques may not be suitable for all types of cells used in cell-based therapies. Since mineralization is a widely accepted marker of the osteogenic differentiation and maturation of cells in culture, it may lead to potentially misleading results and should be taken into account at the stage of planning and interpreting preclinical observations performed in animal models. We also present a cell culture protocol for ovine ADSCs, which do not express ALP activity and do not mineralize under routine pro-osteogenic conditions in vitro. We plan to apply it in preclinical experiments of bone tissue–engineered products performed in an ovine model. PMID:24083091

Influenza Infects Lung Microvascular Endothelium Leading to Microvascular Leak: Role of Apoptosis and Claudin-5

PubMed Central

Armstrong, Susan M.; Wang, Changsen; Tigdi, Jayesh; Si, Xiaoe; Dumpit, Carlo; Charles, Steffany; Gamage, Asela; Moraes, Theo J.; Lee, Warren L.

2012-01-01

Severe influenza infections are complicated by acute lung injury, a syndrome of pulmonary microvascular leak. The pathogenesis of this complication is unclear. We hypothesized that human influenza could directly infect the lung microvascular endothelium, leading to loss of endothelial barrier function. We infected human lung microvascular endothelium with both clinical and laboratory strains of human influenza. Permeability of endothelial monolayers was assessed by spectrofluorimetry and by measurement of the transendothelial electrical resistance. We determined the molecular mechanisms of flu-induced endothelial permeability and developed a mouse model of severe influenza. We found that both clinical and laboratory strains of human influenza can infect and replicate in human pulmonary microvascular endothelium, leading to a marked increase in permeability. This was caused by apoptosis of the lung endothelium, since inhibition of caspases greatly attenuated influenza-induced endothelial leak. Remarkably, replication-deficient virus also caused a significant degree of endothelial permeability, despite displaying no cytotoxic effects to the endothelium. Instead, replication-deficient virus induced degradation of the tight junction protein claudin-5; the adherens junction protein VE-cadherin and the actin cytoskeleton were unaffected. Over-expression of claudin-5 was sufficient to prevent replication-deficient virus-induced permeability. The barrier-protective agent formoterol was able to markedly attenuate flu-induced leak in association with dose-dependent induction of claudin-5. Finally, mice infected with human influenza developed pulmonary edema that was abrogated by parenteral treatment with formoterol. Thus, we describe two distinct mechanisms by which human influenza can induce pulmonary microvascular leak. Our findings have implications for the pathogenesis and treatment of acute lung injury from severe influenza. PMID:23115643

Yeast Studies Lead to a New DNA-Based Model for Research on Development | Poster

Cancer.gov

A paper from Amar J. S. Klar, Ph.D., with the RNA Biology Laboratory in NCI’s Center for Cancer Research, has identified a model for DNA research that explains the congenital disorder of mirror hand movements in humans. A mirror movement is when an intentional movement on one side of the body is mirrored by an involuntary movement on the other.

A decision support system and rule-based algorithm to augment the human interpretation of the 12-lead electrocardiogram.

PubMed

Cairns, Andrew W; Bond, Raymond R; Finlay, Dewar D; Guldenring, Daniel; Badilini, Fabio; Libretti, Guido; Peace, Aaron J; Leslie, Stephen J

The 12-lead Electrocardiogram (ECG) has been used to detect cardiac abnormalities in the same format for more than 70years. However, due to the complex nature of 12-lead ECG interpretation, there is a significant cognitive workload required from the interpreter. This complexity in ECG interpretation often leads to errors in diagnosis and subsequent treatment. We have previously reported on the development of an ECG interpretation support system designed to augment the human interpretation process. This computerised decision support system has been named 'Interactive Progressive based Interpretation' (IPI). In this study, a decision support algorithm was built into the IPI system to suggest potential diagnoses based on the interpreter's annotations of the 12-lead ECG. We hypothesise semi-automatic interpretation using a digital assistant can be an optimal man-machine model for ECG interpretation. To improve interpretation accuracy and reduce missed co-abnormalities. The Differential Diagnoses Algorithm (DDA) was developed using web technologies where diagnostic ECG criteria are defined in an open storage format, Javascript Object Notation (JSON), which is queried using a rule-based reasoning algorithm to suggest diagnoses. To test our hypothesis, a counterbalanced trial was designed where subjects interpreted ECGs using the conventional approach and using the IPI+DDA approach. A total of 375 interpretations were collected. The IPI+DDA approach was shown to improve diagnostic accuracy by 8.7% (although not statistically significant, p-value=0.1852), the IPI+DDA suggested the correct interpretation more often than the human interpreter in 7/10 cases (varying statistical significance). Human interpretation accuracy increased to 70% when seven suggestions were generated. Although results were not found to be statistically significant, we found; 1) our decision support tool increased the number of correct interpretations, 2) the DDA algorithm suggested the correct interpretation more often than humans, and 3) as many as 7 computerised diagnostic suggestions augmented human decision making in ECG interpretation. Statistical significance may be achieved by expanding sample size. Copyright © 2017 Elsevier Inc. All rights reserved.

Maternal blood, plasma, and breast milk lead: lactational transfer and contribution to infant exposure.

PubMed

Ettinger, Adrienne S; Roy, Ananya; Amarasiriwardena, Chitra J; Smith, Donald; Lupoli, Nicola; Mercado-García, Adriana; Lamadrid-Figueroa, Hector; Tellez-Rojo, Martha Maria; Hu, Howard; Hernández-Avila, Mauricio

2014-01-01

Human milk is a potential source of lead exposure. Yet lactational transfer of lead from maternal blood into breast milk and its contribution to infant lead burden remains poorly understood. We explored the dose-response relationships between maternal blood, plasma, and breast milk to better understand lactational transfer of lead from blood and plasma into milk and, ultimately, to the breastfeeding infant. We measured lead in 81 maternal blood, plasma, and breast milk samples at 1 month postpartum and in 60 infant blood samples at 3 months of age. Milk-to-plasma (M/P) lead ratios were calculated. Multivariate linear, piecewise, and generalized additive models were used to examine dose-response relationships between blood, plasma, and milk lead levels. Maternal lead levels (mean±SD) were as follows: blood: 7.7±4.0 μg/dL; plasma: 0.1±0.1 μg/L; milk: 0.8±0.7 μg/L. The average M/P lead ratio was 7.7 (range, 0.6-39.8) with 97% of the ratios being >1. The dose-response relationship between plasma lead and M/P ratio was nonlinear (empirical distribution function=6.5, p=0.0006) with the M/P ratio decreasing by 16.6 and 0.6 per 0.1 μg/L of plasma lead, respectively, below and above 0.1 μg/L plasma lead. Infant blood lead level (3.4±2.2 μg/dL) increased by 1.8 μg/dL per 1 μg/L milk lead (p<0.0001, R2=0.3). The M/P ratio for lead in humans is substantially higher than previously reported, and transfer of lead from plasma to milk may be higher at lower levels of plasma lead. Breast milk is an important determinant of lead burden among breastfeeding infants.

Numerical bifurcation analysis of immunological models with time delays

NASA Astrophysics Data System (ADS)

Luzyanina, Tatyana; Roose, Dirk; Bocharov, Gennady

2005-12-01

In recent years, a large number of mathematical models that are described by delay differential equations (DDEs) have appeared in the life sciences. To analyze the models' dynamics, numerical methods are necessary, since analytical studies can only give limited results. In turn, the availability of efficient numerical methods and software packages encourages the use of time delays in mathematical modelling, which may lead to more realistic models. We outline recently developed numerical methods for bifurcation analysis of DDEs and illustrate the use of these methods in the analysis of a mathematical model of human hepatitis B virus infection.

Identification of anti-filarial leads against aspartate semialdehyde dehydrogenase of Wolbachia endosymbiont of Brugia malayi: combined molecular docking and molecular dynamics approaches.

PubMed

Amala, Mathimaran; Rajamanikandan, Sundaraj; Prabhu, Dhamodharan; Surekha, Kanagarajan; Jeyakanthan, Jeyaraman

2018-02-06

Lymphatic filariasis is a debilitating vector borne parasitic disease that infects human lymphatic system by nematode Brugia malayi. Currently available anti-filarial drugs are effective only on the larval stages of parasite. So far, no effective drugs are available for humans to treat filarial infections. In this regard, aspartate semialdehyde dehydrogenase (ASDase) in lysine biosynthetic pathway from Wolbachia endosymbiont Brugia malayi represents an attractive therapeutic target for the development of novel anti-filarial agents. In this present study, molecular modeling combined with molecular dynamics simulations and structure-based virtual screening were performed to identify potent lead molecules against ASDase. Based on Glide score, toxicity profile, binding affinity and mode of interactions with the ASDase, five potent lead molecules were selected. The molecular docking and dynamics results revealed that the amino acid residues Arg103, Asn133, Cys134, Gln161, Ser164, Lys218, Arg239, His246, and Asn321 plays a crucial role in effective binding of Top leads into the active site of ASDase. The stability of the ASDase-lead complexes was confirmed by running the 30 ns molecular dynamics simulations. The pharmacokinetic properties of the identified lead molecules are in the acceptable range. Furthermore, density functional theory and binding free energy calculations were performed to rank the lead molecules. Thus, the identified lead molecules can be used for the development of anti-filarial agents to combat the pathogenecity of Brugia malayi.

Longitudinal driver model and collision warning and avoidance algorithms based on human driving databases

NASA Astrophysics Data System (ADS)

Lee, Kangwon

Intelligent vehicle systems, such as Adaptive Cruise Control (ACC) or Collision Warning/Collision Avoidance (CW/CA), are currently under development, and several companies have already offered ACC on selected models. Control or decision-making algorithms of these systems are commonly evaluated under extensive computer simulations and well-defined scenarios on test tracks. However, they have rarely been validated with large quantities of naturalistic human driving data. This dissertation utilized two University of Michigan Transportation Research Institute databases (Intelligent Cruise Control Field Operational Test and System for Assessment of Vehicle Motion Environment) in the development and evaluation of longitudinal driver models and CW/CA algorithms. First, to examine how drivers normally follow other vehicles, the vehicle motion data from the databases were processed using a Kalman smoother. The processed data was then used to fit and evaluate existing longitudinal driver models (e.g., the linear follow-the-leader model, the Newell's special model, the nonlinear follow-the-leader model, the linear optimal control model, the Gipps model and the optimal velocity model). A modified version of the Gipps model was proposed and found to be accurate in both microscopic (vehicle) and macroscopic (traffic) senses. Second, to examine emergency braking behavior and to evaluate CW/CA algorithms, the concepts of signal detection theory and a performance index suitable for unbalanced situations (few threatening data points vs. many safe data points) are introduced. Selected existing CW/CA algorithms were found to have a performance index (geometric mean of true-positive rate and precision) not exceeding 20%. To optimize the parameters of the CW/CA algorithms, a new numerical optimization scheme was developed to replace the original data points with their representative statistics. A new CW/CA algorithm was proposed, which was found to score higher than 55% in the performance index. This dissertation provides a model of how drivers follow lead-vehicles that is much more accurate than other models in the literature. Furthermore, the data-based approach was used to confirm that a CW/CA algorithm utilizing lead-vehicle braking was substantially more effective than existing algorithms, leading to collision warning systems that are much more likely to contribute to driver safety.

A Comparison of Pathophysiology in Humans and Rodent Models of Subarachnoid Hemorrhage

PubMed Central

Leclerc, Jenna L.; Garcia, Joshua M.; Diller, Matthew A.; Carpenter, Anne-Marie; Kamat, Pradip K.; Hoh, Brian L.; Doré, Sylvain

2018-01-01

Non-traumatic subarachnoid hemorrhage (SAH) affects an estimated 30,000 people each year in the United States, with an overall mortality of ~30%. Most cases of SAH result from a ruptured intracranial aneurysm, require long hospital stays, and result in significant disability and high fatality. Early brain injury (EBI) and delayed cerebral vasospasm (CV) have been implicated as leading causes of morbidity and mortality in these patients, necessitating intense focus on developing preclinical animal models that replicate clinical SAH complete with delayed CV. Despite the variety of animal models currently available, translation of findings from rodent models to clinical trials has proven especially difficult. While the explanation for this lack of translation is unclear, possibilities include the lack of standardized practices and poor replication of human pathophysiology, such as delayed cerebral vasospasm and ischemia, in rodent models of SAH. In this review, we summarize the different approaches to simulating SAH in rodents, in particular elucidating the key pathophysiology of the various methods and models. Ultimately, we suggest the development of standardized model of rodent SAH that better replicates human pathophysiology for moving forward with translational research. PMID:29623028

Mouse-based genetic modeling and analysis of Down syndrome

PubMed Central

Xing, Zhuo; Li, Yichen; Pao, Annie; Bennett, Abigail S.; Tycko, Benjamin; Mobley, William C.; Yu, Y. Eugene

2016-01-01

Introduction Down syndrome (DS), caused by human trisomy 21 (Ts21), can be considered as a prototypical model for understanding the effects of chromosomal aneuploidies in other diseases. Human chromosome 21 (Hsa21) is syntenically conserved with three regions in the mouse genome. Sources of data A review of recent advances in genetic modeling and analysis of DS. Using Cre/loxP-mediated chromosome engineering, a substantial number of new mouse models of DS have recently been generated, which facilitates better understanding of disease mechanisms in DS. Areas of agreement Based on evolutionary conservation, Ts21 can be modeled by engineered triplication of Hsa21 syntenic regions in mice. The validity of the models is supported by the exhibition of DS-related phenotypes. Areas of controversy Although substantial progress has been made, it remains a challenge to unravel the relative importance of specific candidate genes and molecular mechanisms underlying the various clinical phenotypes. Growing points Further understanding of mechanisms based on data from mouse models, in parallel with human studies, may lead to novel therapies for clinical manifestations of Ts21 and insights to the roles of aneuploidies in other developmental disorders and cancers. PMID:27789459

Computational tools for comparative phenomics; the role and promise of ontologies

PubMed Central

Gkoutos, Georgios V.; Schofield, Paul N.; Hoehndorf, Robert

2012-01-01

A major aim of the biological sciences is to gain an understanding of human physiology and disease. One important step towards such a goal is the discovery of the function of genes that will lead to better understanding of the physiology and pathophysiology of organisms ultimately providing better understanding, diagnosis, and therapy. Our increasing ability to phenotypically characterise genetic variants of model organisms coupled with systematic and hypothesis-driven mutagenesis is resulting in a wealth of information that could potentially provide insight to the functions of all genes in an organism. The challenge we are now facing is to develop computational methods that can integrate and analyse such data. The introduction of formal ontologies that make their semantics explicit and accessible to automated reasoning promises the tantalizing possibility of standardizing biomedical knowledge allowing for novel, powerful queries that bridge multiple domains, disciplines, species and levels of granularity. We review recent computational approaches that facilitate the integration of experimental data from model organisms with clinical observations in humans. These methods foster novel cross species analysis approaches, thereby enabling comparative phenomics and leading to the potential of translating basic discoveries from the model systems into diagnostic and therapeutic advances at the clinical level. PMID:22814867

Genomic Insights into Cardiomyopathies: A Comparative Cross-Species Review

PubMed Central

Simpson, Siobhan; Rutland, Paul; Rutland, Catrin Sian

2017-01-01

In the global human population, the leading cause of non-communicable death is cardiovascular disease. It is predicted that by 2030, deaths attributable to cardiovascular disease will have risen to over 20 million per year. This review compares the cardiomyopathies in both human and non-human animals and identifies the genetic associations for each disorder in each species/taxonomic group. Despite differences between species, advances in human medicine can be gained by utilising animal models of cardiac disease; likewise, gains can be made in animal medicine from human genomic insights. Advances could include undertaking regular clinical checks in individuals susceptible to cardiomyopathy, genetic testing prior to breeding, and careful administration of breeding programmes (in non-human animals), further development of treatment regimes, and drugs and diagnostic techniques. PMID:29056678

Human heart failure with preserved ejection versus feline cardiomyopathy: what can we learn from both veterinary and human medicine?

PubMed

Prat, Valentine; Rozec, Bertrand; Gauthier, Chantal; Lauzier, Benjamin

2017-11-01

Cardiovascular affections are a growing health burden in human populations. Recent advances in cardiology have improved treatments and outcomes for myocardial infarction and arrhythmias, but other conditions still remain poorly understood. To date, the classical approach to study cardiovascular diseases involves rodent models, despite their strong differences with human cardiac physiology. In this context, this review will focus on the common traits between human and feline cardiac diseases, namely heart failure with preserved ejection fraction and feline cardiomyopathies, respectively. These two affections share similar pathological patterns and epidemiological characteristics. An improved knowledge would be of interest for both human and feline patients and could lead to the establishment of a more accurate treatment and therapeutic strategy for medical doctors and veterinary practitioners.

Development of a 3D co-culture model using human stem cells for studying embryonic palatal fusion.

EPA Science Inventory

Morphogenetic tissue fusion is a critical and complex event in embryonic development and failure of this event leads to birth defects, such as cleft palate. Palatal fusion requires adhesion and subsequent dissolution of the medial epithelial layer of the mesenchymal palatal shelv...

A PBPK MODEL FOR EVALUATING THE IMPACT OF ALDEHYDE DEHYDROGENASE POLYMORPHISMS ON COMPARATIVE RAT AND HUMAN NASAL TISSUE ACETALDEHYDE DOSIMETRY

EPA Science Inventory

ABSTRACT: Acetaldehyde is an important intermediate in chemical synthesis and a byproduct of normal oxidative metabolism of several industrially important compounds including ethanol, ethyl acetate and vinyl acetate. Chronic inhalation of acetaldehyde leads to degeneratio...

Assessing the benefits and economic values of trees

Treesearch

David J. Nowak

2017-01-01

Understanding the environmental, economic, and social/community benefits of nature, in particular trees and forests, can lead to better vegetation management and designs to optimize environmental quality and human health for current and future generations. Computer models have been developed to assess forest composition and its associated effects on environmental...

Neurodevelopment and Thyroid Hormone Synthesis Inhibition in the Rat: Quantitative Understanding Within the Adverse Outcome Pathway Framework

EPA Science Inventory

Adequate levels of thyroid hormones (TH) are needed for proper brain development, deficiencies may lead to adverse neurological outcomes in humans and animal models. Environmental chemicals have been linked to TH disruption, yet the relationship between developmental exposures an...

A Conceptual Framework to Address Stress-Associated Human Health Effects of Ecosystem Services Degraded by Disasters

EPA Science Inventory

Chronic stress leads to a variety of mental and physiological disorders, and stress effects are the primary concern after traumatic injury and exposure to infectious diseases or toxic agents from disaster events. We developed a conceptual model to address the question of whether...

Occupational Constraints and Opportunities Faced by School Dropouts

ERIC Educational Resources Information Center

Kim, Kyung-Nyun

2015-01-01

This study investigated the relation between building human capital of former dropouts and their occupational standing and the interaction effects with individual characteristics. By applying the growth curve model, this study highlighted the factors that lead high school dropouts to enhance their occupational standing. An increment in the work…

A PBPK model for evaluating the impact of aldehyde dehydrogenase polymorphisms on comparative rat and human nasal tissue acetaldehyde dosimetry*

EPA Science Inventory

Acetaldehyde is an important intermediate in the chemical synthesis and normal oxidative metabolism of several industrially important compounds, including ethanol, ethyl acetate, and vinyl acetate. Chronic inhalation of acetaldehyde leads to degeneration of the olfactory and resp...

Evaluation of Pharmacokinetic Models for the Disposition of Lead (Pb) in Humans, in Support of Application to Occupational Exposure Limit Derivation

DTIC Science & Technology

2015-11-09

as biokinetic or physiologically-based pharmacokinetic (PBPK) models, can readily incorporate multiple routes of exposure (e.g., baseline dietary ...1998) and in the code provided as a supplement to O’Flaherty (2000), as noted above. An aspect of the O’Flaherty model that contrasts to the... dietary Pb; a stable Pb isotope was substituted for some of the dietary Pb for limited periods. Tracer Pb concentrations were measured in blood

Preclinical models of Graves' disease and associated secondary complications.

PubMed

Moshkelgosha, Sajad; So, Po-Wah; Diaz-Cano, Salvador; Banga, J Paul

2015-01-01

Autoimmune thyroid disease is the most common organ-specific autoimmune disorder which consists of two opposing clinical syndromes, Hashimoto's thyroiditis and Graves' (hyperthyroidism) disease. Graves' disease is characterized by goiter, hyperthyroidism, and the orbital complication known as Graves' orbitopathy (GO), or thyroid eye disease. The hyperthyroidism in Graves' disease is caused by stimulation of function of thyrotropin hormone receptor (TSHR), resulting from the production of agonist antibodies to the receptor. A variety of induced mouse models of Graves' disease have been developed over the past two decades, with some reproducible models leading to high disease incidence of autoimmune hyperthyroidism. However, none of the models show any signs of the orbital manifestation of GO. We have recently developed an experimental mouse model of GO induced by immunization of the plasmid encoded ligand binding domain of human TSHR cDNA by close field electroporation that recapitulates the orbital pathology in GO. As in human GO patients, immune mice with hyperthyroid or hypothyroid disease induced by anti-TSHR antibodies exhibited orbital pathology and chemosis, characterized by inflammation of orbital muscles and extensive adipogenesis leading to expansion of the orbital retrobulbar space. Magnetic resonance imaging of the head region in immune mice showed a significant expansion of the orbital space, concurrent with proptosis. This review discusses the different strategies for developing mouse models in Graves' disease, with a particular focus on GO. Furthermore, it outlines how this new model will facilitate molecular investigations into pathophysiology of the orbital disease and evaluation of new therapeutic interventions.

Immune Response to Human Metapneumovirus Infection: What We Have Learned from the Mouse Model

PubMed Central

Cheemarla, Nagarjuna R.; Guerrero-Plata, Antonieta

2015-01-01

Human Metapneumovirus (hMPV) is a leading respiratory viral pathogen associated with bronchiolitis, pneumonia, and asthma exacerbation in young children, the elderly and immunocompromised individuals. The development of a potential vaccine against hMPV requires detailed understanding of the host immune system, which plays a significant role in hMPV pathogenesis, susceptibility and vaccine efficacy. As a result, animal models have been developed to better understand the mechanisms by which hMPV causes disease. Several animal models have been evaluated and established so far to study the host immune responses and pathophysiology of hMPV infection. However, inbred laboratory mouse strains have been one of the most used animal species for experimental modeling and therefore used for the studies of immunity and immunopathogenesis to hMPV. This review summarizes the contributions of the mouse model to our understanding of the immune response against hMPV infection. PMID:26393657

Immune Response to Human Metapneumovirus Infection: What We Have Learned from the Mouse Model.

PubMed

Cheemarla, Nagarjuna R; Guerrero-Plata, Antonieta

2015-09-18

Human Metapneumovirus (hMPV) is a leading respiratory viral pathogen associated with bronchiolitis, pneumonia, and asthma exacerbation in young children, the elderly and immunocompromised individuals. The development of a potential vaccine against hMPV requires detailed understanding of the host immune system, which plays a significant role in hMPV pathogenesis, susceptibility and vaccine efficacy. As a result, animal models have been developed to better understand the mechanisms by which hMPV causes disease. Several animal models have been evaluated and established so far to study the host immune responses and pathophysiology of hMPV infection. However, inbred laboratory mouse strains have been one of the most used animal species for experimental modeling and therefore used for the studies of immunity and immunopathogenesis to hMPV. This review summarizes the contributions of the mouse model to our understanding of the immune response against hMPV infection.

Intelligence: Real or artificial?

PubMed Central

Schlinger, Henry D.

1992-01-01

Throughout the history of the artificial intelligence movement, researchers have strived to create computers that could simulate general human intelligence. This paper argues that workers in artificial intelligence have failed to achieve this goal because they adopted the wrong model of human behavior and intelligence, namely a cognitive essentialist model with origins in the traditional philosophies of natural intelligence. An analysis of the word “intelligence” suggests that it originally referred to behavior-environment relations and not to inferred internal structures and processes. It is concluded that if workers in artificial intelligence are to succeed in their general goal, then they must design machines that are adaptive, that is, that can learn. Thus, artificial intelligence researchers must discard their essentialist model of natural intelligence and adopt a selectionist model instead. Such a strategic change should lead them to the science of behavior analysis. PMID:22477051

Rosmarinic Acid Restores Complete Transparency of Sonicated Human Cataract Ex Vivo and Delays Cataract Formation In Vivo.

PubMed

Chemerovski-Glikman, Marina; Mimouni, Michael; Dagan, Yarden; Haj, Esraa; Vainer, Igor; Allon, Raviv; Blumenthal, Eytan Z; Adler-Abramovich, Lihi; Segal, Daniel; Gazit, Ehud; Zayit-Soudry, Shiri

2018-06-19

Cataract, the leading cause of vision impairment worldwide, arises from abnormal aggregation of crystallin lens proteins. Presently, surgical removal is the only therapeutic approach. Recent findings have triggered renewed interest in development of non-surgical treatment alternatives. However, emerging treatments are yet to achieve full and consistent lens clearance. Here, the first ex vivo assay to screen for drug candidates that reduce human lenticular protein aggregation was developed. This assay allowed the identification of two leading compounds as facilitating the restoration of nearly-complete transparency of phacoemulsified cataractous preparation ex vivo. Mechanistic studies demonstrated that both compounds reduce cataract microparticle size and modify their amyloid-like features. In vivo studies confirmed that the lead compound, rosmarinic acid, delays cataract formation and reduces the severity of lens opacification in model rats. Thus, the ex vivo assay may provide an initial platform for broad screening of potential novel therapeutic agents towards pharmacological treatment of cataract.

Development of Lead Hammerhead Ribozyme Candidates against Human Rod Opsin mRNA for Retinal Degeneration Therapy

PubMed Central

Abdelmaksoud, Heba E.; Yau, Edwin H.; Zuker, Michael; Sullivan, Jack M.

2011-01-01

To identify lead candidate allele-independent hammerhead ribozymes (hhRz) for the treatment of autosomal dominant mutations in the human rod opsin (RHO) gene, we tested a series of hhRzs for potential to significantly knockdown human RHO gene expression in a human cell expression system. Multiple computational criteria were used to select target mRNA regions likely to be single stranded and accessible to hhRz annealing and cleavage. Target regions are tested for accessibility in a human cell culture expression system where the hhRz RNA and target mRNA and protein are coexpressed. The hhRz RNA is embedded in an adenoviral VAI RNA chimeric RNA of established structure and properties which are critical to the experimental paradigm. The chimeric hhRz-VAI RNA is abundantly transcribed so that the hhRzs are expected to be in great excess over substrate mRNA. HhRz-VAI traffics predominantly to the cytoplasm to colocalize with the RHO mRNA target. Colocalization is essential for second-order annealing reactions. The VAI chimera protects the hhRz RNA from degradation and provides for a long half life. With cell lines chosen for high transfection efficiency and a molar excess of hhRz plasmid over target plasmid, the conditions of this experimental paradigm are specifically designed to evaluate for regions of accessibility of the target mRNA in cellulo. Western analysis was used to measure the impact of hhRz expression on RHO protein expression. Three lead candidate hhRz designs were identified that significantly knockdown target protein expression relative to control (p < 0.05). Successful lead candidates (hhRz CUC↓ 266, hhRz CUC↓ 1411, hhRz AUA↓ 1414) targeted regions of human RHO mRNA that were predicted to be accessible by a bioinformatics approach, whereas regions predicted to be inaccessible supported no knockdown. The maximum opsin protein level knockdown is approximately 30% over a 48 hr paradigm of testing. These results validate a rigorous computational bioinformatics approach to detect accessible regions of target mRNAs in cellulo. The opsin knockdown effect could prove to be clinically significant when integrated over longer periods in photoreceptors. Further optimization and animal testing is the next step in this stratified RNA drug discovery program. A recently developed novel and efficient screening assay based upon expression of a dicistronic mRNA (RHO-IRES-SEAP) containing both RHO and reporter (SEAP) cDNAs was used to compare the hhRz 266 lead candidate to another agent (Rz525/hhRz485) already known to partially rescue retinal degeneration in a rodent model. Lead hhRz 266 CUC↓ proved more efficacious than Rz525/hhRz485 which infers viability for rescue of retinal degeneration in appropriate preclinical models of disease. PMID:19094986

Pathogen survival trajectories: an eco-environmental approach to the modeling of human campylobacteriosis ecology.

PubMed Central

Skelly, Chris; Weinstein, Phil

2003-01-01

Campylobacteriosis, like many human diseases, has its own ecology in which the propagation of human infection and disease depends on pathogen survival and finding new hosts in order to replicate and sustain the pathogen population. The complexity of this process, a process common to other enteric pathogens, has hampered control efforts. Many unknowns remain, resulting in a poorly understood disease ecology. To provide structure to these unknowns and help direct further research and intervention, we propose an eco-environmental modeling approach for campylobacteriosis. This modeling approach follows the pathogen population as it moves through the environments that define the physical structure of its ecology. In this paper, we term the ecologic processes and environments through which these populations move "pathogen survival trajectories." Although such a modeling approach could have veterinary applications, our emphasis is on human campylobacteriosis and focuses on human exposures to Campylobacter through feces, food, and aquatic environments. The pathogen survival trajectories that lead to human exposure include ecologic filters that limit population size, e.g., cooking food to kill Campylobacter. Environmental factors that influence the size of the pathogen reservoirs include temperature, nutrient availability, and moisture availability during the period of time the pathogen population is moving through the environment between infected and susceptible hosts. We anticipate that the modeling approach proposed here will work symbiotically with traditional epidemiologic and microbiologic research to help guide and evaluate the acquisition of new knowledge about the ecology, eventual intervention, and control of campylobacteriosis. PMID:12515674

Simulation of light transport in arthritic- and non-arthritic human fingers

NASA Astrophysics Data System (ADS)

Milanic, Matija; Paluchowski, Lukasz A.; Randeberg, Lise L.

2014-03-01

Rheumatoid arthritis is a disease that frequently leads to joint destruction. It has high incidence rates worldwide, and the disease significantly reduces patient's quality of life due to pain, swelling and stiffness of the affected joints. Early diagnosis is necessary to improve course of the disease, therefore sensitive and accurate diagnostic tools are required. Optical imaging techniques have capability for early diagnosis and monitoring of arthritis. As compared to conventional diagnostic techniques optical technique is a noninvasive, noncontact and fast way of collecting diagnostic information. However, a realistic model of light transport in human joints is needed for understanding and developing of such optical diagnostic tools. The aim of this study is to develop a 3D numerical model of light transport in a human finger. The model will guide development of a hyperspectral imaging (HSI) diagnostic modality for arthritis in human fingers. The implemented human finger geometry is based on anatomical data. Optical data of finger tissues are adjusted to represent either an arthritic or an unaffected finger. The geometry and optical data serve as input into a 3D Monte Carlo method, which calculate diffuse reflectance, transmittance and absorbed energy distributions. The parameters of the model are optimized based on HIS-measurements of human fingers. The presented model serves as an important tool for understanding and development of HSI as an arthritis diagnostic modality. Yet, it can be applied to other optical techniques and finger diseases.

Lead exposure potentiates predatory attack behavior in the cat.

PubMed

Li, Wenjie; Han, Shenggao; Gregg, Thomas R; Kemp, Francis W; Davidow, Amy L; Louria, Donald B; Siegel, Allan; Bogden, John D

2003-07-01

Epidemiologic studies have demonstrated that environmental lead exposure is associated with aggressive behavior in children; however, numerous confounding variables limit the ability of these studies to establish a causal relationship. The study of aggressive behavior using a validated animal model was used to test the hypothesis that there is a causal relationship between lead exposure and aggression in the absence of confounding variables. We studied the effects of lead exposure on a feline model of aggression: predatory (quiet biting) attack of an anesthetized rat. Five cats were stimulated with a precisely controlled electrical current via electrodes inserted into the lateral hypothalamus. The response measure was the predatory attack threshold current (i.e., the current required to elicit an attack response on 50% of the trials). Blocks of trials were administered in which predatory attack threshold currents were measured three times a week for a total of 6-10 weeks, including before, during, and after lead exposure. Lead was incorporated into cat food "treats" at doses of 50-150 mg/kg/day. Two of the five cats received a second period of lead exposure. Blood lead concentrations were measured twice a week and were <1, 21-77, and <20 micro g/dL prior to, during, and after lead exposure, respectively. The predatory attack threshold decreased significantly during initial lead exposure in three of five cats and increased after the cessation of lead exposure in four of the five cats (P<0.01). The predatory attack thresholds and blood lead concentrations for each cat were inversely correlated (r=-0.35 to -0.74). A random-effects mixed model demonstrated a significant (P=0.0019) negative association between threshold current and blood lead concentration. The data of this study demonstrate that lead exposure enhances predatory aggression in the cat and provide experimental support for a causal relationship between lead exposure and aggressive behavior in humans.

