Punctuated equilibrium dynamics in human communications

NASA Astrophysics Data System (ADS)

Peng, Dan; Han, Xiao-Pu; Wei, Zong-Wen; Wang, Bing-Hong

2015-10-01

A minimal model based on network incorporating individual interactions is proposed to study the non-Poisson statistical properties of human behavior: individuals in system interact with their neighbors, the probability of an individual acting correlates to its activity, and all the individuals involved in action will change their activities randomly. The model reproduces varieties of spatial-temporal patterns observed in empirical studies of human daily communications, providing insight into various human activities and embracing a range of realistic social interacting systems, particularly, intriguing bimodal phenomenon. This model bridges priority queueing theory and punctuated equilibrium dynamics, and our modeling and analysis is likely to shed light on non-Poisson phenomena in many complex systems.

HUMAN EXPOSURE ACTIVITY PATTERNS

EPA Science Inventory

Human activity/uptake rate data are necessary to estimate potential human exposure and intake dose to environmental pollutants and to refine human exposure models. Personal exposure monitoring studies have demonstrated the critical role that activities play in explaining and pre...

A NEW METHOD OF LONGITUDINAL DIARY ASSEMBLY FOR HUMAN EXPOSURE MODELING

EPA Science Inventory

Human exposure time-series modeling requires longitudinal time-activity diaries to evaluate the sequence of concentrations encountered, and hence, pollutant exposure for the simulated individuals. However, most of the available data on human activities are from cross-sectional su...

Xenobiotic metabolism capacities of human skin in comparison with a 3D-epidermis model and keratinocyte-based cell culture as in vitro alternatives for chemical testing: phase II enzymes.

PubMed

Götz, Christine; Pfeiffer, Roland; Tigges, Julia; Ruwiedel, Karsten; Hübenthal, Ulrike; Merk, Hans F; Krutmann, Jean; Edwards, Robert J; Abel, Josef; Pease, Camilla; Goebel, Carsten; Hewitt, Nicola; Fritsche, Ellen

2012-05-01

The 7th Amendment to the EU Cosmetics Directive prohibits the use of animals in cosmetic testing for certain endpoints, such as genotoxicity. Therefore, skin in vitro models have to replace chemical testing in vivo. However, the metabolic competence neither of human skin nor of alternative in vitro models has so far been fully characterized, although skin is the first-pass organ for accidentally or purposely (cosmetics and pharmaceuticals) applied chemicals. Thus, there is an urgent need to understand the xenobiotic-metabolizing capacities of human skin and to compare these activities to models developed to replace animal testing. We have measured the activity of the phase II enzymes glutathione S-transferase, UDP-glucuronosyltransferase and N-acetyltransferase in ex vivo human skin, the 3D epidermal model EpiDerm 200 (EPI-200), immortalized keratinocyte-based cell lines (HaCaT and NCTC 2544) and primary normal human epidermal keratinocytes. We show that all three phase II enzymes are present and highly active in skin as compared to phase I. Human skin, therefore, represents a more detoxifying than activating organ. This work systematically compares the activities of three important phase II enzymes in four different in vitro models directly to human skin. We conclude from our studies that 3D epidermal models, like the EPI-200 employed here, are superior over monolayer cultures in mimicking human skin xenobiotic metabolism and thus better suited for dermatotoxicity testing. © 2012 John Wiley & Sons A/S.

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

PubMed

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

2016-12-01

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

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.

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.

AN OVERVIEW OF HUMAN EXPOSURE MODELING ACTIVITIES AT THE U.S. EPA'S NATIONAL EXPOSURE RESEARCH LABORATORY

EPA Science Inventory

The computational modeling of human exposure to environmental pollutants is one of the primary activities of the US Environmental Protection Agency (USEPA)'s National Exposure Research Laboratory (NERL). Assessment of human exposures is a critical part of the overall risk assessm...

Systems Approach to Understanding Electromechanical Activity in the Human Heart

PubMed Central

Rudy, Yoram; Ackerman, Michael J.; Bers, Donald M.; Clancy, Colleen E.; Houser, Steven R.; London, Barry; McCulloch, Andrew D.; Przywara, Dennis A.; Rasmusson, Randall L.; Solaro, R. John; Trayanova, Natalia A.; Van Wagoner, David R.; Varró, András; Weiss, James N.; Lathrop, David A.

2010-01-01

The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of cardiologists, cardiac electrophysiologists, cell biophysicists, and computational modelers on August 20 and 21, 2007, in Washington, DC, to advise the NHLBI on new research directions needed to develop integrative approaches to elucidate human cardiac function. The workshop strove to identify limitations in the use of data from nonhuman animal species for elucidation of human electromechanical function/activity and to identify what specific information on ion channel kinetics, calcium handling, and dynamic changes in the intracellular/extracellular milieu is needed from human cardiac tissues to develop more robust computational models of human cardiac electromechanical activity. This article summarizes the workshop discussions and recommendations on the following topics: (1) limitations of animal models and differences from human electrophysiology, (2) modeling ion channel structure/function in the context of whole-cell electrophysiology, (3) excitation–contraction coupling and regulatory pathways, (4) whole-heart simulations of human electromechanical activity, and (5) what human data are currently needed and how to obtain them. The recommendations can be found on the NHLBI Web site at http://www.nhlbi.nih.gov/meetings/workshops/electro.htm. PMID:18779456

Developing the Practising Model in Physical Education: An Expository Outline Focusing on Movement Capability

ERIC Educational Resources Information Center

Barker, D. M.; Aggerholm, K.; Standal, O.; Larsson, H.

2018-01-01

Background: Physical educators currently have a number of pedagogical (or curricular) models at their disposal. While existing models have been well-received in educational contexts, these models seek to extend students' capacities within a limited number of "human activities" (Arendt, 1958). The activity of "human practising,"…

PM ACTIVITY PATTERN RESEARCH

EPA Science Inventory

Human activity/uptake rate data are necessary to estimate potential human exposure and intake dose to environmental pollutants and to refine human exposure models. Personal exposure monitoring studies have demonstrated the critical role that activities play in explaining and pre...

Double-well dynamics of noise-driven control activation in human intermittent control: the case of stick balancing.

PubMed

Zgonnikov, Arkady; Lubashevsky, Ihor

2015-11-01

When facing a task of balancing a dynamic system near an unstable equilibrium, humans often adopt intermittent control strategy: Instead of continuously controlling the system, they repeatedly switch the control on and off. Paradigmatic example of such a task is stick balancing. Despite the simplicity of the task itself, the complexity of human intermittent control dynamics in stick balancing still puzzles researchers in motor control. Here we attempt to model one of the key mechanisms of human intermittent control, control activation, using as an example the task of overdamped stick balancing. In doing so, we focus on the concept of noise-driven activation, a more general alternative to the conventional threshold-driven activation. We describe control activation as a random walk in an energy potential, which changes in response to the state of the controlled system. By way of numerical simulations, we show that the developed model captures the core properties of human control activation observed previously in the experiments on overdamped stick balancing. Our results demonstrate that the double-well potential model provides tractable mathematical description of human control activation at least in the considered task and suggest that the adopted approach can potentially aid in understanding human intermittent control in more complex processes.

In-vehicle group activity modeling and simulation in sensor-based virtual environment

NASA Astrophysics Data System (ADS)

Shirkhodaie, Amir; Telagamsetti, Durga; Poshtyar, Azin; Chan, Alex; Hu, Shuowen

2016-05-01

Human group activity recognition is a very complex and challenging task, especially for Partially Observable Group Activities (POGA) that occur in confined spaces with limited visual observability and often under severe occultation. In this paper, we present IRIS Virtual Environment Simulation Model (VESM) for the modeling and simulation of dynamic POGA. More specifically, we address sensor-based modeling and simulation of a specific category of POGA, called In-Vehicle Group Activities (IVGA). In VESM, human-alike animated characters, called humanoids, are employed to simulate complex in-vehicle group activities within the confined space of a modeled vehicle. Each articulated humanoid is kinematically modeled with comparable physical attributes and appearances that are linkable to its human counterpart. Each humanoid exhibits harmonious full-body motion - simulating human-like gestures and postures, facial impressions, and hands motions for coordinated dexterity. VESM facilitates the creation of interactive scenarios consisting of multiple humanoids with different personalities and intentions, which are capable of performing complicated human activities within the confined space inside a typical vehicle. In this paper, we demonstrate the efficiency and effectiveness of VESM in terms of its capabilities to seamlessly generate time-synchronized, multi-source, and correlated imagery datasets of IVGA, which are useful for the training and testing of multi-source full-motion video processing and annotation. Furthermore, we demonstrate full-motion video processing of such simulated scenarios under different operational contextual constraints.

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.

Modelling temporal networks of human face-to-face contacts with public activity and individual reachability

NASA Astrophysics Data System (ADS)

Zhang, Yi-Qing; Cui, Jing; Zhang, Shu-Min; Zhang, Qi; Li, Xiang

2016-02-01

Modelling temporal networks of human face-to-face contacts is vital both for understanding the spread of airborne pathogens and word-of-mouth spreading of information. Although many efforts have been devoted to model these temporal networks, there are still two important social features, public activity and individual reachability, have been ignored in these models. Here we present a simple model that captures these two features and other typical properties of empirical face-to-face contact networks. The model describes agents which are characterized by an attractiveness to slow down the motion of nearby people, have event-triggered active probability and perform an activity-dependent biased random walk in a square box with periodic boundary. The model quantitatively reproduces two empirical temporal networks of human face-to-face contacts which are testified by their network properties and the epidemic spread dynamics on them.

Active muscle response using feedback control of a finite element human arm model.

PubMed

Östh, Jonas; Brolin, Karin; Happee, Riender

2012-01-01

Mathematical human body models (HBMs) are important research tools that are used to study the human response in car crash situations. Development of automotive safety systems requires the implementation of active muscle response in HBM, as novel safety systems also interact with vehicle occupants in the pre-crash phase. In this study, active muscle response was implemented using feedback control of a nonlinear muscle model in the right upper extremity of a finite element (FE) HBM. Hill-type line muscle elements were added, and the active and passive properties were assessed. Volunteer tests with low impact loading resulting in elbow flexion motions were performed. Simulations of posture maintenance in a gravity field and the volunteer tests were successfully conducted. It was concluded that feedback control of a nonlinear musculoskeletal model can be used to obtain posture maintenance and human-like reflexive responses in an FE HBM.

Using NASA's GRACE and SMAP satellites to measure human impacts on the water cycle

NASA Astrophysics Data System (ADS)

Reager, J. T., II; Castle, S.; Turmon, M.; Famiglietti, J. S.; Fournier, S.

2017-12-01

Two satellite missions, the Gravity Recovery and Climate Experiment (GRACE) mission and the Soil Moisture Active Passive (SMAP) mission are enabling the measurement of the dynamic state of the water cycle globally, offering a unique opportunity for the study of human impacts on terrestrial hydrology and an opportunity to quantify the direct augmentation of natural cycles by human activities. While many model-data fusion studies aim to apply observations to improve model performance, we present recent studies on measuring the multi-scale impacts of human activities by differencing or contrasting model simulations and observations. Results that will be presented include studies on: the measurement of human impacts on evapotranspiration in the Colorado River Basin; the estimation of the human portion of groundwater depletion in the Southwestern U.S.; and the influence of irrigation on runoff generation in the Mississippi River basin. Each of these cases has a unique implications for the sustainable use of natural resources by humans, and indicate the relevant extent and magnitude of human influence on natural processes, suggesting their importance for inclusion in hydrology and land-surface models.

Learning dictionaries of sparse codes of 3D movements of body joints for real-time human activity understanding.

PubMed

Qi, Jin; Yang, Zhiyong

2014-01-01

Real-time human activity recognition is essential for human-robot interactions for assisted healthy independent living. Most previous work in this area is performed on traditional two-dimensional (2D) videos and both global and local methods have been used. Since 2D videos are sensitive to changes of lighting condition, view angle, and scale, researchers begun to explore applications of 3D information in human activity understanding in recently years. Unfortunately, features that work well on 2D videos usually don't perform well on 3D videos and there is no consensus on what 3D features should be used. Here we propose a model of human activity recognition based on 3D movements of body joints. Our method has three steps, learning dictionaries of sparse codes of 3D movements of joints, sparse coding, and classification. In the first step, space-time volumes of 3D movements of body joints are obtained via dense sampling and independent component analysis is then performed to construct a dictionary of sparse codes for each activity. In the second step, the space-time volumes are projected to the dictionaries and a set of sparse histograms of the projection coefficients are constructed as feature representations of the activities. Finally, the sparse histograms are used as inputs to a support vector machine to recognize human activities. We tested this model on three databases of human activities and found that it outperforms the state-of-the-art algorithms. Thus, this model can be used for real-time human activity recognition in many applications.

A NEW METHOD OF LONGITUDINAL DIARY ASSEMBLY FOR EXPOSURE MODELING

EPA Science Inventory

Many stochastic human exposure models require the construction of longitudinal time-activity diaries to evaluate the time sequence of concentrations encountered, and hence, the pollutant exposure for the simulated individuals. However, most of the available data on human activiti...

Xenobiotic metabolism capacities of human skin in comparison with a 3D epidermis model and keratinocyte-based cell culture as in vitro alternatives for chemical testing: activating enzymes (Phase I).

PubMed

Götz, Christine; Pfeiffer, Roland; Tigges, Julia; Blatz, Veronika; Jäckh, Christine; Freytag, Eva-Maria; Fabian, Eric; Landsiedel, Robert; Merk, Hans F; Krutmann, Jean; Edwards, Robert J; Pease, Camilla; Goebel, Carsten; Hewitt, Nicola; Fritsche, Ellen

2012-05-01

Skin is important for the absorption and metabolism of exposed chemicals such as cosmetics or pharmaceuticals. The Seventh Amendment to the EU Cosmetics Directive prohibits the use of animals for cosmetic testing for certain endpoints, such as genotoxicity; therefore, there is an urgent need to understand the xenobiotic metabolizing capacities of human skin and to compare these activities with reconstructed 3D skin models developed to replace animal testing. We have measured Phase I enzyme activities of cytochrome P450 (CYP) and cyclooxygenase (COX) in ex vivo human skin, the 3D skin model EpiDerm™ (EPI-200), immortalized keratinocyte-based cell lines and primary normal human epidermal keratinocytes. Our data demonstrate that basal CYP enzyme activities are very low in whole human skin and EPI-200 as well as keratinocytes. In addition, activities in monolayer cells differed from organotypic tissues after induction. COX activity was similar in skin, EPI-200 and NHEK cells, but was significantly lower in immortalized keratinocytes. Hence, the 3D model EPI-200 might represent a more suitable model for dermatotoxicological studies. Altogether, these data help to better understand skin metabolism and expand the knowledge of in vitro alternatives used for dermatotoxicity testing. © 2012 John Wiley & Sons A/S.

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.

Simulation-Based Mission Rehearsal as a Human Activity System.

DTIC Science & Technology

1996-09-01

explain this demonstrated importance of the people involved in MR, a human activity system model of simulation-based rehearsal was developed. It provides...Implications of this human activity system view are discussed, including: places in the mission preparation process where simulation can benefit operations

3D Data Acquisition Platform for Human Activity Understanding

DTIC Science & Technology

2016-03-02

address fundamental research problems of representation and invariant description of3D data, human motion modeling and applications of human activity analysis, and computational optimization of large-scale 3D data.

3D Data Acquisition Platform for Human Activity Understanding

DTIC Science & Technology

2016-03-02

address fundamental research problems of representation and invariant description of 3D data, human motion modeling and applications of human activity analysis, and computational optimization of large-scale 3D data.

Antitumor activity of the investigational proteasome inhibitor MLN9708 in mouse models of B-cell and plasma cell malignancies.

PubMed

Lee, Edmund C; Fitzgerald, Michael; Bannerman, Bret; Donelan, Jill; Bano, Kristen; Terkelsen, Jennifer; Bradley, Daniel P; Subakan, Ozlem; Silva, Matthew D; Liu, Ray; Pickard, Michael; Li, Zhi; Tayber, Olga; Li, Ping; Hales, Paul; Carsillo, Mary; Neppalli, Vishala T; Berger, Allison J; Kupperman, Erik; Manfredi, Mark; Bolen, Joseph B; Van Ness, Brian; Janz, Siegfried

2011-12-01

The clinical success of the first-in-class proteasome inhibitor bortezomib (VELCADE) has validated the proteasome as a therapeutic target for treating human cancers. MLN9708 is an investigational proteasome inhibitor that, compared with bortezomib, has improved pharmacokinetics, pharmacodynamics, and antitumor activity in preclinical studies. Here, we focused on evaluating the in vivo activity of MLN2238 (the biologically active form of MLN9708) in a variety of mouse models of hematologic malignancies, including tumor xenograft models derived from a human lymphoma cell line and primary human lymphoma tissue, and genetically engineered mouse (GEM) models of plasma cell malignancies (PCM). Both cell line-derived OCI-Ly10 and primary human lymphoma-derived PHTX22L xenograft models of diffuse large B-cell lymphoma were used to evaluate the pharmacodynamics and antitumor effects of MLN2238 and bortezomib. The iMyc(Cα)/Bcl-X(L) GEM model was used to assess their effects on de novo PCM and overall survival. The newly developed DP54-Luc-disseminated model of iMyc(Cα)/Bcl-X(L) was used to determine antitumor activity and effects on osteolytic bone disease. MLN2238 has an improved pharmacodynamic profile and antitumor activity compared with bortezomib in both OCI-Ly10 and PHTX22L models. Although both MLN2238 and bortezomib prolonged overall survival, reduced splenomegaly, and attenuated IgG2a levels in the iMyc(Cα)/Bcl-X(L) GEM model, only MLN2238 alleviated osteolytic bone disease in the DP54-Luc model. Our results clearly showed the antitumor activity of MLN2238 in a variety of mouse models of B-cell lymphoma and PCM, supporting its clinical development. MLN9708 is being evaluated in multiple phase I and I/II trials. ©2011 AACR.

Identification of human-selective analogues of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA)

PubMed Central

Tijono, S M; Guo, K; Henare, K; Palmer, B D; Wang, L-C S; Albelda, S M; Ching, L-M

2013-01-01

Background: Species selectivity of DMXAA (5,6-dimethylxanthenone-4-acetic acid, Vadimezan) for murine cells over human cells could explain in part the recent disappointing phase III trials clinical results when preclinical studies were so promising. To identify analogues with greater human clinical potential, we compared the activity of xanthenone-4-acetic acid (XAA) analogues in murine or human cellular models. Methods: Analogues with a methyl group systematically substituted at different positions of the XAA backbone were evaluated for cytokine induction in cultured murine or human leukocytes; and for anti-vascular effects on endothelial cells on matrigel. In vivo antitumour activity and cytokine production by stromal or cancer cells was measured in human A375 and HCT116 xenografts. Results: Mono-methyl XAA analogues with substitutions at the seventh and eighth positions were the most active in stimulating human leukocytes to produce IL-6 and IL-8; and for inhibition of tube formation by ECV304 human endothelial-like cells, while 5- and 6-substituted analogues were the most active in murine cell systems. Conclusion: Xanthenone-4-acetic acid analogues exhibit extreme species selectivity. Analogues that are the most active in human systems are inactive in murine models, highlighting the need for the use of appropriate in vivo animal models in selecting clinical candidates for this class of compounds. PMID:23481185

High Resolution Spatial Mapping of Human Footprint across Antarctica and Its Implications for the Strategic Conservation of Avifauna

PubMed Central

Hughes, Kevin A.; Vega, Greta C.; Olalla-Tárraga, Miguel Á.