A Novel Antibody Humanization Method Based on Epitopes Scanning and Molecular Dynamics Simulation

PubMed Central

Zhao, Bin-Bin; Gong, Lu-Lu; Jin, Wen-Jing; Liu, Jing-Jun; Wang, Jing-Fei; Wang, Tian-Tian; Yuan, Xiao-Hui; He, You-Wen

2013-01-01

1-17-2 is a rat anti-human DEC-205 monoclonal antibody that induces internalization and delivers antigen to dendritic cells (DCs). The potentially clinical application of this antibody is limited by its murine origin. Traditional humanization method such as complementarity determining regions (CDRs) graft often leads to a decreased or even lost affinity. Here we have developed a novel antibody humanization method based on computer modeling and bioinformatics analysis. First, we used homology modeling technology to build the precise model of Fab. A novel epitope scanning algorithm was designed to identify antigenic residues in the framework regions (FRs) that need to be mutated to human counterpart in the humanization process. Then virtual mutation and molecular dynamics (MD) simulation were used to assess the conformational impact imposed by all the mutations. By comparing the root-mean-square deviations (RMSDs) of CDRs, we found five key residues whose mutations would destroy the original conformation of CDRs. These residues need to be back-mutated to rescue the antibody binding affinity. Finally we constructed the antibodies in vitro and compared their binding affinity by flow cytometry and surface plasmon resonance (SPR) assay. The binding affinity of the refined humanized antibody was similar to that of the original rat antibody. Our results have established a novel method based on epitopes scanning and MD simulation for antibody humanization. PMID:24278299

Controlled fire use in early humans might have triggered the evolutionary emergence of tuberculosis.

PubMed

Chisholm, Rebecca H; Trauer, James M; Curnoe, Darren; Tanaka, Mark M

2016-08-09

Tuberculosis (TB) is caused by the Mycobacterium tuberculosis complex (MTBC), a wildly successful group of organisms and the leading cause of death resulting from a single bacterial pathogen worldwide. It is generally accepted that MTBC established itself in human populations in Africa and that animal-infecting strains diverged from human strains. However, the precise causal factors of TB emergence remain unknown. Here, we propose that the advent of controlled fire use in early humans created the ideal conditions for the emergence of TB as a transmissible disease. This hypothesis is supported by mathematical modeling together with a synthesis of evidence from epidemiology, evolutionary genetics, and paleoanthropology.

Collaborative Biomechanics Data Network (CBDN): Promoting Human Protection and Performance in Hazardous Environments Through Modeling and Data Mining of Human-Centric Data Bases

DTIC Science & Technology

2011-09-01

unique data requirements. For an excellent primer on the CBDN process see Keller and Plaga [2010]. This report shows an example of a database, in...data [Buhrman, Plaga , Cheng, Mosher, 2001]. 2.1.2.2 Web application development All technologies are based upon and run on top of the .NET...builds). Better manikin design leads to better assessment of personnel equipment under acceleration [such as helmet systems, see Plaga and Boehmer

Selective destruction of mouse islet beta cells by human T lymphocytes in a newly-established humanized type 1 diabetic model

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

Zhao, Yong, E-mail: yongzhao@uic.edu; Guo, Chengshan; Hwang, David

2010-09-03

Research highlights: {yields} Establish a human immune-mediated type 1 diabetic model in NOD-scid IL2r{gamma}{sup null} mice. {yields} Using the irradiated diabetic NOD mouse spleen mononuclear cells as trigger. {yields} The islet {beta} cells were selectively destroyed by infiltrated human T cells. {yields} The model can facilitate translational research to find a cure for type 1 diabetes. -- Abstract: Type 1 diabetes (T1D) is caused by a T cell-mediated autoimmune response that leads to the loss of insulin-producing {beta} cells. The optimal preclinical testing of promising therapies would be aided by a humanized immune-mediated T1D model. We develop this model inmore » NOD-scid IL2r{gamma}{sup null} mice. The selective destruction of pancreatic islet {beta} cells was mediated by human T lymphocytes after an initial trigger was supplied by the injection of irradiated spleen mononuclear cells (SMC) from diabetic nonobese diabetic (NOD) mice. This resulted in severe insulitis, a marked loss of total {beta}-cell mass, and other related phenotypes of T1D. The migration of human T cells to pancreatic islets was controlled by the {beta} cell-produced highly conserved chemokine stromal cell-derived factor 1 (SDF-1) and its receptor C-X-C chemokine receptor (CXCR) 4, as demonstrated by in vivo blocking experiments using antibody to CXCR4. The specificity of humanized T cell-mediated immune responses against islet {beta} cells was generated by the local inflammatory microenvironment in pancreatic islets including human CD4{sup +} T cell infiltration and clonal expansion, and the mouse islet {beta}-cell-derived CD1d-mediated human iNKT activation. The selective destruction of mouse islet {beta} cells by a human T cell-mediated immune response in this humanized T1D model can mimic those observed in T1D patients. This model can provide a valuable tool for translational research into T1D.« less

Human-animal chimera: a neuro driven discussion? Comparison of three leading European research countries.

PubMed

Cabrera Trujillo, Laura Yenisa; Engel-Glatter, Sabrina

2015-06-01

Research with human-animal chimera raises a number of ethical concerns, especially when neural stem cells are transplanted into the brains of non-human primates (NHPs). Besides animal welfare concerns and ethical issues associated with the use of embryonic stem cells, the research is also regarded as controversial from the standpoint of NHPs developing cognitive or behavioural capabilities that are regarded as "unique" to humans. However, scientists are urging to test new therapeutic approaches for neurological diseases in primate models as they better mimic human physiology than all current animal models. As a response, various countries have issued reports on the topic. Our paper summarizes the ethical issues raised by research with human-animal brain chimeras and compares the relevant regulatory instruments and different recommendations issued in national reports from three important European research nations: Germany, Switzerland and the United Kingdom. We assess and discuss the focus and priorities set by the different reports, review various reasons for and perspectives on the importance of the brain in chimera research, and identify critical points in the reports that warrant further specification and debate.

Influence of Permeant Lipophilicity on Permeation Across Human Sclera

PubMed Central

Wen, He; Li, S. Kevin

2010-01-01

Purpose The objectives of this study were to determine the effects of permeant lipophilicity on permeant uptake into and transport across human sclera for transscleral delivery. Methods Model permeants with a wide range of lipophilicities were selected and studied with human sclera. Uptake experiments were carried out to measure permeant partitioning into the sclera. Transport experiments were performed in side-by-side diffusion cells, and the permeability coefficients and transport lag times of the permeants across the sclera were evaluated. Results Permeants with higher lipophilicity showed higher partition coefficients to human sclera, and the apparent transport lag time also increased significantly as the permeant lipophilicity increased. No correlation between the permeability coefficients and lipophilicity of the model permeants was observed in this study with human sclera. A hypothesis on the different findings between the present and previous studies was proposed. Conclusions Permeants with higher lipophilicity exhibited stronger binding to human sclera and would therefore lead to larger permeant partitioning to the sclera and longer transport lag time. The steady-state permeability coefficients of the permeants were not significantly affected by permeant lipophilicity. PMID:20734114

We Are Not Alone: The iMOP Initiative and Its Roles in a Biology- and Disease-Driven Human Proteome Project.

PubMed

Tholey, Andreas; Taylor, Nicolas L; Heazlewood, Joshua L; Bendixen, Emøke

2017-12-01

Mapping of the human proteome has advanced significantly in recent years and will provide a knowledge base to accelerate our understanding of how proteins and protein networks can affect human health and disease. However, providing solutions to human health challenges will likely fail if insights are exclusively based on studies of human samples and human proteomes. In recent years, it has become evident that human health depends on an integrated understanding of the many species that make human life possible. These include the commensal microorganisms that are essential to human life, pathogens, and food species as well as the classic model organisms that enable studies of biological mechanisms. The Human Proteome Organization (HUPO) initiative on multiorganism proteomes (iMOP) works to support proteome research undertaken on nonhuman species that remain widely under-studied compared with the progress in human proteome research. This perspective argues the need for further research on multiple species that impact human life. We also present an update on recent progress in model organisms, microbiota, and food species, address the emerging problem of antibiotics resistance, and outline how iMOP activities could lead to a more inclusive approach for the human proteome project (HPP) to better support proteome research aimed at improving human health and furthering knowledge on human biology.

Application of in Vitro Biotransformation Data and ...

EPA Pesticide Factsheets

The adverse biological effects of toxic substances are dependent upon the exposure concentration and the duration of exposure. Pharmacokinetic models can quantitatively relate the external concentration of a toxicant in the environment to the internal dose of the toxicant in the target tissues of an exposed organism. The exposure concentration of a toxic substance is usually not the same as the concentration of the active form of the toxicant that reaches the target tissues following absorption, distribution, and biotransformation of the parent toxicant. Biotransformation modulates the biological activity of chemicals through bioactivation and detoxication pathways. Many toxicants require biotransformation to exert their adverse biological effects. Considerable species differences in biotransformation and other pharmacokinetic processes can make extrapolation of toxicity data from laboratory animals to humans problematic. Additionally, interindividual differences in biotransformation among human populations with diverse genetics and lifestyles can lead to considerable variability in the bioactivation of toxic chemicals. Compartmental pharmacokinetic models of animals and humans are needed to understand the quantitative relationships between chemical exposure and target tissue dose as well as animal to human differences and interindividual differences in human populations. The data-based compartmental pharmacokinetic models widely used in clinical pharmacology ha

Model-based safety analysis of human-robot interactions: the MIRAS walking assistance robot.

PubMed

Guiochet, Jérémie; Hoang, Quynh Anh Do; Kaaniche, Mohamed; Powell, David

2013-06-01

Robotic systems have to cope with various execution environments while guaranteeing safety, and in particular when they interact with humans during rehabilitation tasks. These systems are often critical since their failure can lead to human injury or even death. However, such systems are difficult to validate due to their high complexity and the fact that they operate within complex, variable and uncertain environments (including users), in which it is difficult to foresee all possible system behaviors. Because of the complexity of human-robot interactions, rigorous and systematic approaches are needed to assist the developers in the identification of significant threats and the implementation of efficient protection mechanisms, and in the elaboration of a sound argumentation to justify the level of safety that can be achieved by the system. For threat identification, we propose a method called HAZOP-UML based on a risk analysis technique adapted to system description models, focusing on human-robot interaction models. The output of this step is then injected in a structured safety argumentation using the GSN graphical notation. Those approaches have been successfully applied to the development of a walking assistant robot which is now in clinical validation.

Disease modeling and drug screening for neurological diseases using human induced pluripotent stem cells.

PubMed

Xu, Xiao-hong; Zhong, Zhong

2013-06-01

With the general decline of pharmaceutical research productivity, there are concerns that many components of the drug discovery process need to be redesigned and optimized. For example, the human immortalized cell lines or animal primary cells commonly used in traditional drug screening may not faithfully recapitulate the pathological mechanisms of human diseases, leading to biases in assays, targets, or compounds that do not effectively address disease mechanisms. Recent advances in stem cell research, especially in the development of induced pluripotent stem cell (iPSC) technology, provide a new paradigm for drug screening by permitting the use of human cells with the same genetic makeup as the patients without the typical quantity constraints associated with patient primary cells. In this article, we will review the progress made to date on cellular disease models using human stem cells, with a focus on patient-specific iPSCs for neurological diseases. We will discuss the key challenges and the factors that associated with the success of using stem cell models for drug discovery through examples from monogenic diseases, diseases with various known genetic components, and complex diseases caused by a combination of genetic, environmental and other factors.

Climate-driven endemic cholera is modulated by human mobility in a megacity

NASA Astrophysics Data System (ADS)

Perez-Saez, Javier; King, Aaron A.; Rinaldo, Andrea; Yunus, Mohammad; Faruque, Abu S. G.; Pascual, Mercedes

2017-10-01

Although a differential sensitivity of cholera dynamics to climate variability has been reported in the spatially heterogeneous megacity of Dhaka, Bangladesh, the specific patterns of spread of the resulting risk within the city remain unclear. We build on an established probabilistic spatial model to investigate the importance and role of human mobility in modulating spatial cholera transmission. Mobility fluxes were inferred using a straightforward and generalizable methodology that relies on mapping population density based on a high resolution urban footprint product, and a parameter-free human mobility model. In accordance with previous findings, we highlight the higher sensitivity to the El Niño Southern Oscillation (ENSO) in the highly populated urban center than in the more rural periphery. More significantly, our results show that cholera risk is largely transmitted from the climate-sensitive core to the periphery of the city, with implications for the planning of control efforts. In addition, including human mobility improves the outbreak prediction performance of the model with an 11 month lead. The interplay between climatic and human mobility factors in cholera transmission is discussed from the perspective of the rapid growth of megacities across the developing world.

Genetics of human hydrocephalus

PubMed Central

Williams, Michael A.; Rigamonti, Daniele

2006-01-01

Human hydrocephalus is a common medical condition that is characterized by abnormalities in the flow or resorption of cerebrospinal fluid (CSF), resulting in ventricular dilatation. Human hydrocephalus can be classified into two clinical forms, congenital and acquired. Hydrocephalus is one of the complex and multifactorial neurological disorders. A growing body of evidence indicates that genetic factors play a major role in the pathogenesis of hydrocephalus. An understanding of the genetic components and mechanism of this complex disorder may offer us significant insights into the molecular etiology of impaired brain development and an accumulation of the cerebrospinal fluid in cerebral compartments during the pathogenesis of hydrocephalus. Genetic studies in animal models have started to open the way for understanding the underlying pathology of hydrocephalus. At least 43 mutants/loci linked to hereditary hydrocephalus have been identified in animal models and humans. Up to date, 9 genes associated with hydrocephalus have been identified in animal models. In contrast, only one such gene has been identified in humans. Most of known hydrocephalus gene products are the important cytokines, growth factors or related molecules in the cellular signal pathways during early brain development. The current molecular genetic evidence from animal models indicate that in the early development stage, impaired and abnormal brain development caused by abnormal cellular signaling and functioning, all these cellular and developmental events would eventually lead to the congenital hydrocephalus. Owing to our very primitive knowledge of the genetics and molecular pathogenesis of human hydrocephalus, it is difficult to evaluate whether data gained from animal models can be extrapolated to humans. Initiation of a large population genetics study in humans will certainly provide invaluable information about the molecular and cellular etiology and the developmental mechanisms of human hydrocephalus. This review summarizes the recent findings on this issue among human and animal models, especially with reference to the molecular genetics, pathological, physiological and cellular studies, and identifies future research directions. PMID:16773266

Modeling Human Cancers in Drosophila.

PubMed

Sonoshita, M; Cagan, R L

2017-01-01

Cancer is a complex disease that affects multiple organs. Whole-body animal models provide important insights into oncology that can lead to clinical impact. Here, we review novel concepts that Drosophila studies have established for cancer biology, drug discovery, and patient therapy. Genetic studies using Drosophila have explored the roles of oncogenes and tumor-suppressor genes that when dysregulated promote cancer formation, making Drosophila a useful model to study multiple aspects of transformation. Not limited to mechanism analyses, Drosophila has recently been showing its value in facilitating drug development. Flies offer rapid, efficient platforms by which novel classes of drugs can be identified as candidate anticancer leads. Further, we discuss the use of Drosophila as a platform to develop therapies for individual patients by modeling the tumor's genetic complexity. Drosophila provides both a classical and a novel tool to identify new therapeutics, complementing other more traditional cancer tools. © 2017 Elsevier Inc. All rights reserved.

A systems model for immune cell interactions unravels the mechanism of inflammation in human skin.

PubMed

Valeyev, Najl V; Hundhausen, Christian; Umezawa, Yoshinori; Kotov, Nikolay V; Williams, Gareth; Clop, Alex; Ainali, Crysanthi; Ouzounis, Christos; Tsoka, Sophia; Nestle, Frank O

2010-12-02

Inflammation is characterized by altered cytokine levels produced by cell populations in a highly interdependent manner. To elucidate the mechanism of an inflammatory reaction, we have developed a mathematical model for immune cell interactions via the specific, dose-dependent cytokine production rates of cell populations. The model describes the criteria required for normal and pathological immune system responses and suggests that alterations in the cytokine production rates can lead to various stable levels which manifest themselves in different disease phenotypes. The model predicts that pairs of interacting immune cell populations can maintain homeostatic and elevated extracellular cytokine concentration levels, enabling them to operate as an immune system switch. The concept described here is developed in the context of psoriasis, an immune-mediated disease, but it can also offer mechanistic insights into other inflammatory pathologies as it explains how interactions between immune cell populations can lead to disease phenotypes.

The Presence of Multiple Cellular Defects Associated with a Novel G50E Iron-Sulfur Cluster Scaffold Protein (ISCU) Mutation Leads to Development of Mitochondrial Myopathy*

PubMed Central

Saha, Prasenjit Prasad; Kumar, S. K. Praveen; Srivastava, Shubhi; Sinha, Devanjan; Pareek, Gautam; D'Silva, Patrick

2014-01-01

Iron-sulfur (Fe-S) clusters are versatile cofactors involved in regulating multiple physiological activities, including energy generation through cellular respiration. Initially, the Fe-S clusters are assembled on a conserved scaffold protein, iron-sulfur cluster scaffold protein (ISCU), in coordination with iron and sulfur donor proteins in human mitochondria. Loss of ISCU function leads to myopathy, characterized by muscle wasting and cardiac hypertrophy. In addition to the homozygous ISCU mutation (g.7044G→C), compound heterozygous patients with severe myopathy have been identified to carry the c.149G→A missense mutation converting the glycine 50 residue to glutamate. However, the physiological defects and molecular mechanism associated with G50E mutation have not been elucidated. In this report, we uncover mechanistic insights concerning how the G50E ISCU mutation in humans leads to the development of severe ISCU myopathy, using a human cell line and yeast as the model systems. The biochemical results highlight that the G50E mutation results in compromised interaction with the sulfur donor NFS1 and the J-protein HSCB, thus impairing the rate of Fe-S cluster synthesis. As a result, electron transport chain complexes show significant reduction in their redox properties, leading to loss of cellular respiration. Furthermore, the G50E mutant mitochondria display enhancement in iron level and reactive oxygen species, thereby causing oxidative stress leading to impairment in the mitochondrial functions. Thus, our findings provide compelling evidence that the respiration defect due to impaired biogenesis of Fe-S clusters in myopathy patients leads to manifestation of complex clinical symptoms. PMID:24573684

The development of a 3D immunocompetent model of human skin.

PubMed

Chau, David Y S; Johnson, Claire; MacNeil, Sheila; Haycock, John W; Ghaemmaghami, Amir M

2013-09-01

As the first line of defence, skin is regularly exposed to a variety of biological, physical and chemical insults. Therefore, determining the skin sensitization potential of new chemicals is of paramount importance from the safety assessment and regulatory point of view. Given the questionable biological relevance of animal models to human as well as ethical and regulatory pressure to limit or stop the use of animal models for safety testing, there is a need for developing simple yet physiologically relevant models of human skin. Herein, we describe the construction of a novel immunocompetent 3D human skin model comprising of dendritic cells co-cultured with keratinocytes and fibroblasts. This model culture system is simple to assemble with readily-available components and importantly, can be separated into its constitutive individual layers to allow further insight into cell-cell interactions and detailed studies of the mechanisms of skin sensitization. In this study, using non-degradable microfibre scaffolds and a cell-laden gel, we have engineered a multilayer 3D immunocompetent model comprised of keratinocytes and fibroblasts that are interspersed with dendritic cells. We have characterized this model using a combination of confocal microscopy, immuno-histochemistry and scanning electron microscopy and have shown differentiation of the epidermal layer and formation of an epidermal barrier. Crucially the immune cells in the model are able to migrate and remain responsive to stimulation with skin sensitizers even at low concentrations. We therefore suggest this new biologically relevant skin model will prove valuable in investigating the mechanisms of allergic contact dermatitis and other skin pathologies in human. Once fully optimized, this model can also be used as a platform for testing the allergenic potential of new chemicals and drug leads.

Probabilistic Nowcasting of Low-Visibility Procedure States at Vienna International Airport During Cold Season

NASA Astrophysics Data System (ADS)

Kneringer, Philipp; Dietz, Sebastian J.; Mayr, Georg J.; Zeileis, Achim

2018-04-01

Airport operations are sensitive to visibility conditions. Low-visibility events may lead to capacity reduction, delays and economic losses. Different levels of low-visibility procedures (lvp) are enacted to ensure aviation safety. A nowcast of the probabilities for each of the lvp categories helps decision makers to optimally schedule their operations. An ordered logistic regression (OLR) model is used to forecast these probabilities directly. It is applied to cold season forecasts at Vienna International Airport for lead times of 30-min out to 2 h. Model inputs are standard meteorological measurements. The skill of the forecasts is accessed by the ranked probability score. OLR outperforms persistence, which is a strong contender at the shortest lead times. The ranked probability score of the OLR is even better than the one of nowcasts from human forecasters. The OLR-based nowcasting system is computationally fast and can be updated instantaneously when new data become available.

Human Disease Models in Drosophila melanogaster and the Role of the Fly in Therapeutic Drug Discovery

PubMed Central

Pandey, Udai Bhan

2011-01-01

The common fruit fly, Drosophila melanogaster, is a well studied and highly tractable genetic model organism for understanding molecular mechanisms of human diseases. Many basic biological, physiological, and neurological properties are conserved between mammals and D. melanogaster, and nearly 75% of human disease-causing genes are believed to have a functional homolog in the fly. In the discovery process for therapeutics, traditional approaches employ high-throughput screening for small molecules that is based primarily on in vitro cell culture, enzymatic assays, or receptor binding assays. The majority of positive hits identified through these types of in vitro screens, unfortunately, are found to be ineffective and/or toxic in subsequent validation experiments in whole-animal models. New tools and platforms are needed in the discovery arena to overcome these limitations. The incorporation of D. melanogaster into the therapeutic discovery process holds tremendous promise for an enhanced rate of discovery of higher quality leads. D. melanogaster models of human diseases provide several unique features such as powerful genetics, highly conserved disease pathways, and very low comparative costs. The fly can effectively be used for low- to high-throughput drug screens as well as in target discovery. Here, we review the basic biology of the fly and discuss models of human diseases and opportunities for therapeutic discovery for central nervous system disorders, inflammatory disorders, cardiovascular disease, cancer, and diabetes. We also provide information and resources for those interested in pursuing fly models of human disease, as well as those interested in using D. melanogaster in the drug discovery process. PMID:21415126

Designing for Feel: Contrasts between Human and Automated Parametric Capture of Knob Physics.

PubMed

Swindells, C; MacLean, K E; Booth, K S

2009-01-01

We examine a crucial aspect of a tool intended to support designing for feel: the ability of an objective physical-model identification method to capture perceptually relevant parameters, relative to human identification performance. The feel of manual controls, such as knobs, sliders, and buttons, becomes critical when these controls are used in certain settings. Appropriate feel enables designers to create consistent control behaviors that lead to improved usability and safety. For example, a heavy knob with stiff detents for a power plant boiler setting may afford better feedback and safer operations, whereas subtle detents in an automobile radio volume knob may afford improved ergonomics and driver attention to the road. To assess the quality of our identification method, we compared previously reported automated model captures for five real mechanical reference knobs with captures by novice and expert human participants who were asked to adjust four parameters of a rendered knob model to match the feel of each reference knob. Participants indicated their satisfaction with the matches their renderings produced. We observed similar relative inertia, friction, detent strength, and detent spacing parameterizations by human experts and our automatic estimation methods. Qualitative results provided insight on users' strategies and confidence. While experts (but not novices) were better able to ascertain an underlying model in the presence of unmodeled dynamics, the objective algorithm outperformed all humans when an appropriate physical model was used. Our studies demonstrate that automated model identification can capture knob dynamics as perceived by a human, and they also establish limits to that ability; they comprise a step towards pragmatic design guidelines for embedded physical interfaces in which methodological expedience is informed by human perceptual requirements.

Hunting of roe deer and wild boar in Germany: Is non-lead ammunition suitable for hunting?

PubMed

Martin, Annett; Gremse, Carl; Selhorst, Thomas; Bandick, Niels; Müller-Graf, Christine; Greiner, Matthias; Lahrssen-Wiederholt, Monika

2017-01-01

Non-lead hunting ammunition is an alternative to bullets that contain lead. The use of lead ammunition can result in severe contamination of game meat, thus posing a health risk to consumers. With any kind of ammunition for hunting, the terminal effectiveness of bullets is an animal welfare issue. Doubts about the effectiveness of non-lead bullets for a humane kill of game animals in hunting have been discussed. The length of the escape distance after the shot has been used previously as an indicator for bullet performance. The object of this study was to determine how the bullet material (lead or non-lead) influences the observed escape distances. 1,234 records of the shooting of roe deer (Capreolus capreolus) and 825 records of the shooting of wild boar (Sus scrofa) were evaluated. As the bullet material cannot be regarded as the sole cause of variability of escape distances, interactions of other potential influencing variables like shot placement, shooting distance, were analyzed using conditional regression trees and two-part hurdle models. The length of the escape distance is not influenced by the use of lead or non-lead ammunition with either roe deer or wild boar. With roe deer, the length of the escape distance is influenced significantly by the shot placement and the type of hunting. Increasing shooting distances increased the length of the escape distance. With wild boar, shot placement and the age of the animals were found to be a significant influencing factor on the length of the escape distance. The length of the escape distance can be used as an indicator for adequate bullet effectiveness for humane killings of game animals in hunting.Non-lead bullets already exist which have an equally reliable killing effect as lead bullets.

Complement inhibition in pre-clinical models of periodontitis and prospects for clinical application.

PubMed

Hajishengallis, George; Hajishengallis, Evlambia; Kajikawa, Tetsuhiro; Wang, Baomei; Yancopoulou, Despina; Ricklin, Daniel; Lambris, John D

2016-06-01

Periodontitis is a dysbiotic inflammatory disease leading to the destruction of the tooth-supporting tissues. Current therapies are not always effective and this prevalent oral disease continues to be a significant health and economic burden. Early clinical studies have associated periodontitis with elevated complement activity. Consistently, subsequent genetic and pharmacological studies in rodents have implicated the central complement component C3 and downstream signaling pathways in periodontal host-microbe interactions that promote dysbiosis and inflammatory bone loss. This review discusses these mechanistic advances and moreover focuses on the compstatin family of C3 inhibitors as a novel approach to treat periodontitis. In this regard, local application of the current lead analog Cp40 was recently shown to block both inducible and naturally occurring periodontitis in non-human primates. These promising results from non-human primate studies and the parallel development of Cp40 for clinical use highlight the feasibility for developing an adjunctive, C3-targeted therapy for human periodontitis. Copyright © 2016 Elsevier Ltd. All rights reserved.

The role of the Hippo pathway in human disease and tumorigenesis

PubMed Central

2014-01-01

Understanding the molecular nature of human cancer is essential to the development of effective and personalized therapies. Several different molecular signal transduction pathways drive tumorigenesis when deregulated and respond to different types of therapeutic interventions. The Hippo signaling pathway has been demonstrated to play a central role in the regulation of tissue and organ size during development. The deregulation of Hippo signaling leads to a concurrent combination of uncontrolled cellular proliferation and inhibition of apoptosis, two key hallmarks in cancer development. The molecular nature of this pathway was first uncovered in Drosophila melanogaster through genetic screens to identify regulators of cell growth and cell division. The pathway is strongly conserved in humans, rendering Drosophila a suitable and efficient model system to better understand the molecular nature of this pathway. In the present study, we review the current understanding of the molecular mechanism and clinical impact of the Hippo pathway. Current studies have demonstrated that a variety of deregulated molecules can alter Hippo signaling, leading to the constitutive activation of the transcriptional activator YAP or its paralog TAZ. Additionally, the Hippo pathway integrates inputs from a number of growth signaling pathways, positioning the Hippo pathway in a central role in the regulation of tissue size. Importantly, deregulated Hippo signaling is frequently observed in human cancers. YAP is commonly activated in a number of in vitro and in vivo models of tumorigenesis, as well as a number of human cancers. The common activation of YAP in many different tumor types provides an attractive target for potential therapeutic intervention. PMID:25097728

Ultrasonic vocalizations in mouse models for speech and socio-cognitive disorders: insights into the evolution of vocal communication

PubMed Central

Fischer, J; Hammerschmidt, K

2011-01-01

Comparative analyses used to reconstruct the evolution of traits associated with the human language faculty, including its socio-cognitive underpinnings, highlight the importance of evolutionary constraints limiting vocal learning in non-human primates. After a brief overview of this field of research and the neural basis of primate vocalizations, we review studies that have addressed the genetic basis of usage and structure of ultrasonic communication in mice, with a focus on the gene FOXP2 involved in specific language impairments and neuroligin genes (NL-3 and NL-4) involved in autism spectrum disorders. Knockout of FoxP2 leads to reduced vocal behavior and eventually premature death. Introducing the human variant of FoxP2 protein into mice, in contrast, results in shifts in frequency and modulation of pup ultrasonic vocalizations. Knockout of NL-3 and NL-4 in mice diminishes social behavior and vocalizations. Although such studies may provide insights into the molecular and neural basis of social and communicative behavior, the structure of mouse vocalizations is largely innate, limiting the suitability of the mouse model to study human speech, a learned mode of production. Although knockout or replacement of single genes has perceptible effects on behavior, these genes are part of larger networks whose functions remain poorly understood. In humans, for instance, deficiencies in NL-4 can lead to a broad spectrum of disorders, suggesting that further factors (experiential and/or genetic) contribute to the variation in clinical symptoms. The precise nature as well as the interaction of these factors is yet to be determined. PMID:20579107

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

Collins, William D.; Craig, Anthony P.; Truesdale, John E.

The integrated Earth System Model (iESM) has been developed as a new tool for pro- jecting the joint human/climate system. The iESM is based upon coupling an Integrated Assessment Model (IAM) and an Earth System Model (ESM) into a common modeling in- frastructure. IAMs are the primary tool for describing the human–Earth system, including the sources of global greenhouse gases (GHGs) and short-lived species, land use and land cover change, and other resource-related drivers of anthropogenic climate change. ESMs are the primary scientific tools for examining the physical, chemical, and biogeochemical impacts of human-induced changes to the climate system. Themore » iESM project integrates the economic and human dimension modeling of an IAM and a fully coupled ESM within a sin- gle simulation system while maintaining the separability of each model if needed. Both IAM and ESM codes are developed and used by large communities and have been extensively applied in recent national and international climate assessments. By introducing heretofore- omitted feedbacks between natural and societal drivers, we can improve scientific under- standing of the human–Earth system dynamics. Potential applications include studies of the interactions and feedbacks leading to the timing, scale, and geographic distribution of emissions trajectories and other human influences, corresponding climate effects, and the subsequent impacts of a changing climate on human and natural systems. This paper de- scribes the formulation, requirements, implementation, testing, and resulting functionality of the first version of the iESM released to the global climate community.« less

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

Collins, W. D.; Craig, A. P.; Truesdale, J. E.

The integrated Earth system model (iESM) has been developed as a new tool for projecting the joint human/climate system. The iESM is based upon coupling an integrated assessment model (IAM) and an Earth system model (ESM) into a common modeling infrastructure. IAMs are the primary tool for describing the human–Earth system, including the sources of global greenhouse gases (GHGs) and short-lived species (SLS), land use and land cover change (LULCC), and other resource-related drivers of anthropogenic climate change. ESMs are the primary scientific tools for examining the physical, chemical, and biogeochemical impacts of human-induced changes to the climate system. Themore » iESM project integrates the economic and human-dimension modeling of an IAM and a fully coupled ESM within a single simulation system while maintaining the separability of each model if needed. Both IAM and ESM codes are developed and used by large communities and have been extensively applied in recent national and international climate assessments. By introducing heretofore-omitted feedbacks between natural and societal drivers, we can improve scientific understanding of the human–Earth system dynamics. Potential applications include studies of the interactions and feedbacks leading to the timing, scale, and geographic distribution of emissions trajectories and other human influences, corresponding climate effects, and the subsequent impacts of a changing climate on human and natural systems. This paper describes the formulation, requirements, implementation, testing, and resulting functionality of the first version of the iESM released to the global climate community.« less

Workshop Report: The Medaka Model for Comparative Assessment of Human Disease Mechanisms

PubMed Central

Obara, Tomoko

2015-01-01

Results of recent studies showing the utility of medaka as a model of various human disease states were presented at the 7th Aquatic Models of Human Disease Conference (December 13–18, 2014, Austin, TX). This conference brought together many of the most highly regarded national and international scientists that employ the medaka model in their investigations. To take advantage of this opportunity, a cohort of established medaka researchers were asked to stay an extra day and represent the medaka scientific community in a workshop entitled “The Medaka Model for Comparative Assessment of Human Disease Mechanisms”. The central purpose of this medaka workshop was to assess current use and project the future resource needs of the American medaka research community. The workshop sought to spur discussions of issues that would promote more informative comparative disease model studies. Finally, workshop attendees met together to propose, discuss, and agree on recommendations regarding the most effective research resources needed to enable US scientists to perform experiments leading to impacting experimental results that directly translate to human disease. Consistent with this central purpose, the workshop was divided into two sessions of invited speakers having expertise and experience in the session topics. The workshop hosted 20 scientific participants (Appendices 1 and 2) and of these, nine scientists presented formal talks. Here, we present a summary report stemming from workshop presentations and subsequent round table discussions, and forward recommendations from this group that we believe represent views of the overall medaka research community. PMID:26099189

Faecal microbiota transplantation: Where did it start? What have studies taught us? Where is it going?