2017-01-01

Human footprint models allow visualization of human spatial pressure across the globe. Up until now, Antarctica has been omitted from global footprint models, due possibly to the lack of a permanent human population and poor accessibility to necessary datasets. Yet Antarctic ecosystems face increasing cumulative impacts from the expanding tourism industry and national Antarctic operator activities, the management of which could be improved with footprint assessment tools. Moreover, Antarctic ecosystem dynamics could be modelled to incorporate human drivers. Here we present the first model of estimated human footprint across predominantly ice-free areas of Antarctica. To facilitate integration into global models, the Antarctic model was created using methodologies applied elsewhere with land use, density and accessibility features incorporated. Results showed that human pressure is clustered predominantly in the Antarctic Peninsula, southern Victoria Land and several areas of East Antarctica. To demonstrate the practical application of the footprint model, it was used to investigate the potential threat to Antarctica’s avifauna by local human activities. Relative footprint values were recorded for all 204 of Antarctica’s Important Bird Areas (IBAs) identified by BirdLife International and the Scientific Committee on Antarctic Research (SCAR). Results indicated that formal protection of avifauna under the Antarctic Treaty System has been unsystematic and is lacking for penguin and flying bird species in some of the IBAs most vulnerable to human activity and impact. More generally, it is hoped that use of this human footprint model may help Antarctic Treaty Consultative Meeting policy makers in their decision making concerning avifauna protection and other issues including cumulative impacts, environmental monitoring, non-native species and terrestrial area protection. PMID:28085889

High Resolution Spatial Mapping of Human Footprint across Antarctica and Its Implications for the Strategic Conservation of Avifauna.

PubMed

Pertierra, Luis R; Hughes, Kevin A; Vega, Greta C; Olalla-Tárraga, Miguel Á

2017-01-01

Human footprint models allow visualization of human spatial pressure across the globe. Up until now, Antarctica has been omitted from global footprint models, due possibly to the lack of a permanent human population and poor accessibility to necessary datasets. Yet Antarctic ecosystems face increasing cumulative impacts from the expanding tourism industry and national Antarctic operator activities, the management of which could be improved with footprint assessment tools. Moreover, Antarctic ecosystem dynamics could be modelled to incorporate human drivers. Here we present the first model of estimated human footprint across predominantly ice-free areas of Antarctica. To facilitate integration into global models, the Antarctic model was created using methodologies applied elsewhere with land use, density and accessibility features incorporated. Results showed that human pressure is clustered predominantly in the Antarctic Peninsula, southern Victoria Land and several areas of East Antarctica. To demonstrate the practical application of the footprint model, it was used to investigate the potential threat to Antarctica's avifauna by local human activities. Relative footprint values were recorded for all 204 of Antarctica's Important Bird Areas (IBAs) identified by BirdLife International and the Scientific Committee on Antarctic Research (SCAR). Results indicated that formal protection of avifauna under the Antarctic Treaty System has been unsystematic and is lacking for penguin and flying bird species in some of the IBAs most vulnerable to human activity and impact. More generally, it is hoped that use of this human footprint model may help Antarctic Treaty Consultative Meeting policy makers in their decision making concerning avifauna protection and other issues including cumulative impacts, environmental monitoring, non-native species and terrestrial area protection.

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.

Phenylquinoxalinone CFTR activator as potential prosecretory therapy for constipation

PubMed Central

CIL, ONUR; PHUAN, PUAY-WAH; SON, JUNG-HO; ZHU, JIE S.; KU, COLTON K.; TABIB, NILOUFAR AKHAVAN; TEUTHORN, ANDREW P.; FERRERA, LORETTA; ZACHOS, NICHOLAS C.; LIN, RUXIAN; GALIETTA, LUIS J. V.; DONOWITZ, MARK; KURTH, MARK J.; VERKMAN, ALAN S.

2017-01-01

Constipation is a common condition for which current treatments can have limited efficacy. By high-throughput screening, we recently identified a phenylquinoxalinone activator of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel that stimulated intestinal fluid secretion and normalized stool output in a mouse model of opioid-induced constipation. Here, we report phenylquinoxalinone structure-activity analysis, mechanism of action, animal efficacy data in acute and chronic models of constipation, and functional data in ex vivo primary cultured human enterocytes. Structure-activity analysis was done on 175 phenylquinoxalinone analogs, including 15 synthesized compounds. The most potent compound, CFTRact-J027, activated CFTR with EC50 ~ 200 nM, with patch-clamp analysis showing a linear CFTR current-voltage relationship with direct CFTR activation. CFTRact-J027 corrected reduced stool output and hydration in a mouse model of acute constipation produced by scopolamine and in a chronically constipated mouse strain (C3H/HeJ). Direct comparison with the approved prosecretory drugs lubiprostone and linaclotide showed substantially greater intestinal fluid secretion with CFTRact-J027, as well as greater efficacy in a constipation model. As evidence to support efficacy in human constipation, CFTRact-J027 increased transepithelial fluid transport in enteroids generated from normal human small intestine. Also, CFTRact-J027 was rapidly metabolized in vitro in human hepatic microsomes, suggesting minimal systemic exposure upon oral administration. These data establish structure-activity and mechanistic data for phenylquinoxalinone CFTR activators, and support their potential efficacy in human constipation. PMID:27815136

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.

An age-specific biokinetic model for iodine

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

Leggett, Richard Wayne

This study reviews age-specific biokinetic data for iodine in humans and extends to pre-adult ages the baseline parameter values of the author’s previously published model for systemic iodine in adult humans. Compared with the ICRP’s current age-specific model for iodine introduced in Publication 56 (1989), the present model provides a more detailed description of the behavior of iodine in the human body; predicts greater cumulative (integrated) activity in the thyroid for short-lived isotopes of iodine; predicts similar cumulative activity in the thyroid for isotopes with half-time greater than a few hours; and, for most iodine isotopes, predicts much greater cumulativemore » activity in salivary glands, stomach wall, liver, and kidneys.« less

An age-specific biokinetic model for iodine

DOE PAGES

Leggett, Richard Wayne

2017-10-26

This study reviews age-specific biokinetic data for iodine in humans and extends to pre-adult ages the baseline parameter values of the author’s previously published model for systemic iodine in adult humans. Compared with the ICRP’s current age-specific model for iodine introduced in Publication 56 (1989), the present model provides a more detailed description of the behavior of iodine in the human body; predicts greater cumulative (integrated) activity in the thyroid for short-lived isotopes of iodine; predicts similar cumulative activity in the thyroid for isotopes with half-time greater than a few hours; and, for most iodine isotopes, predicts much greater cumulativemore » activity in salivary glands, stomach wall, liver, and kidneys.« less

Acquiring neural signals for developing a perception and cognition model

NASA Astrophysics Data System (ADS)

Li, Wei; Li, Yunyi; Chen, Genshe; Shen, Dan; Blasch, Erik; Pham, Khanh; Lynch, Robert

2012-06-01

The understanding of how humans process information, determine salience, and combine seemingly unrelated information is essential to automated processing of large amounts of information that is partially relevant, or of unknown relevance. Recent neurological science research in human perception, and in information science regarding contextbased modeling, provides us with a theoretical basis for using a bottom-up approach for automating the management of large amounts of information in ways directly useful for human operators. However, integration of human intelligence into a game theoretic framework for dynamic and adaptive decision support needs a perception and cognition model. For the purpose of cognitive modeling, we present a brain-computer-interface (BCI) based humanoid robot system to acquire brainwaves during human mental activities of imagining a humanoid robot-walking behavior. We use the neural signals to investigate relationships between complex humanoid robot behaviors and human mental activities for developing the perception and cognition model. The BCI system consists of a data acquisition unit with an electroencephalograph (EEG), a humanoid robot, and a charge couple CCD camera. An EEG electrode cup acquires brainwaves from the skin surface on scalp. The humanoid robot has 20 degrees of freedom (DOFs); 12 DOFs located on hips, knees, and ankles for humanoid robot walking, 6 DOFs on shoulders and arms for arms motion, and 2 DOFs for head yaw and pitch motion. The CCD camera takes video clips of the human subject's hand postures to identify mental activities that are correlated to the robot-walking behaviors. We use the neural signals to investigate relationships between complex humanoid robot behaviors and human mental activities for developing the perception and cognition model.

Active site similarity between human and Plasmodium falciparum phosphodiesterases: considerations for antimalarial drug design

NASA Astrophysics Data System (ADS)

Howard, Brittany L.; Thompson, Philip E.; Manallack, David T.