PubMed

Chanyi, Ryan M; Craven, Laura; Harvey, Brandon; Reid, Gregor; Silverman, Michael J; Burton, Jeremy P

2017-01-01

The composition and activity of microorganisms in the gut, the microbiome, is emerging as an important factor to consider with regard to the treatment of many diseases. Dysbiosis of the normal community has been implicated in inflammatory bowel disease, Crohn's disease, diabetes and, most notoriously, Clostridium difficile infection. In Canada, the leading treatment strategy for recalcitrant C. difficile infection is to receive faecal material which by nature is filled with microorganisms and their metabolites, from a healthy individual, known as a faecal microbiota transplantation. This influx of bacteria into the gut helps to restore the microbiota to a healthy state, preventing C. difficile from causing further disease. Much of what is known with respect to the microbiota and faecal microbiota transplantation comes from animal studies simulating the human disease. Although these models allow researchers to perform studies that would be difficult in humans, they do not always recapitulate the human microbiome. This makes the translation of these results to humans somewhat questionable. The purpose of this review is to analyse these animal models and discuss the advantages and the disadvantages of them in relation to human translation. By understanding some of the limitation of animal models, we will be better able to design and perform experiments of most relevance to human applications.

Developmental neurotoxicity screening using human embryonic stem cells.

PubMed

Bosnjak, Zeljko J

2012-09-01

Research in the area of stem cell biology and regenerative medicine, along with neuroscience, will further our understanding of drug-induced death of neurons during their development. With the development of an in vitro model of stem cell-derived human neural cell lines investigators can, under control conditions and during intense neuronal growth, examine molecular mechanisms of various drugs and conditions on early developmental neuroapoptosis in humans. If the use of this model will lead to fewer risks, or identification of drugs and anesthetics that are less likely to cause the death of neurons, this approach will be a major stride toward assuring the safety of drugs during the brain development. The ultimate goal would be not only to find the trigger for the catastrophic chain of events, but also to prevent neuronal cell death itself. Copyright © 2012. Published by Elsevier Inc.

The domestic pig as a potential model for Borrelia skin infection.

PubMed

Reiter, Michael; Knecht, Christian; Müller, Andreas; Schötta, Anna-Margarita; Leschnik, Michael; Wijnveld, Michiel; Weissenböck, Herbert; Stockinger, Hannes; Stanek, Gerold; Sipos, Wolfgang

2017-02-01

The skin lesion erythema migrans is a characteristic early manifestation of Lyme borreliosis in humans. However, the pathomechanisms leading to development of this erythema are not fully understood. Models that mimic human skin would enhance research in this field. Human and porcine skin structures strongly resemble each other. Therefore, we attempted to induce erythema migrans lesions in experimental Borrelia burgdorferi sensu lato infection in the skin of domestic pigs. The formation of erythema migrans-like lesions was observed after intradermal injection of these spirochetes, with the lesions forming very clearly in 2/6 animals when a strain of B. garinii was used. However, no molecular or clinical proof of systemic infection of the pigs with B. afzelii, B. burgdorferi sensu stricto, or B. garinii could be achieved. Copyright © 2016 Elsevier GmbH. All rights reserved.

Modeling and control of a brushless DC axial flow ventricular assist device.

PubMed

Giridharan, Guruprasad A; Skliar, Mikhail; Olsen, Donald B; Pantalos, George M

2002-01-01

This article presents an integrated model of the human circulatory system that incorporates circulatory support by a brushless DC axial flow ventricular assist device (VAD), and a feedback VAD controller designed to maintain physiologically sufficient perfusion. The developed integrated model combines a network type model of the circulatory system with a nonlinear dynamic model of the brushless DC pump We show that maintaining a reference differential pressure between the left ventricle and aorta leads to adequate perfusion for different pathologic cases, ranging from normal heart to left heart asystole, and widely varying physical activity scenarios from rest to exercise.

A model of pathways to artificial superintelligence catastrophe for risk and decision analysis

NASA Astrophysics Data System (ADS)

Barrett, Anthony M.; Baum, Seth D.

2017-03-01

An artificial superintelligence (ASI) is an artificial intelligence that is significantly more intelligent than humans in all respects. Whilst ASI does not currently exist, some scholars propose that it could be created sometime in the future, and furthermore that its creation could cause a severe global catastrophe, possibly even resulting in human extinction. Given the high stakes, it is important to analyze ASI risk and factor the risk into decisions related to ASI research and development. This paper presents a graphical model of major pathways to ASI catastrophe, focusing on ASI created via recursive self-improvement. The model uses the established risk and decision analysis modelling paradigms of fault trees and influence diagrams in order to depict combinations of events and conditions that could lead to AI catastrophe, as well as intervention options that could decrease risks. The events and conditions include select aspects of the ASI itself as well as the human process of ASI research, development and management. Model structure is derived from published literature on ASI risk. The model offers a foundation for rigorous quantitative evaluation and decision-making on the long-term risk of ASI catastrophe.

Modeling static and dynamic human cardiovascular responses to exercise.

PubMed

Stremel, R W; Bernauer, E M; Harter, L W; Schultz, R A; Walters, R F

1975-08-01

A human performance model has been developed and described [9] which portrays the human circulatory, thermo regulatory and energy-exchange systems as an intercoupled set. In this model, steady state or static relationships are used to describe oxygen consumption and blood flow. For example, heart rate (HTRT) is calculated as a function of the oxygen and the thermo-regulatory requirements of each body compartment, using the steady state work values of cardiac output (CO, sum of all compartment blood flows) and stroke volume (SV, assumed maximal after 40% maximal oxygen consumption): HTRT=CO/SV. The steady state model has proven to be an acceptable first approximation, but the inclusion of transient characteristics are essential in describing the overall systems' adjustment to exercise stress. In the present study, the dynamic transient characteristics of heart rate, stroke volume and cardiac output were obtained from experiments utilizing step and sinusoidal forcing of work. The gain and phase relationships reveal a probable first order system with a six minute time constant, and are utilized to model the transient characteristics of these parameters. This approach leads to a more complex model but a more accurate representation of the physiology involved. The instrumentation and programming essential to these experiments are described.

Quantitative systems pharmacology analysis of drug combination and scaling to humans: the interaction between noradrenaline and vasopressin on vasoconstriction.

PubMed

Yin, Anyue; Yamada, Akihiro; Stam, Wiro B; van Hasselt, Johan G C; van der Graaf, Piet H

2018-06-02

Development of combination therapies has received significant interest in recent years. Previously a two-receptor one-transducer (2R-1T) model was proposed to characterize drug interactions with two receptors that lead to the same phenotypic response through a common transducer pathway. We applied, for the first time, the 2R-1T model to characterize the interaction of noradrenaline and arginine-vasopressin on vasoconstriction, and performed inter-species scaling to humans using this mechanism-based model. Contractile data was obtained from in vitro rat small mesenteric arteries after exposure to single or combined challenges of noradrenaline and arginine-vasopressin with or without pre-treatment with the irreversible α-adrenoceptor antagonist, phenoxybenzamine. Data was analysed using the 2R-1T model to characterize the observed exposure-response relationships and drug-drug interaction. The model was then scaled to humans by accounting for differences in receptor density. With receptor affinities set to literature values, the 2R-1T model satisfactorily characterized the interaction between noradrenaline and arginine-vasopressin in rat small mesenteric arteries (relative standard error ≤ 20%), as well as the effect of phenoxybenzamine. Furthermore, after scaling the model to human vascular tissue, the model also adequately predicted the interaction between both agents on human renal arteries. The 2R-1T model can be of relevance to quantitatively characterize the interaction between two drugs that interact via different receptors and a common transducer pathway. Its mechanistic properties are valuable for scaling the model across species. This approach is therefore of significant value to rationally optimize novel combination treatments. This article is protected by copyright. All rights reserved.

Leptin- and Leptin Receptor-Deficient Rodent Models: Relevance for Human Type 2 Diabetes

PubMed Central

Wang, Bingxuan; P., Charukeshi Chandrasekera; Pippin, John J.

2014-01-01

Among the most widely used animal models in obesity-induced type 2 diabetes mellitus (T2DM) research are the congenital leptin- and leptin receptor-deficient rodent models. These include the leptin-deficient ob/ob mice and the leptin receptor-deficient db/db mice, Zucker fatty rats, Zucker diabetic fatty rats, SHR/N-cp rats, and JCR:LA-cp rats. After decades of mechanistic and therapeutic research schemes with these animal models, many species differences have been uncovered, but researchers continue to overlook these differences, leading to untranslatable research. The purpose of this review is to analyze and comprehensively recapitulate the most common leptin/leptin receptor-based animal models with respect to their relevance and translatability to human T2DM. Our analysis revealed that, although these rodents develop obesity due to hyperphagia caused by abnormal leptin/leptin receptor signaling with the subsequent appearance of T2DM-like manifestations, these are in fact secondary to genetic mutations that do not reflect disease etiology in humans, for whom leptin or leptin receptor deficiency is not an important contributor to T2DM. A detailed comparison of the roles of genetic susceptibility, obesity, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetic complications as well as leptin expression, signaling, and other factors that confound translation are presented here. There are substantial differences between these animal models and human T2DM that limit reliable, reproducible, and translatable insight into human T2DM. Therefore, it is imperative that researchers recognize and acknowledge the limitations of the leptin/leptin receptor-based rodent models and invest in research methods that would be directly and reliably applicable to humans in order to advance T2DM management. PMID:24809394

Leptin- and leptin receptor-deficient rodent models: relevance for human type 2 diabetes.

PubMed

Wang, Bingxuan; Chandrasekera, P Charukeshi; Pippin, John J

2014-03-01

Among the most widely used animal models in obesity-induced type 2 diabetes mellitus (T2DM) research are the congenital leptin- and leptin receptor-deficient rodent models. These include the leptin-deficient ob/ob mice and the leptin receptor-deficient db/db mice, Zucker fatty rats, Zucker diabetic fatty rats, SHR/N-cp rats, and JCR:LA-cp rats. After decades of mechanistic and therapeutic research schemes with these animal models, many species differences have been uncovered, but researchers continue to overlook these differences, leading to untranslatable research. The purpose of this review is to analyze and comprehensively recapitulate the most common leptin/leptin receptor-based animal models with respect to their relevance and translatability to human T2DM. Our analysis revealed that, although these rodents develop obesity due to hyperphagia caused by abnormal leptin/leptin receptor signaling with the subsequent appearance of T2DM-like manifestations, these are in fact secondary to genetic mutations that do not reflect disease etiology in humans, for whom leptin or leptin receptor deficiency is not an important contributor to T2DM. A detailed comparison of the roles of genetic susceptibility, obesity, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetic complications as well as leptin expression, signaling, and other factors that confound translation are presented here. There are substantial differences between these animal models and human T2DM that limit reliable, reproducible, and translatable insight into human T2DM. Therefore, it is imperative that researchers recognize and acknowledge the limitations of the leptin/leptin receptor- based rodent models and invest in research methods that would be directly and reliably applicable to humans in order to advance T2DM management.

The Vestibular System and Human Dynamic Space Orientation

NASA Technical Reports Server (NTRS)

Meiry, J. L.

1966-01-01

The motion sensors of the vestibular system are studied to determine their role in human dynamic space orientation and manual vehicle control. The investigation yielded control models for the sensors, descriptions of the subsystems for eye stabilization, and demonstrations of the effects of motion cues on closed loop manual control. Experiments on the abilities of subjects to perceive a variety of linear motions provided data on the dynamic characteristics of the otoliths, the linear motion sensors. Angular acceleration threshold measurements supplemented knowledge of the semicircular canals, the angular motion sensors. Mathematical models are presented to describe the known control characteristics of the vestibular sensors, relating subjective perception of motion to objective motion of a vehicle. The vestibular system, the neck rotation proprioceptors and the visual system form part of the control system which maintains the eye stationary relative to a target or a reference. The contribution of each of these systems was identified through experiments involving head and body rotations about a vertical axis. Compensatory eye movements in response to neck rotation were demonstrated and their dynamic characteristics described by a lag-lead model. The eye motions attributable to neck rotations and vestibular stimulation obey superposition when both systems are active. Human operator compensatory tracking is investigated in simple vehicle orientation control system with stable and unstable controlled elements. Control of vehicle orientation to a reference is simulated in three modes: visual, motion and combined. Motion cues sensed by the vestibular system through tactile sensation enable the operator to generate more lead compensation than in fixed base simulation with only visual input. The tracking performance of the human in an unstable control system near the limits of controllability is shown to depend heavily upon the rate information provided by the vestibular sensors.

Development of a methodology to assess man-made risks in Germany

NASA Astrophysics Data System (ADS)

Borst, D.; Jung, D.; Murshed, S. M.; Werner, U.

2006-09-01

Risk is a concept used to describe future potential outcomes of certain actions or events. Within the project "CEDIM - Risk Map Germany - Man-made Hazards" it is intended to develop methods for assessing and mapping the risk due to different human-induced hazards. This is a task that has not been successfully performed for Germany so far. Concepts of catastrophe modelling are employed including the spatial modelling of hazard, the compilation of different kinds of exposed elements, the estimation of their vulnerability and the direct loss potential in terms of human life and health. The paper is divided in two sections: First, an analytic framework for assessing the broad spectrum of human-induced risks is introduced. This approach is then applied for three important types of human-induced hazards that are representative for a whole class of hazards: Accidents due to nuclear power plants (NPP) or air traffic, and terrorism. For the analysis of accidents, risk is measured with respect to getting injured or dying when living in certain buffer zones around hazard locations. NPP hazard expert knowledge is used and supplemented with observations on aging effects leading to a proprietary index value for the risk. Air traffic risk is modelled as an area related phenomenon based on available accident statistics leading to an expected value of risk. Terrorism risk is assessed by the attraction certain elements (like embassies in the case of conventional threats) display in the eye of potential aggressors. For non-conventional targets like football games, a detailed approach measuring their susceptibility to different kinds of attacks within predefined scenarios was developed; this also allows a ranking of attack modes.

Signaling in Human and Murine Lymphocytes in Microgravity: Parallels and Contrasts

NASA Technical Reports Server (NTRS)

Neal, Pellis; Alamelu, Sundaresan; Kulkarni, A. D.; Yamauchi, K.

2006-01-01

Immune function in space undergoes dramatic changes, some of which are detrimental to lymphocyte function. These changes may lead to significant immune suppression. Studies with human lymphocytes both in space flight and with ground-based models (NASA in vitro ground-based microgravity analog) indicate that T cell activation is inhibited in microgravity. Other lymphocyte functions, such as locomotion, are also inhibited. There is about an 80 percent homology in the immune response of mice to that of humans. A murine model was investigated because of its ability to parallel some microgravity using hind limb suspension. In in vivo antiorthostatically (AOS)-suspended mice, T cell activation is greatly suppressed, with the majority of activation related cytokines being inhibited. PHA activation in lymphocytes derived from AOS mice (in vivo ground-based microgravity analog) is also suppressed. Calcium ionophore studies in human lymphocytes exposed to modeled microgravity indicate that the calcium pathways are probably unaffected in microgravity. IP3 (inositol triphosphate) receptor expression in both human and mouse lymphocytes cultured in modeled microgravity indicate no suppression of calcium signaling. In the human system, microgravity seems to inhibit signaling cascades either at the level of, or up-stream of, Protein Kinase C (PKC). In particular, a membrane event, such as phospholipase C gamma 1 activity in human lymphocytes is affected, with its direct upstream effector, LAT, being deficiently expressed. In the mouse pathway, LAT is undiminished while another critical intermediate, SLP-76, is diminished significantly. This study identifies critical stages in the human and mouse immune systems and in lymphocytes as a function of microgravity.

Validation of a digital mammographic unit model for an objective and highly automated clinical image quality assessment.

PubMed

Perez-Ponce, Hector; Daul, Christian; Wolf, Didier; Noel, Alain

2013-08-01

In mammography, image quality assessment has to be directly related to breast cancer indicator (e.g. microcalcifications) detectability. Recently, we proposed an X-ray source/digital detector (XRS/DD) model leading to such an assessment. This model simulates very realistic contrast-detail phantom (CDMAM) images leading to gold disc (representing microcalcifications) detectability thresholds that are very close to those of real images taken under the simulated acquisition conditions. The detection step was performed with a mathematical observer. The aim of this contribution is to include human observers into the disc detection process in real and virtual images to validate the simulation framework based on the XRS/DD model. Mathematical criteria (contrast-detail curves, image quality factor, etc.) are used to assess and to compare, from the statistical point of view, the cancer indicator detectability in real and virtual images. The quantitative results given in this paper show that the images simulated by the XRS/DD model are useful for image quality assessment in the case of all studied exposure conditions using either human or automated scoring. Also, this paper confirms that with the XRS/DD model the image quality assessment can be automated and the whole time of the procedure can be drastically reduced. Compared to standard quality assessment methods, the number of images to be acquired is divided by a factor of eight. Copyright © 2012 IPEM. Published by Elsevier Ltd. All rights reserved.

16 CFR 1500.90 - Procedures and requirements for exclusions from lead limits under section 101(b) of the Consumer...

Code of Federal Regulations, 2010 CFR

2010-01-01

... inaccessible to a child or prevent the absorption of any lead in the human body through normal and reasonably... in the absorption of any lead into the human body, taking into account normal and reasonably... sought, will not result in the absorption of any lead into the human body, nor have any other adverse...

16 CFR 1500.90 - Procedures and requirements for exclusions from lead limits under section 101(b) of the Consumer...

Code of Federal Regulations, 2011 CFR

2011-01-01

... inaccessible to a child or prevent the absorption of any lead in the human body through normal and reasonably... in the absorption of any lead into the human body, taking into account normal and reasonably... sought, will not result in the absorption of any lead into the human body, nor have any other adverse...

Rodent models of insomnia: a review of experimental procedures that induce sleep disturbances.

PubMed

Revel, Florent G; Gottowik, Juergen; Gatti, Sylvia; Wettstein, Joseph G; Moreau, Jean-Luc

2009-06-01

Insomnia, the most common sleep disorder, is characterized by persistent difficulty in falling or staying asleep despite adequate opportunity to sleep, leading to daytime fatigue and mental dysfunction. As sleep is a sophisticated physiological process generated by a network of neuronal systems that cannot be reproduced in-vitro, pre-clinical development of hypnotic drugs requires in-vivo investigations. Accordingly, this review critically evaluates current and putative rodent models of insomnia which could be used to screen novel hypnotics. Only few valid insomnia models are currently available, although many experimental conditions lead to disturbance of physiological sleep. We categorized these conditions as a function of the procedure used to induce perturbation of sleep, and we discuss their respective advantages and pitfalls with respect to validity, feasibility and translational value to human research.

Human waste: An underestimated source of nutrient pollution in coastal seas of Bangladesh, India and Pakistan.

PubMed

Amin, Md Nurul; Kroeze, Carolien; Strokal, Maryna

2017-05-15

Many people practice open defecation in south Asia. As a result, lot of human waste containing nutrients such as nitrogen (N) and phosphorus (P) enter rivers. Rivers transport these nutrients to coastal waters, resulting in marine pollution. This source of nutrient pollution is, however, ignored in many nutrient models. We quantify nutrient export by large rivers to coastal seas of Bangladesh, India and Pakistan, and the associated eutrophication potential in 2000 and 2050. Our new estimates for N and P inputs from human waste are one to two orders of magnitude higher than earlier model calculations. This leads to higher river export of nutrients to coastal seas, increasing the risk of coastal eutrophication potential (ICEP). The newly calculated future ICEP, for instance, Godavori river is 3 times higher than according to earlier studies. Our modeling approach is simple and transparent and can easily be applied to other data-poor basins. Copyright © 2017 Elsevier Ltd. All rights reserved.

Protection against UVB-induced oxidative stress in human skin cells and skin models by methionine sulfoxide reductase A.

PubMed

Pelle, Edward; Maes, Daniel; Huang, Xi; Frenkel, Krystyna; Pernodet, Nadine; Yarosh, Daniel B; Zhang, Qi

2012-01-01

Environmental trauma to human skin can lead to oxidative damage of proteins and affect their activity and structure. When methionine becomes oxidized to its sulfoxide form, methionine sulfoxide reductase A (MSRA) reduces it back to methionine. We report here the increase in MSRA in normal human epidermal keratinocytes (NHEK) after ultraviolet B (UVB) radiation, as well as the reduction in hydrogen peroxide levels in NHEK pre-treated with MSRA after exposure. Further, when NHEK were pre-treated with a non-cytotoxic pentapeptide containing methionine sulfoxide (metSO), MSRA expression increased by 18.2%. Additionally, when the media of skin models were supplemented with the metSO pentapeptide and then exposed to UVB, a 31.1% reduction in sunburn cells was evident. We conclude that the presence of MSRA or an externally applied peptide reduces oxidative damage in NHEK and skin models and that MSRA contributes to the protection of proteins against UVB-induced damage in skin.

Modeling Hydrological Extremes in the Anthropocene

NASA Astrophysics Data System (ADS)

Di Baldassarre, Giuliano; Martinez, Fabian; Kalantari, Zahra; Viglione, Alberto

2017-04-01

Hydrological studies have investigated human impacts on hydrological extremes, i.e. droughts and floods, while social studies have explored human responses and adaptation to them. Yet, there is still little understanding about the dynamics resulting from two-way feedbacks, i.e. both impacts and responses. Traditional risk assessment methods therefore fail to assess future dynamics, and thus risk reduction strategies built on these methods can lead to unintended consequences in the medium-long term. Here we review the dynamics resulting from the reciprocal links between society and hydrological extremes, and describe initial efforts to model floods and droughts in the Anthropocene. In particular, we first discuss the need for a novel approach to explicitly account for human interactions with both hydrological extremes, and then present a stylized model simulating the reciprocal effects between droughts, foods and reservoir operation rules. Unprecedented opportunities offered by the growing availability of global data and worldwide archives to uncover the mutual shaping of hydrological extremes and society across places and scales are also discussed.

Reconstruction of Exposure to m-Xylene from Human Biomonitoring Data Using PBPK Modelling, Bayesian Inference, and Markov Chain Monte Carlo Simulation

PubMed Central

McNally, Kevin; Cotton, Richard; Cocker, John; Jones, Kate; Bartels, Mike; Rick, David; Price, Paul; Loizou, George

2012-01-01

There are numerous biomonitoring programs, both recent and ongoing, to evaluate environmental exposure of humans to chemicals. Due to the lack of exposure and kinetic data, the correlation of biomarker levels with exposure concentrations leads to difficulty in utilizing biomonitoring data for biological guidance values. Exposure reconstruction or reverse dosimetry is the retrospective interpretation of external exposure consistent with biomonitoring data. We investigated the integration of physiologically based pharmacokinetic modelling, global sensitivity analysis, Bayesian inference, and Markov chain Monte Carlo simulation to obtain a population estimate of inhalation exposure to m-xylene. We used exhaled breath and venous blood m-xylene and urinary 3-methylhippuric acid measurements from a controlled human volunteer study in order to evaluate the ability of our computational framework to predict known inhalation exposures. We also investigated the importance of model structure and dimensionality with respect to its ability to reconstruct exposure. PMID:22719759

The Global Burden of Lead Toxicity Attributable to Informal Used Lead-Acid Battery Sites.

PubMed

Ericson, Bret; Landrigan, Phillip; Taylor, Mark Patrick; Frostad, Joseph; Caravanos, Jack; Keith, John; Fuller, Richard

Prior calculations of the burden of disease from environmental lead exposure in low- and middle-income countries (LMICs) have not included estimates of the burden from lead-contaminated sites because of a lack of exposure data, resulting in an underestimation of a serious public health problem. We used publicly available statistics and detailed site assessment data to model the number of informal used lead-acid battery (ULAB) recyclers and the resulting exposures in 90 LMICs. We estimated blood lead levels (BLLs) using the US Environment Protection Agency's Integrated Exposure Uptake Biokinetic Model for Lead in Children and Adult Lead Model. Finally, we used data and algorithms generated by the World Health Organization to calculate the number of attributable disability adjusted life years (DALYs). We estimated that there are 10,599 to 29,241 informal ULAB processing sites where human health is at risk in the 90 countries we reviewed. We further estimated that 6 to 16.8 million people are exposed at these sites and calculate a geometric mean BLL for exposed children (0-4 years of age) of 31.15 μg/dL and a geometric mean BLL for adults of 21.2 μg/dL. We calculated that these exposures resulted in 127,248 to 1,612,476 DALYs in 2013. Informal ULAB processing is currently causing widespread lead poisoning in LMICs. There is an urgent need to identify and mitigate exposures at existing sites and to develop appropriate policy responses to minimize the creation of new sites. Copyright © 2016 Icahn School of Medicine at Mount Sinai. Published by Elsevier Inc. All rights reserved.

An Optic Nerve Crush Injury Murine Model to Study Retinal Ganglion Cell Survival

PubMed Central

Tang, Zhongshu; Zhang, Shuihua; Lee, Chunsik; Kumar, Anil; Arjunan, Pachiappan; Li, Yang; Zhang, Fan; Li, Xuri

2011-01-01

Injury to the optic nerve can lead to axonal degeneration, followed by a gradual death of retinal ganglion cells (RGCs), which results in irreversible vision loss. Examples of such diseases in human include traumatic optic neuropathy and optic nerve degeneration in glaucoma. It is characterized by typical changes in the optic nerve head, progressive optic nerve degeneration, and loss of retinal ganglion cells, if uncontrolled, leading to vision loss and blindness. The optic nerve crush (ONC) injury mouse model is an important experimental disease model for traumatic optic neuropathy, glaucoma, etc. In this model, the crush injury to the optic nerve leads to gradual retinal ganglion cells apoptosis. This disease model can be used to study the general processes and mechanisms of neuronal death and survival, which is essential for the development of therapeutic measures. In addition, pharmacological and molecular approaches can be used in this model to identify and test potential therapeutic reagents to treat different types of optic neuropathy. Here, we provide a step by step demonstration of (I) Baseline retrograde labeling of retinal ganglion cells (RGCs) at day 1, (II) Optic nerve crush injury at day 4, (III) Harvest the retinae and analyze RGC survival at day 11, and (IV) Representative result. PMID:21540827

A transcribed ultraconserved noncoding RNA, Uc.173, is a key molecule for the inhibition of lead-induced neuronal apoptosis

PubMed Central

Chen, Lijian; Liu, Meiling; Zhang, Nan; Zhang, Li; Luo, Yuanwei; Liu, Zhenzhong; Dai, Lijun; Jiang, Yiguo

2016-01-01

As a common toxic metal, lead has significant neurotoxicity to brain development. Long non-coding RNAs (lncRNAs) function in multiple biological processes. However, whether lncRNAs are involved in lead-induced neurotoxicity remains unclear. Uc.173 is a lncRNA from a transcribed ultra-conservative region (T-UCR) of human, mouse and rat genomes. We established a lead-induced nerve injury mouse model. It showed the levels of Uc.173 decreased significantly in hippocampus tissue and serum of the model. We further tested the expression of Uc.173 in serum of lead-exposed children, which also showed a tendency to decrease. To explore the effects of Uc.173 on lead-induced nerve injury, we overexpressed Uc.173 in an N2a mouse nerve cell line and found Uc.173 had an inhibitory effect on lead-induced apoptosis of N2a. To investigate the molecular mechanisms of Uc.173 in apoptosis associated with lead-induced nerve injury, we predicted the target microRNAs of Uc.173 by using miRanda, TargetScan and RegRNA. After performing quantitative real-time PCR and bioinformatics analysis, we showed Uc.173 might inter-regulate with miR-291a-3p in lead-induced apoptosis and regulate apoptosis-associated genes. Our study suggests Uc.173 significantly inhibits the apoptosis of nerve cells, which may be mediated by inter-regulation with miRNAs in lead-induced nerve injury. PMID:26683706

Control of Mycobacterial Infections in Mice Expressing Human Tumor Necrosis Factor (TNF) but Not Mouse TNF.

PubMed

Olleros, Maria L; Chavez-Galan, Leslie; Segueni, Noria; Bourigault, Marie L; Vesin, Dominique; Kruglov, Andrey A; Drutskaya, Marina S; Bisig, Ruth; Ehlers, Stefan; Aly, Sahar; Walter, Kerstin; Kuprash, Dmitry V; Chouchkova, Miliana; Kozlov, Sergei V; Erard, François; Ryffel, Bernard; Quesniaux, Valérie F J; Nedospasov, Sergei A; Garcia, Irene

2015-09-01

Tumor necrosis factor (TNF) is an important cytokine for host defense against pathogens but is also associated with the development of human immunopathologies. TNF blockade effectively ameliorates many chronic inflammatory conditions but compromises host immunity to tuberculosis. The search for novel, more specific human TNF blockers requires the development of a reliable animal model. We used a novel mouse model with complete replacement of the mouse TNF gene by its human ortholog (human TNF [huTNF] knock-in [KI] mice) to determine resistance to Mycobacterium bovis BCG and M. tuberculosis infections and to investigate whether TNF inhibitors in clinical use reduce host immunity. Our results show that macrophages from huTNF KI mice responded to BCG and lipopolysaccharide similarly to wild-type macrophages by NF-κB activation and cytokine production. While TNF-deficient mice rapidly succumbed to mycobacterial infection, huTNF KI mice survived, controlling the bacterial burden and activating bactericidal mechanisms. Administration of TNF-neutralizing biologics disrupted the control of mycobacterial infection in huTNF KI mice, leading to an increased bacterial burden and hyperinflammation. Thus, our findings demonstrate that human TNF can functionally replace murine TNF in vivo, providing mycobacterial resistance that could be compromised by TNF neutralization. This new animal model will be helpful for the testing of specific biologics neutralizing human TNF. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Roles for the endocannabinoid system in ethanol-motivated behavior.

PubMed

Henderson-Redmond, Angela N; Guindon, Josée; Morgan, Daniel J

2016-02-04

Alcohol use disorder represents a significant human health problem that leads to substantial loss of human life and financial cost to society. Currently available treatment options do not adequately address this human health problem, and thus, additional therapies are desperately needed. The endocannabinoid system has been shown, using animal models, to modulate ethanol-motivated behavior, and it has also been demonstrated that chronic ethanol exposure can have potentially long-lasting effects on the endocannabinoid system. For example, chronic exposure to ethanol, in either cell culture or preclinical rodent models, causes an increase in endocannabinoid levels that results in down-regulation of the cannabinoid receptor 1 (CB1) and uncoupling of this receptor from downstream G protein signaling pathways. Using positron emission tomography (PET), similar down-regulation of CB1 has been noted in multiple regions of the brain in human alcoholic patients. In rodents, treatment with the CB1 inverse agonist SR141716A (Rimonabant), or genetic deletion of CB1 leads to a reduction in voluntary ethanol drinking, ethanol-stimulated dopamine release in the nucleus accumbens, operant self-administration of ethanol, sensitization to the locomotor effects of ethanol, and reinstatement/relapse of ethanol-motivated behavior. Although the clinical utility of Rimonabant or other antagonists/inverse agonists for CB1 is limited due to negative neuropsychiatric side effects, negative allosteric modulators of CB1 and inhibitors of endocannabinoid catabolism represent therapeutic targets worthy of additional examination. Copyright © 2015 Elsevier Inc. All rights reserved.

Exploring NASA Human Spaceflight and Pioneering Scenarios

NASA Technical Reports Server (NTRS)

Zapata, Edgar; Wilhite, Alan

2015-01-01

The life cycle cost analysis of space exploration scenarios is explored via a merger of (1) scenario planning, separating context and (2) modeling and analysis of specific content. Numerous scenarios are presented, leading to cross-cutting recommendations addressing life cycle costs, productivity, and approaches applicable to any scenarios. Approaches address technical and non-technical factors.

A Conversational Intelligent Tutoring System to Automatically Predict Learning Styles

ERIC Educational Resources Information Center

Latham, Annabel; Crockett, Keeley; McLean, David; Edmonds, Bruce

2012-01-01

This paper proposes a generic methodology and architecture for developing a novel conversational intelligent tutoring system (CITS) called Oscar that leads a tutoring conversation and dynamically predicts and adapts to a student's learning style. Oscar aims to mimic a human tutor by implicitly modelling the learning style during tutoring, and…

Using perceptual cues for brake response to a lead vehicle: Comparing threshold and accumulator models of visual looming.