2011-08-01

The similarity between Plasmodium falciparum phosphodiesterase enzymes ( PfPDEs) and their human counterparts have been examined and human PDE9A was found to be a suitable template for the construction of homology models for each of the four PfPDE isoforms. In contrast, the architecture of the active sites of each model was most similar to human PDE1. Molecular docking was able to model cyclic guanosine monophosphate (cGMP) substrate binding in each case but a docking mode supporting cyclic adenosine monophosphate (cAMP) binding could not be found. Anticipating the potential of PfPDE inhibitors as anti-malarial drugs, a range of reported PDE inhibitors including zaprinast and sildenafil were docked into the model of PfPDEα. The results were consistent with their reported biological activities, and the potential of PDE1/9 inhibitor analogues was also supported by docking.

Simulating forest landscape disturbances as coupled human and natural systems

USGS Publications Warehouse

Wimberly, Michael; Sohl, Terry L.; Liu, Zhihua; Lamsal, Aashis

2015-01-01

Anthropogenic disturbances resulting from human land use affect forest landscapes over a range of spatial and temporal scales, with diverse influences on vegetation patterns and dynamics. These processes fall within the scope of the coupled human and natural systems (CHANS) concept, which has emerged as an important framework for understanding the reciprocal interactions and feedbacks that connect human activities and ecosystem responses. Spatial simulation modeling of forest landscape change is an important technique for exploring the dynamics of CHANS over large areas and long time periods. Landscape models for simulating interactions between human activities and forest landscape dynamics can be grouped into two main categories. Forest landscape models (FLMs) focus on landscapes where forests are the dominant land cover and simulate succession and natural disturbances along with forest management activities. In contrast, land change models (LCMs) simulate mosaics of different land cover and land use classes that include forests in addition to other land uses such as developed areas and agricultural lands. There are also several examples of coupled models that combine elements of FLMs and LCMs. These integrated models are particularly useful for simulating human–natural interactions in landscapes where human settlement and agriculture are expanding into forested areas. Despite important differences in spatial scale and disciplinary scope, FLMs and LCMs have many commonalities in conceptual design and technical implementation that can facilitate continued integration. The ultimate goal will be to implement forest landscape disturbance modeling in a CHANS framework that recognizes the contextual effects of regional land use and other human activities on the forest ecosystem while capturing the reciprocal influences of forests and their disturbances on the broader land use mosaic.

Generation of the Human Biped Stance by a Neural Controller Able to Compensate Neurological Time Delay

PubMed Central

Jiang, Ping; Chiba, Ryosuke; Takakusaki, Kaoru; Ota, Jun

2016-01-01

The development of a physiologically plausible computational model of a neural controller that can realize a human-like biped stance is important for a large number of potential applications, such as assisting device development and designing robotic control systems. In this paper, we develop a computational model of a neural controller that can maintain a musculoskeletal model in a standing position, while incorporating a 120-ms neurological time delay. Unlike previous studies that have used an inverted pendulum model, a musculoskeletal model with seven joints and 70 muscular-tendon actuators is adopted to represent the human anatomy. Our proposed neural controller is composed of both feed-forward and feedback controls. The feed-forward control corresponds to the constant activation input necessary for the musculoskeletal model to maintain a standing posture. This compensates for gravity and regulates stiffness. The developed neural controller model can replicate two salient features of the human biped stance: (1) physiologically plausible muscle activations for quiet standing; and (2) selection of a low active stiffness for low energy consumption. PMID:27655271

INTEGRATED PROBABILISTIC AND DETERMINISTIC MODELING TECHNIQUES IN ESTIMATING EXPOSURE TO WATER-BORNE CONTAMINANTS: PART 1 EXPOSURE MODELING

EPA Science Inventory

Exposure to contaminants originating in the domestic water supply is influenced by a number of factors, including human activities, water use behavior, and physical and chemical processes. The key role of human activities is very apparent in exposure related to volatile water-...

Predicting Rat and Human Pregnane X Receptor Activators Using Bayesian Classification Models.

PubMed

AbdulHameed, Mohamed Diwan M; Ippolito, Danielle L; Wallqvist, Anders

2016-10-17

The pregnane X receptor (PXR) is a ligand-activated transcription factor that acts as a master regulator of metabolizing enzymes and transporters. To avoid adverse drug-drug interactions and diseases such as steatosis and cancers associated with PXR activation, identifying drugs and chemicals that activate PXR is of crucial importance. In this work, we developed ligand-based predictive computational models for both rat and human PXR activation, which allowed us to identify potentially harmful chemicals and evaluate species-specific effects of a given compound. We utilized a large publicly available data set of nearly 2000 compounds screened in cell-based reporter gene assays to develop Bayesian quantitative structure-activity relationship models using physicochemical properties and structural descriptors. Our analysis showed that PXR activators tend to be hydrophobic and significantly different from nonactivators in terms of their physicochemical properties such as molecular weight, logP, number of rings, and solubility. Our Bayesian models, evaluated by using 5-fold cross-validation, displayed a sensitivity of 75% (76%), specificity of 76% (75%), and accuracy of 89% (89%) for human (rat) PXR activation. We identified structural features shared by rat and human PXR activators as well as those unique to each species. We compared rat in vitro PXR activation data to in vivo data by using DrugMatrix, a large toxicogenomics database with gene expression data obtained from rats after exposure to diverse chemicals. Although in vivo gene expression data pointed to cross-talk between nuclear receptor activators that is captured only by in vivo assays, overall we found broad agreement between in vitro and in vivo PXR activation. Thus, the models developed here serve primarily as efficient initial high-throughput in silico screens of in vitro activity.

Human impact parameterization in global hydrological models improves estimates of monthly discharges and hydrological extremes: a multi-model validation study

NASA Astrophysics Data System (ADS)

Veldkamp, Ted; Ward, Philip; de Moel, Hans; Aerts, Jeroen; Muller Schmied, Hannes; Portmann, Felix; Zhao, Fang; Gerten, Dieter; Masaki, Yoshimitsu; Pokhrel, Yadu; Satoh, Yusuke; Gosling, Simon; Zaherpour, Jamal; Wada, Yoshihide

2017-04-01

Human impacts on freshwater resources and hydrological features form the core of present-day water related hazards, like flooding, droughts, water scarcity, and water quality issues. Driven by the societal and scientific needs to correctly model such water related hazards a fair amount of resources has been invested over the past decades to represent human activities and their interactions with the hydrological cycle in global hydrological models (GHMs). Use of these GHMs - including the human dimension - is widespread, especially in water resources research. Evaluation or comparative assessments of the ability of such GHMs to represent real-world hydrological conditions are, unfortunately, however often limited to (near-)natural river basins. Such studies are, therefore, not able to test the model representation of human activities and its associated impact on estimates of freshwater resources or assessments of hydrological extremes. Studies that did perform a validation exercise - including the human dimension and looking into managed catchments - either focused only on one hydrological model, and/or incorporated only a few data points (i.e. river basins) for validation. To date, a comprehensive comparative analysis that evaluates whether and where incorporating the human dimension actually improves the performance of different GHMs with respect to their representation of real-world hydrological conditions and extremes is missing. The absence of such study limits the potential benchmarking of GHMs and their outcomes in hydrological hazard and risk assessments significantly, potentially hampering incorporation of GHMs and their modelling results in actual policy making and decision support with respect to water resources management. To address this issue, we evaluate in this study the performance of five state-of-the-art GHMs that include anthropogenic activities in their modelling scheme, with respect to their representation of monthly discharges and hydrological extremes. To this end, we compared their monthly discharge simulations under a naturalized and a time-dependent human impact simulation, with monthly GRDC river discharge observations of 2,412 stations over the period 1971-2010. Evaluation metrics that were used to assess the performance of the GHMs included the modified Kling-Gupta Efficiency index, and its individual parameters describing the linear correlation coefficient, the bias ratio, and the variability ratio, as well as indicators for hydrological extremes (Q90, Q10). Our results show that inclusion of anthropogenic activities in the modelling framework generally enhances the overall performance of the GHMs studied, mainly driven by bias-improvements, and to a lesser extent due to changes in modelled hydrological variability. Whilst the inclusion of anthropogenic activities takes mainly effect in the managed catchments, a significant share of the (near-)natural catchments is influenced as well. To get estimates of hydrological extremes right, especially when looking at low-flows, inclusion of human activities is paramount. Whilst high-flow estimates are mainly decreased, impact of human activities on low-flows is ambiguous, i.e. due to the relative importance of the timing of return flows and reservoir operations. Even with inclusion of the human dimension we find, nevertheless, a persistent overestimation of hydrological extremes across all models, which should be accounted for in future assessments.

Single unit approaches to human vision and memory.

PubMed

Kreiman, Gabriel

2007-08-01

Research on the visual system focuses on using electrophysiology, pharmacology and other invasive tools in animal models. Non-invasive tools such as scalp electroencephalography and imaging allow examining humans but show a much lower spatial and/or temporal resolution. Under special clinical conditions, it is possible to monitor single-unit activity in humans when invasive procedures are required due to particular pathological conditions including epilepsy and Parkinson's disease. We review our knowledge about the visual system and visual memories in the human brain at the single neuron level. The properties of the human brain seem to be broadly compatible with the knowledge derived from animal models. The possibility of examining high-resolution brain activity in conscious human subjects allows investigators to ask novel questions that are challenging to address in animal models.

IASM: Individualized activity space modeler

NASA Astrophysics Data System (ADS)

Hasanzadeh, Kamyar

2018-01-01

Researchers from various disciplines have long been interested in analyzing and describing human mobility patterns. Activity space (AS), defined as an area encapsulating daily human mobility and activities, has been at the center of this interest. However, given the applied nature of research in this field and the complexity that advanced geographical modeling can pose to its users, the proposed models remain simplistic and inaccurate in many cases. Individualized Activity Space Modeler (IASM) is a geographic information system (GIS) toolbox, written in Python programming language using ESRI's Arcpy module, comprising four tools aiming to facilitate the use of advanced activity space models in empirical research. IASM provides individual-based and context-sensitive tools to estimate home range distances, delineate activity spaces, and model place exposures using individualized geographical data. In this paper, we describe the design and functionality of IASM, and provide an example of how it performs on a spatial dataset collected through an online map-based survey.