PubMed

Xue, Qingwan; Markkula, Gustav; Yan, Xuedong; Merat, Natasha

2018-06-18

Previous studies have shown the effect of a lead vehicle's speed, deceleration rate and headway distance on drivers' brake response times. However, how drivers perceive this information and use it to determine when to apply braking is still not quite clear. To better understand the underlying mechanisms, a driving simulator experiment was performed where each participant experienced nine deceleration scenarios. Previously reported effects of the lead vehicle's speed, deceleration rate and headway distance on brake response time were firstly verified in this paper, using a multilevel model. Then, as an alternative to measures of speed, deceleration rate and distance, two visual looming-based metrics (angular expansion rate θ˙ of the lead vehicle on the driver's retina, and inverse tau τ -1 , the ratio between θ˙ and the optical size θ), considered to be more in line with typical human psycho-perceptual responses, were adopted to quantify situation urgency. These metrics were used in two previously proposed mechanistic models predicting brake onset: either when looming surpasses a threshold, or when the accumulated evidence (looming and other cues) reaches a threshold. Results showed that the looming threshold model did not capture the distribution of brake response time. However, regardless of looming metric, the accumulator models fitted the distribution of brake response times better than the pure threshold models. Accumulator models, including brake lights, provided a better model fit than looming-only versions. For all versions of the mechanistic models, models using τ -1 as the measure of looming fitted better than those using θ˙, indicating that the visual cues drivers used during rear-end collision avoidance may be more close to τ -1 . Copyright © 2018 Elsevier Ltd. All rights reserved.

Strategies to improve electrode positioning and safety in cochlear implants.

PubMed

Rebscher, S J; Heilmann, M; Bruszewski, W; Talbot, N H; Snyder, R L; Merzenich, M M

1999-03-01

An injection-molded internal supporting rib has been produced to control the flexibility of silicone rubber encapsulated electrodes designed to electrically stimulate the auditory nerve in human subjects with severe to profound hearing loss. The rib molding dies, and molds for silicone rubber encapsulation of the electrode, were designed and machined using AutoCad and MasterCam software packages in a PC environment. After molding, the prototype plastic ribs were iteratively modified based on observations of the performance of the rib/silicone composite insert in a clear plastic model of the human scala tympani cavity. The rib-based electrodes were reliably inserted farther into these models, required less insertion force and were positioned closer to the target auditory neural elements than currently available cochlear implant electrodes. With further design improvements the injection-molded rib may also function to accurately support metal stimulating contacts and wire leads during assembly to significantly increase the manufacturing efficiency of these devices. This method to reliably control the mechanical properties of miniature implantable devices with multiple electrical leads may be valuable in other areas of biomedical device design.

Early Lineage Priming by Trisomy of Erg Leads to Myeloproliferation in a Down Syndrome Model

PubMed Central

Ng, Ashley P.; Hu, Yifang; Metcalf, Donald; Hyland, Craig D.; Ierino, Helen; Phipson, Belinda; Wu, Di; Baldwin, Tracey M.; Kauppi, Maria; Kiu, Hiu; Di Rago, Ladina; Hilton, Douglas J.; Smyth, Gordon K.; Alexander, Warren S.

2015-01-01

Down syndrome (DS), with trisomy of chromosome 21 (HSA21), is the commonest human aneuploidy. Pre-leukemic myeloproliferative changes in DS foetal livers precede the acquisition of GATA1 mutations, transient myeloproliferative disorder (DS-TMD) and acute megakaryocytic leukemia (DS-AMKL). Trisomy of the Erg gene is required for myeloproliferation in the Ts(1716)65Dn DS mouse model. We demonstrate here that genetic changes specifically attributable to trisomy of Erg lead to lineage priming of primitive and early multipotential progenitor cells in Ts(1716)65Dn mice, excess megakaryocyte-erythroid progenitors, and malignant myeloproliferation. Gene expression changes dependent on trisomy of Erg in Ts(1716)65Dn multilineage progenitor cells were correlated with those associated with trisomy of HSA21 in human DS hematopoietic stem and primitive progenitor cells. These data suggest a role for ERG as a regulator of hematopoietic lineage potential, and that trisomy of ERG in the context of DS foetal liver hemopoiesis drives the pre-leukemic changes that predispose to subsequent DS-TMD and DS-AMKL. PMID:25973911

Coupled economic-coastline modeling with suckers and free riders

NASA Astrophysics Data System (ADS)

Williams, Zachary C.; McNamara, Dylan E.; Smith, Martin D.; Murray, A. Brad.; Gopalakrishnan, Sathya

2013-06-01

erosion is a natural trend along most sandy coastlines. Humans often respond to shoreline erosion with beach nourishment to maintain coastal property values. Locally extending the shoreline through nourishment alters alongshore sediment transport and changes shoreline dynamics in adjacent coastal regions. If left unmanaged, sandy coastlines can have spatially complex or simple patterns of erosion due to the relationship of large-scale morphology and the local wave climate. Using a numerical model that simulates spatially decentralized and locally optimal nourishment decisions characteristic of much of U.S. East Coast beach management, we find that human erosion intervention does not simply reflect the alongshore erosion pattern. Spatial interactions generate feedbacks in economic and physical variables that lead to widespread emergence of "free riders" and "suckers" with subsequent inequality in the alongshore distribution of property value. Along cuspate coastlines, such as those found along the U.S. Southeast Coast, these long-term property value differences span an order of magnitude. Results imply that spatially decentralized management of nourishment can lead to property values that are divorced from spatial erosion signals; this management approach is unlikely to be optimal.

Prolonged recovery of retinal structure/function after gene therapy in an Rs1h-deficient mouse model of x-linked juvenile retinoschisis.

PubMed

Min, Seok H; Molday, Laurie L; Seeliger, Mathias W; Dinculescu, Astra; Timmers, Adrian M; Janssen, Andreas; Tonagel, Felix; Tanimoto, Naoyuki; Weber, Bernhard H F; Molday, Robert S; Hauswirth, William W

2005-10-01

X-linked juvenile retinoschisis (RS) is a common cause of juvenile macular degeneration in males. RS is characterized by cystic spoke-wheel-like maculopathy, peripheral schisis, and a negative (b-wave more reduced than a-wave) electroretinogram (ERG). These symptoms are due to mutations in the RS1 gene in Xp22.2 leading to loss of functional protein. No medical treatment is currently available. We show here that in an Rs1h-deficient mouse model of human RS, delivery of the human RS1 cDNA with an AAV vector restored expression of retinoschisin to both photoreceptors and the inner retina essentially identical to that seen in wild-type mice. More importantly, unlike an earlier study with a different AAV vector and promoter, this work shows for the first time that therapeutic gene delivery using a highly specific AAV5-opsin promoter vector leads to progressive and significant improvement in both retinal function (ERG) and morphology, with preservation of photoreceptor cells that, without treatment, progressively degenerate.

A neural network simulating human reach-grasp coordination by continuous updating of vector positioning commands.

PubMed

Ulloa, Antonio; Bullock, Daniel

2003-10-01

We developed a neural network model to simulate temporal coordination of human reaching and grasping under variable initial grip apertures and perturbations of object size and object location/orientation. The proposed model computes reach-grasp trajectories by continuously updating vector positioning commands. The model hypotheses are (1) hand/wrist transport, grip aperture, and hand orientation control modules are coupled by a gating signal that fosters synchronous completion of the three sub-goals. (2) Coupling from transport and orientation velocities to aperture control causes maximum grip apertures that scale with these velocities and exceed object size. (3) Part of the aperture trajectory is attributable to an aperture-reducing passive biomechanical effect that is stronger for larger apertures. (4) Discrepancies between internal representations of targets partially inhibit the gating signal, leading to movement time increases that compensate for perturbations. Simulations of the model replicate key features of human reach-grasp kinematics observed under three experimental protocols. Our results indicate that no precomputation of component movement times is necessary for online temporal coordination of the components of reaching and grasping.

CRISPR/Cas9-mediated mutation of PHEX in rabbit recapitulates human X-linked hypophosphatemia (XLH).

PubMed

Sui, Tingting; Yuan, Lin; Liu, Huan; Chen, Mao; Deng, Jichao; Wang, Yong; Li, Zhanjun; Lai, Liangxue

2016-07-01

X-linked hypophosphatemia (XLH) is the most common cause of inheritable rickets, with an incidence of 1/20 000 in humans. Inactivation or mutation of the gene PHEX, a phosphate-regulating endopeptidase, leads to hypophosphatemia and defective bone mineralization in XLH patients. Presently, there is no adequate animal model for safety assessments of physiotherapies and drug screening for XLH rickets. In this study, an XLH model was generated via PHEX gene knockout (KO) through coinjection of clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9)/sgRNA mRNA into rabbit zygotes. The typical phenotypes of growth retardation, hypophosphatemia, elevated serum FGF23 and bone mineralization were observed in the PHEX KO rabbits but not in normal controls. In summary, for the first time, we have successfully obtained PHEX KO rabbits and recapitulated human XLH using the CRISPR/Cas9 system. This novel XLH rabbit model could be utilized as a drug screening model for XLH prevention and preclinical therapy. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Genealogy and gene trees.

PubMed

Rasmuson, Marianne

2008-02-01

Heredity can be followed in persons or in genes. Persons can be identified only a few generations back, but simplified models indicate that universal ancestors to all now living persons have occurred in the past. Genetic variability can be characterized as variants of DNA sequences. Data are available only from living persons, but from the pattern of variation gene trees can be inferred by means of coalescence models. The merging of lines backwards in time leads to a MRCA (most recent common ancestor). The time and place of living for this inferred person can give insights in human evolutionary history. Demographic processes are incorporated in the model, but since culture and customs are known to influence demography the models used ought to be tested against available genealogy. The Icelandic data base offers a possibility to do so and points to some discrepancies. Mitochondrial DNA and Y chromosome patterns give a rather consistent view of human evolutionary history during the latest 100 000 years but the earlier epochs of human evolution demand gene trees with longer branches. The results of such studies reveal as yet unsolved problems about the sources of our genome.

The integrated Earth system model version 1: formulation and functionality

DOE PAGES

Collins, W. D.; Craig, A. P.; Truesdale, J. E.; ...

2015-07-23

The integrated Earth system model (iESM) has been developed as a new tool for projecting the joint human/climate system. The iESM is based upon coupling an integrated assessment model (IAM) and an Earth system model (ESM) into a common modeling infrastructure. IAMs are the primary tool for describing the human–Earth system, including the sources of global greenhouse gases (GHGs) and short-lived species (SLS), land use and land cover change (LULCC), and other resource-related drivers of anthropogenic climate change. ESMs are the primary scientific tools for examining the physical, chemical, and biogeochemical impacts of human-induced changes to the climate system. Themore » iESM project integrates the economic and human-dimension modeling of an IAM and a fully coupled ESM within a single simulation system while maintaining the separability of each model if needed. Both IAM and ESM codes are developed and used by large communities and have been extensively applied in recent national and international climate assessments. By introducing heretofore-omitted feedbacks between natural and societal drivers, we can improve scientific understanding of the human–Earth system dynamics. Potential applications include studies of the interactions and feedbacks leading to the timing, scale, and geographic distribution of emissions trajectories and other human influences, corresponding climate effects, and the subsequent impacts of a changing climate on human and natural systems. This paper describes the formulation, requirements, implementation, testing, and resulting functionality of the first version of the iESM released to the global climate community.« less

Expression of human PQBP-1 in Drosophila impairs long-term memory and induces abnormal courtship.

PubMed

Yoshimura, Natsue; Horiuchi, Daisuke; Shibata, Masao; Saitoe, Minoru; Qi, Mei-Ling; Okazawa, Hitoshi

2006-04-17

Frame shift mutations of the polyglutamine binding protein-1 (PQBP1) gene lead to total or partial truncation of the C-terminal domain (CTD) and cause mental retardation in human patients. Interestingly, normal Drosophila homologue of PQBP-1 lacks CTD. As a model to analyze the molecular network of PQBP-1 affecting intelligence, we generated transgenic flies expressing human PQBP-1 with CTD. Pavlovian olfactory conditioning revealed that the transgenic flies showed disturbance of long-term memory. In addition, they showed abnormal courtship that male flies follow male flies. Abnormal functions of PQBP-1 or its binding partner might be linked to these symptoms.

Human Correlates of Provocative Questions in Pancreatic Pathology

PubMed Central

McDonald, Oliver G.; Maitra, Anirban; Hruban, Ralph H.

2012-01-01

Studies of cell lines and of animal models of pancreatic cancer have raised a number of provocative questions about the nature and origins of human pancreatic cancer and have provided several leads into exciting new approaches for the treatment of this deadly cancer. In addition, clinicians with little or no contact with human pathology have challenged the way that pancreatic pathology is practiced, suggesting that “genetic signals” may be more accurate than today’s multi-modal approach to diagnoses. In this review we consider eight provocative issues in pancreas pathology, with an emphasis on “the evidence derived from man.” PMID:23060061

Friendship Dissolution Within Social Networks Modeled Through Multilevel Event History Analysis

PubMed Central

Dean, Danielle O.; Bauer, Daniel J.; Prinstein, Mitchell J.

2018-01-01

A social network perspective can bring important insight into the processes that shape human behavior. Longitudinal social network data, measuring relations between individuals over time, has become increasingly common—as have the methods available to analyze such data. A friendship duration model utilizing discrete-time multilevel survival analysis with a multiple membership random effect structure is developed and applied here to study the processes leading to undirected friendship dissolution within a larger social network. While the modeling framework is introduced in terms of understanding friendship dissolution, it can be used to understand microlevel dynamics of a social network more generally. These models can be fit with standard generalized linear mixed-model software, after transforming the data to a pair-period data set. An empirical example highlights how the model can be applied to understand the processes leading to friendship dissolution between high school students, and a simulation study is used to test the use of the modeling framework under representative conditions that would be found in social network data. Advantages of the modeling framework are highlighted, and potential limitations and future directions are discussed. PMID:28463022

A comparison of the suppression of human transferrin synthesis by lead and lipopolysaccharide.

PubMed

Barnum-Huckins, K M; Martinez, A O; Rivera, E V; Adrian, E K; Herbert, D C; Weaker, F J; Walter, C A; Adrian, G S

1997-03-14

Transferrin, as the major iron-transport protein in serum and other body fluids, has a central role in managing iron the body receives. Liver is a major site of transferrin synthesis, and in this study we present evidence that liver synthesis of human transferrin is suppressed by both the toxic metal lead and bacterial lipopolysaccharide, an inducer of the hepatic acute phase response. The responses of intact endogenous transferrin in the human hepatoma cell line HepG2 and chimeric human transferrin-chloramphenicol acetyltransferase genes in transgenic mice were examined. In HepG2 cells, 35S-transferrin protein synthesis and mRNA levels were suppressed by 100 microM and 10 microM lead acetate as early as 24 h after the initial treatment. Yet, synthesis of two proteins known to respond in the hepatic acute phase reaction, complement C3 and albumin, was not altered by the lead treatment. In transgenic mouse liver, lead suppressed expression of chimeric human transferrin genes at both the protein and mRNA levels, but LPS only suppressed at the protein level. The study indicates that lead suppresses human transferrin synthesis by a mechanism that differs from the hepatic acute phase response and that lead may also affect iron metabolism in humans by interfering with transferrin levels.

Flow field and oscillatory shear stress in a tuning-fork-shaped model of the average human carotid bifurcation.

PubMed

Ding, Z; Wang, K; Li, J; Cong, X

2001-12-01

The oscillatory shear index (OSI) was developed based on the hypothesis that intimal hyperplasia was correlated with oscillatory shear stresses. However, the validity of the OSI was in question since the correlation between intimal thickness and the OSI at the side walls of the sinus in the Y-shaped model of the average human carotid bifurcation (Y-AHCB) was weak. The objectives of this paper are to examine whether the reason for the weak correlation lies in the deviation in geometry of Y-AHCB from real human carotid bifurcation, and whether this correlation is clearly improved in the tuning-fork-shaped model of the average human carotid bifurcation (TF-AHCB). The geometry of the TF-AHCB model was based on observation and statistical analysis of specimens from 74 cadavers. The flow fields in both models were studied and compared by using flow visualization methods under steady flow conditions and by using laser Doppler anemometer (LDA) under pulsatile flow conditions. The TF-shaped geometry leads to a more complex flow field than the Y-shaped geometry. This added complexity includes strengthened helical movements in the sinus, new flow separation zone, and directional changes in the secondary flow patterns. The results show that the OSI-values at the side walls of the sinus in the TF-shaped model were more than two times as large as those in the Y-shaped model. This study confirmed the stronger correlation between the OSI and intimal thickness in the tuning-fork geometry of human carotid bifurcation, and the TF-AHCB model is a significant improvement over the traditional Y-shaped model.

Lead phytotoxicity on wheat (Triticum aestivum L.) seed germination and seedlings growth.

PubMed

Lamhamdi, Mostafa; Bakrim, Ahmed; Aarab, Ahmed; Lafont, René; Sayah, Fouad

2011-02-01

Lead (Pb) is an environmental pollutant extremely toxic to plants and other living organisms including humans. To assess Pb phytotoxicity, experiments focusing on germination of wheat seeds were germinated in a solution containing Pb (NO(3))(2) (0.05; 0.1; 0.5; 1g/L) during 6 days. Lead accumulation in seedlings was positively correlated with the external concentrations, and negatively correlated with morphological parameters of plant growth. Lead increased lipid peroxidation, enhanced soluble protein concentrations and induced a significant accumulation of proline in roots. Esterase activity was enhanced in the presence of lead, whereas α-amylase activity was significantly inhibited. Antioxidant enzymes activities, such as, ascorbate peroxidase, peroxidase, superoxide dismutase, catalase and glutathione S-transferase were generally significantly increased in the presence of lead in a dose-dependent manner. The present results thus provide a model system to screen for natural compounds able to counteract the deleterious effects of lead. Copyright © 2010 Académie des sciences. Published by Elsevier SAS. All rights reserved.

Effect of Vandetanib on Andes virus survival in the hamster model of Hantavirus pulmonary syndrome.

PubMed

Bird, Brian H; Shrivastava-Ranjan, Punya; Dodd, Kimberly A; Erickson, Bobbie R; Spiropoulou, Christina F

2016-08-01

Hantavirus pulmonary syndrome (HPS) is a severe disease caused by hantavirus infection of pulmonary microvascular endothelial cells leading to microvascular leakage, pulmonary edema, pleural effusion and high case fatality. Previously, we demonstrated that Andes virus (ANDV) infection caused up-regulation of vascular endothelial growth factor (VEGF) and concomitant downregulation of the cellular adhesion molecule VE-cadherin leading to increased permeability. Analyses of human HPS-patient sera have further demonstrated increased circulating levels of VEGF. Here we investigate the impact of a small molecule antagonist of the VEGF receptor 2 (VEGFR-2) activation in vitro, and overall impact on survival in the Syrian hamster model of HPS. Copyright © 2016. Published by Elsevier B.V.

Sensitivity of mountain ecosystems to human-accelerated soil erosion. Contrasting geomorphic response between tropical and semi-arid ecosystems.

NASA Astrophysics Data System (ADS)

Vanacker, Veerle; Bellin, Nicolas; Schoonejans, Jerome; Molina, Armando; Kubik, Peter W.

2014-05-01

Human-induced land cover changes are causing important adverse effects on the ecological services rendered by mountain ecosystems, and the number of case-studies of the impact of humans on soil erosion and sediment yield has mounted rapidly. A modelling framework that is specifically adapted to mountain environments is currently lacking. Most studies make use of general river basin models that were originally parameterized and calibrated for temperate, low relief landscapes. Transposing these modelling concepts directly to steep environments with shallow and stony soils often leads to unrealistic model predictions, as model input parameters are rarely calibrated for the range of environmental conditions found in mountain regions. Here, we present a conceptual model that evaluates erosion regulation as a function of human disturbances in vegetation cover. The basic idea behind this model is that soil erosion mechanisms are independent of human impact, but that the frequency-magnitude distributions of erosion rates change as a response to human disturbances. Pre-disturbance (or natural) erosion rates are derived from in-situ produced 10Be concentrations in river sediment, while post-disturbance (or modern) erosion rates are derived from sedimentation rates in small catchments. In its simplicity, the model uses vegetation cover change as a proxy of human disturbance in a given vegetation system. The model is then calibrated with field measurements from two mountainous sites with strongly different vegetation dynamics, climatic and geological settings: the Tropical Andes, and the Spanish Betic Cordillera. Natural erosion processes are important in mountainous sites, and natural erosion benchmarks are primordial to assess human-induced changes in erosion rates. While the Spanish Betic Cordillera is commonly characterized as a degraded landscape, there is no significant change in erosion due to human disturbance for uncultivated sites. The opposite is true for the Tropical Andes where the share of natural erosion in the modern erosion rate is minimal for most disturbed sites. When pooling pre- and post-disturbance erosion data from both sites, it becomes evident that the human acceleration of erosion is significantly related to vegetation disturbance. It may therefore be expected that the potential for erosion regulation is larger in well-vegetated ecosystem where strong differences may exist in vegetation cover between human disturbed and undisturbed or restored sites.

Dual Rationality and Deliberative Agents

NASA Astrophysics Data System (ADS)

Debenham, John; Sierra, Carles

Human agents deliberate using models based on reason for only a minute proportion of the decisions that they make. In stark contrast, the deliberation of artificial agents is heavily dominated by formal models based on reason such as game theory, decision theory and logic—despite that fact that formal reasoning will not necessarily lead to superior real-world decisions. Further the Nobel Laureate Friedrich Hayek warns us of the ‘fatal conceit’ in controlling deliberative systems using models based on reason as the particular model chosen will then shape the system’s future and either impede, or eventually destroy, the subtle evolutionary processes that are an integral part of human systems and institutions, and are crucial to their evolution and long-term survival. We describe an architecture for artificial agents that is founded on Hayek’s two rationalities and supports the two forms of deliberation used by mankind.

Analysis of the effects of non-supine sleeping positions on the stress, strain, deformation and intraocular pressure of the human eye

NASA Astrophysics Data System (ADS)

Volpe, Peter A.

This thesis presents analytical models, finite element models and experimental data to investigate the response of the human eye to loads that can be experienced when in a non-supine sleeping position. The hypothesis being investigated is that non-supine sleeping positions can lead to stress, strain and deformation of the eye as well as changes in intraocular pressure (IOP) that may exacerbate vision loss in individuals who have glaucoma. To investigate the quasi-static changes in stress and internal pressure, a Fluid-Structure Interaction simulation was performed on an axisymmetrical model of an eye. Common Aerospace Engineering methods for analyzing pressure vessels and hyperelastic structural walls are applied to developing a suitable model. The quasi-static pressure increase was used in an iterative code to analyze changes in IOP over time.

Modeling Acute Health Effects of Astronauts from Exposure to Large Solar Particle Events

NASA Technical Reports Server (NTRS)

Hu, Shaowen; Kim, Myung-Hee Y.; Cucinotta, Francis A.

2011-01-01

In space exploration outside the Earth s geomagnetic field, radiation exposure from solar particle events (SPE) presents a health concern for astronauts, that could impair their performance and result in possible failure of the mission. Acute risks are of special concern during extra-vehicular activities because of the rapid onset of SPE. However, most SPEs will not lead to acute risks but can lead to mission disruption if accurate projection methods are not available. Acute Radiation Sickness (ARS) is a group of clinical syndromes developing acutely (within several seconds to 3 days) after high dose whole-body or significant partial-body ionizing radiation exposures. The manifestation of these syndromes reflects the disturbance of physiological processes of various cellular groups damaged by radiation. Hematopoietic cells, skin, epithelium, intestine, and vascular endothelium are among the most sensitive tissues of human body to ionizing radiation. Most ARS symptoms are directly related to these tissues and other systems (nervous, endocrine, and cardiovascular, etc.) with coupled regulations. Here we report the progress in bio-mathematical models to describe the dose and time-dependent early human responses to ionizing radiation. The responses include lymphocyte depression, granulocyte modulation, fatigue and weakness syndrome, and upper gastrointestinal distress. The modest dose and dose-rates of SPEs are predicted to lead to large sparing of ARS, however detailed experimental data on a range of proton dose-rates for organ doses from 0.5 to 2 Gy is needed to validate the models. We also report on the ARRBOD code that integrates the BRYNTRN and SUMDOSE codes, which are used to estimate the SPE organ doses for astronauts under various space travel scenarios, with our models of ARS. The more recent effort is to provide easy web access to space radiation risk assessment using the ARRBOD code.

Experimental anti-GBM nephritis as an analytical tool for studying spontaneous lupus nephritis.

PubMed

Du, Yong; Fu, Yuyang; Mohan, Chandra

2008-01-01

Systemic lupus erythematosus (SLE) is an autoimmune disease that results in immune-mediated damage to multiple organs. Among these, kidney involvement is the most common and fatal. Spontaneous lupus nephritis (SLN) in mouse models has provided valuable insights into the underlying mechanisms of human lupus nephritis. However, SLN in mouse models takes 6-12 months to manifest; hence there is clearly the need for a mouse model that can be used to unveil the pathogenic processes that lead to immune nephritis over a shorter time frame. In this article more than 25 different molecules are reviewed that have been studied both in the anti-glomerular basement membrane (anti-GBM) model and in SLN and it was found that these molecules influence both diseases in a parallel fashion, suggesting that the two disease settings share common molecular mechanisms. Based on these observations, the authors believe the experimental anti-GBM disease model might be one of the best tools currently available for uncovering the downstream molecular mechanisms leading to SLN.

Spatially explicit modelling of cholera epidemics

NASA Astrophysics Data System (ADS)

Finger, F.; Bertuzzo, E.; Mari, L.; Knox, A. C.; Gatto, M.; Rinaldo, A.

2013-12-01

Epidemiological models can provide crucial understanding about the dynamics of infectious diseases. Possible applications range from real-time forecasting and allocation of health care resources to testing alternative intervention mechanisms such as vaccines, antibiotics or the improvement of sanitary conditions. We apply a spatially explicit model to the cholera epidemic that struck Haiti in October 2010 and is still ongoing. The dynamics of susceptibles as well as symptomatic and asymptomatic infectives are modelled at the scale of local human communities. Dissemination of Vibrio cholerae through hydrological transport and human mobility along the road network is explicitly taken into account, as well as the effect of rainfall as a driver of increasing disease incidence. The model is calibrated using a dataset of reported cholera cases. We further model the long term impact of several types of interventions on the disease dynamics by varying parameters appropriately. Key epidemiological mechanisms and parameters which affect the efficiency of treatments such as antibiotics are identified. Our results lead to conclusions about the influence of different intervention strategies on the overall epidemiological dynamics.

Inventory of Novel Animal Models Addressing Etiology of Preeclampsia in the Development of New Therapeutic/Intervention Opportunities.

PubMed

Erlandsson, Lena; Nääv, Åsa; Hennessy, Annemarie; Vaiman, Daniel; Gram, Magnus; Åkerström, Bo; Hansson, Stefan R

2016-03-01

Preeclampsia is a pregnancy-related disease afflicting 3-7% of pregnancies worldwide and leads to maternal and infant morbidity and mortality. The disease is of placental origin and is commonly described as a disease of two stages. A variety of preeclampsia animal models have been proposed, but all of them have limitations in fully recapitulating the human disease. Based on the research question at hand, different or multiple models might be suitable. Multiple animal models in combination with in vitro or ex vivo studies on human placenta together offer a synergistic platform to further our understanding of the etiology of preeclampsia and potential therapeutic interventions. The described animal models of preeclampsia divide into four categories (i) spontaneous, (ii) surgically induced, (iii) pharmacologically/substance induced, and (iv) transgenic. This review aims at providing an inventory of novel models addressing etiology of the disease and or therapeutic/intervention opportunities. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Humanized Rag1−/−γc−/− Mice Support Multilineage Hematopoiesis and Are Susceptible to HIV-1 Infection via Systemic and Vaginal Routes

PubMed Central

Akkina, Ramesh; Berges, Bradford K.; Palmer, Brent E.; Remling, Leila; Neff, C. Preston; Kuruvilla, Jes; Connick, Elizabeth; Folkvord, Joy; Gagliardi, Kathy; Kassu, Afework; Akkina, Sarah R.

2011-01-01

Several new immunodeficient mouse models for human cell engraftment have recently been introduced that include the Rag2−/−γc−/−, NOD/SCID, NOD/SCIDγc−/− and NOD/SCIDβ2m−/− strains. Transplantation of these mice with CD34+ human hematopoietic stem cells leads to prolonged engraftment, multilineage hematopoiesis and the capacity to generate human immune responses against a variety of antigens. However, the various mouse strains used and different methods of engrafting human cells are beginning to illustrate strain specific variations in engraftment levels, duration and longevity of mouse life span. In these proof-of-concept studies we evaluated the Balb/c-Rag1−/−γ−/− strain for engraftment by human fetal liver derived CD34+ hematopoietic cells using the same protocol found to be effective for Balb/c-Rag2−/−γc−/− mice. We demonstrate that these mice can be efficiently engrafted and show multilineage human hematopoiesis with human cells populating different lymphoid organs. Generation of human cells continues beyond a year and production of human immunoglobulins is noted. Infection with HIV-1 leads to chronic viremia with a resultant CD4 T cell loss. To mimic the predominant sexual viral transmission, we challenged humanized Rag1−/−γc−/− mice with HIV-1 via vaginal route which also resulted in chronic viremia and helper T cell loss. Thus these mice can be further exploited for studying human pathogens that infect the human hematopoietic system in an in vivo setting. PMID:21695116

Perspectives of human verification via binary QRS template matching of single-lead and 12-lead electrocardiogram.

PubMed

Krasteva, Vessela; Jekova, Irena; Schmid, Ramun

2018-01-01

This study aims to validate the 12-lead electrocardiogram (ECG) as a biometric modality based on two straightforward binary QRS template matching characteristics. Different perspectives of the human verification problem are considered, regarding the optimal lead selection and stability over sample size, gender, age, heart rate (HR). A clinical 12-lead resting ECG database, including a population of 460 subjects with two-session recordings (>1 year apart) is used. Cost-effective strategies for extraction of personalized QRS patterns (100ms) and binary template matching estimate similarity in the time scale (matching time) and dissimilarity in the amplitude scale (mismatch area). The two-class person verification task, taking the decision to validate or to reject the subject identity is managed by linear discriminant analysis (LDA). Non-redundant LDA models for different lead configurations (I,II,III,aVF,aVL,aVF,V1-V6) are trained on the first half of 230 subjects by stepwise feature selection until maximization of the area under the receiver operating characteristic curve (ROC AUC). The operating point on the training ROC at equal error rate (EER) is tested on the independent dataset (second half of 230 subjects) to report unbiased validation of test-ROC AUC and true verification rate (TVR = 100-EER). The test results are further evaluated in groups by sample size, gender, age, HR. The optimal QRS pattern projection for single-lead ECG biometric modality is found in the frontal plane sector (60°-0°) with best (Test-AUC/TVR) for lead II (0.941/86.8%) and slight accuracy drop for -aVR (-0.017/-1.4%), I (-0.01/-1.5%). Chest ECG leads have degrading accuracy from V1 (0.885/80.6%) to V6 (0.799/71.8%). The multi-lead ECG improves verification: 6-chest (0.97/90.9%), 6-limb (0.986/94.3%), 12-leads (0.995/97.5%). The QRS pattern matching model shows stable performance for verification of 10 to 230 individuals; insignificant degradation of TVR in women by (1.2-3.6%), adults ≥70 years (3.7%), younger <40 years (1.9%), HR<60bpm (1.2%), HR>90bpm (3.9%), no degradation for HR change (0 to >20bpm).

Cumulative role of rare and common putative functional genetic variants at NPAS3 in schizophrenia susceptibility.

PubMed

González-Peñas, Javier; Arrojo, Manuel; Paz, Eduardo; Brenlla, Julio; Páramo, Mario; Costas, Javier

2015-10-01

Schizophrenia may be considered a human-specific disorder arisen as a maladaptive by-product of human-specific brain evolution. Therefore, genetic variants involved in susceptibility to schizophrenia may be identified among those genes related to acquisition of human-specific traits. NPAS3, a transcription factor involved in central nervous system development and neurogenesis, seems to be implicated in the evolution of human brain, as it is the human gene with most human-specific accelerated elements (HAEs), i.e., .mammalian conserved regulatory sequences with accelerated evolution in the lineage leading to humans after human-chimpanzee split. We hypothesize that any nucleotide variant at the NPAS3 HAEs may lead to altered susceptibility to schizophrenia. Twenty-one variants at these HAEs detected by the 1000 genomes Project, as well as five additional variants taken from psychiatric genome-wide association studies, were genotyped in 538 schizophrenic patients and 539 controls from Galicia. Analyses at the haplotype level or based on the cumulative role of the variants assuming different susceptibility models did not find any significant association in spite of enough power under several plausible scenarios regarding direction of effect and the specific role of rare and common variants. These results suggest that, contrary to our hypothesis, the special evolution of the NPAS3 HAEs in Homo relaxed the strong constraint on sequence that characterized these regions during mammalian evolution, allowing some sequence changes without any effect on schizophrenia risk. © 2015 Wiley Periodicals, Inc.