Testing the Role of p21 Activated Kinases in Schwannoma Formation Using a Novel Genetically Engineered Murine Model that Closely Phenocopies Human NF2 Disease

DTIC Science & Technology

2017-06-01

Kinases in Schwannoma Formation Using a Novel Genetically Engineered Murine Model that Closely Phenocopies Human NF2 Disease The views, opinions and...Role of p21 Activated Kinases in Schwannoma Formation Using a Novel Genetically Engineered Murine Model that Closely Phenocopies Human NF2 Disease Form...NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. The major goal of this research project was to genetically and pharmacologically test the requirement of PAK

A Lower Limb-Pelvis Finite Element Model with 3D Active Muscles.

PubMed

Mo, Fuhao; Li, Fan; Behr, Michel; Xiao, Zhi; Zhang, Guanjun; Du, Xianping

2018-01-01

A lower limb-pelvis finite element (FE) model with active three-dimensional (3D) muscles was developed in this study for biomechanical analysis of human body. The model geometry was mainly reconstructed from a male volunteer close to the anthropometry of a 50th percentile Chinese male. Tissue materials and structural features were established based on the literature and new implemented experimental tests. In particular, the muscle was modeled with a combination of truss and hexahedral elements to define its passive and active properties as well as to follow the detailed anatomy structure. Both passive and active properties of the model were validated against the experiments of Post-Mortem Human Surrogate (PMHS) and volunteers, respectively. The model was then used to simulate driver's emergency braking during frontal crashes and investigate Knee-Thigh-Hip (KTH) injury mechanisms and tolerances of the human body. A significant force and bending moment variance was noted for the driver's femur due to the effects of active muscle forces during emergency braking. In summary, the present lower limb-pelvis model can be applied in various research fields to support expensive and complex physical tests or corresponding device design.

Prioritizing Conservation of Ungulate Calving Resources in Multiple-Use Landscapes

PubMed Central

Dzialak, Matthew R.; Harju, Seth M.; Osborn, Robert G.; Wondzell, John J.; Hayden-Wing, Larry D.; Winstead, Jeffrey B.; Webb, Stephen L.

2011-01-01

Background Conserving animal populations in places where human activity is increasing is an ongoing challenge in many parts of the world. We investigated how human activity interacted with maternal status and individual variation in behavior to affect reliability of spatially-explicit models intended to guide conservation of critical ungulate calving resources. We studied Rocky Mountain elk (Cervus elaphus) that occupy a region where 2900 natural gas wells have been drilled. Methodology/Principal Findings We present novel applications of generalized additive modeling to predict maternal status based on movement, and of random-effects resource selection models to provide population and individual-based inference on the effects of maternal status and human activity. We used a 2×2 factorial design (treatment vs. control) that included elk that were either parturient or non-parturient and in areas either with or without industrial development. Generalized additive models predicted maternal status (parturiency) correctly 93% of the time based on movement. Human activity played a larger role than maternal status in shaping resource use; elk showed strong spatiotemporal patterns of selection or avoidance and marked individual variation in developed areas, but no such pattern in undeveloped areas. This difference had direct consequences for landscape-level conservation planning. When relative probability of use was calculated across the study area, there was disparity throughout 72–88% of the landscape in terms of where conservation intervention should be prioritized depending on whether models were based on behavior in developed areas or undeveloped areas. Model validation showed that models based on behavior in developed areas had poor predictive accuracy, whereas the model based on behavior in undeveloped areas had high predictive accuracy. Conclusions/Significance By directly testing for differences between developed and undeveloped areas, and by modeling resource selection in a random-effects framework that provided individual-based inference, we conclude that: 1) amplified selection or avoidance behavior and individual variation, as responses to increasing human activity, complicate conservation planning in multiple-use landscapes, and 2) resource selection behavior in places where human activity is predictable or less dynamic may provide a more reliable basis from which to prioritize conservation action. PMID:21297866

AC field exposure study: human exposure to 60-Hz electric fields

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

Silva, J.M.

1985-04-01

The objective of this study was to develop a method of estimating human exposure to the 60 Hz electric fields created by transmission lines. The Activity Systems Model simulates human activities in a variety of situations where exposure to electric fields is possible. The model combines maps of electric fields, activity maps, and experimentally determined activity factors to provide histograms of time spent in electric fields of various strengths in the course of agricultural, recreational, and domestic activities. For corroboration, the study team measured actual human exposure at locations across the United States near transmission lines ranging in voltage frommore » 115 to 1200 kV. The data were collected with a specially designed vest that measures exposure. These data demonstrate the accuracy of the exposure model presented in this report and revealed that most exposure time is spent in fields of magnitudes similar to many household situations. The report provides annual exposure estimates for human activities near transmission lines and in the home and compares them with exposure data from typical laboratory animal experiments. For one exposure index, the cumulative product of time and electric field, exposure during some of the laboratory animal experiments is two to four orders of magnitude greater than cumulative exposure for a human during one year of outdoor work on a farm crossed by a transmission line.« less

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

EPA Science Inventory

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

Spatiotemporal property and predictability of large-scale human mobility

NASA Astrophysics Data System (ADS)

Zhang, Hai-Tao; Zhu, Tao; Fu, Dongfei; Xu, Bowen; Han, Xiao-Pu; Chen, Duxin

2018-04-01

Spatiotemporal characteristics of human mobility emerging from complexity on individual scale have been extensively studied due to the application potential on human behavior prediction and recommendation, and control of epidemic spreading. We collect and investigate a comprehensive data set of human activities on large geographical scales, including both websites browse and mobile towers visit. Numerical results show that the degree of activity decays as a power law, indicating that human behaviors are reminiscent of scale-free random walks known as Lévy flight. More significantly, this study suggests that human activities on large geographical scales have specific non-Markovian characteristics, such as a two-segment power-law distribution of dwelling time and a high possibility for prediction. Furthermore, a scale-free featured mobility model with two essential ingredients, i.e., preferential return and exploration, and a Gaussian distribution assumption on the exploration tendency parameter is proposed, which outperforms existing human mobility models under scenarios of large geographical scales.

Antitumor Activity of the Investigational Proteasome Inhibitor MLN9708 in Mouse Models of B-cell and Plasma Cell Malignancies

PubMed Central

Lee, Edmund C.; Fitzgerald, Michael; Bannerman, Bret; Donelan, Jill; Bano, Kristen; Terkelsen, Jennifer; Bradley, Daniel P.; Subakan, Ozlem; Silva, Matthew D.; Liu, Ray; Pickard, Michael; Li, Zhi; Tayber, Olga; Li, Ping; Hales, Paul; Carsillo, Mary; Neppalli, Vishala T.; Berger, Allison J.; Kupperman, Erik; Manfredi, Mark; Bolen, Joseph B.; Van Ness, Brian; Janz, Siegfried

2012-01-01

Purpose The clinical success of the first-in-class proteasome inhibitor bortezomib (VELCADE) has validated the proteasome as a therapeutic target for treating human cancers. MLN9708 is an investigational proteasome inhibitor that, compared with bortezomib, has improved pharmacokinetics, pharmacodynamics, and antitumor activity in preclinical studies. Here, we focused on evaluating the in vivo activity of MLN2238 (the biologically active form of MLN9708) in a variety of mouse models of hematologic malignancies, including tumor xenograft models derived from a human lymphoma cell line and primary human lymphoma tissue, and genetically engineered mouse (GEM) models of plasma cell malignancies (PCM). Experimental Design Both cell line–derived OCI-Ly10 and primary human lymphoma–derived PHTX22L xenograft models of diffuse large B-cell lymphoma were used to evaluate the pharmacodynamics and antitumor effects of MLN2238 and bortezomib. The iMycCα/Bcl-XL GEM model was used to assess their effects on de novo PCM and overall survival. The newly developed DP54-Luc–disseminated model of iMycCα/ Bcl-XL was used to determine antitumor activity and effects on osteolytic bone disease. Results MLN2238 has an improved pharmacodynamic profile and antitumor activity compared with bortezomib in both OCI-Ly10 and PHTX22L models. Although both MLN2238 and bortezomib prolonged overall survival, reduced splenomegaly, and attenuated IgG2a levels in the iMycCα/Bcl-XL GEM model, only MLN2238 alleviated osteolytic bone disease in the DP54-Luc model. Conclusions Our results clearly showed the antitumor activity of MLN2238 in a variety of mouse models of B-cell lymphoma and PCM, supporting its clinical development. MLN9708 is being evaluated in multiple phase I and I/II trials. PMID:21903769

Assessment of physical activity of the human body considering the thermodynamic system.