Transplacental Nutrient Transport Mechanisms of Intrauterine Growth Restriction in Rodent Models and Humans.

PubMed

Winterhager, Elke; Gellhaus, Alexandra

2017-01-01

Although the causes of intrauterine growth restriction (IUGR) have been intensively investigated, important information is still lacking about the role of the placenta as a link from adverse maternal environment to adverse pregnancy outcomes of IUGR and preterm birth. IUGR is associated with an increased risk of cardiovascular, metabolic, and neurological diseases later in life. Determination of the most important pathways that regulate transplacental transport systems is necessary for identifying marker genes as diagnostic tools and for developing drugs that target the molecular pathways. Besides oxygen, the main nutrients required for appropriate fetal development and growth are glucose, amino acids, and fatty acids. Dysfunction in transplacental transport is caused by impairments in both placental morphology and blood flow, as well as by factors such as alterations in the expression of insulin-like growth factors and changes in the mTOR signaling pathway leading to a change in nutrient transport. Animal models are important tools for systematically studying such complex events. Debate centers on whether the rodent placenta is an appropriate tool for investigating the alterations in the human placenta that result in IUGR. This review provides an overview of the alterations in expression and activity of nutrient transporters and alterations in signaling associated with IUGR and compares these findings in rodents and humans. In general, the data obtained by studies of the various types of rodent and human nutrient transporters are similar. However, direct comparison is complicated by the fact that the results of such studies are controversial even within the same species, making the interpretation of the results challenging. This difficulty could be due to the absence of guidelines of the experimental design and, especially in humans, the use of trophoblast cell culture studies instead of clinical trials. Nonetheless, developing new therapy concepts for IUGR will require the use of animal models for gathering robust data about mechanisms leading to IUGR and for testing the effectiveness and safety of the intervention among pregnant women.

Transplacental Nutrient Transport Mechanisms of Intrauterine Growth Restriction in Rodent Models and Humans

PubMed Central

Winterhager, Elke; Gellhaus, Alexandra

2017-01-01

Although the causes of intrauterine growth restriction (IUGR) have been intensively investigated, important information is still lacking about the role of the placenta as a link from adverse maternal environment to adverse pregnancy outcomes of IUGR and preterm birth. IUGR is associated with an increased risk of cardiovascular, metabolic, and neurological diseases later in life. Determination of the most important pathways that regulate transplacental transport systems is necessary for identifying marker genes as diagnostic tools and for developing drugs that target the molecular pathways. Besides oxygen, the main nutrients required for appropriate fetal development and growth are glucose, amino acids, and fatty acids. Dysfunction in transplacental transport is caused by impairments in both placental morphology and blood flow, as well as by factors such as alterations in the expression of insulin-like growth factors and changes in the mTOR signaling pathway leading to a change in nutrient transport. Animal models are important tools for systematically studying such complex events. Debate centers on whether the rodent placenta is an appropriate tool for investigating the alterations in the human placenta that result in IUGR. This review provides an overview of the alterations in expression and activity of nutrient transporters and alterations in signaling associated with IUGR and compares these findings in rodents and humans. In general, the data obtained by studies of the various types of rodent and human nutrient transporters are similar. However, direct comparison is complicated by the fact that the results of such studies are controversial even within the same species, making the interpretation of the results challenging. This difficulty could be due to the absence of guidelines of the experimental design and, especially in humans, the use of trophoblast cell culture studies instead of clinical trials. Nonetheless, developing new therapy concepts for IUGR will require the use of animal models for gathering robust data about mechanisms leading to IUGR and for testing the effectiveness and safety of the intervention among pregnant women. PMID:29230179

HSPB3 protein is expressed in motoneurons and induces their survival after lesion-induced degeneration.

PubMed

La Padula, Veronica; Staszewski, Ori; Nestel, Sigrun; Busch, Hauke; Boerries, Melanie; Roussa, Eleni; Prinz, Marco; Krieglstein, Kerstin

2016-12-01

The human small heat shock proteins (HSPBs) form a family of molecular chaperones comprising ten members (HSPB1-HSPB10), whose functions span from protein quality control to cytoskeletal dynamics and cell death control. Mutations in HSPBs can lead to human disease and particularly point mutations in HSPB1 and HSPB8 are known to lead to peripheral neuropathies. Recently, a missense mutation (R7S) in yet another member of this family, HSPB3, was found to cause an axonal motor neuropathy (distal hereditary motor neuropathy type 2C, dHMN2C). Until now, HSPB3 protein localization and function in motoneurons (MNs) have not yet been characterized. Therefore, we studied the endogenous HSPB3 protein distribution in the spinal cords of chicken and mouse embryos and in the postnatal nervous system (central and peripheral) of chicken, mouse and human. We further investigated the impact of wild-type and mutated HSPB3 on MN cell death via overexpressing these genes in ovo in an avian model of MN degeneration, the limb-bud removal. Altogether, our findings represent a first step for a better understanding of the cellular and molecular mechanisms leading to dHMN2C. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Evaluation of the HadGEM3-A simulations in view of detection and attribution of human influence on extreme events in Europe

NASA Astrophysics Data System (ADS)

Vautard, Robert; Christidis, Nikolaos; Ciavarella, Andrew; Alvarez-Castro, Carmen; Bellprat, Omar; Christiansen, Bo; Colfescu, Ioana; Cowan, Tim; Doblas-Reyes, Francisco; Eden, Jonathan; Hauser, Mathias; Hegerl, Gabriele; Hempelmann, Nils; Klehmet, Katharina; Lott, Fraser; Nangini, Cathy; Orth, René; Radanovics, Sabine; Seneviratne, Sonia I.; van Oldenborgh, Geert Jan; Stott, Peter; Tett, Simon; Wilcox, Laura; Yiou, Pascal

2018-04-01

A detailed analysis is carried out to assess the HadGEM3-A global atmospheric model skill in simulating extreme temperatures, precipitation and storm surges in Europe in the view of their attribution to human influence. The analysis is performed based on an ensemble of 15 atmospheric simulations forced with observed sea surface temperature of the 54 year period 1960-2013. These simulations, together with dual simulations without human influence in the forcing, are intended to be used in weather and climate event attribution. The analysis investigates the main processes leading to extreme events, including atmospheric circulation patterns, their links with temperature extremes, land-atmosphere and troposphere-stratosphere interactions. It also compares observed and simulated variability, trends and generalized extreme value theory parameters for temperature and precipitation. One of the most striking findings is the ability of the model to capture North-Atlantic atmospheric weather regimes as obtained from a cluster analysis of sea level pressure fields. The model also reproduces the main observed weather patterns responsible for temperature and precipitation extreme events. However, biases are found in many physical processes. Slightly excessive drying may be the cause of an overestimated summer interannual variability and too intense heat waves, especially in central/northern Europe. However, this does not seem to hinder proper simulation of summer temperature trends. Cold extremes appear well simulated, as well as the underlying blocking frequency and stratosphere-troposphere interactions. Extreme precipitation amounts are overestimated and too variable. The atmospheric conditions leading to storm surges were also examined in the Baltics region. There, simulated weather conditions appear not to be leading to strong enough storm surges, but winds were found in very good agreement with reanalyses. The performance in reproducing atmospheric weather patterns indicates that biases mainly originate from local and regional physical processes. This makes local bias adjustment meaningful for climate change attribution.

Short template switch events explain mutation clusters in the human genome.

PubMed

Löytynoja, Ari; Goldman, Nick

2017-06-01

Resequencing efforts are uncovering the extent of genetic variation in humans and provide data to study the evolutionary processes shaping our genome. One recurring puzzle in both intra- and inter-species studies is the high frequency of complex mutations comprising multiple nearby base substitutions or insertion-deletions. We devised a generalized mutation model of template switching during replication that extends existing models of genome rearrangement and used this to study the role of template switch events in the origin of short mutation clusters. Applied to the human genome, our model detects thousands of template switch events during the evolution of human and chimp from their common ancestor and hundreds of events between two independently sequenced human genomes. Although many of these are consistent with a template switch mechanism previously proposed for bacteria, our model also identifies new types of mutations that create short inversions, some flanked by paired inverted repeats. The local template switch process can create numerous complex mutation patterns, including hairpin loop structures, and explains multinucleotide mutations and compensatory substitutions without invoking positive selection, speculative mechanisms, or implausible coincidence. Clustered sequence differences are challenging for current mapping and variant calling methods, and we show that many erroneous variant annotations exist in human reference data. Local template switch events may have been neglected as an explanation for complex mutations because of biases in commonly used analyses. Incorporation of our model into reference-based analysis pipelines and comparisons of de novo assembled genomes will lead to improved understanding of genome variation and evolution. © 2017 Löytynoja and Goldman; Published by Cold Spring Harbor Laboratory Press.

Human adaptive immune system Rag2-/-gamma(c)-/- mice.

PubMed

Chicha, Laurie; Tussiwand, Roxane; Traggiai, Elisabetta; Mazzucchelli, Luca; Bronz, Lucio; Piffaretti, Jean-Claude; Lanzavecchia, Antonio; Manz, Markus G

2005-06-01

Although many biologic principles are conserved in mice and humans, species-specific differences exist, for example, in susceptibility and response to pathogens, that often do not allow direct implementation of findings in experimental mice to humans. Research in humans, however, for ethical and practical reasons, is largely restricted to in vitro assays that lack components and the complexity of a living organism. To nevertheless study the human hematopoietic and immune system in vivo, xenotransplantation assays have been developed that substitute human components to small animals. Here, we summarize our recent findings that transplantation of human cord blood CD34(+) cells to newborn Rag2(-/-)gamma(c)(-/-) mice leads to de novo development of major functional components of the human adaptive immune system. These human adaptive immune system Rag2(-/-)gamma(c)(-/-) (huAIS-RG) mice can now be used as a technically straightforward preclinical model to evaluate in vivo human adaptive immune system development as well as immune responses, for example, to vaccines or live infectious pathogens.

An innovative expression model of human health risk based on the quantitative analysis of soil metals sources contribution in different spatial scales.

PubMed

Zhang, Yimei; Li, Shuai; Wang, Fei; Chen, Zhuang; Chen, Jie; Wang, Liqun

2018-09-01

Toxicity of heavy metals from industrialization poses critical concern, and analysis of sources associated with potential human health risks is of unique significance. Assessing human health risk of pollution sources (factored health risk) concurrently in the whole and the sub region can provide more instructive information to protect specific potential victims. In this research, we establish a new expression model of human health risk based on quantitative analysis of sources contribution in different spatial scales. The larger scale grids and their spatial codes are used to initially identify the level of pollution risk, the type of pollution source and the sensitive population at high risk. The smaller scale grids and their spatial codes are used to identify the contribution of various sources of pollution to each sub region (larger grid) and to assess the health risks posed by each source for each sub region. The results of case study show that, for children (sensitive populations, taking school and residential area as major region of activity), the major pollution source is from the abandoned lead-acid battery plant (ALP), traffic emission and agricultural activity. The new models and results of this research present effective spatial information and useful model for quantifying the hazards of source categories and human health a t complex industrial system in the future. Copyright © 2018 Elsevier Ltd. All rights reserved.

Microscopic information processing and communication in crowd dynamics

NASA Astrophysics Data System (ADS)

Henein, Colin Marc; White, Tony

2010-11-01

Due, perhaps, to the historical division of crowd dynamics research into psychological and engineering approaches, microscopic crowd models have tended toward modelling simple interchangeable particles with an emphasis on the simulation of physical factors. Despite the fact that people have complex (non-panic) behaviours in crowd disasters, important human factors in crowd dynamics such as information discovery and processing, changing goals and communication have not yet been well integrated at the microscopic level. We use our Microscopic Human Factors methodology to fuse a microscopic simulation of these human factors with a popular microscopic crowd model. By tightly integrating human factors with the existing model we can study the effects on the physical domain (movement, force and crowd safety) when human behaviour (information processing and communication) is introduced. In a large-room egress scenario with ample exits, information discovery and processing yields a crowd of non-interchangeable individuals who, despite close proximity, have different goals due to their different beliefs. This crowd heterogeneity leads to complex inter-particle interactions such as jamming transitions in open space; at high crowd energies, we found a freezing by heating effect (reminiscent of the disaster at Central Lenin Stadium in 1982) in which a barrier formation of naïve individuals trying to reach blocked exits prevented knowledgeable ones from exiting. Communication, when introduced, reduced this barrier formation, increasing both exit rates and crowd safety.

The human subject: an integrative animal model for 21st century heart failure research

PubMed Central

Chandrasekera, P Charukeshi; Pippin, John J

2015-01-01

Heart failure remains a leading cause of death and it is a major cause of morbidity and mortality affecting tens of millions of people worldwide. Despite decades of extensive research conducted at enormous expense, only a handful of interventions have significantly impacted survival in heart failure. Even the most widely prescribed treatments act primarily to slow disease progression, do not provide sustained survival advantage, and have adverse side effects. Since mortality remains about 50% within five years of diagnosis, the need to increase our understanding of heart failure disease mechanisms and development of preventive and reparative therapies remains critical. Currently, the vast majority of basic science heart failure research is conducted using animal models ranging from fruit flies to primates; however, insights gleaned from decades of animal-based research efforts have not been proportional to research success in terms of deciphering human heart failure and developing effective therapeutics for human patients. Here we discuss the reasons for this translational discrepancy which can be equally attributed to the use of erroneous animal models and the lack of widespread use of human-based research methodologies and address why and how we must position our own species at center stage as the quintessential animal model for 21st century heart failure research. If the ultimate goal of the scientific community is to tackle the epidemic status of heart failure, the best way to achieve that goal is through prioritizing human-based, human-relevant research. PMID:26550463

Assessment of oral transmission using cell-free human immunodeficiency virus-1 in mice reconstituted with human peripheral blood leucocyte

PubMed Central

Nakao, Ryoma; Hanada, Nobuhiro; Asano, Toshihiko; Hara, Takashi; Abdus Salam, MD; Matin, Khairul; Shimazu, Yoshihito; Nakasone, Tadashi; Horibata, Shigeo; Aoba, Takaaki; Honda, Mitsuo; Amagasa, Teruo; Senpuku, Hidenobu

2003-01-01

Oral–genital contact is one of the risk factors for the transmission of human immunodeficiency virus (HIV) in adults. In recent reports, oral exposure to simian immunodeficiency virus (SIV) was found to have important implications for the achievement of mucosal transmission of HIV in a rhesus monkey animal model. In the present study, we aimed first to establish a small animal model which did not develop tonsils suitable for HIV oral mucosa transmission, using non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice and NOD/SCID B2mnull mice grafted with human peripheral blood leucocytes (hu-PBL) and stimulated with interleukin (IL)-4, and second to investigate whether oral exposure to cell-free R5 and X4 HIV-1 could lead to oral transmission of HIV through intact or traumatized mucosal tissues in humanized mice. Both low and high concentrations of cell-free R5 and X4 viruses failed to cause oral transmission with or without trauma in hu-PBL-NOD/SCID and NOD/SCID Β2mnull mice, which presented a number of CD4+ cells in gingival tissues and oral cavities with or without tissue injury. The present results show that IL-4-administrated NOD/SCID B2mnull mice are useful as a small-humanized model for the study of HIV oral infection, which may help to define the window of opportunity for oral transmission by the HIV virus in animal model experiments. PMID:12757623

Drosophila as a model to study the genetic mechanisms of obesity-associated heart dysfunction.

PubMed

Diop, Soda Balla; Bodmer, Rolf

2012-05-01

Obesity and cardiovascular disease are among the world's leading causes of death, especially in Western countries where consumption of high caloric food is commonly accompanied by low physical activity. This lifestyle often leads to energy imbalance, obesity, diabetes and their associated metabolic disorders, including cardiovascular diseases. It has become increasingly recognized that obesity and cardiovascular disease are metabolically linked, and a better understanding of this relationship requires that we uncover the fundamental genetic mechanisms controlling obesity-related heart dysfunction, a goal that has been difficult to achieve in higher organisms with intricate metabolic complexity. However, the high degree of evolutionary conservation of genes and signalling pathways allows researchers to use lower animal models such as Drosophila, which is the simplest genetic model with a heart, to uncover the mechanistic basis of obesity-related heart disease and its likely relevance to humans. Here, we discuss recent advances made by using the power of the Drosophila as a powerful model to investigate the genetic pathways by which a high fat diet may lead to heart dysfunction. © 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Phenotypic outcomes in Mouse and Human Foxc1 dependent Dandy-Walker cerebellar malformation suggest shared mechanisms

PubMed Central

Haldipur, Parthiv; Dang, Derek; Aldinger, Kimberly A; Janson, Olivia K; Guimiot, Fabien; Adle-Biasette, Homa; Dobyns, William B; Siebert, Joseph R; Russo, Rosa; Millen, Kathleen J

2017-01-01

FOXC1 loss contributes to Dandy-Walker malformation (DWM), a common human cerebellar malformation. Previously, we found that complete Foxc1 loss leads to aberrations in proliferation, neuronal differentiation and migration in the embryonic mouse cerebellum (Haldipur et al., 2014). We now demonstrate that hypomorphic Foxc1 mutant mice have granule and Purkinje cell abnormalities causing subsequent disruptions in postnatal cerebellar foliation and lamination. Particularly striking is the presence of a partially formed posterior lobule which echoes the posterior vermis DW 'tail sign' observed in human imaging studies. Lineage tracing experiments in Foxc1 mutant mouse cerebella indicate that aberrant migration of granule cell progenitors destined to form the posterior-most lobule causes this unique phenotype. Analyses of rare human del chr 6p25 fetal cerebella demonstrate extensive phenotypic overlap with our Foxc1 mutant mouse models, validating our DWM models and demonstrating that many key mechanisms controlling cerebellar development are likely conserved between mouse and human. DOI: http://dx.doi.org/10.7554/eLife.20898.001 PMID:28092268

Understanding human activity patterns based on space-time-semantics

NASA Astrophysics Data System (ADS)

Huang, Wei; Li, Songnian

2016-11-01

Understanding human activity patterns plays a key role in various applications in an urban environment, such as transportation planning and traffic forecasting, urban planning, public health and safety, and emergency response. Most existing studies in modeling human activity patterns mainly focus on spatiotemporal dimensions, which lacks consideration of underlying semantic context. In fact, what people do and discuss at some places, inferring what is happening at the places, cannot be simple neglected because it is the root of human mobility patterns. We believe that the geo-tagged semantic context, representing what individuals do and discuss at a place and a specific time, drives a formation of specific human activity pattern. In this paper, we aim to model human activity patterns not only based on space and time but also with consideration of associated semantics, and attempt to prove a hypothesis that similar mobility patterns may have different motivations. We develop a spatiotemporal-semantic model to quantitatively express human activity patterns based on topic models, leading to an analysis of space, time and semantics. A case study is conducted using Twitter data in Toronto based on our model. Through computing the similarities between users in terms of spatiotemporal pattern, semantic pattern and spatiotemporal-semantic pattern, we find that only a small number of users (2.72%) have very similar activity patterns, while the majority (87.14%) show different activity patterns (i.e., similar spatiotemporal patterns and different semantic patterns, similar semantic patterns and different spatiotemporal patterns, or different in both). The population of users that has very similar activity patterns is decreased by 56.41% after incorporating semantic information in the corresponding spatiotemporal patterns, which can quantitatively prove the hypothesis.

Use of ex vivo and in vitro cultures of the human respiratory tract to study the tropism and host responses of highly pathogenic avian influenza A (H5N1) and other influenza viruses.

PubMed

Chan, Renee W Y; Chan, Michael C W; Nicholls, John M; Malik Peiris, J S

2013-12-05

The tropism of influenza viruses for the human respiratory tract is a key determinant of host-range, and consequently, of pathogenesis and transmission. Insights can be obtained from clinical and autopsy studies of human disease and relevant animal models. Ex vivo cultures of the human respiratory tract and in vitro cultures of primary human cells can provide complementary information provided they are physiologically comparable in relevant characteristics to human tissues in vivo, e.g. virus receptor distribution, state of differentiation. We review different experimental models for their physiological relevance and summarize available data using these cultures in relation to highly pathogenic avian influenza H5N1, in comparison where relevant, with other influenza viruses. Transformed continuous cell-lines often differ in important ways to the corresponding tissues in vivo. The state of differentiation of primary human cells (respiratory epithelium, macrophages) can markedly affect virus tropism and host responses. Ex vivo cultures of human respiratory tissues provide a close resemblance to tissues in vivo and may be used to risk assess animal viruses for pandemic threat. Physiological factors (age, inflammation) can markedly affect virus receptor expression and virus tropism. Taken together with data from clinical studies on infected humans and relevant animal models, data from ex vivo and in vitro cultures of human tissues and cells can provide insights into virus transmission and pathogenesis and may provide understanding that leads to novel therapeutic interventions. Copyright © 2013 Elsevier B.V. All rights reserved.

Validation of visualized transgenic zebrafish as a high throughput model to assay bradycardia related cardio toxicity risk candidates.

PubMed

Wen, Dingsheng; Liu, Aiming; Chen, Feng; Yang, Julin; Dai, Renke

2012-10-01

Drug-induced QT prolongation usually leads to torsade de pointes (TdP), thus for drugs in the early phase of development this risk should be evaluated. In the present study, we demonstrated a visualized transgenic zebrafish as an in vivo high-throughput model to assay the risk of drug-induced QT prolongation. Zebrafish larvae 48 h post-fertilization expressing green fluorescent protein in myocardium were incubated with compounds reported to induce QT prolongation or block the human ether-a-go-go-related gene (hERG) K⁺ current. The compounds sotalol, indapaminde, erythromycin, ofoxacin, levofloxacin, sparfloxacin and roxithromycin were additionally administrated by microinjection into the larvae yolk sac. The ventricle heart rate was recorded using the automatic monitoring system after incubation or microinjection. As a result, 14 out of 16 compounds inducing dog QT prolongation caused bradycardia in zebrafish. A similar result was observed with 21 out of 26 compounds which block hERG current. Among the 30 compounds which induced human QT prolongation, 25 caused bradycardia in this model. Thus, the risk of compounds causing bradycardia in this transgenic zebrafish correlated with that causing QT prolongation and hERG K⁺ current blockage in established models. The tendency that high logP values lead to high risk of QT prolongation in this model was indicated, and non-sensitivity of this model to antibacterial agents was revealed. These data suggest application of this transgenic zebrafish as a high-throughput model to screen QT prolongation-related cardio toxicity of the drug candidates. Copyright © 2012 John Wiley & Sons, Ltd.

Computational modeling of pedunculopontine nucleus deep brain stimulation

NASA Astrophysics Data System (ADS)

Zitella, Laura M.; Mohsenian, Kevin; Pahwa, Mrinal; Gloeckner, Cory; Johnson, Matthew D.

2013-08-01

Objective. Deep brain stimulation (DBS) near the pedunculopontine nucleus (PPN) has been posited to improve medication-intractable gait and balance problems in patients with Parkinson's disease. However, clinical studies evaluating this DBS target have not demonstrated consistent therapeutic effects, with several studies reporting the emergence of paresthesia and oculomotor side effects. The spatial and pathway-specific extent to which brainstem regions are modulated during PPN-DBS is not well understood. Approach. Here, we describe two computational models that estimate the direct effects of DBS in the PPN region for human and translational non-human primate (NHP) studies. The three-dimensional models were constructed from segmented histological images from each species, multi-compartment neuron models and inhomogeneous finite element models of the voltage distribution in the brainstem during DBS. Main Results. The computational models predicted that: (1) the majority of PPN neurons are activated with -3 V monopolar cathodic stimulation; (2) surgical targeting errors of as little as 1 mm in both species decrement activation selectivity; (3) specifically, monopolar stimulation in caudal, medial, or anterior PPN activates a significant proportion of the superior cerebellar peduncle (up to 60% in the human model and 90% in the NHP model at -3 V) (4) monopolar stimulation in rostral, lateral or anterior PPN activates a large percentage of medial lemniscus fibers (up to 33% in the human model and 40% in the NHP model at -3 V) and (5) the current clinical cylindrical electrode design is suboptimal for isolating the modulatory effects to PPN neurons. Significance. We show that a DBS lead design with radially-segmented electrodes may yield improved functional outcome for PPN-DBS.

New Experimental Models of Diabetic Nephropathy in Mice Models of Type 2 Diabetes: Efforts to Replicate Human Nephropathy

PubMed Central

Soler, María José; Riera, Marta; Batlle, Daniel

2012-01-01

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. The use of experimental models of DN has provided valuable information regarding many aspects of DN, including pathophysiology, progression, implicated genes, and new therapeutic strategies. A large number of mouse models of diabetes have been identified and their kidney disease was characterized to various degrees. Most experimental models of type 2 DN are helpful in studying early stages of DN, but these models have not been able to reproduce the characteristic features of more advanced DN in humans such as nodules in the glomerular tuft or glomerulosclerosis. The generation of new experimental models of DN created by crossing, knockdown, or knockin of genes continues to provide improved tools for studying DN. These models provide an opportunity to search for new mechanisms involving the development of DN, but their shortcomings should be recognized as well. Moreover, it is important to recognize that the genetic background has a substantial effect on the susceptibility to diabetes and kidney disease development in the various models of diabetes. PMID:22461787

Quantifying effects of humans and climate on groundwater resources through modeling of volcanic-rock aquifers of Hawaii

NASA Astrophysics Data System (ADS)

Rotzoll, K.; Izuka, S. K.; Nishikawa, T.; Fienen, M. N.; El-Kadi, A. I.

2015-12-01

The volcanic-rock aquifers of Kauai, Oahu, and Maui are heavily developed, leading to concerns related to the effects of groundwater withdrawals on saltwater intrusion and streamflow. A numerical modeling analysis using the most recently available data (e.g., information on recharge, withdrawals, hydrogeologic framework, and conceptual models of groundwater flow) will substantially advance current understanding of groundwater flow and provide insight into the effects of human activity and climate change on Hawaii's water resources. Three island-wide groundwater-flow models were constructed using MODFLOW 2005 coupled with the Seawater-Intrusion Package (SWI2), which simulates the transition between saltwater and freshwater in the aquifer as a sharp interface. This approach allowed relatively fast model run times without ignoring the freshwater-saltwater system at the regional scale. Model construction (FloPy3), automated-parameter estimation (PEST), and analysis of results were streamlined using Python scripts. Model simulations included pre-development (1870) and current (average of 2001-10) scenarios for each island. Additionally, scenarios for future withdrawals and climate change were simulated for Oahu. We present our streamlined approach and preliminary results showing estimated effects of human activity on the groundwater resource by quantifying decline in water levels, reduction in stream base flow, and rise of the freshwater-saltwater interface.

Tissue specific mutagenic and carcinogenic responses in NER defective mouse models.

PubMed

Wijnhoven, Susan W P; Hoogervorst, Esther M; de Waard, Harm; van der Horst, Gijsbertus T J; van Steeg, Harry

2007-01-03

Several mouse models with defects in genes encoding components of the nucleotide excision repair (NER) pathway have been developed. In NER two different sub-pathways are known, i.e. transcription-coupled repair (TC-NER) and global-genome repair (GG-NER). A defect in one particular NER protein can lead to a (partial) defect in GG-NER, TC-NER or both. GG-NER defects in mice predispose to cancer, both spontaneous as well as UV-induced. As such these models (Xpa, Xpc and Xpe) recapitulate the human xeroderma pigmentosum (XP) syndrome. Defects in TC-NER in humans are associated with Cockayne syndrome (CS), a disease not linked to tumor development. Mice with TC-NER defects (Csa and Csb) are - except for the skin - not susceptible to develop (carcinogen-induced) tumors. Some NER factors, i.e. XPB, XPD, XPF, XPG and ERCC1 have functions outside NER, like transcription initiation and inter-strand crosslink repair. Deficiencies in these processes in mice lead to very severe phenotypes, like trichothiodystrophy (TTD) or a combination of XP and CS. In most cases these animals have a (very) short life span, display segmental progeria, but do not develop tumors. Here we will overview the available NER-related mouse models and will discuss their phenotypes in terms of (chemical-induced) tissue-specific tumor development, mutagenesis and premature aging features.

Progressive Vascular Functional and Structural Damage in a Bronchopulmonary Dysplasia Model in Preterm Rabbits Exposed to Hyperoxia.

PubMed

Jiménez, Julio; Richter, Jute; Nagatomo, Taro; Salaets, Thomas; Quarck, Rozenn; Wagennar, Allard; Wang, Hongmei; Vanoirbeek, Jeroen; Deprest, Jan; Toelen, Jaan

2016-10-24

Bronchopulmonary dysplasia (BPD) is caused by preterm neonatal lung injury and results in oxygen dependency and pulmonary hypertension. Current clinical management fails to reduce the incidence of BPD, which calls for novel therapies. Fetal rabbits have a lung development that mimics humans and can be used as a translational model to test novel treatment options. In preterm rabbits, exposure to hyperoxia leads to parenchymal changes, yet vascular damage has not been studied in this model. In this study we document the early functional and structural changes of the lung vasculature in preterm rabbits that are induced by hyperoxia after birth. Pulmonary artery Doppler measurements, micro-CT barium angiograms and media thickness of peripheral pulmonary arteries were affected after seven days of hyperoxia when compared to controls. The parenchyma was also affected both at the functional and structural level. Lung function testing showed higher tissue resistance and elastance, with a decreased lung compliance and lung capacity. Histologically hyperoxia leads to fewer and larger alveoli with thicker walls, less developed distal airways and more inflammation than normoxia. In conclusion, we show that the rabbit model develops pulmonary hypertension and developmental lung arrest after preterm lung injury, which parallel the early changes in human BPD. Thus it enables the testing of pharmaceutical agents that target the cardiovascular compartment of the lung for further translation towards the clinic.

A Socio-hydrological Flood Model for the Elbe

NASA Astrophysics Data System (ADS)

Barendrecht, M.; Viglione, A.; Kreibich, H.; Vorogushyn, S.; Merz, B.; Bloeschl, G.

2017-12-01

Long-term feedbacks between humans and floods may lead to complex phenomena such as coping strategies, levee effects, call effects, adaptation effects, and poverty traps. Dynamic coupled human-flood models are a promising tool to represent such phenomena and the feedbacks leading to them. These socio-hydrological models may play an important role in integrated flood risk management when they are applied to real world case studies. They can help develop hypotheses about the phenomena that have been observed in the case study of interest, by describing the interactions between the social and hydrological variables as well as other relevant variables, such as economic, environmental, political or technical, that play a role in the system. We discuss the case of Dresden where the 2002 flood, which was preceded by a period without floods but was less severe, resulted in a higher damage than the 2013 flood, which was preceded by the 2002 flood and a couple of less severe floods. The lower damage in 2013 may be explained by the fact that society has become aware of the flood risk and has adapted to it. Developing and applying a socio-hydrological flood model to the case of Dresden can help discover whether it is possible that the lower damage is caused by an adaptation effect, or if there are other feedbacks that can explain the observed phenomenon.

Progressive Vascular Functional and Structural Damage in a Bronchopulmonary Dysplasia Model in Preterm Rabbits Exposed to Hyperoxia

PubMed Central

Jiménez, Julio; Richter, Jute; Nagatomo, Taro; Salaets, Thomas; Quarck, Rozenn; Wagennar, Allard; Wang, Hongmei; Vanoirbeek, Jeroen; Deprest, Jan; Toelen, Jaan

2016-01-01

Bronchopulmonary dysplasia (BPD) is caused by preterm neonatal lung injury and results in oxygen dependency and pulmonary hypertension. Current clinical management fails to reduce the incidence of BPD, which calls for novel therapies. Fetal rabbits have a lung development that mimics humans and can be used as a translational model to test novel treatment options. In preterm rabbits, exposure to hyperoxia leads to parenchymal changes, yet vascular damage has not been studied in this model. In this study we document the early functional and structural changes of the lung vasculature in preterm rabbits that are induced by hyperoxia after birth. Pulmonary artery Doppler measurements, micro-CT barium angiograms and media thickness of peripheral pulmonary arteries were affected after seven days of hyperoxia when compared to controls. The parenchyma was also affected both at the functional and structural level. Lung function testing showed higher tissue resistance and elastance, with a decreased lung compliance and lung capacity. Histologically hyperoxia leads to fewer and larger alveoli with thicker walls, less developed distal airways and more inflammation than normoxia. In conclusion, we show that the rabbit model develops pulmonary hypertension and developmental lung arrest after preterm lung injury, which parallel the early changes in human BPD. Thus it enables the testing of pharmaceutical agents that target the cardiovascular compartment of the lung for further translation towards the clinic. PMID:27783043

Biopharma business models in Canada.