PubMed

Hochstein, Stefan; Rauschenberger, Philipp; Weigand, Bernhard; Siebert, Tobias; Schmitt, Syn; Schlicht, Wolfgang; Převorovská, Světlana; Maršík, František

2016-01-01

Correctly dosed physical activity is the basis of a vital and healthy life, but the measurement of physical activity is certainly rather empirical resulting in limited individual and custom activity recommendations. Certainly, very accurate three-dimensional models of the cardiovascular system exist, however, requiring the numeric solution of the Navier-Stokes equations of the flow in blood vessels. These models are suitable for the research of cardiac diseases, but computationally very expensive. Direct measurements are expensive and often not applicable outside laboratories. This paper offers a new approach to assess physical activity using thermodynamical systems and its leading quantity of entropy production which is a compromise between computation time and precise prediction of pressure, volume, and flow variables in blood vessels. Based on a simplified (one-dimensional) model of the cardiovascular system of the human body, we develop and evaluate a setup calculating entropy production of the heart to determine the intensity of human physical activity in a more precise way than previous parameters, e.g. frequently used energy considerations. The knowledge resulting from the precise real-time physical activity provides the basis for an intelligent human-technology interaction allowing to steadily adjust the degree of physical activity according to the actual individual performance level and thus to improve training and activity recommendations.

Group-Based Active Learning of Classification Models.

PubMed

Luo, Zhipeng; Hauskrecht, Milos

2017-05-01

Learning of classification models from real-world data often requires additional human expert effort to annotate the data. However, this process can be rather costly and finding ways of reducing the human annotation effort is critical for this task. The objective of this paper is to develop and study new ways of providing human feedback for efficient learning of classification models by labeling groups of examples. Briefly, unlike traditional active learning methods that seek feedback on individual examples, we develop a new group-based active learning framework that solicits label information on groups of multiple examples. In order to describe groups in a user-friendly way, conjunctive patterns are used to compactly represent groups. Our empirical study on 12 UCI data sets demonstrates the advantages and superiority of our approach over both classic instance-based active learning work, as well as existing group-based active-learning methods.

OVERVIEW OF THE U.S. EPA NERL'S HUMAN EXPOSURE MODELING

EPA Science Inventory

Computational modeling of human exposure to environmental pollutants is one of the primary activities of the US Environmental Protection Agency's National Exposure Research Laboratory (NERL). Assessment of human exposures is a critical part of the overall risk assessment para...

Unfolding large-scale online collaborative human dynamics

PubMed Central

Zha, Yilong; Zhou, Tao; Zhou, Changsong

2016-01-01

Large-scale interacting human activities underlie all social and economic phenomena, but quantitative understanding of regular patterns and mechanism is very challenging and still rare. Self-organized online collaborative activities with a precise record of event timing provide unprecedented opportunity. Our empirical analysis of the history of millions of updates in Wikipedia shows a universal double–power-law distribution of time intervals between consecutive updates of an article. We then propose a generic model to unfold collaborative human activities into three modules: (i) individual behavior characterized by Poissonian initiation of an action, (ii) human interaction captured by a cascading response to previous actions with a power-law waiting time, and (iii) population growth due to the increasing number of interacting individuals. This unfolding allows us to obtain an analytical formula that is fully supported by the universal patterns in empirical data. Our modeling approaches reveal “simplicity” beyond complex interacting human activities. PMID:27911766

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

PubMed

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

2012-10-01

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

Modeling bursts and heavy tails in human dynamics

NASA Astrophysics Data System (ADS)

Vázquez, Alexei; Oliveira, João Gama; Dezsö, Zoltán; Goh, Kwang-Il; Kondor, Imre; Barabási, Albert-László

2006-03-01

The dynamics of many social, technological and economic phenomena are driven by individual human actions, turning the quantitative understanding of human behavior into a central question of modern science. Current models of human dynamics, used from risk assessment to communications, assume that human actions are randomly distributed in time and thus well approximated by Poisson processes. Here we provide direct evidence that for five human activity patterns, such as email and letter based communications, web browsing, library visits and stock trading, the timing of individual human actions follow non-Poisson statistics, characterized by bursts of rapidly occurring events separated by long periods of inactivity. We show that the bursty nature of human behavior is a consequence of a decision based queuing process: when individuals execute tasks based on some perceived priority, the timing of the tasks will be heavy tailed, most tasks being rapidly executed, while a few experiencing very long waiting times. In contrast, priority blind execution is well approximated by uniform interevent statistics. We discuss two queuing models that capture human activity. The first model assumes that there are no limitations on the number of tasks an individual can hadle at any time, predicting that the waiting time of the individual tasks follow a heavy tailed distribution P(τw)˜τw-α with α=3/2 . The second model imposes limitations on the queue length, resulting in a heavy tailed waiting time distribution characterized by α=1 . We provide empirical evidence supporting the relevance of these two models to human activity patterns, showing that while emails, web browsing and library visitation display α=1 , the surface mail based communication belongs to the α=3/2 universality class. Finally, we discuss possible extension of the proposed queuing models and outline some future challenges in exploring the statistical mechanics of human dynamics.

Modeling bursts and heavy tails in human dynamics.

PubMed

Vázquez, Alexei; Oliveira, João Gama; Dezsö, Zoltán; Goh, Kwang-Il; Kondor, Imre; Barabási, Albert-László

2006-03-01

The dynamics of many social, technological and economic phenomena are driven by individual human actions, turning the quantitative understanding of human behavior into a central question of modern science. Current models of human dynamics, used from risk assessment to communications, assume that human actions are randomly distributed in time and thus well approximated by Poisson processes. Here we provide direct evidence that for five human activity patterns, such as email and letter based communications, web browsing, library visits and stock trading, the timing of individual human actions follow non-Poisson statistics, characterized by bursts of rapidly occurring events separated by long periods of inactivity. We show that the bursty nature of human behavior is a consequence of a decision based queuing process: when individuals execute tasks based on some perceived priority, the timing of the tasks will be heavy tailed, most tasks being rapidly executed, while a few experiencing very long waiting times. In contrast, priority blind execution is well approximated by uniform interevent statistics. We discuss two queuing models that capture human activity. The first model assumes that there are no limitations on the number of tasks an individual can handle at any time, predicting that the waiting time of the individual tasks follow a heavy tailed distribution P(tau(w)) approximately tau(w)(-alpha) with alpha=3/2. The second model imposes limitations on the queue length, resulting in a heavy tailed waiting time distribution characterized by alpha=1. We provide empirical evidence supporting the relevance of these two models to human activity patterns, showing that while emails, web browsing and library visitation display alpha=1, the surface mail based communication belongs to the alpha=3/2 universality class. Finally, we discuss possible extension of the proposed queuing models and outline some future challenges in exploring the statistical mechanics of human dynamics.

Sulforaphane is not an effective antagonist of the human pregnane X-receptor in vivo

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

Poulton, Emma Jane; Department of Environmental and Occupational Health Sciences, University of Washington; Levy, Lisa

2013-01-01

Sulforaphane (SFN), is an effective in vitro antagonist of ligand activation of the human pregnane and xenobiotic receptor (PXR). PXR mediated CYP3A4 up-regulation is implicated in adverse drug-drug interactions making identification of small molecule antagonists a desirable therapeutic goal. SFN is not an antagonist to mouse or rat PXR in vitro; thus, normal rodent species are not suitable as in vivo models for human response. To evaluate whether SFN can effectively antagonize ligand activation of human PXR in vivo, a three-armed, randomized, crossover trial was conducted with 24 healthy adults. The potent PXR ligand — rifampicin (300 mg/d) was givenmore » alone for 7 days in arm 1, or in daily combination with 450 μmol SFN (Broccoli Sprout extract) in arm 2; SFN was given alone in arm 3. Midazolam as an in vivo phenotype marker of CYP3A was administered before and after each treatment arm. Rifampicin alone decreased midazolam AUC by 70%, indicative of the expected increase in CYP3A4 activity. Co-treatment with SFN did not reduce CYP3A4 induction. Treatment with SFN alone also did not affect CYP3A4 activity in the cohort as a whole, although in the subset with the highest basal CYP3A4 activity there was a statistically significant increase in midazolam AUC (i.e., decrease in CYP3A4 activity). A parallel study in humanized PXR mice yielded similar results. The parallel effects of SFN between humanized PXR mice and human subjects demonstrate the predictive value of humanized mouse models in situations where species differences in ligand-receptor interactions preclude the use of a native mouse model for studying human ligand-receptor pharmacology. -- Highlights: ► The effects of SFN on PXR mediated CYP3A4 induction in humanized PXR mice and humans were examined. ► SFN had no effect on rifampicin mediated CYP3A4 induction in humans or humanized mice. ► SFN had a modest effect on basal CYP3A4 activity among subjects with higher baseline activity. ► Humanized PXR mice were generally predictive of the in vivo human response.« less

Active numerical model of human body for reconstruction of falls from height.

PubMed

Milanowicz, Marcin; Kędzior, Krzysztof

2017-01-01

Falls from height constitute the largest group of incidents out of approximately 90,000 occupational accidents occurring each year in Poland. Reconstruction of the exact course of a fall from height is generally difficult due to lack of sufficient information from the accident scene. This usually results in several contradictory versions of an incident and impedes, for example, determination of the liability in a judicial process. In similar situations, in many areas of human activity, researchers apply numerical simulation. They use it to model physical phenomena to reconstruct their real course over time; e.g. numerical human body models are frequently used for investigation and reconstruction of road accidents. However, they are validated in terms of specific road traffic accidents and are considerably limited when applied to the reconstruction of other types of accidents. The objective of the study was to develop an active numerical human body model to be used for reconstruction of accidents associated with falling from height. Development of the model involved extension and adaptation of the existing Pedestrian human body model (available in the MADYMO package database) for the purposes of reconstruction of falls from height by taking into account the human reaction to the loss of balance. The model was developed by using the results of experimental tests of the initial phase of the fall from height. The active numerical human body model covering 28 sets of initial conditions related to various human reactions to the loss of balance was developed. The application of the model was illustrated by using it to reconstruct a real fall from height. From among the 28 sets of initial conditions, those whose application made it possible to reconstruct the most probable version of the incident was selected. The selection was based on comparison of the results of the reconstruction with information contained in the accident report. Results in the form of estimated injuries overlap with the real injuries sustained by the casualty. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Effects of human activity of breeding American Oystercatchers, Cumberland Island National Seashore, Georgia, USA

USGS Publications Warehouse

Sabine, J.B.; Meyers, J.M.; Moore, C.T.; Schweitzer, Sara H.

2008-01-01

Abstract.-Increased human use of coastal areas threatens the United States population of American Oystercatchers (Haematopus palliatus), a species of special concern. Biologists often attribute its low numbers and reproductive success to human disturbance, but the mechanism by which human presence reduces reproductive success is not well understood. During the 2003 and 2004 breeding seasons, 32 nesting attempts of American Oystercatchers were studied on Cumberland Island National Seashore (CINS). Behavior was examined with and without human activity in the area to determine how human activity affected behavior. The oystercatchers' behavioral responses (proportion time) were analyzed with and without human or intraspecific disturbances using mixed models regression analysis. Proportions of time human activities were present (137 m and vehicular activity should be minimized at current levels or less.

Xenobiotic-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models.

PubMed

Oesch, F; Fabian, E; Guth, K; Landsiedel, R

2014-12-01

The exposure of the skin to medical drugs, skin care products, cosmetics, and other chemicals renders information on xenobiotic-metabolizing enzymes (XME) in the skin highly interesting. Since the use of freshly excised human skin for experimental investigations meets with ethical and practical limitations, information on XME in models comes in the focus including non-human mammalian species and in vitro skin models. This review attempts to summarize the information available in the open scientific literature on XME in the skin of human, rat, mouse, guinea pig, and pig as well as human primary skin cells, human cell lines, and reconstructed human skin models. The most salient outcome is that much more research on cutaneous XME is needed for solid metabolism-dependent efficacy and safety predictions, and the cutaneous metabolism comparisons have to be viewed with caution. Keeping this fully in mind at least with respect to some cutaneous XME, some models may tentatively be considered to approximate reasonable closeness to human skin. For dermal absorption and for skin irritation among many contributing XME, esterase activity is of special importance, which in pig skin, some human cell lines, and reconstructed skin models appears reasonably close to human skin. With respect to genotoxicity and sensitization, activating XME are not yet judgeable, but reactive metabolite-reducing XME in primary human keratinocytes and several reconstructed human skin models appear reasonably close to human skin. For a more detailed delineation and discussion of the severe limitations see the "Overview and Conclusions" section in the end of this review.

Development of a computational model on the neural activity patterns of a visual working memory in a hierarchical feedforward Network

NASA Astrophysics Data System (ADS)

An, Soyoung; Choi, Woochul; Paik, Se-Bum

2015-11-01

Understanding the mechanism of information processing in the human brain remains a unique challenge because the nonlinear interactions between the neurons in the network are extremely complex and because controlling every relevant parameter during an experiment is difficult. Therefore, a simulation using simplified computational models may be an effective approach. In the present study, we developed a general model of neural networks that can simulate nonlinear activity patterns in the hierarchical structure of a neural network system. To test our model, we first examined whether our simulation could match the previously-observed nonlinear features of neural activity patterns. Next, we performed a psychophysics experiment for a simple visual working memory task to evaluate whether the model could predict the performance of human subjects. Our studies show that the model is capable of reproducing the relationship between memory load and performance and may contribute, in part, to our understanding of how the structure of neural circuits can determine the nonlinear neural activity patterns in the human brain.

Intra-Urban Human Mobility and Activity Transition: Evidence from Social Media Check-In Data

PubMed Central

Wu, Lun; Zhi, Ye; Sui, Zhengwei; Liu, Yu

2014-01-01

Most existing human mobility literature focuses on exterior characteristics of movements but neglects activities, the driving force that underlies human movements. In this research, we combine activity-based analysis with a movement-based approach to model the intra-urban human mobility observed from about 15 million check-in records during a yearlong period in Shanghai, China. The proposed model is activity-based and includes two parts: the transition of travel demands during a specific time period and the movement between locations. For the first part, we find the transition probability between activities varies over time, and then we construct a temporal transition probability matrix to represent the transition probability of travel demands during a time interval. For the second part, we suggest that the travel demands can be divided into two classes, locationally mandatory activity (LMA) and locationally stochastic activity (LSA), according to whether the demand is associated with fixed location or not. By judging the combination of predecessor activity type and successor activity type we determine three trip patterns, each associated with a different decay parameter. To validate the model, we adopt the mechanism of an agent-based model and compare the simulated results with the observed pattern from the displacement distance distribution, the spatio-temporal distribution of activities, and the temporal distribution of travel demand transitions. The results show that the simulated patterns fit the observed data well, indicating that these findings open new directions for combining activity-based analysis with a movement-based approach using social media check-in data. PMID:24824892

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…

Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro.

PubMed

Bardy, Cedric; van den Hurk, Mark; Eames, Tameji; Marchand, Cynthia; Hernandez, Ruben V; Kellogg, Mariko; Gorris, Mark; Galet, Ben; Palomares, Vanessa; Brown, Joshua; Bang, Anne G; Mertens, Jerome; Böhnke, Lena; Boyer, Leah; Simon, Suzanne; Gage, Fred H

2015-05-19

Human cell reprogramming technologies offer access to live human neurons from patients and provide a new alternative for modeling neurological disorders in vitro. Neural electrical activity is the essence of nervous system function in vivo. Therefore, we examined neuronal activity in media widely used to culture neurons. We found that classic basal media, as well as serum, impair action potential generation and synaptic communication. To overcome this problem, we designed a new neuronal medium (BrainPhys basal + serum-free supplements) in which we adjusted the concentrations of inorganic salts, neuroactive amino acids, and energetic substrates. We then tested that this medium adequately supports neuronal activity and survival of human neurons in culture. Long-term exposure to this physiological medium also improved the proportion of neurons that were synaptically active. The medium was designed to culture human neurons but also proved adequate for rodent neurons. The improvement in BrainPhys basal medium to support neurophysiological activity is an important step toward reducing the gap between brain physiological conditions in vivo and neuronal models in vitro.

Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro

PubMed Central

Bardy, Cedric; van den Hurk, Mark; Eames, Tameji; Marchand, Cynthia; Hernandez, Ruben V.; Kellogg, Mariko; Gorris, Mark; Galet, Ben; Palomares, Vanessa; Brown, Joshua; Bang, Anne G.; Mertens, Jerome; Böhnke, Lena; Boyer, Leah; Simon, Suzanne; Gage, Fred H.

2015-01-01

Human cell reprogramming technologies offer access to live human neurons from patients and provide a new alternative for modeling neurological disorders in vitro. Neural electrical activity is the essence of nervous system function in vivo. Therefore, we examined neuronal activity in media widely used to culture neurons. We found that classic basal media, as well as serum, impair action potential generation and synaptic communication. To overcome this problem, we designed a new neuronal medium (BrainPhys basal + serum-free supplements) in which we adjusted the concentrations of inorganic salts, neuroactive amino acids, and energetic substrates. We then tested that this medium adequately supports neuronal activity and survival of human neurons in culture. Long-term exposure to this physiological medium also improved the proportion of neurons that were synaptically active. The medium was designed to culture human neurons but also proved adequate for rodent neurons. The improvement in BrainPhys basal medium to support neurophysiological activity is an important step toward reducing the gap between brain physiological conditions in vivo and neuronal models in vitro. PMID:25870293

Time-specific ecological niche modeling predicts spatial dynamics of vector insects and human dengue cases.

PubMed

Peterson, A Townsend; Martínez-Campos, Carmen; Nakazawa, Yoshinori; Martínez-Meyer, Enrique

2005-09-01

Numerous human diseases-malaria, dengue, yellow fever and leishmaniasis, to name a few-are transmitted by insect vectors with brief life cycles and biting activity that varies in both space and time. Although the general geographic distributions of these epidemiologically important species are known, the spatiotemporal variation in their emergence and activity remains poorly understood. We used ecological niche modeling via a genetic algorithm to produce time-specific predictive models of monthly distributions of Aedes aegypti in Mexico in 1995. Significant predictions of monthly mosquito activity and distributions indicate that predicting spatiotemporal dynamics of disease vector species is feasible; significant coincidence with human cases of dengue indicate that these dynamics probably translate directly into transmission of dengue virus to humans. This approach provides new potential for optimizing use of resources for disease prevention and remediation via automated forecasting of disease transmission risk.

Accelerometry-based classification of human activities using Markov modeling.

PubMed

Mannini, Andrea; Sabatini, Angelo Maria

2011-01-01

Accelerometers are a popular choice as body-motion sensors: the reason is partly in their capability of extracting information that is useful for automatically inferring the physical activity in which the human subject is involved, beside their role in feeding biomechanical parameters estimators. Automatic classification of human physical activities is highly attractive for pervasive computing systems, whereas contextual awareness may ease the human-machine interaction, and in biomedicine, whereas wearable sensor systems are proposed for long-term monitoring. This paper is concerned with the machine learning algorithms needed to perform the classification task. Hidden Markov Model (HMM) classifiers are studied by contrasting them with Gaussian Mixture Model (GMM) classifiers. HMMs incorporate the statistical information available on movement dynamics into the classification process, without discarding the time history of previous outcomes as GMMs do. An example of the benefits of the obtained statistical leverage is illustrated and discussed by analyzing two datasets of accelerometer time series.