PubMed

March-Chordà, I; Yagüe-Perales, R M

2011-08-01

This article provides new insights into the different strategy paths or business models currently being implemented by Canadian biopharma companies. Through a case-study methodology, seven biopharma companies pertaining to three business models were analyzed, leading to a broad set of results emerging from the following areas: activity, business model and strategy; management and human resources; and R&D, technology and innovation strategy. The three business models represented were: model 1 (conventional biotech oriented to new drug development, radical innovation and search for discoveries); model 2 (development of a technology platform, usually in proteomics and bioinformatics); and model 3 (incremental innovation, with shorter and less risky development timelines). Copyright © 2011 Elsevier Ltd. All rights reserved.

Sustainability Indicators for Coupled Human-Earth Systems

NASA Astrophysics Data System (ADS)

Motesharrei, S.; Rivas, J. R.; Kalnay, E.

2014-12-01

Over the last two centuries, the Human System went from having a small impact on the Earth System (including the Climate System) to becoming dominant, because both population and per capita consumption have grown extremely fast, especially since about 1950. We therefore argue that Human System Models must be included into Earth System Models through bidirectional couplings with feedbacks. In particular, population should be modeled endogenously, rather than exogenously as done currently in most Integrated Assessment Models. The growth of the Human System threatens to overwhelm the Carrying Capacity of the Earth System, and may be leading to catastrophic climate change and collapse. We propose a set of Ecological and Economic "Sustainability Indicators" that can employ large data-sets for developing and assessing effective mitigation and adaptation policies. Using the Human and Nature Dynamical Model (HANDY) and Coupled Human-Climate-Water Model (COWA), we carry out experiments with this set of Sustainability Indicators and show that they are applicable to various coupled systems including Population, Climate, Water, Energy, Agriculture, and Economy. Impact of nonrenewable resources and fossil fuels could also be understood using these indicators. We demonstrate interconnections of Ecological and Economic Indicators. Coupled systems often include feedbacks and can thus display counterintuitive dynamics. This makes it difficult for even experts to see coming catastrophes from just the raw data for different variables. Sustainability Indicators boil down the raw data into a set of simple numbers that cross their sustainability thresholds with a large time-lag before variables enter their catastrophic regimes. Therefore, we argue that Sustainability Indicators constitute a powerful but simple set of tools that could be directly used for making policies for sustainability.

NASA Human Health and Performance Strategy

NASA Technical Reports Server (NTRS)

Davis, Jeffrey R.

2012-01-01

In May 2007, what was then the Space Life Sciences Directorate, issued the 2007 Space Life Sciences Strategy for Human Space Exploration. In January 2012, leadership and key directorate personnel were once again brought together to assess the current and expected future environment against its 2007 Strategy and the Agency and Johnson Space Center goals and strategies. The result was a refined vision and mission, and revised goals, objectives, and strategies. One of the first changes implemented was to rename the directorate from Space Life Sciences to Human Health and Performance to better reflect our vision and mission. The most significant change in the directorate from 2007 to the present is the integration of the Human Research Program and Crew Health and Safety activities. Subsequently, the Human Health and Performance Directorate underwent a reorganization to achieve enhanced integration of research and development with operations to better support human spaceflight and International Space Station utilization. These changes also enable a more effective and efficient approach to human system risk mitigation. Since 2007, we have also made significant advances in external collaboration and implementation of new business models within the directorate and the Agency, and through two newly established virtual centers, the NASA Human Health and Performance Center and the Center of Excellence for Collaborative Innovation. Our 2012 Strategy builds upon these successes to address the Agency s increased emphasis on societal relevance and being a leader in research and development and innovative business and communications practices. The 2012 Human Health and Performance Vision is to lead the world in human health and performance innovations for life in space and on Earth. Our mission is to enable optimization of human health and performance throughout all phases of spaceflight. All HHPD functions are ultimately aimed at achieving this mission. Our activities enable mission success, optimizing human health and productivity in space before, during, and after the actual spaceflight experience of our crews, and include support for ground-based functions. Many of our spaceflight innovations also provide solutions for terrestrial challenges, thereby enhancing life on Earth. Our strategic goals are aimed at leading human exploration and ISS utilization, leading human health and performance internationally, excelling in management and advancement of innovations in health and human system integration, and expanding relevance to life on Earth and creating enduring support and enthusiasm for space exploration.

NASA Human Health and Performance Strategy

NASA Technical Reports Server (NTRS)

Davis, Jeffrey R.

2012-01-01

In May 2007, what was then the Space Life Sciences Directorate, issued the 2007 Space Life Sciences Strategy for Human Space Exploration. In January 2012, leadership and key directorate personnel were once again brought together to assess the current and expected future environment against its 2007 Strategy and the Agency and Johnson Space Center goals and strategies. The result was a refined vision and mission, and revised goals, objectives, and strategies. One of the first changes implemented was to rename the directorate from Space Life Sciences to Human Health and Performance to better reflect our vision and mission. The most significant change in the directorate from 2007 to the present is the integration of the Human Research Program and Crew Health and Safety activities. Subsequently, the Human Health and Performance Directorate underwent a reorganization to achieve enhanced integration of research and development with operations to better support human spaceflight and International Space Station utilization. These changes also enable a more effective and efficient approach to human system risk mitigation. Since 2007, we have also made significant advances in external collaboration and implementation of new business models within the directorate and the Agency, and through two newly established virtual centers, the NASA Human Health and Performance Center and the Center of Excellence for Collaborative Innovation. Our 2012 Strategy builds upon these successes to address the Agency's increased emphasis on societal relevance and being a leader in research and development and innovative business and communications practices. The 2012 Human Health and Performance Vision is to lead the world in human health and performance innovations for life in space and on Earth. Our mission is to enable optimization of human health and performance throughout all phases of spaceflight. All HH&P functions are ultimately aimed at achieving this mission. Our activities enable mission success, optimizing human health and productivity in space before, during, and after the actual spaceflight experience of our crews, and include support for ground-­- based functions. Many of our spaceflight innovations also provide solutions for terrestrial challenges, thereby enhancing life on Earth. Our strategic goals are aimed at leading human exploration and ISS utilization, leading human health and performance internationally, excelling in management and advancement of innovations in health and human system integration, and expanding relevance to life on Earth and creating enduring support and enthusiasm for space exploration.

Measuring the Environmental Dimensions of Human Migration: The Demographer's Toolkit.

PubMed

Fussell, Elizabeth; Hunter, Lori M; Gray, Clark L

2014-09-01

In recent years, the empirical literature linking environmental factors and human migration has grown rapidly and gained increasing visibility among scholars and the policy community. Still, this body of research uses a wide range of methodological approaches for assessing environment-migration relationships. Without comparable data and measures across a range of contexts, it is impossible to make generalizations that would facilitate the development of future migration scenarios. Demographic researchers have a large methodological toolkit for measuring migration as well as modeling its drivers. This toolkit includes population censuses, household surveys, survival analysis and multi-level modeling. This paper's purpose is to introduce climate change researchers to demographic data and methods and to review exemplary studies of the environmental dimensions of human migration. Our intention is to foster interdisciplinary understanding and scholarship, and to promote high quality research on environment and migration that will lead toward broader knowledge of this association.

Measuring the Environmental Dimensions of Human Migration: The Demographer’s Toolkit

PubMed Central

Hunter, Lori M.; Gray, Clark L.

2014-01-01

In recent years, the empirical literature linking environmental factors and human migration has grown rapidly and gained increasing visibility among scholars and the policy community. Still, this body of research uses a wide range of methodological approaches for assessing environment-migration relationships. Without comparable data and measures across a range of contexts, it is impossible to make generalizations that would facilitate the development of future migration scenarios. Demographic researchers have a large methodological toolkit for measuring migration as well as modeling its drivers. This toolkit includes population censuses, household surveys, survival analysis and multi-level modeling. This paper’s purpose is to introduce climate change researchers to demographic data and methods and to review exemplary studies of the environmental dimensions of human migration. Our intention is to foster interdisciplinary understanding and scholarship, and to promote high quality research on environment and migration that will lead toward broader knowledge of this association. PMID:25177108

Auditory object perception: A neurobiological model and prospective review.

PubMed

Brefczynski-Lewis, Julie A; Lewis, James W

2017-10-01

Interaction with the world is a multisensory experience, but most of what is known about the neural correlates of perception comes from studying vision. Auditory inputs enter cortex with its own set of unique qualities, and leads to use in oral communication, speech, music, and the understanding of emotional and intentional states of others, all of which are central to the human experience. To better understand how the auditory system develops, recovers after injury, and how it may have transitioned in its functions over the course of hominin evolution, advances are needed in models of how the human brain is organized to process real-world natural sounds and "auditory objects". This review presents a simple fundamental neurobiological model of hearing perception at a category level that incorporates principles of bottom-up signal processing together with top-down constraints of grounded cognition theories of knowledge representation. Though mostly derived from human neuroimaging literature, this theoretical framework highlights rudimentary principles of real-world sound processing that may apply to most if not all mammalian species with hearing and acoustic communication abilities. The model encompasses three basic categories of sound-source: (1) action sounds (non-vocalizations) produced by 'living things', with human (conspecific) and non-human animal sources representing two subcategories; (2) action sounds produced by 'non-living things', including environmental sources and human-made machinery; and (3) vocalizations ('living things'), with human versus non-human animals as two subcategories therein. The model is presented in the context of cognitive architectures relating to multisensory, sensory-motor, and spoken language organizations. The models' predictive values are further discussed in the context of anthropological theories of oral communication evolution and the neurodevelopment of spoken language proto-networks in infants/toddlers. These phylogenetic and ontogenetic frameworks both entail cortical network maturations that are proposed to at least in part be organized around a number of universal acoustic-semantic signal attributes of natural sounds, which are addressed herein. Copyright © 2017. Published by Elsevier Ltd.

Identification of Novel Activators of Constitutive Androstane Receptor from FDA-approved Drugs by Integrated Computational and Biological Approaches

PubMed Central

Lynch, Caitlin; Pan, Yongmei; Li, Linhao; Ferguson, Stephen S.; Xia, Menghang; Swaan, Peter W.; Wang, Hongbing

2012-01-01

Purpose The constitutive androstane receptor (CAR, NR1I3) is a xenobiotic sensor governing the transcription of numerous hepatic genes associated with drug metabolism and clearance. Recent evidence suggests that CAR also modulates energy homeostasis and cancer development. Thus, identification of novel human (h) CAR activators is of both clinical importance and scientific interest. Methods Docking and ligand-based structure-activity models were used for virtual screening of a database containing over 2000 FDA-approved drugs. Identified lead compounds were evaluated in cell-based reporter assays to determine hCAR activation. Potential activators were further tested in human primary hepatocytes (HPHs) for the expression of the prototypical hCAR target gene CYP2B6. Results Nineteen lead compounds with optimal modeling parameters were selected for biological evaluation. Seven of the 19 leads exhibited moderate to potent activation of hCAR. Five out of the seven compounds translocated hCAR from the cytoplasm to the nucleus of HPHs in a concentration-dependent manner. These compounds also induce the expression of CYP2B6 in HPHs with rank-order of efficacies closely resembling that of hCAR activation. Conclusion These results indicate that our strategically integrated approaches are effective in the identification of novel hCAR modulators, which may function as valuable research tools or potential therapeutic molecules. PMID:23090669

Prenatal Ethanol Exposure and Neocortical Development: A Transgenerational Model of FASD.

PubMed

Abbott, Charles W; Rohac, David J; Bottom, Riley T; Patadia, Sahil; Huffman, Kelly J

2017-07-06

Fetal Alcohol Spectrum Disorders, or FASD, represent a range of adverse developmental conditions caused by prenatal ethanol exposure (PrEE) from maternal consumption of alcohol. PrEE induces neurobiological damage in the developing brain leading to cognitive-perceptual and behavioral deficits in the offspring. Alcohol-mediated alterations to epigenetic function may underlie PrEE-related brain dysfunction, with these changes potentially carried across generations to unexposed offspring. To determine the transgenerational impact of PrEE on neocortical development, we generated a mouse model of FASD and identified numerous stable phenotypes transmitted via the male germline to the unexposed third generation. These include alterations in ectopic intraneocortical connectivity, upregulation of neocortical Rzrβ and Id2 expression accompanied by both promoter hypomethylation of these genes and decreased global DNA methylation levels. DNMT expression was also suppressed in newborn PrEE cortex, providing further insight into how ethanol perturbs DNA methylation leading to altered regulation of gene transcription. These PrEE-induced, transgenerational phenotypes may be responsible for cognitive, sensorimotor, and behavioral deficits seen in humans with FASD. Thus, understanding the possible epigenetic mechanisms by which these phenotypes are generated may reveal novel targets for therapeutic intervention of FASD and lead to advances in human health. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

RNA Interference and BMP-2 Stimulation Allows Equine Chondrocytes Redifferentiation in 3D-Hypoxia Cell Culture Model: Application for Matrix-Induced Autologous Chondrocyte Implantation

PubMed Central

Rakic, Rodolphe; Bourdon, Bastien; Hervieu, Magalie; Branly, Thomas; Legendre, Florence; Saulnier, Nathalie; Audigié, Fabrice; Maddens, Stéphane; Demoor, Magali; Galera, Philippe

2017-01-01

As in humans, osteoarthritis (OA) causes considerable economic loss to the equine industry. New hopes for cartilage repair have emerged with the matrix-associated autologous chondrocyte implantation (MACI). Nevertheless, its limitation is due to the dedifferentiation occurring during the chondrocyte amplification phase, leading to the loss of its capacity to produce a hyaline extracellular matrix (ECM). To enhance the MACI therapy efficiency, we have developed a strategy for chondrocyte redifferentiation, and demonstrated its feasibility in the equine model. Thus, to mimic the cartilage microenvironment, the equine dedifferentiated chondrocytes were cultured in type I/III collagen sponges for 7 days under hypoxia in the presence of BMP-2. In addition, chondrocytes were transfected by siRNA targeting Col1a1 and Htra1 mRNAs, which are overexpressed during dedifferentiation and OA. To investigate the quality of the neo-synthesized ECM, specific and atypical cartilage markers were evaluated by RT-qPCR and Western blot. Our results show that the combination of 3D hypoxia cell culture, BMP-2 (Bone morphogenetic protein-2), and RNA interference, increases the chondrocytes functional indexes (Col2a1/Col1a1, Acan/Col1a1), leading to an effective chondrocyte redifferentiation. These data represent a proof of concept for this process of application, in vitro, in the equine model, and will lead to the improvement of the MACI efficiency for cartilage tissue engineering therapy in preclinical/clinical trials, both in equine and human medicine. PMID:28837082

RNA Interference and BMP-2 Stimulation Allows Equine Chondrocytes Redifferentiation in 3D-Hypoxia Cell Culture Model: Application for Matrix-Induced Autologous Chondrocyte Implantation.

PubMed

Rakic, Rodolphe; Bourdon, Bastien; Hervieu, Magalie; Branly, Thomas; Legendre, Florence; Saulnier, Nathalie; Audigié, Fabrice; Maddens, Stéphane; Demoor, Magali; Galera, Philippe

2017-08-24

As in humans, osteoarthritis (OA) causes considerable economic loss to the equine industry. New hopes for cartilage repair have emerged with the matrix-associated autologous chondrocyte implantation (MACI). Nevertheless, its limitation is due to the dedifferentiation occurring during the chondrocyte amplification phase, leading to the loss of its capacity to produce a hyaline extracellular matrix (ECM). To enhance the MACI therapy efficiency, we have developed a strategy for chondrocyte redifferentiation, and demonstrated its feasibility in the equine model. Thus, to mimic the cartilage microenvironment, the equine dedifferentiated chondrocytes were cultured in type I/III collagen sponges for 7 days under hypoxia in the presence of BMP-2. In addition, chondrocytes were transfected by siRNA targeting Col1a1 and Htra1 mRNAs, which are overexpressed during dedifferentiation and OA. To investigate the quality of the neo-synthesized ECM, specific and atypical cartilage markers were evaluated by RT-qPCR and Western blot. Our results show that the combination of 3D hypoxia cell culture, BMP-2 (Bone morphogenetic protein-2), and RNA interference, increases the chondrocytes functional indexes ( Col2a1 / Col1a1 , Acan / Col1a1 ), leading to an effective chondrocyte redifferentiation. These data represent a proof of concept for this process of application, in vitro, in the equine model, and will lead to the improvement of the MACI efficiency for cartilage tissue engineering therapy in preclinical/clinical trials, both in equine and human medicine.

Mathematical simulations of photon interactions using Monte Carlo analysis to evaluate the uncertainty associated with in vivo K X-ray fluorescence measurements of stable lead in bone

NASA Astrophysics Data System (ADS)

Lodwick, Camille J.

This research utilized Monte Carlo N-Particle version 4C (MCNP4C) to simulate K X-ray fluorescent (K XRF) measurements of stable lead in bone. Simulations were performed to investigate the effects that overlying tissue thickness, bone-calcium content, and shape of the calibration standard have on detector response in XRF measurements at the human tibia. Additional simulations of a knee phantom considered uncertainty associated with rotation about the patella during XRF measurements. Simulations tallied the distribution of energy deposited in a high-purity germanium detector originating from collimated 88 keV 109Cd photons in backscatter geometry. Benchmark measurements were performed on simple and anthropometric XRF calibration phantoms of the human leg and knee developed at the University of Cincinnati with materials proven to exhibit radiological characteristics equivalent to human tissue and bone. Initial benchmark comparisons revealed that MCNP4C limits coherent scatter of photons to six inverse angstroms of momentum transfer and a Modified MCNP4C was developed to circumvent the limitation. Subsequent benchmark measurements demonstrated that Modified MCNP4C adequately models photon interactions associated with in vivo K XRF of lead in bone. Further simulations of a simple leg geometry possessing tissue thicknesses from 0 to 10 mm revealed increasing overlying tissue thickness from 5 to 10 mm reduced predicted lead concentrations an average 1.15% per 1 mm increase in tissue thickness (p < 0.0001). An anthropometric leg phantom was mathematically defined in MCNP to more accurately reflect the human form. A simulated one percent increase in calcium content (by mass) of the anthropometric leg phantom's cortical bone demonstrated to significantly reduce the K XRF normalized ratio by 4.5% (p < 0.0001). Comparison of the simple and anthropometric calibration phantoms also suggested that cylindrical calibration standards can underestimate lead content of a human leg up to 4%. The patellar bone structure in which the fluorescent photons originate was found to vary dramatically with measurement angle. The relative contribution of lead signal from the patella declined from 65% to 27% when rotated 30°. However, rotation of the source-detector about the patella from 0 to 45° demonstrated no significant effect on the net K XRF response at the knee.

A Trans-omics Mathematical Analysis Reveals Novel Functions of the Ornithine Metabolic Pathway in Cancer Stem Cells

NASA Astrophysics Data System (ADS)

Koseki, Jun; Matsui, Hidetoshi; Konno, Masamitsu; Nishida, Naohiro; Kawamoto, Koichi; Kano, Yoshihiro; Mori, Masaki; Doki, Yuichiro; Ishii, Hideshi

2016-02-01

Bioinformatics and computational modelling are expected to offer innovative approaches in human medical science. In the present study, we performed computational analyses and made predictions using transcriptome and metabolome datasets obtained from fluorescence-based visualisations of chemotherapy-resistant cancer stem cells (CSCs) in the human oesophagus. This approach revealed an uncharacterized role for the ornithine metabolic pathway in the survival of chemotherapy-resistant CSCs. The present study fastens this rationale for further characterisation that may lead to the discovery of innovative drugs against robust CSCs.

The sweet spots in human communication.

PubMed

Salem, Philip

2011-07-01

In baseball, the sweet spot is a special place on a bat where the batter can hit the ball with the most power. It is the place where the performances of the batter and pitcher collide with maximum effect. It is the place where the dynamic tension between opponents leads to transformation. The dynamic tension in all living systems is between similarity and difference. Chaos and complexity scholars recognized this tension as amounts of information. When the amounts of information were high, but not too high, the system moved to the edge of chaos, to the complexity regime, to strange attractors, or to chaos, depending on the model. The sweet spot is that range of relative variety, just the proper mix of similarity and difference, leading to transformation. This essay contains a model of human communication as an emergent social process with its own sweet spots. The essay also includes a description of current literature highlighting tensions between similarity and difference, and there is an exploration of the potential to move from one basin of attraction to another. The primary constraints on finding communication sweet spots are paradigmatic - adopting a process orientation, discovering the proper parameters, bracketing sequences to define initial conditions, and understanding the strengths and weaknesses of various modeling techniques.

Effects of canyon geometry on the distribution of traffic-related air pollution in a large urban area: Implications of a multi-canyon air pollution dispersion model

NASA Astrophysics Data System (ADS)

Fu, Xiangwen; Liu, Junfeng; Ban-Weiss, George A.; Zhang, Jiachen; Huang, Xin; Ouyang, Bin; Popoola, Olalekan; Tao, Shu

2017-09-01

Street canyons are ubiquitous in urban areas. Traffic-related air pollutants in street canyons can adversely affect human health. In this study, an urban-scale traffic pollution dispersion model is developed considering street distribution, canyon geometry, background meteorology, traffic assignment, traffic emissions and air pollutant dispersion. In the model, vehicle exhausts generated from traffic flows first disperse inside street canyons along the micro-scale wind field generated by computational fluid dynamics (CFD) model. Then, pollutants leave the street canyon and further disperse over the urban area. On the basis of this model, the effects of canyon geometry on the distribution of NOx and CO from traffic emissions were studied over the center of Beijing. We found that an increase in building height leads to heavier pollution inside canyons and lower pollution outside canyons at pedestrian level, resulting in higher domain-averaged concentrations over the area. In addition, canyons with highly even or highly uneven building heights on each side of the street tend to lower the urban-scale air pollution concentrations at pedestrian level. Further, increasing street widths tends to lead to lower pollutant concentrations by reducing emissions and enhancing ventilation simultaneously. Our results indicate that canyon geometry strongly influences human exposure to traffic pollutants in the populated urban area. Carefully planning street layout and canyon geometry while considering traffic demand as well as local weather patterns may significantly reduce inhalation of unhealthy air by urban residents.

Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia.

PubMed

Fukawa, Tomoya; Yan-Jiang, Benjamin Chua; Min-Wen, Jason Chua; Jun-Hao, Elwin Tan; Huang, Dan; Qian, Chao-Nan; Ong, Pauline; Li, Zhimei; Chen, Shuwen; Mak, Shi Ya; Lim, Wan Jun; Kanayama, Hiro-Omi; Mohan, Rosmin Elsa; Wang, Ruiqi Rachel; Lai, Jiunn Herng; Chua, Clarinda; Ong, Hock Soo; Tan, Ker-Kan; Ho, Ying Swan; Tan, Iain Beehuat; Teh, Bin Tean; Shyh-Chang, Ng

2016-06-01

Cachexia is a devastating muscle-wasting syndrome that occurs in patients who have chronic diseases. It is most commonly observed in individuals with advanced cancer, presenting in 80% of these patients, and it is one of the primary causes of morbidity and mortality associated with cancer. Additionally, although many people with cachexia show hypermetabolism, the causative role of metabolism in muscle atrophy has been unclear. To understand the molecular basis of cachexia-associated muscle atrophy, it is necessary to develop accurate models of the condition. By using transcriptomics and cytokine profiling of human muscle stem cell-based models and human cancer-induced cachexia models in mice, we found that cachectic cancer cells secreted many inflammatory factors that rapidly led to high levels of fatty acid metabolism and to the activation of a p38 stress-response signature in skeletal muscles, before manifestation of cachectic muscle atrophy occurred. Metabolomics profiling revealed that factors secreted by cachectic cancer cells rapidly induce excessive fatty acid oxidation in human myotubes, which leads to oxidative stress, p38 activation and impaired muscle growth. Pharmacological blockade of fatty acid oxidation not only rescued human myotubes, but also improved muscle mass and body weight in cancer cachexia models in vivo. Therefore, fatty acid-induced oxidative stress could be targeted to prevent cancer-induced cachexia.

Accounting for pH heterogeneity and variability in modelling human health risks from cadmium in contaminated land.

PubMed

Gay, J Rebecca; Korre, Anna

2009-07-01

The authors have previously published a methodology which combines quantitative probabilistic human health risk assessment and spatial statistical methods (geostatistics) to produce an assessment, incorporating uncertainty, of risks to human health from exposure to contaminated land. The model assumes a constant soil to plant concentration factor (CF(veg)) when calculating intake of contaminants. This model is modified here to enhance its use in a situation where CF(veg) varies according to soil pH, as is the case for cadmium. The original methodology uses sequential indicator simulation (SIS) to map soil concentration estimates for one contaminant across a site. A real, age-stratified population is mapped across the contaminated area, and intake of soil contaminants by individuals is calculated probabilistically using an adaptation of the Contaminated Land Exposure Assessment (CLEA) model. The proposed improvement involves not only the geostatistical estimation of the contaminant concentration, but also that of soil pH, which in turn leads to a variable CF(veg) estimate which influences the human intake results. The results presented demonstrate that taking pH into account can influence the outcome of the risk assessment greatly. It is proposed that a similar adaptation could be used for other combinations of soil variables which influence CF(veg).

Telomerase activation by c-Myc in human mammary epithelial cells requires additional genomic changes.

PubMed

Bazarov, Alexey V; Hines, William C; Mukhopadhyay, Rituparna; Beliveau, Alain; Melodyev, Sonya; Zaslavsky, Yuri; Yaswen, Paul

2009-10-15

A central question in breast cancer biology is how cancer cells acquire telomerase activity required for unlimited proliferation. According to one model, proliferation of telomerase(-) pre-malignant cells leads to telomere dysfunction and increased genomic instability. Such instability leads in rare cases to reactivation of telomerase and immortalization. The mechanism of telomerase reactivation remains unknown. We have studied immortalization of cultured human mammary epithelial cells by c-Myc, a positive transcriptional regulator of the hTERT gene encoding the catalytic subunit of telomerase. Retrovirally introduced c-Myc cDNA resulted in immortalization of human mammary epithelial cells in which the cyclin dependent kinase inhibitor, p16(INK4A), was inactivated by an shRNA-encoding retrovirus. However, while c-Myc introduction immediately resulted in increased activity of transiently transfected hTERT promoter reporter constructs, endogenous hTERT mRNA levels did not change until about 60 population doublings after c-Myc introduction. Increased endogenous hTERT transcripts and stabilization of telomeric DNA in cells expressing exogenous c-Myc coincided with telomere dysfunction-associated senescence in control cultures. Genome copy number analyses of immortalized cells indicated amplifications of some or all of chromosome 5, where hTERT genes are located. hTERT gene copy number, however, was not increased in one case. The results are consistent with the hypothesis that changes in chromosome 5, while not necessarily increasing hTERT gene copy number, resulted in removal of repressive chromatin structures around hTERT loci, allowing induction of hTERT transcription. These in vitro results model one possible sequence of events leading to immortalization of breast epithelial cells during cancer progression.

The Psen1-L166P-knock-in mutation leads to amyloid deposition in human wild-type amyloid precursor protein YAC transgenic mice

PubMed Central

Vidal, Ruben; Sammeta, Neeraja; Garringer, Holly J.; Sambamurti, Kumar; Miravalle, Leticia; Lamb, Bruce T.; Ghetti, Bernardino

2012-01-01

Genetically engineered mice have been generated to model cerebral β-amyloidosis, one of the hallmarks of Alzheimer disease (AD) pathology, based on the overexpression of a mutated cDNA of the amyloid-β precursor protein (AβPP) or by knock-in of the murine Aβpp gene alone or with presenilin1 mutations. Here we describe the generation and initial characterization of a new mouse line based on the presence of 2 copies of the human genomic region encoding the wild-type AβPP and the L166P presenilin 1 mutation. At ∼6 mo of age, double-mutant mice develop amyloid pathology, with signs of neuritic dystrophy, intracellular Aβ accumulation, and glial inflammation, an increase in AβPP C-terminal fragments, and an 8 times increase in Aβ42 levels with a 40% decrease in Aβ40 levels, leading to a significant increase (14 times) of Aβ42/Aβ40 ratios, with minimal effects on presenilin or the Notch1 pathway in the brain. We conclude that in mice, neither mutations in AβPP nor overexpression of an AβPP isoform are a prerequisite for Aβ pathology. This model will allow the study of AD pathogenesis and testing of therapeutic strategies in a more relevant environment without experimental artifacts due to the overexpression of a single-mutant AβPP isoform using exogenous promoters.—Vidal, R., Sammeta, N., Garringer, H. J., Sambamurti, K., Miravalle, L., Lamb B. T., Ghetti, B. The Psen1-L166P-knock-in mutation leads to amyloid deposition in human wild-type amyloid precursor protein YAC transgenic mice. PMID:22459153

Altering hemodynamics leads to congenital heart defects (Conference Presentation)

NASA Astrophysics Data System (ADS)

Ford, Stephanie M.; McPheeters, Matthew T.; Wang, Yves T.; Gu, Shi; Doughman, Yong Qiu; Strainic, James P.; Rollins, Andrew M.; Watanabe, Michiko; Jenkins, Michael W.

2016-03-01

The role of hemodynamics in early heart development is poorly understood. In order to successfully assess the impact of hemodynamics on development, we need to monitor and perturb blood flow, and quantify the resultant effects on morphology. Here, we have utilized cardiac optical pacing to create regurgitant flow in embryonic hearts and OCT to quantify regurgitation percentage and resultant morphology. Embryonic quail in a shell-less culture were optically paced at 3 Hz (well above the intrinsic rate or 1.33-1.67 Hz) on day 2 of development (3-4 weeks human) for 5 minutes. The pacing fatigued the heart and led to a prolonged period (> 1 hour) of increased regurgitant flow. Embryos were kept alive until day 3 (cardiac looping - 4-5 weeks human) or day 8 (4 chambered heart - 8 weeks human) to quantify resultant morphologic changes with OCT. All paced embryos imaged at day 3 displayed cardiac defects. The extent of regurgitant flow immediately after pacing was correlated with cardiac cushion size 24-hours post pacing (p-value < 0.01) with higher regurgitation leading to smaller cushions. Almost all embryos (16/18) surviving to day 8 exhibited congenital heart defects (CHDs) including 11/18 with valve defects, 5/18 with ventricular septal defects and 5/18 with hypoplastic right ventricles. Our data suggests that regurgitant flow leads to smaller cushions, which develop into abnormal valves and septa. Our model produces similar phenotypes as found in our fetal alcohol syndrome and velo-cardio-facial/DiGeorge syndrome models suggesting that hemodynamics plays a role in these syndromes as well. Utilizing OCT and optical pacing to understand hemodynamics in development is an important step towards determining CHD mechanisms and ultimately developing earlier treatments.

Severe Life Stress and Oxidative Stress in the Brain: From Animal Models to Human Pathology

PubMed Central

Jaquet, Vincent; Trabace, Luigia; Krause, Karl-Heinz

2013-01-01

Abstract Significance: Severe life stress (SLS), as opposed to trivial everyday stress, is defined as a serious psychosocial event with the potential of causing an impacting psychological traumatism. Recent Advances: Numerous studies have attempted to understand how the central nervous system (CNS) responds to SLS. This response includes a variety of morphological and neurochemical modifications; among them, oxidative stress is almost invariably observed. Oxidative stress is defined as disequilibrium between oxidant generation and the antioxidant response. Critical Issues: In this review, we discuss how SLS leads to oxidative stress in the CNS, and how the latter impacts pathophysiological outcomes. We also critically discuss experimental methods that measure oxidative stress in the CNS. The review covers animal models and human observations. Animal models of SLS include sleep deprivation, maternal separation, and social isolation in rodents, and the establishment of hierarchy in non-human primates. In humans, SLS, which is caused by traumatic events such as child abuse, war, and divorce, is also accompanied by oxidative stress in the CNS. Future Directions: The outcome of SLS in humans ranges from resilience, over post-traumatic stress disorder, to development of chronic mental disorders. Defining the sources of oxidative stress in SLS might in the long run provide new therapeutic avenues. Antioxid. Redox Signal. 18, 1475–1490. PMID:22746161

Identification of biomarkers that distinguish human papillomavirus (HPV)-positive versus HPV-negative head and neck cancers in a mouse model.

PubMed

Strati, Katerina; Pitot, Henry C; Lambert, Paul F

2006-09-19

Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer mortality worldwide. Recent reports have associated a subset of HNSCC with high-risk human papillomaviruses (HPVs), particularly HPV16, the same subset of HPVs responsible for the majority of cervical and anogenital cancers. In this study we describe a mouse model for HPV-associated HNSCC that employs mice transgenic for the HPV16 oncogenes E6 and E7. In these mice, E6 and E7 induce aberrant epithelial proliferation and, in the presence of a chemical carcinogen, they increase dramatically the animal's susceptibility to HNSCC. The cancers arising in the HPV16-transgenic mice mirror the molecular and histopathological characteristics of human HPV-positive HNSCC that distinguish the latter from human HPV-negative HNSCC, including overexpression of p16 protein and formation of more basaloid cancers. This validated model of HPV-associated HNSCC provides the means to define the contributions of individual HPV oncogenes to HNSCC and to understand the molecular basis for the differing clinical properties of HPV-positive and HPV-negative human HNSCC. From this study, we identify minichromosome maintenance protein 7 (MCM7) and p16 as potentially useful biomarkers for HPV-positive head and neck cancer.

Blackmailing: the keystone in the human mating system

PubMed Central

2011-01-01

Background The human mating system is characterized by bi-parental care and faithful monogamy is highly valued in most cultures. Marriage has evolved as a social institution and punishment for extra pair mating (EPM) or adultery is common. However, similar to other species with bi-parental care, both males and females frequently indulge in EPM in secrecy since it confers certain gender specific genetic benefits. Stability of faithful monogamy is therefore a conundrum. We model human mating system using game theory framework to study the effects of factors that can stabilize or destabilize faithful committed monogamy. Results Although mate guarding can partly protect the genetic interests, we show that it does not ensure monogamy. Social policing enabled by gossiping is another line of defense against adultery unique to humans. However, social policing has a small but positive cost to an individual and therefore is prone to free riding. We suggest that since exposure of adultery can invite severe punishment, the policing individuals can blackmail opportunistically whenever the circumstances permit. If the maximum probabilistic benefit of blackmailing is greater than the cost of policing, policing becomes a non-altruistic act and stabilizes in the society. We show that this dynamics leads to the coexistence of different strategies in oscillations, with obligate monogamy maintained at a high level. Deletion of blackmailing benefit from the model leads to the complete disappearance of obligate monogamy. Conclusions Obligate monogamy can be maintained in the population in spite of the advantages of EPM. Blackmailing, which makes policing a non-altruistic act, is crucial for the maintenance of faithful monogamy. Although biparental care, EPM, mate guarding and punishment are shared by many species, gossiping and blackmailing make the human mating system unique. PMID:22122975

Density and Duration of Pneumococcal Carriage Is Maintained by Transforming Growth Factor β1 and T Regulatory Cells

PubMed Central

Coward, William R.; Gritzfeld, Jenna F.; Richards, Luke; Garcia-Garcia, Francesc J.; Dotor, Javier; Gordon, Stephen B.

2014-01-01

Rationale: Nasopharyngeal carriage of Streptococcus pneumoniae is a prerequisite for invasive disease, but the majority of carriage episodes are asymptomatic and self-resolving. Interactions determining the development of carriage versus invasive disease are poorly understood but will influence the effectiveness of vaccines or therapeutics that disrupt nasal colonization. Objectives: We sought to elucidate immunological mechanisms underlying noninvasive pneumococcal nasopharyngeal carriage. Methods: Pneumococcal interactions with human nasopharyngeal and bronchial fibroblasts and epithelial cells were investigated in vitro. A murine model of nasopharyngeal carriage and an experimental human pneumococcal challenge model were used to characterize immune responses in the airways during carriage. Measurements and Main Results: We describe the previously unknown immunological basis of noninvasive carriage and highlight mechanisms whose perturbation may lead to invasive disease. We identify the induction of active transforming growth factor (TGF)-β1 by S. pneumoniae in human host cells and highlight the key role for TGF-β1 and T regulatory cells in the establishment and maintenance of nasopharyngeal carriage in mice and humans. We identify the ability of pneumococci to drive TGF-β1 production from nasopharyngeal cells in vivo and show that an immune tolerance profile, characterized by elevated TGF-β1 and high nasopharyngeal T regulatory cell numbers, is crucial for prolonged carriage of pneumococci. Blockade of TGF-β1 signaling prevents prolonged carriage and leads to clearance of pneumococci from the nasopharynx. Conclusions: These data explain the mechanisms by which S. pneumoniae colonize the human nasopharynx without inducing damaging host inflammation and provide insight into the role of bacterial and host constituents that allow and maintain carriage. PMID:24749506

Sound Heart: Spiritual Nursing Care Model from Religious Viewpoint.

PubMed

Asadzandi, Minoo

2017-12-01

Different methods of epistemology create different philosophical views. None of the nursing theories have employed the revelational epistemology and the philosophical views of Abrahamic religions. According to Abrahamic religions, the universe and human being have been created based on God's affection. Human being should deserve the position of God's representative on earth after achieving all ethical merits. Humans have willpower to shape their destiny by choosing manner of their relationship with God, people, themselves and the whole universe. They can adopt the right behavior by giving a divine color to their thoughts and intentions and thus attain peace and serenity in their heart. Health means having a sound heart (calm spirit with a sense of hope and love, security and happiness) that is achievable through faith and piety. Moral vices lead to diseases. Human beings are able to purge their inside (heart) through establishing a relationship with God and then take actions to reform the outside world. The worlds are run by God's will based on prudence and mercy. All events happen with God's authorization, and human beings have to respond to them. Nurses should try to recognize the patient's spiritual response to illness that can appear as symptoms of an unsound heart (fear, sadness, disappointment, anger, jealousy, cruelty, grudge, suspicion, etc.) due to the pains caused by illness and then alleviate the patient's suffering by appropriate approaches. Nurses help the patient to achieve the sound heart by hope in divine mercy and love, and they help the patient see good in any evil and relieve their fear and sadness by viewing their illness positively and then attain the status of calm, satisfaction, peace and serenity in their heart and being content with the divine fate. By invitation to religious morality, the model leads the patients to spiritual health.

Review of the physiology of human thermal comfort while exercising in urban landscapes and implications for bioclimatic design.

PubMed

Vanos, Jennifer K; Warland, Jon S; Gillespie, Terry J; Kenny, Natasha A

2010-07-01

This review comprehensively examines scientific literature pertaining to human physiology during exercise, including mechanisms of heat formation and dissipation, heat stress on the body, the importance of skin temperature monitoring, the effects of clothing, and microclimatic measurements. This provides a critical foundation for microclimatologists and biometeorologists in the understanding of experiments involving human physiology. The importance of the psychological aspects of how an individual perceives an outdoor environment are also reviewed, emphasizing many factors that can indirectly affect thermal comfort (TC). Past and current efforts to develop accurate human comfort models are described, as well as how these models can be used to develop resilient and comfortable outdoor spaces for physical activity. Lack of suitable spaces plays a large role in the deterioration of human health due to physical inactivity, leading to higher rates of illness, heart disease, obesity and heat-related casualties. This trend will continue if urban designers do not make use of current knowledge of bioclimatic urban design, which must be synthesized with physiology, psychology and microclimatology. Increased research is required for furthering our knowledge on the outdoor human energy balance concept and bioclimatic design for health and well-being in urban areas.

Review of the physiology of human thermal comfort while exercising in urban landscapes and implications for bioclimatic design

NASA Astrophysics Data System (ADS)

Vanos, Jennifer K.; Warland, Jon S.; Gillespie, Terry J.; Kenny, Natasha A.

2010-07-01

This review comprehensively examines scientific literature pertaining to human physiology during exercise, including mechanisms of heat formation and dissipation, heat stress on the body, the importance of skin temperature monitoring, the effects of clothing, and microclimatic measurements. This provides a critical foundation for microclimatologists and biometeorologists in the understanding of experiments involving human physiology. The importance of the psychological aspects of how an individual perceives an outdoor environment are also reviewed, emphasizing many factors that can indirectly affect thermal comfort (TC). Past and current efforts to develop accurate human comfort models are described, as well as how these models can be used to develop resilient and comfortable outdoor spaces for physical activity. Lack of suitable spaces plays a large role in the deterioration of human health due to physical inactivity, leading to higher rates of illness, heart disease, obesity and heat-related casualties. This trend will continue if urban designers do not make use of current knowledge of bioclimatic urban design, which must be synthesized with physiology, psychology and microclimatology. Increased research is required for furthering our knowledge on the outdoor human energy balance concept and bioclimatic design for health and well-being in urban areas.

The Potential Impact of Labor Choices on the Efficacy of Marine Conservation Strategies

PubMed Central

Hughes, Zachary D.; Fenichel, Eli P.; Gerber, Leah R.

2011-01-01

Conservation of marine resources is critical to the wellbeing of human communities. Coastal artisanal fishing communities are particularly reliant on marine resources for food and for their livelihoods. Management actions aimed at marine conservation may lead to unanticipated changes in human behavior that influence the ability of conservation programs to achieve their goals. We examine how marine conservation strategies may impact labor decisions that influence both the ecosystem and human livelihoods using simulation modeling. We consider two conservation strategies in the model: direct action through fisheries regulation enforcement, and indirect action through land conservation. Our results indicate that both strategies can increase the abundance of fish, and thus contribute to the maintenance of marine resources. However, our results also show that marine fisheries enforcement may negatively impact the livelihoods of human communities. Land conservation, on the other hand, potentially enhances the livelihood of the human populations. Thus, depending on management objectives, indirect or a combination of direct and indirect conservation strategies may be effective at achieving conservation and sustainability goals. These results highlight the importance of accounting for changes in human behavior resulting from management actions in conservation and management. PMID:21887306

Connecting Brain Proteomics with Behavioural Neuroscience in Translational Animal Models of Neuropsychiatric Disorders.

PubMed

Sarnyai, Zoltán; Guest, Paul C

2017-01-01

Modelling psychiatric disorders in animals has been hindered by several challenges related to our poor understanding of the disease causes. This chapter describes recent advances in translational research which may lead to animal models and relevant proteomic biomarkers that can be informative about disease mechanisms and potential new therapeutic targets. The review focuses on the behavioural and molecular correlates in models of schizophrenia and major depressive disorder, as guided by recently established Research Domain Criteria (RDoC). This approach is based on providing proteomic data for aetiologically driven, behaviourally well-characterised animal models to link discovered biomarker candidates with the human disease.

Self-Deferral, HIV Infection, and the Blood Supply: Evaluating an AIDS Intervention.

ERIC Educational Resources Information Center

Kaplan, Edward H.; Novick, Alvin

1990-01-01

This paper evaluates the effectiveness of self-deferral, a social screen implemented to protect the U.S. blood supply from human immunodeficiency virus (HIV) infection prior to the advent of laboratory testing. Mathematical models are developed to estimate the number of infectious transfusions ultimately leading to AIDS prior to self-deferral.…

Parenting Practices in Preschool Leading to Later Cognitive Competence: A Family Stress Model

ERIC Educational Resources Information Center

Nievar, M. Angela; Moske, Amanda Kay; Johnson, Deborah Jean; Chen, Qi

2014-01-01

Research Findings: This study investigates the effect of the early home environment on self-regulation in preschoolers, and how self-regulation relates to later school achievement, while taking into account family resources. Participants were part of the National Institute of Child Health and Human Development's Study of Early Child Care and Youth…

Inhibition of Ovarian Cancer Chemoresistance and Metastasis with Antagonists of Hyaluronan-CD44-CD147 Interactions

DTIC Science & Technology

2013-07-01

oligosaccharides , which have previously been shown to antagonize hyaluronan-receptor interactions, sensitize cisplatin-resistant human ovarian...carcinoma cells to cisplatin treatment in a mouse xenograft model, as well as in cell culture. Hyaluronan oligosaccharide -decorated nanoparticles... oligosaccharides antagonize hyaluronan-receptor signaling by disrupting constitutive hyaluronan polymer- receptor interaction, thus leading to

LINKING ETIOLOGIES IN HUMANS AND ANIMAL MODELS: STUDIES OF AUTISM. (R824758)

EPA Science Inventory

Abstract

Thalidomide has been shown to lead to a high rate of autism when exposure occurs during the 20th to 24th d of gestation. Both the critical period and the neurological deficits of the autistic cases indicate that they have sustained injuries to the cranial nerv...

HUMAN ACTIVITIES THAT MAY LEAD TO HIGH INHALED INTAKE DOSES IN CHILDREN AGED 6-13

EPA Science Inventory

The paper focuses on possible activities of children aged 6-13 that may make them susceptible to high hourly intake doses of ozone (O3) air pollution. Data from an O3 exposure modeling exercise indicates that a relatively few hours can account for a significant amount of the t...

The role of free radicals in traumatic brain injury.

PubMed

O'Connell, Karen M; Littleton-Kearney, Marguerite T

2013-07-01

Traumatic brain injury (TBI) is a significant cause of death and disability in both the civilian and the military populations. The primary impact causes initial tissue damage, which initiates biochemical cascades, known as secondary injury, that expand the damage. Free radicals are implicated as major contributors to the secondary injury. Our review of recent rodent and human research reveals the prominent role of the free radicals superoxide anion, nitric oxide, and peroxynitrite in secondary brain injury. Much of our current knowledge is based on rodent studies, and the authors identified a gap in the translation of findings from rodent to human TBI. Rodent models are an effective method for elucidating specific mechanisms of free radical-induced injury at the cellular level in a well-controlled environment. However, human TBI does not occur in a vacuum, and variables controlled in the laboratory may affect the injury progression. Additionally, multiple experimental TBI models are accepted in rodent research, and no one model fully reproduces the heterogeneous injury seen in humans. Free radical levels are measured indirectly in human studies based on assumptions from the findings from rodent studies that use direct free radical measurements. Further study in humans should be directed toward large samples to validate the findings in rodent studies. Data obtained from these studies may lead to more targeted treatment to interrupt the secondary injury cascades.

Evidence for a bimodal distribution in human communication.

PubMed

Wu, Ye; Zhou, Changsong; Xiao, Jinghua; Kurths, Jürgen; Schellnhuber, Hans Joachim

2010-11-02

Interacting human activities underlie the patterns of many social, technological, and economic phenomena. Here we present clear empirical evidence from Short Message correspondence that observed human actions are the result of the interplay of three basic ingredients: Poisson initiation of tasks and decision making for task execution in individual humans as well as interaction among individuals. This interplay leads to new types of interevent time distribution, neither completely Poisson nor power-law, but a bimodal combination of them. We show that the events can be separated into independent bursts which are generated by frequent mutual interactions in short times following random initiations of communications in longer times by the individuals. We introduce a minimal model of two interacting priority queues incorporating the three basic ingredients which fits well the distributions using the parameters extracted from the empirical data. The model can also embrace a range of realistic social interacting systems such as e-mail and letter communications when taking the time scale of processing into account. Our findings provide insight into various human activities both at the individual and network level. Our analysis and modeling of bimodal activity in human communication from the viewpoint of the interplay between processes of different time scales is likely to shed light on bimodal phenomena in other complex systems, such as interevent times in earthquakes, rainfall, forest fire, and economic systems, etc.

Evidence for a bimodal distribution in human communication

PubMed Central

Wu, Ye; Zhou, Changsong; Xiao, Jinghua; Kurths, Jürgen; Schellnhuber, Hans Joachim

2010-01-01

Interacting human activities underlie the patterns of many social, technological, and economic phenomena. Here we present clear empirical evidence from Short Message correspondence that observed human actions are the result of the interplay of three basic ingredients: Poisson initiation of tasks and decision making for task execution in individual humans as well as interaction among individuals. This interplay leads to new types of interevent time distribution, neither completely Poisson nor power-law, but a bimodal combination of them. We show that the events can be separated into independent bursts which are generated by frequent mutual interactions in short times following random initiations of communications in longer times by the individuals. We introduce a minimal model of two interacting priority queues incorporating the three basic ingredients which fits well the distributions using the parameters extracted from the empirical data. The model can also embrace a range of realistic social interacting systems such as e-mail and letter communications when taking the time scale of processing into account. Our findings provide insight into various human activities both at the individual and network level. Our analysis and modeling of bimodal activity in human communication from the viewpoint of the interplay between processes of different time scales is likely to shed light on bimodal phenomena in other complex systems, such as interevent times in earthquakes, rainfall, forest fire, and economic systems, etc. PMID:20959414

Regulatory B cells in human inflammatory and autoimmune diseases: from mouse models to clinical research.

PubMed

Miyagaki, Tomomitsu; Fujimoto, Manabu; Sato, Shinichi

2015-10-01

B cells have been generally considered to be positive regulators of immune responses because of their ability to produce antigen-specific antibodies and to activate T cells through antigen presentation. Impairment of B cell development and function may cause inflammatory and autoimmune diseases. Recently, specific B cell subsets that can negatively regulate immune responses have been described in mouse models of a wide variety of inflammatory and autoimmune diseases. The concept of those B cells, termed regulatory B cells, is now recognized as important in the murine immune system. Among several regulatory B cell subsets, IL-10-producing regulatory B cells are the most widely investigated. On the basis of discoveries from studies of such mice, human regulatory B cells that produce IL-10 in most cases are becoming an active area of research. There have been emerging data suggesting the importance of human regulatory B cells in various diseases. Revealing the immune regulation mechanisms of human regulatory B cells in human inflammatory and autoimmune diseases could lead to the development of novel B cell targeted therapies. This review highlights the current knowledge on regulatory B cells, mainly IL-10-producing regulatory B cells, in animal models of inflammatory and autoimmune diseases and in clinical research using human samples. © The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A Review of the Molecular Mechanisms of Chemically-Induced Neoplasia in Rat and Mouse Models in National Toxicology Program Bioassays and Their Relevance to Human Cancer

PubMed Central

Hoenerhoff, Mark J.; Hong, Hue Hua; Ton, Tai-Vu; Lahousse, Stephanie A.; Sills, Robert C.

2012-01-01

Tumor response in the B6C3F1 mouse, F344 rat, and other animal models following exposure to various compounds provides evidence that people exposed to these or similar compounds may be at risk for developing cancer. Although tumors in rodents and humans are often morphologically similar, underlying mechanisms of tumorigenesis are often unknown and may be different between the species. Therefore, the relevance of an animal tumor response to human health would be better determined if the molecular pathogenesis were understood. The underlying molecular mechanisms leading to carcinogenesis are complex and involve multiple genetic and epigenetic events and other factors. To address the molecular pathogenesis of environmental carcinogens, we examine rodent tumors (e.g., lung, colon, mammary gland, skin, brain, mesothelioma) for alterations in cancer genes and epigenetic events that are associated with human cancer. Our NTP studies have identified several genetic alterations in chemically induced rodent neoplasms that are important in human cancer. Identification of such alterations in rodent models of chemical carcinogenesis caused by exposure to environmental contaminants, occupational chemicals, and other compounds lends further support that they are of potential human health risk. These studies also emphasize the importance of molecular evaluation of chemically induced rodent tumors for providing greater public health significance for NTP evaluated compounds. PMID:19846892

Comparative biology of cystic fibrosis animal models.

PubMed

Fisher, John T; Zhang, Yulong; Engelhardt, John F

2011-01-01

Animal models of human diseases are critical for dissecting mechanisms of pathophysiology and developing therapies. In the context of cystic fibrosis (CF), mouse models have been the dominant species by which to study CF disease processes in vivo for the past two decades. Although much has been learned through these CF mouse models, limitations in the ability of this species to recapitulate spontaneous lung disease and several other organ abnormalities seen in CF humans have created a need for additional species on which to study CF. To this end, pig and ferret CF models have been generated by somatic cell nuclear transfer and are currently being characterized. These new larger animal models have phenotypes that appear to closely resemble human CF disease seen in newborns, and efforts to characterize their adult phenotypes are ongoing. This chapter will review current knowledge about comparative lung cell biology and cystic fibrosis transmembrane conductance regulator (CFTR) biology among mice, pigs, and ferrets that has implications for CF disease modeling in these species. We will focus on methods used to compare the biology and function of CFTR between these species and their relevance to phenotypes seen in the animal models. These cross-species comparisons and the development of both the pig and the ferret CF models may help elucidate pathophysiologic mechanisms of CF lung disease and lead to new therapeutic approaches.

Development of a 3D co-culture model using human stem ...

EPA Pesticide Factsheets

Morphogenetic tissue fusion is a critical and complex event in embryonic development and failure of this event leads to birth defects, such as cleft palate. Palatal fusion requires adhesion and subsequent dissolution of the medial epithelial layer of the mesenchymal palatal shelves, and is regulated by the growth factors EGF and TGFβ, and others, although the complete regulatory mechanism is not understood. Three dimensional (3D) organotypic models allow us to mimic the native architecture of human tissue to facilitate the study of tissue dynamics and their responses to developmental toxicants. Our goal was to develop and characterize a spheroidal model of palatal fusion to investigate the mechanisms regulating fusion with exposure to growth factors and chemicals in the ToxCast program known to disrupt this event. We present a spheroidal model using human umbilical-derived mesenchymal stem cells (hMSC) spheroid cores cultured for 13 days and then coated with MaxGel™ basement membrane and a layer of human progenitor epithelial keratinocytes (hPEK) (hMSC+hPEK spheroids). We characterized the growth, differentiation, proliferation and fusion activity of the model. Spheroid diameter was dependent on hMSC seeding density, size of the seeding wells, time in culture, and type of medium. hMSC spheroid growth was enhanced with osteogenic differentiation medium. Alkaline phosphatase activity in the hMSC spheroid, indicating osteogenic differentiation, increased in inte

Spatial pattern of risk of common raven predation on desert tortoises

USGS Publications Warehouse

Kristan, W. B.; Boarman, W.I.

2003-01-01

Common Ravens (Corvus corax) in the Mojave Desert of California, USA are subsidized by anthropogenic resources. Large numbers of nonbreeding ravens are attracted to human developments and thus are spatially restricted, whereas breeding ravens are distributed more evenly throughout the area. We investigated whether the spatial distribution of risk of predation by ravens to juveniles of the threatened desert tortoise (Gopherus agassizii) was determined by the spatial distribution of (1) nonbreeding ravens at human developments (leading to "spillover" predation) or (2) breeding individuals throughout developed and undeveloped areas (leading to " hyperpredation"). Predation risk, measured using styrofoam models of juvenile desert tortoises, was high near places attracting large numbers of nonbreeding ravens, near successful nests, and far from successful nests when large numbers of nonbreeding ravens were present. Patterns consistent with both "spillover" predation and "hyperpredation" were thus observed, attributed to the nonbreeding and breeding segments of the population, respectively. Furthermore, because locations of successful nests changed almost annually, consistent low-predation refugia for juvenile desert tortoises were nearly nonexistent. Consequently, anthropogenic resources for ravens could indirectly lead to the suppression, decline, or even extinction of desert tortoise populations.

Iron does not cause arrhythmias in the guinea pig model of transfusional iron overload.

PubMed

Kaiser, Lana; Davis, John; Patterson, Jon; Boyd, Ryan F; Olivier, N Bari; Bohart, George; Schwartz, Kenneth A

2007-08-01

Cardiac events, including heart failure and arrhythmias, are the leading cause of death in patients with beta thalassemia. Although cardiac arrhythmias in humans are believed to result from iron overload, excluding confounding factors in the human population is difficult. The goal of the current study was to determine whether cardiac arrhythmias occurred in the guinea pig model of secondary iron overload. Electrocardiograms were recorded by using surgically implanted telemetry devices in guinea pigs loaded intraperitoneally with iron dextran (test animals) or dextran alone (controls). Loading occurred over approximately 6 wk. Electrocardiograms were recorded for 1 wk prior to loading, throughout loading, and for approximately 4 wk after loading was complete. Cardiac and liver iron concentrations were significantly increased in the iron-loaded animals compared with controls and were in the range of those reported for humans with thalassemia. Arrhythmias were rare in both iron-loaded and control guinea pigs. No life-threatening arrhythmias were detected in either group. These data suggest that iron alone may be insufficient to cause cardiac arrhythmias in the iron-loaded guinea pig model and that arrhythmias detected in human patients with iron overload may be the result of a complex interplay of factors.

Predicting Zoonotic Risk of Influenza A Viruses from Host Tropism Protein Signature Using Random Forest

PubMed Central

Eng, Christine L. P.; Tong, Joo Chuan; Tan, Tin Wee

2017-01-01

Influenza A viruses remain a significant health problem, especially when a novel subtype emerges from the avian population to cause severe outbreaks in humans. Zoonotic viruses arise from the animal population as a result of mutations and reassortments, giving rise to novel strains with the capability to evade the host species barrier and cause human infections. Despite progress in understanding interspecies transmission of influenza viruses, we are no closer to predicting zoonotic strains that can lead to an outbreak. We have previously discovered distinct host tropism protein signatures of avian, human and zoonotic influenza strains obtained from host tropism predictions on individual protein sequences. Here, we apply machine learning approaches on the signatures to build a computational model capable of predicting zoonotic strains. The zoonotic strain prediction model can classify avian, human or zoonotic strains with high accuracy, as well as providing an estimated zoonotic risk. This would therefore allow us to quickly determine if an influenza virus strain has the potential to be zoonotic using only protein sequences. The swift identification of potential zoonotic strains in the animal population using the zoonotic strain prediction model could provide us with an early indication of an imminent influenza outbreak. PMID:28587080

Predicting Zoonotic Risk of Influenza A Viruses from Host Tropism Protein Signature Using Random Forest.

PubMed

Eng, Christine L P; Tong, Joo Chuan; Tan, Tin Wee

2017-05-25

Influenza A viruses remain a significant health problem, especially when a novel subtype emerges from the avian population to cause severe outbreaks in humans. Zoonotic viruses arise from the animal population as a result of mutations and reassortments, giving rise to novel strains with the capability to evade the host species barrier and cause human infections. Despite progress in understanding interspecies transmission of influenza viruses, we are no closer to predicting zoonotic strains that can lead to an outbreak. We have previously discovered distinct host tropism protein signatures of avian, human and zoonotic influenza strains obtained from host tropism predictions on individual protein sequences. Here, we apply machine learning approaches on the signatures to build a computational model capable of predicting zoonotic strains. The zoonotic strain prediction model can classify avian, human or zoonotic strains with high accuracy, as well as providing an estimated zoonotic risk. This would therefore allow us to quickly determine if an influenza virus strain has the potential to be zoonotic using only protein sequences. The swift identification of potential zoonotic strains in the animal population using the zoonotic strain prediction model could provide us with an early indication of an imminent influenza outbreak.

Patient-Specific Pluripotent Stem Cells in Neurological Diseases

PubMed Central

Durnaoglu, Serpen; Genc, Sermin; Genc, Kursad

2011-01-01

Many human neurological diseases are not currently curable and result in devastating neurologic sequelae. The increasing availability of induced pluripotent stem cells (iPSCs) derived from adult human somatic cells provides new prospects for cellreplacement strategies and disease-related basic research in a broad spectrum of human neurologic diseases. Patient-specific iPSC-based modeling of neurogenetic and neurodegenerative diseases is an emerging efficient tool for in vitro modeling to understand disease and to screen for genes and drugs that modify the disease process. With the exponential increase in iPSC research in recent years, human iPSCs have been successfully derived with different technologies and from various cell types. Although there remain a great deal to learn about patient-specific iPSC safety, the reprogramming mechanisms, better ways to direct a specific reprogramming, ideal cell source for cellular grafts, and the mechanisms by which transplanted stem cells lead to an enhanced functional recovery and structural reorganization, the discovery of the therapeutic potential of iPSCs offers new opportunities for the treatment of incurable neurologic diseases. However, iPSC-based therapeutic strategies need to be thoroughly evaluated in preclinical animal models of neurological diseases before they can be applied in a clinical setting. PMID:21776279

A neural model of motion processing and visual navigation by cortical area MST.

PubMed

Grossberg, S; Mingolla, E; Pack, C

1999-12-01

Cells in the dorsal medial superior temporal cortex (MSTd) process optic flow generated by self-motion during visually guided navigation. A neural model shows how interactions between well-known neural mechanisms (log polar cortical magnification, Gaussian motion-sensitive receptive fields, spatial pooling of motion-sensitive signals and subtractive extraretinal eye movement signals) lead to emergent properties that quantitatively simulate neurophysiological data about MSTd cell properties and psychophysical data about human navigation. Model cells match MSTd neuron responses to optic flow stimuli placed in different parts of the visual field, including position invariance, tuning curves, preferred spiral directions, direction reversals, average response curves and preferred locations for stimulus motion centers. The model shows how the preferred motion direction of the most active MSTd cells can explain human judgments of self-motion direction (heading), without using complex heading templates. The model explains when extraretinal eye movement signals are needed for accurate heading perception, and when retinal input is sufficient, and how heading judgments depend on scene layouts and rotation rates.

New Paradigms for the Study of Ocular Alphaherpesvirus Infections: Insights into the Use of Non-Traditional Host Model Systems

PubMed Central

Ledbetter, Eric C.; Van de Walle, Gerlinde R.

2017-01-01

Ocular herpesviruses, most notably human alphaherpesvirus 1 (HSV-1), canid alphaherpesvirus 1 (CHV-1) and felid alphaherpesvirus 1 (FHV-1), infect and cause severe disease that may lead to blindness. CHV-1 and FHV-1 have a pathogenesis and induce clinical disease in their hosts that is similar to HSV-1 ocular infections in humans, suggesting that infection of dogs and cats with CHV-1 and FHV-1, respectively, can be used as a comparative natural host model of herpesvirus-induced ocular disease. In this review, we discuss both strengths and limitations of the various available model systems to study ocular herpesvirus infection, with a focus on the use of these non-traditional virus-natural host models. Recent work has demonstrated the robustness and reproducibility of experimental ocular herpesvirus infections in dogs and cats, and, therefore, these non-traditional models can provide additional insights into the pathogenesis of ocular herpesvirus infections. PMID:29156583

A mathematical model of avian influenza with half-saturated incidence.

PubMed

Chong, Nyuk Sian; Tchuenche, Jean Michel; Smith, Robert J

2014-03-01

The widespread impact of avian influenza viruses not only poses risks to birds, but also to humans. The viruses spread from birds to humans and from human to human In addition, mutation in the primary strain will increase the infectiousness of avian influenza. We developed a mathematical model of avian influenza for both bird and human populations. The effect of half-saturated incidence on transmission dynamics of the disease is investigated. The half-saturation constants determine the levels at which birds and humans contract avian influenza. To prevent the spread of avian influenza, the associated half-saturation constants must be increased, especially the half-saturation constant H m for humans with mutant strain. The quantity H m plays an essential role in determining the basic reproduction number of this model. Furthermore, by decreasing the rate β m at which human-to-human mutant influenza is contracted, an outbreak can be controlled more effectively. To combat the outbreak, we propose both pharmaceutical (vaccination) and non-pharmaceutical (personal protection and isolation) control methods to reduce the transmission of avian influenza. Vaccination and personal protection will decrease β m, while isolation will increase H m. Numerical simulations demonstrate that all proposed control strategies will lead to disease eradication; however, if we only employ vaccination, it will require slightly longer to eradicate the disease than only applying non-pharmaceutical or a combination of pharmaceutical and non-pharmaceutical control methods. In conclusion, it is important to adopt a combination of control methods to fight an avian influenza outbreak.

Including irrigation in niche modelling of the invasive wasp Vespula germanica (Fabricius) improves model fit to predict potential for further spread

PubMed Central

Kriticos, Darren J.; Veldtman, Ruan

2017-01-01

The European wasp, Vespula germanica (Fabricius) (Hymenoptera: Vespidae), is of Palaearctic origin, being native to Europe, northern Africa and Asia, and introduced into North America, Chile, Argentina, Iceland, Ascension Island, South Africa, Australia and New Zealand. Due to its polyphagous nature and scavenging behaviour, V. germanica threatens agriculture and silviculture, and negatively affects biodiversity, while its aggressive nature and venomous sting pose a health risk to humans. In areas with warmer winters and longer summers, queens and workers can survive the winter months, leading to the build-up of large nests during the following season; thereby increasing the risk posed by this species. To prevent or prepare for such unwanted impacts it is important to know where the wasp may be able to establish, either through natural spread or through introduction as a result of human transport. Distribution data from Argentina and Australia, and seasonal phenology data from Argentina were used to determine the potential distribution of V. germanica using CLIMEX modelling. In contrast to previous models, the influence of irrigation on its distribution was also investigated. Under a natural rainfall scenario, the model showed similarities to previous models. When irrigation is applied, dry stress is alleviated, leading to larger areas modelled climatically suitable compared with previous models, which provided a better fit with the actual distribution of the species. The main areas at risk of invasion by V. germanica include western USA, Mexico, small areas in Central America and in the north-western region of South America, eastern Brazil, western Russia, north-western China, Japan, the Mediterranean coastal regions of North Africa, and parts of southern and eastern Africa. PMID:28715452

An efficient model of human endometriosis by induced unopposed estrogenicity in baboons.

PubMed

Nair, Hareesh B; Baker, Robert; Owston, Michael A; Escalona, Renee; Dick, Edward J; VandeBerg, John L; Nickisch, Klaus J

2016-03-08

Endometriosis is a chronic estrogen-dependent disease that occurs in approximately 10% of reproductive age women. Baboons offer a clear benefit for studying the initiation and progression of endometriosis since baboon is very close to humans phylogenetically. Progestins are used in the treatment of endometriosis. The therapeutic window of progestins depends on the ratio of its affinity towards progesterone receptor agonism verses antagonism. The present study is to determine the role of pure antiprogestin in baboon endometriosis. We hypothesize that pure antiprogestin will induce unopposed estrogenicity and spontaneous endometriosis in baboons. The rate of endometrial invasion and attachment through modeled peritoneum in the presence and absence of progesterone and antiprogestin was evaluated in this study. A baboon model of endometriosis induced by unopposed estrogenicity using progesterone receptor antagonist (EC304) was used in this study. We observed EC304 has induced unopposed estrogenicity that deregulated proteins involved in attachment, invasion, cell growth, and steroid hormone receptors in this model. Our data suggest that depleting progesterone levels in the endometrium will increase estrogen hyper-responsiveness that leads to increased endometriotic lesion progression in the baboon (Papio anubis) model. This study reports a refined model of human endometriosis in baboons that could potentially be used to develop new diagnostic and therapeutic strategies for the benefit of women suffering from endometriosis.

A Completely Blind Video Integrity Oracle.

PubMed

Mittal, Anish; Saad, Michele A; Bovik, Alan C

2016-01-01

Considerable progress has been made toward developing still picture perceptual quality analyzers that do not require any reference picture and that are not trained on human opinion scores of distorted images. However, there do not yet exist any such completely blind video quality assessment (VQA) models. Here, we attempt to bridge this gap by developing a new VQA model called the video intrinsic integrity and distortion evaluation oracle (VIIDEO). The new model does not require the use of any additional information other than the video being quality evaluated. VIIDEO embodies models of intrinsic statistical regularities that are observed in natural vidoes, which are used to quantify disturbances introduced due to distortions. An algorithm derived from the VIIDEO model is thereby able to predict the quality of distorted videos without any external knowledge about the pristine source, anticipated distortions, or human judgments of video quality. Even with such a paucity of information, we are able to show that the VIIDEO algorithm performs much better than the legacy full reference quality measure MSE on the LIVE VQA database and delivers performance comparable with a leading human judgment trained blind VQA model. We believe that the VIIDEO algorithm is a significant step toward making real-time monitoring of completely blind video quality possible.

Establishment of a Neonatal Rhesus Macaque Model to Study Mycobacterium tuberculosis Infection

PubMed Central

Cepeda, Magdalena; Salas, Mary; Folwarczny, Jessica; Leandro, Ana C.; Hodara, Vida L.; de la Garza, Melissa A.; Dick, Edward J.; Owston, Michael; Armitige, Lisa Y.; Gauduin, Marie-Claire

2014-01-01

Summary Mycobacterium tuberculosis (Mtb) is the causative agent of human tuberculosis (TB) with an estimated 8.8 million new TB cases and 1.4 million deaths annually. Tuberculosis is the leading cause of death in AIDS patients worldwide but very little is known about early TB infection or TB/HIV co-infection in infants. A clinically relevant newborn animal model to study TB infection is urgently needed. We have successfully established an aerosol newborn/infant model in neonatal nonhuman primates (NHPs) that mimics clinical and bacteriological characteristics of Mtb infection as seen in human newborns/infants. Further, this model will allow the establishment of a TB coinfection model of pediatric AIDS. Aerosol versus intra broncho-alveolar Mtb infection was studied. Interestingly, 42 days post infection specific lesions were detected suggestive of the classic Ghon focus in human children. Concurrently, specific cellular immune responses developed 4–6 weeks after Mtb infection. Using the enzyme-linked immunospot (ELISPOT) assays, we found that IL-12 production correlated with early Mtb infection lesions seen by routine thoracic radiographs. Overall, this work represents the first example of early Mtb infection of newborn macaques. This study gives us a unique opportunity to further characterize immunopathogenesis and establish a TB/SIV co-infection model for pediatric AIDS. PMID:24388650

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

Quantitative Targeted Absolute Proteomics (QTAP)-based Pharmacoproteomics: The Importance of International Collaboration.

PubMed

Terasaki, Tetsuya

2017-01-01

Proteins such as membrane transporters, enzymes, receptors and channels play key roles in drug absorption, distribution, metabolism, and elimination, and also influence efficacy and the likelihood of adverse reactions. Therefore, if we can quantify the activities of these molecules, it may be possible to predict the behavior of candidate drugs in humans in disease states; such methodology would be extremely helpful for efficient drug development. We have developed an in silico method to select appropriate peptides within amino acid sequences in order to quantify targeted proteins by LC-MS/MS in selected reaction monitoring (SRM) mode. We have applied this method for the quantification of functional proteins in order to validate various in vitro and in vivo models. We found fairly good correlation between protein amounts and the enzymatic activities of microsomal cytochrome P450 (CYP) isoforms and uridine 5'-diphospho-glucuronosyltransferase (UGT) in human liver, as well as between protein amounts and the transport activities of multiple transporters in human lung cells. These results suggest that protein quantification can be useful in predicting activity. We have applied this approach to evaluate the usefulness and limitations of an immortalized human brain capillary endothelial cell line (D3 cells) and a P-glycoprotein humanized (hMDR1) mouse model by comparing the amounts of functional proteins in the models with those in isolated capillaries from human brain. In order to obtain sufficient human tissue specimens for further studies leading to clinical applications, we believe that international collaboration will be crucial.

Porcine retinal cell line VIDO R1 and Chlamydia suis to modelize ocular chlamydiosis.

PubMed

Käser, Tobias; Cnudde, Thomas; Hamonic, Glenn; Rieder, Meghanne; Pasternak, J Alex; Lai, Ken; Tikoo, Suresh K; Wilson, Heather L; Meurens, François

2015-08-15

Human ocular Chlamydia trachomatis infections can lead to trachoma, the major cause of infectious blindness worldwide. Trachoma control strategies are very helpful but logistically challenging, and a trachoma vaccine is needed but not available. Pigs are a valuable large animal model for various immunological questions and could facilitate the study of human ocular chlamydial infections. In addition, a recent study identified the zoonotic potential of Chlamydia suis, the natural pathogen of pigs. In terms of the One Health Initiative, understanding the host-pathogen-interactions and finding a vaccine for porcine chlamydia infections would also benefit human health. Thus, we infected the porcine retinal cell line VIDO R1 with C. suis and analyzed the chlamydial life cycle and the innate immune response of the infected cells. Our results indicate that C. suis completes its life cycle in VIDO R1 cells within 48 h, comparable to C. trachomatis in humans. C. suis infection of VIDO R1 cells led to increased levels of various innate immune mediators like pathogen recognition receptors, cytokines and chemokines including IL6, TNFα, and MMP9, also most relevant in human C. trachomatis infections. These results illustrate the first steps in the host-pathogen-interactions of ocular C. suis infections in pigs and show their similarity to C. trachomatis infections in humans, justifying further testing of pigs as an animal model for human trachoma. Copyright © 2015 Elsevier B.V. All rights reserved.

Autophagy is essential for maintaining the growth of a human (mini-)organ: Evidence from scalp hair follicle organ culture

PubMed Central

Allavena, Giulia; Marotta, Roberto; Catelani, Tiziano; Bertolini, Marta; Paus, Ralf

2018-01-01

Autophagy plays a crucial role in health and disease, regulating central cellular processes such as adaptive stress responses, differentiation, tissue development, and homeostasis. However, the role of autophagy in human physiology is poorly understood, highlighting a need for a model human organ system to assess the efficacy and safety of strategies to therapeutically modulate autophagy. As a complete, cyclically remodelled (mini-)organ, the organ culture of human scalp hair follicles (HFs), which, after massive growth (anagen), spontaneously enter into an apoptosis-driven organ involution (catagen) process, may provide such a model. Here, we reveal that in anagen, hair matrix keratinocytes (MKs) of organ-cultured HFs exhibit an active autophagic flux, as documented by evaluation of endogenous lipidated Light Chain 3B (LC3B) and sequestosome 1 (SQSTM1/p62) proteins and the ultrastructural visualization of autophagosomes at all stages of the autophagy process. This autophagic flux is altered during catagen, and genetic inhibition of autophagy promotes catagen development. Conversely, an anti–hair loss product markedly enhances intrafollicular autophagy, leading to anagen prolongation. Collectively, our data reveal a novel role of autophagy in human hair growth. Moreover, we show that organ-cultured scalp HFs are an excellent preclinical research model for exploring the role of autophagy in human tissue physiology and for evaluating the efficacy and tissue toxicity of candidate autophagy-modulatory agents in a living human (mini-)organ. PMID:29590104

A simple rule of direct reciprocity leads to the stable coexistence of cooperation and defection in the Prisoner's Dilemma game.

PubMed

Zheng, Xiu-Deng; Li, Cong; Yu, Jie-Ru; Wang, Shi-Chang; Fan, Song-Jia; Zhang, Bo-Yu; Tao, Yi

2017-05-07

The long-term coexistence of cooperation and defection is a common phenomenon in nature and human society. However, none of the theoretical models based on the Prisoner's Dilemma (PD) game can provide a concise theoretical model to explain what leads to the stable coexistence of cooperation and defection in the long-term even though some rules for promoting cooperation have been summarized (Nowak, 2006, Science 314, 1560-1563). Here, based on the concept of direct reciprocity, we develop an elementary model to show why stable coexistence of cooperation and defection in the PD game is possible. The basic idea behind our theoretical model is that all players in a PD game prefer a cooperator as an opponent, and our results show that considering strategies allowing opting out against defection provide a general and concise way of understanding the fundamental importance of direct reciprocity in driving the evolution of cooperation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Virus Neutralisation: New Insights from Kinetic Neutralisation Curves

PubMed Central

Magnus, Carsten

2013-01-01

Antibodies binding to the surface of virions can lead to virus neutralisation. Different theories have been proposed to determine the number of antibodies that must bind to a virion for neutralisation. Early models are based on chemical binding kinetics. Applying these models lead to very low estimates of the number of antibodies needed for neutralisation. In contrast, according to the more conceptual approach of stoichiometries in virology a much higher number of antibodies is required for virus neutralisation by antibodies. Here, we combine chemical binding kinetics with (virological) stoichiometries to better explain virus neutralisation by antibody binding. This framework is in agreement with published data on the neutralisation of the human immunodeficiency virus. Knowing antibody reaction constants, our model allows us to estimate stoichiometrical parameters from kinetic neutralisation curves. In addition, we can identify important parameters that will make further analysis of kinetic neutralisation curves more valuable in the context of estimating stoichiometries. Our model gives a more subtle explanation of kinetic neutralisation curves in terms of single-hit and multi-hit kinetics. PMID:23468602

Understanding diagnostic errors in medicine: a lesson from aviation

PubMed Central

Singh, H; Petersen, L A; Thomas, E J

2006-01-01

The impact of diagnostic errors on patient safety in medicine is increasingly being recognized. Despite the current progress in patient safety research, the understanding of such errors and how to prevent them is inadequate. Preliminary research suggests that diagnostic errors have both cognitive and systems origins. Situational awareness is a model that is primarily used in aviation human factors research that can encompass both the cognitive and the systems roots of such errors. This conceptual model offers a unique perspective in the study of diagnostic errors. The applicability of this model is illustrated by the analysis of a patient whose diagnosis of spinal cord compression was substantially delayed. We suggest how the application of this framework could lead to potential areas of intervention and outline some areas of future research. It is possible that the use of such a model in medicine could help reduce errors in diagnosis and lead to significant improvements in patient care. Further research is needed, including the measurement of situational awareness and correlation with health outcomes. PMID:16751463

Norovirus Regulation by Host and Microbe

PubMed Central

Baldridge, Megan T.; Turula, Holly; Wobus, Christiane E.

2016-01-01

Norovirus (NoV) infection is the leading cause of epidemic gastroenteritis globally, and can lead to detrimental chronic infection in immunocompromised hosts. Despite its prevalence as a cause of diarrheal illness, the study of human NoVs (HNoVs) has historically been limited by a paucity of models. The use of murine NoV (MNoV) to interrogate mechanisms of host control of viral infection has facilitated the exploration of different genetic mouse models, revealing roles for both innate and adaptive immunity in viral regulation. MNoV studies have also recently identified important interactions between the commensal micro-biota and NoV with clear extensions to HNoVs. In this review, we discuss the most current understanding of how the host, the microbiome, and their interactions regulate NoV infections. PMID:27887808

Comparative modelling of human β tubulin isotypes and implications for drug binding

NASA Astrophysics Data System (ADS)

Torin Huzil, J.; Ludueña, Richard F.; Tuszynski, Jack

2006-02-01

The protein tubulin is a target for several anti-mitotic drugs, which affect microtubule dynamics, ultimately leading to cell cycle arrest and apoptosis. Many of these drugs, including the taxanes and Vinca alkaloids, are currently used clinically in the treatment of several types of cancer. Another tubulin binding drug, colchicine, although too toxic to be used as a chemotherapeutic agent, is commonly used for the treatment of gout. The main disadvantage that all of these drugs share is that they bind tubulin indiscriminately, leading to the death of both cancerous and healthy cells. However, the broad cellular distribution of several tubulin isotypes provides a platform upon which to construct novel chemotherapeutic drugs that could differentiate between different cell types, reducing the undesirable side effects associated with current chemotherapeutic treatments. Here, we report an analysis of ten human β tubulin isotypes and discuss differences within each of the previously characterized paclitaxel, colchicine and vinblastine binding sites.

Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation.

PubMed

Wang, Jing; Luo, Cheng; Shan, Changliang; You, Qiancheng; Lu, Junyan; Elf, Shannon; Zhou, Yu; Wen, Yi; Vinkenborg, Jan L; Fan, Jun; Kang, Heebum; Lin, Ruiting; Han, Dali; Xie, Yuxin; Karpus, Jason; Chen, Shijie; Ouyang, Shisheng; Luan, Chihao; Zhang, Naixia; Ding, Hong; Merkx, Maarten; Liu, Hong; Chen, Jing; Jiang, Hualiang; He, Chuan

2015-12-01

Copper is a transition metal that plays critical roles in many life processes. Controlling the cellular concentration and trafficking of copper offers a route to disrupt these processes. Here we report small molecules that inhibit the human copper-trafficking proteins Atox1 and CCS, and so provide a selective approach to disrupt cellular copper transport. The knockdown of Atox1 and CCS or their inhibition leads to a significantly reduced proliferation of cancer cells, but not of normal cells, as well as to attenuated tumour growth in mouse models. We show that blocking copper trafficking induces cellular oxidative stress and reduces levels of cellular ATP. The reduced level of ATP results in activation of the AMP-activated protein kinase that leads to reduced lipogenesis. Both effects contribute to the inhibition of cancer cell proliferation. Our results establish copper chaperones as new targets for future developments in anticancer therapies.

Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation

PubMed Central

Wang, Jing; Luo, Cheng; Shan, Changliang; You, Qiancheng; Lu, Junyan; Elf, Shannon; Zhou, Yu; Wen, Yi; Vinkenborg, Jan L.; Fan, Jun; Kang, Heebum; Lin, Ruiting; Han, Dali; Xie, Yuxin; Karpus, Jason; Chen, Shijie; Ouyang, Shisheng; Luan, Chihao; Zhang, Naixia; Ding, Hong; Merkx, Maarten; Liu, Hong; Chen, Jing; Jiang, Hualiang; He, Chuan

2016-01-01

Copper is a transition metal that plays critical roles in many life processes. Controlling the cellular concentration and trafficking of copper offers a route to disrupt these processes. Here we report small molecules that inhibit the human copper-trafficking proteins Atox1 and CCS, and so provide a selective approach to disrupt cellular copper transport. The knockdown of Atox1 and CCS or their inhibition leads to a significantly reduced proliferation of cancer cells, but not of normal cells, as well as to attenuated tumour growth in mouse models. We show that blocking copper trafficking induces cellular oxidative stress and reduces levels of cellular ATP. The reduced level of ATP results in activation of the AMP-activated protein kinase that leads to reduced lipogenesis. Both effects contribute to the inhibition of cancer cell proliferation. Our results establish copper chaperones as new targets for future developments in anticancer therapies. PMID:26587712

Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation

NASA Astrophysics Data System (ADS)

Wang, Jing; Luo, Cheng; Shan, Changliang; You, Qiancheng; Lu, Junyan; Elf, Shannon; Zhou, Yu; Wen, Yi; Vinkenborg, Jan L.; Fan, Jun; Kang, Heebum; Lin, Ruiting; Han, Dali; Xie, Yuxin; Karpus, Jason; Chen, Shijie; Ouyang, Shisheng; Luan, Chihao; Zhang, Naixia; Ding, Hong; Merkx, Maarten; Liu, Hong; Chen, Jing; Jiang, Hualiang; He, Chuan

2015-12-01

Copper is a transition metal that plays critical roles in many life processes. Controlling the cellular concentration and trafficking of copper offers a route to disrupt these processes. Here we report small molecules that inhibit the human copper-trafficking proteins Atox1 and CCS, and so provide a selective approach to disrupt cellular copper transport. The knockdown of Atox1 and CCS or their inhibition leads to a significantly reduced proliferation of cancer cells, but not of normal cells, as well as to attenuated tumour growth in mouse models. We show that blocking copper trafficking induces cellular oxidative stress and reduces levels of cellular ATP. The reduced level of ATP results in activation of the AMP-activated protein kinase that leads to reduced lipogenesis. Both effects contribute to the inhibition of cancer cell proliferation. Our results establish copper chaperones as new targets for future developments in anticancer therapies.

Roughness threshold for cell attachment and proliferation on plasma micro-nanotextured polymeric surfaces: the case of primary human skin fibroblasts and mouse immortalized 3T3 fibroblasts

NASA Astrophysics Data System (ADS)

Bourkoula, A.; Constantoudis, V.; Kontziampasis, D.; Petrou, P. S.; Kakabakos, S. E.; Tserepi, A.; Gogolides, E.

2016-08-01

Poly(methyl methacrylate) surfaces have been micro-nanotextured in oxygen plasmas with increasing ion energy, leading to micro-nanotopography characterized by increased root mean square roughness, correlation length and fractal dimension. Primary human skin fibroblasts and mouse immortalized 3T3 fibroblasts were cultured on these surfaces and the number of adhering cells, their proliferation rate and morphology (cytoplasm and nucleus area) were evaluated as a function of roughness height, correlation length, and fractal dimension. A roughness threshold behavior was observed for both types of cells leading to dramatic cell number decrease above this threshold, which is almost similar for the two types of cells, despite their differences in size and stiffness. The results are discussed based on two theoretical models, which are reconciled and unified when the elastic moduli and the size of the cells are taken into account.

Control of Huntington's Disease-Associated Phenotypes by the Striatum-Enriched Transcription Factor Foxp2.

PubMed

Hachigian, Lea J; Carmona, Vitor; Fenster, Robert J; Kulicke, Ruth; Heilbut, Adrian; Sittler, Annie; Pereira de Almeida, Luís; Mesirov, Jill P; Gao, Fan; Kolaczyk, Eric D; Heiman, Myriam

2017-12-05

Alteration of corticostriatal glutamatergic function is an early pathophysiological change associated with Huntington's disease (HD). The factors that regulate the maintenance of corticostriatal glutamatergic synapses post-developmentally are not well understood. Recently, the striatum-enriched transcription factor Foxp2 was implicated in the development of these synapses. Here, we show that, in mice, overexpression of Foxp2 in the adult striatum of two models of HD leads to rescue of HD-associated behaviors, while knockdown of Foxp2 in wild-type mice leads to development of HD-associated behaviors. We note that Foxp2 encodes the longest polyglutamine repeat protein in the human reference genome, and we show that it can be sequestered into aggregates with polyglutamine-expanded mutant Huntingtin protein (mHTT). Foxp2 overexpression in HD model mice leads to altered expression of several genes associated with synaptic function, genes that present additional targets for normalization of corticostriatal dysfunction in HD. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Leading non-Gaussian corrections for diffusion orientation distribution function.

PubMed

Jensen, Jens H; Helpern, Joseph A; Tabesh, Ali

2014-02-01

An analytical representation of the leading non-Gaussian corrections for a class of diffusion orientation distribution functions (dODFs) is presented. This formula is constructed from the diffusion and diffusional kurtosis tensors, both of which may be estimated with diffusional kurtosis imaging (DKI). By incorporating model-independent non-Gaussian diffusion effects, it improves on the Gaussian approximation used in diffusion tensor imaging (DTI). This analytical representation therefore provides a natural foundation for DKI-based white matter fiber tractography, which has potential advantages over conventional DTI-based fiber tractography in generating more accurate predictions for the orientations of fiber bundles and in being able to directly resolve intra-voxel fiber crossings. The formula is illustrated with numerical simulations for a two-compartment model of fiber crossings and for human brain data. These results indicate that the inclusion of the leading non-Gaussian corrections can significantly affect fiber tractography in white matter regions, such as the centrum semiovale, where fiber crossings are common. 2013 John Wiley & Sons, Ltd.

Leading Non-Gaussian Corrections for Diffusion Orientation Distribution Function

PubMed Central

Jensen, Jens H.; Helpern, Joseph A.; Tabesh, Ali

2014-01-01

An analytical representation of the leading non-Gaussian corrections for a class of diffusion orientation distribution functions (dODFs) is presented. This formula is constructed out of the diffusion and diffusional kurtosis tensors, both of which may be estimated with diffusional kurtosis imaging (DKI). By incorporating model-independent non-Gaussian diffusion effects, it improves upon the Gaussian approximation used in diffusion tensor imaging (DTI). This analytical representation therefore provides a natural foundation for DKI-based white matter fiber tractography, which has potential advantages over conventional DTI-based fiber tractography in generating more accurate predictions for the orientations of fiber bundles and in being able to directly resolve intra-voxel fiber crossings. The formula is illustrated with numerical simulations for a two-compartment model of fiber crossings and for human brain data. These results indicate that the inclusion of the leading non-Gaussian corrections can significantly affect fiber tractography in white matter regions, such as the centrum semiovale, where fiber crossings are common. PMID:24738143

Pharmacophore-Map-Pick: A Method to Generate Pharmacophore Models for All Human GPCRs.

PubMed

Dai, Shao-Xing; Li, Gong-Hua; Gao, Yue-Dong; Huang, Jing-Fei

2016-02-01

GPCR-based drug discovery is hindered by a lack of effective screening methods for most GPCRs that have neither ligands nor high-quality structures. With the aim to identify lead molecules for these GPCRs, we developed a new method called Pharmacophore-Map-Pick to generate pharmacophore models for all human GPCRs. The model of ADRB2 generated using this method not only predicts the binding mode of ADRB2-ligands correctly but also performs well in virtual screening. Findings also demonstrate that this method is powerful for generating high-quality pharmacophore models. The average enrichment for the pharmacophore models of the 15 targets in different GPCR families reached 15-fold at 0.5 % false-positive rate. Therefore, the pharmacophore models can be applied in virtual screening directly with no requirement for any ligand information or shape constraints. A total of 2386 pharmacophore models for 819 different GPCRs (99 % coverage (819/825)) were generated and are available at http://bsb.kiz.ac.cn/GPCRPMD. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Ubiquitous Nature of Fluoroquinolones: The Oscillation between Antibacterial and Anticancer Activities

PubMed Central

Schweizer, Frank

2017-01-01

Fluoroquinolones are synthetic antibacterial agents that stabilize the ternary complex of prokaryotic topoisomerase II enzymes (gyrase and Topo IV), leading to extensive DNA fragmentation and bacteria death. Despite the similar structural folds within the critical regions of prokaryotic and eukaryotic topoisomerases, clinically relevant fluoroquinolones display a remarkable selectivity for prokaryotic topoisomerase II, with excellent safety records in humans. Typical agents that target human topoisomerases (such as etoposide, doxorubicin and mitoxantrone) are associated with significant toxicities and secondary malignancies, whereas clinically relevant fluoroquinolones are not known to exhibit such propensities. Although many fluoroquinolones have been shown to display topoisomerase-independent antiproliferative effects against various human cancer cells, those that are significantly active against eukaryotic topoisomerase show the same DNA damaging properties as other topoisomerase poisons. Empirical models also show that fluoroquinolones mediate some unique immunomodulatory activities of suppressing pro-inflammatory cytokines and super-inducing interleukin-2. This article reviews the extended roles of fluoroquinolones and their prospects as lead for the unmet needs of “small and safe” multimodal-targeting drug scaffolds. PMID:29112154

Exploring the Pregnant Guinea Pig as a Model for Group B Streptococcus Intrauterine Infection.

PubMed

Harrell, Maria I; Burnside, Kellie; Whidbey, Christopher; Vornhagen, Jay; Adams Waldorf, Kristina M; Rajagopal, Lakshmi

2017-09-01

Infection of the amniotic cavity remains a major cause of preterm birth, stillbirth, fetal injury and early onset, fulminant infections in newborns. Currently, there are no effective therapies to prevent in utero infection and consequent co-morbidities. This is in part due to the lack of feasible and appropriate animal models to understand mechanisms that lead to in utero infections. Use of mouse and rat models do not fully recapitulate human pregnancy, while pregnant nonhuman primate models are limited by ethical considerations, technical constraints, and cost. Given these limitations, the guinea pig is an attractive animal model for studying pregnancy infections, particularly as the placental structure is quite similar to the human placenta. Here, we describe our studies that explored the pregnant guinea pig as a model to study in utero Group B Streptococci (GBS) infections. We observed that intrauterine inoculation of wild type GBS in pregnant guinea pigs resulted in bacterial invasion and dissemination to the placenta, amniotic fluid and fetal organs. Also, hyperhemolytic GBS such as those lacking the hemolysin repressor CovR/S showed increased dissemination into the amniotic fluid and fetal organs such as the fetal lung and brain. These results are similar to those observed in mouse and non-human primate models of in utero infection, and support use of the guinea pig as a model for studying GBS infections in pregnancy.

Management concerns about known and potential impacts of lead use in shooting and in fishing activities

USGS Publications Warehouse

Goddard, C.I.; Leonard, N.J.; Stang, D.L.; Wingate, P.J.; Rattner, B.A.; Franson, J.C.; Sheffield, S.R.

2008-01-01

We present a summary of the technical review, jointly requested by the American Fisheries Society and The Wildlife Society, addressing the hazards to wildlife resulting from lead objects or fragments introduced into aquatic and terrestrial environments from the use of ammunition and fishing tackle. Impacts from lead are well documented in humans, as well as in terrestrial and aquatic organisms. Concern about impacts from lead ammunition and fishing tackle has resulted in the development of non-lead alternatives, educational campaigns, and regulations to restrict their use. This article discusses the general biological impacts of lead exposure from fishing and shooting activities to fish, wildlife, and humans; summarizes existing and proposed regulations to reduce lead exposure to biota; reviews alternatives to lead materials that are currently available for fishing; and outlines options for further actions to reduce wildlife and human exposure to lead from fishing activities.

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.

A three-dimensional human neural cell culture model of Alzheimer's disease.

PubMed

Choi, Se Hoon; Kim, Young Hye; Hebisch, Matthias; Sliwinski, Christopher; Lee, Seungkyu; D'Avanzo, Carla; Chen, Hechao; Hooli, Basavaraj; Asselin, Caroline; Muffat, Julien; Klee, Justin B; Zhang, Can; Wainger, Brian J; Peitz, Michael; Kovacs, Dora M; Woolf, Clifford J; Wagner, Steven L; Tanzi, Rudolph E; Kim, Doo Yeon

2014-11-13

Alzheimer's disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-β plaques and neurofibrillary tangles. The amyloid hypothesis of Alzheimer's disease posits that the excessive accumulation of amyloid-β peptide leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau. However, to date, no single disease model has serially linked these two pathological events using human neuronal cells. Mouse models with familial Alzheimer's disease (FAD) mutations exhibit amyloid-β-induced synaptic and memory deficits but they do not fully recapitulate other key pathological events of Alzheimer's disease, including distinct neurofibrillary tangle pathology. Human neurons derived from Alzheimer's disease patients have shown elevated levels of toxic amyloid-β species and phosphorylated tau but did not demonstrate amyloid-β plaques or neurofibrillary tangles. Here we report that FAD mutations in β-amyloid precursor protein and presenilin 1 are able to induce robust extracellular deposition of amyloid-β, including amyloid-β plaques, in a human neural stem-cell-derived three-dimensional (3D) culture system. More importantly, the 3D-differentiated neuronal cells expressing FAD mutations exhibited high levels of detergent-resistant, silver-positive aggregates of phosphorylated tau in the soma and neurites, as well as filamentous tau, as detected by immunoelectron microscopy. Inhibition of amyloid-β generation with β- or γ-secretase inhibitors not only decreased amyloid-β pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated amyloid-β-mediated tau phosphorylation. We have successfully recapitulated amyloid-β and tau pathology in a single 3D human neural cell culture system. Our unique strategy for recapitulating Alzheimer's disease pathology in a 3D neural cell culture model should also serve to facilitate the development of more precise human neural cell models of other neurodegenerative disorders.

Hunting of roe deer and wild boar in Germany: Is non-lead ammunition suitable for hunting?

PubMed Central

Gremse, Carl; Selhorst, Thomas; Bandick, Niels; Müller-Graf, Christine; Greiner, Matthias; Lahrssen-Wiederholt, Monika

2017-01-01

Background Non-lead hunting ammunition is an alternative to bullets that contain lead. The use of lead ammunition can result in severe contamination of game meat, thus posing a health risk to consumers. With any kind of ammunition for hunting, the terminal effectiveness of bullets is an animal welfare issue. Doubts about the effectiveness of non-lead bullets for a humane kill of game animals in hunting have been discussed. The length of the escape distance after the shot has been used previously as an indicator for bullet performance. Objective The object of this study was to determine how the bullet material (lead or non-lead) influences the observed escape distances. Methods 1,234 records of the shooting of roe deer (Capreolus capreolus) and 825 records of the shooting of wild boar (Sus scrofa) were evaluated. As the bullet material cannot be regarded as the sole cause of variability of escape distances, interactions of other potential influencing variables like shot placement, shooting distance, were analyzed using conditional regression trees and two-part hurdle models. Results The length of the escape distance is not influenced by the use of lead or non-lead ammunition with either roe deer or wild boar. With roe deer, the length of the escape distance is influenced significantly by the shot placement and the type of hunting. Increasing shooting distances increased the length of the escape distance. With wild boar, shot placement and the age of the animals were found to be a significant influencing factor on the length of the escape distance. Conclusions The length of the escape distance can be used as an indicator for adequate bullet effectiveness for humane killings of game animals in hunting.Non-lead bullets already exist which have an equally reliable killing effect as lead bullets. PMID:28926620

Human gastric cancer modelling using organoids.

PubMed

Seidlitz, Therese; Merker, Sebastian R; Rothe, Alexander; Zakrzewski, Falk; von Neubeck, Cläre; Grützmann, Konrad; Sommer, Ulrich; Schweitzer, Christine; Schölch, Sebastian; Uhlemann, Heike; Gaebler, Anne-Marlene; Werner, Kristin; Krause, Mechthild; Baretton, Gustavo B; Welsch, Thilo; Koo, Bon-Kyoung; Aust, Daniela E; Klink, Barbara; Weitz, Jürgen; Stange, Daniel E

2018-04-27

Gastric cancer is the second leading cause of cancer-related deaths and the fifth most common malignancy worldwide. In this study, human and mouse gastric cancer organoids were generated to model the disease and perform drug testing to delineate treatment strategies. Human gastric cancer organoid cultures were established, samples classified according to their molecular profile and their response to conventional chemotherapeutics tested. Targeted treatment was performed according to specific druggable mutations. Mouse gastric cancer organoid cultures were generated carrying molecular subtype-specific alterations. Twenty human gastric cancer organoid cultures were established and four selected for a comprehensive in-depth analysis. Organoids demonstrated divergent growth characteristics and morphologies. Immunohistochemistry showed similar characteristics to the corresponding primary tissue. A divergent response to 5-fluoruracil, oxaliplatin, irinotecan, epirubicin and docetaxel treatment was observed. Whole genome sequencing revealed a mutational spectrum that corresponded to the previously identified microsatellite instable, genomic stable and chromosomal instable subtypes of gastric cancer. The mutational landscape allowed targeted therapy with trastuzumab for ERBB2 alterations and palbociclib for CDKN2A loss. Mouse cancer organoids carrying Kras and Tp53 or Apc and Cdh1 mutations were characterised and serve as model system to study the signalling of induced pathways. We generated human and mouse gastric cancer organoids modelling typical characteristics and altered pathways of human gastric cancer. Successful interference with activated pathways demonstrates their potential usefulness as living biomarkers for therapy response testing. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Comparison of different wavefront measurement setups to judge the position tolerance of intraocular lenses in a model eye

NASA Astrophysics Data System (ADS)

Traxler, Lukas; Reutterer, Bernd; Bayer, Natascha; Drauschke, Andreas

2017-04-01

To treat cataract intraocular lenses (IOLs) are used to replace the clouded human eye lens. Due to postoperative healing processes the IOL can displace within the eye, which can lead to deteriorated quality of vision. To test and characterize these effect an IOL can be embedded into a model of the humane eye. One informative measure are wavefront aberrations. In this paper three different setups, the typical double-pass configuration (DP), a single-pass (SP1) where the measured light travels in the same direction as in DP and a single-pass (SP2) with reversed direction, are investigated. All three setups correctly measure the aberrations of the eye, where SP1 is found to be the simplest to set up and align. Because of the lowest complexity it is the proposed method for wavefront measurement in model eyes.