QSAR modeling for anti-human African trypanosomiasis activity of substituted 2-Phenylimidazopyridines

NASA Astrophysics Data System (ADS)

Masand, Vijay H.; El-Sayed, Nahed N. E.; Mahajan, Devidas T.; Mercader, Andrew G.; Alafeefy, Ahmed M.; Shibi, I. G.

2017-02-01

In the present work, sixty substituted 2-Phenylimidazopyridines previously reported with potent anti-human African trypanosomiasis (HAT) activity were selected to build genetic algorithm (GA) based QSAR models to determine the structural features that have significant correlation with the activity. Multiple QSAR models were built using easily interpretable descriptors that are directly associated with the presence or the absence of a structural scaffold, or a specific atom. All the QSAR models have been thoroughly validated according to the OECD principles. All the QSAR models are statistically very robust (R2 = 0.80-0.87) with high external predictive ability (CCCex = 0.81-0.92). The QSAR analysis reveals that the HAT activity has good correlation with the presence of five membered rings in the molecule.

A framework for the use of agent based modeling to simulate ...

EPA Pesticide Factsheets

Simulation of human behavior in exposure modeling is a complex task. Traditionally, inter-individual variation in human activity has been modeled by drawing from a pool of single day time-activity diaries such as the US EPA Consolidated Human Activity Database (CHAD). Here, an agent-based model (ABM) is used to simulate population distributions of longitudinal patterns of four macro activities (sleeping, eating, working, and commuting) in populations of adults over a period of one year. In this ABM, an individual is modeled as an agent whose movement through time and space is determined by a set of decision rules. The rules are based on the agent having time-varying “needs” that are satisfied by performing actions. Needs are modeled as increasing over time, and taking an action reduces the need. Need-satisfying actions include sleeping (meeting the need for rest), eating (meeting the need for food), and commuting/working (meeting the need for income). Every time an action is completed, the model determines the next action the agent will take based on the magnitude of each of the agent’s needs at that point in time. Different activities advertise their ability to satisfy various needs of the agent (such as food to eat or sleeping in a bed or on a couch). The model then chooses the activity that satisfies the greatest of the agent’s needs. When multiple actions could address a need, the model will choose the most effective of the actions (bed over the couc

A Perspective on Computational Human Performance Models as Design Tools

NASA Technical Reports Server (NTRS)

Jones, Patricia M.

2010-01-01

The design of interactive systems, including levels of automation, displays, and controls, is usually based on design guidelines and iterative empirical prototyping. A complementary approach is to use computational human performance models to evaluate designs. An integrated strategy of model-based and empirical test and evaluation activities is particularly attractive as a methodology for verification and validation of human-rated systems for commercial space. This talk will review several computational human performance modeling approaches and their applicability to design of display and control requirements.

Cascading Walks Model for Human Mobility Patterns

PubMed Central

Han, Xiao-Pu; Wang, Xiang-Wen; Yan, Xiao-Yong; Wang, Bing-Hong

2015-01-01

Background Uncovering the mechanism behind the scaling laws and series of anomalies in human trajectories is of fundamental significance in understanding many spatio-temporal phenomena. Recently, several models, e.g. the explorations-returns model (Song et al., 2010) and the radiation model for intercity travels (Simini et al., 2012), have been proposed to study the origin of these anomalies and the prediction of human movements. However, an agent-based model that could reproduce most of empirical observations without priori is still lacking. Methodology/Principal Findings In this paper, considering the empirical findings on the correlations of move-lengths and staying time in human trips, we propose a simple model which is mainly based on the cascading processes to capture the human mobility patterns. In this model, each long-range movement activates series of shorter movements that are organized by the law of localized explorations and preferential returns in prescribed region. Conclusions/Significance Based on the numerical simulations and analytical studies, we show more than five statistical characters that are well consistent with the empirical observations, including several types of scaling anomalies and the ultraslow diffusion properties, implying the cascading processes associated with the localized exploration and preferential returns are indeed a key in the understanding of human mobility activities. Moreover, the model shows both of the diverse individual mobility and aggregated scaling displacements, bridging the micro and macro patterns in human mobility. In summary, our model successfully explains most of empirical findings and provides deeper understandings on the emergence of human mobility patterns. PMID:25860140

Cascading walks model for human mobility patterns.

PubMed

Han, Xiao-Pu; Wang, Xiang-Wen; Yan, Xiao-Yong; Wang, Bing-Hong

2015-01-01

Uncovering the mechanism behind the scaling laws and series of anomalies in human trajectories is of fundamental significance in understanding many spatio-temporal phenomena. Recently, several models, e.g. the explorations-returns model (Song et al., 2010) and the radiation model for intercity travels (Simini et al., 2012), have been proposed to study the origin of these anomalies and the prediction of human movements. However, an agent-based model that could reproduce most of empirical observations without priori is still lacking. In this paper, considering the empirical findings on the correlations of move-lengths and staying time in human trips, we propose a simple model which is mainly based on the cascading processes to capture the human mobility patterns. In this model, each long-range movement activates series of shorter movements that are organized by the law of localized explorations and preferential returns in prescribed region. Based on the numerical simulations and analytical studies, we show more than five statistical characters that are well consistent with the empirical observations, including several types of scaling anomalies and the ultraslow diffusion properties, implying the cascading processes associated with the localized exploration and preferential returns are indeed a key in the understanding of human mobility activities. Moreover, the model shows both of the diverse individual mobility and aggregated scaling displacements, bridging the micro and macro patterns in human mobility. In summary, our model successfully explains most of empirical findings and provides deeper understandings on the emergence of human mobility patterns.

Human activities recognition by head movement using partial recurrent neural network

NASA Astrophysics Data System (ADS)

Tan, Henry C. C.; Jia, Kui; De Silva, Liyanage C.

2003-06-01

Traditionally, human activities recognition has been achieved mainly by the statistical pattern recognition methods or the Hidden Markov Model (HMM). In this paper, we propose a novel use of the connectionist approach for the recognition of ten simple human activities: walking, sitting down, getting up, squatting down and standing up, in both lateral and frontal views, in an office environment. By means of tracking the head movement of the subjects over consecutive frames from a database of different color image sequences, and incorporating the Elman model of the partial recurrent neural network (RNN) that learns the sequential patterns of relative change of the head location in the images, the proposed system is able to robustly classify all the ten activities performed by unseen subjects from both sexes, of different race and physique, with a recognition rate as high as 92.5%. This demonstrates the potential of employing partial RNN to recognize complex activities in the increasingly popular human-activities-based applications.

Exploring an Alternative Model of Human Reproductive Capability: A Creative Learning Activity

ERIC Educational Resources Information Center

Cherif, Abour H.; Jedlicka, Dianne M.

2012-01-01

Biological and social evolutionary processes, along with social and cultural developments, have allowed humans to separate procreation from pleasurable/recreational sexual activity. As a class learning project, an alternative, hypothetical reproductive scenario is presented: "What if humans were biologically ready to conceive only during one…

Fire, Climate, and Human Activity: A Combustive Combination

NASA Astrophysics Data System (ADS)

Kehrwald, N. M.; Battistel, D.; Argiriadis, E.; Barbante, C.; Barber, L. B.; Fortner, S. K.; Jasmann, J.; Kirchgeorg, T.; Zennaro, P.

2017-12-01

Ice and lake core records demonstrate that fires caused by human activity can dominate regional biomass burning records in the Common Era. These major increases in fires are often associated with extensive land use change such as an expansion in agriculture. Regions with few humans, relatively stable human populations and/or unvarying land use often have fire histories that are dominated by climate parameters such as temperature and precipitation. Here, we examine biomass burning recorded in ice cores from northern Greenland (NEEM, (77°27'N; 51°3.6'W), Alaska (Juneau Icefield, 58° 35' N; 134° 29'W) and East Antarctica (EPICA DOME C; 75°06'S; 123°21'E), along with New Zealand lake cores to investigate interactions between climate, fire and human activity. Biomarkers such as levoglucosan, and its isomers mannosan and galactosan, can only be produced by cellulose combustion and therefore are specific indicators of past fire activity archived in ice and lake cores. These fire histories add another factor to climate proxies from the same core, and provide a comparison to regional fire syntheses from charcoal records and climate models. For example, fire data from the JSBACH-Spitfire model for the past 2000 years demonstrates that a climate-only scenario would not increase biomass burning in high northern latitudes for the past 2000 years, while NEEM ice core and regional pollen records demonstrate both increased fire activity and land use change that may be ascribed to human activity. Additional biomarkers such as fecal sterols in lake sediments can determine when people were in an area, and can help establish if an increased human presence in an area corresponds with intensified fire activity. This combination of specific biomarkers, other proxy data, and model output can help determine the relative impact of humans versus climate factors on regional fire activity.

Computational analysis of the human sinus node action potential: model development and effects of mutations

PubMed Central

Fabbri, Alan; Fantini, Matteo; Wilders, Ronald

2017-01-01

Key points We constructed a comprehensive mathematical model of the spontaneous electrical activity of a human sinoatrial node (SAN) pacemaker cell, starting from the recent Severi–DiFrancesco model of rabbit SAN cells.Our model is based on electrophysiological data from isolated human SAN pacemaker cells and closely matches the action potentials and calcium transient that were recorded experimentally.Simulated ion channelopathies explain the clinically observed changes in heart rate in corresponding mutation carriers, providing an independent qualitative validation of the model.The model shows that the modulatory role of the ‘funny current’ (I f) in the pacing rate of human SAN pacemaker cells is highly similar to that of rabbit SAN cells, despite its considerably lower amplitude.The model may prove useful in the design of experiments and the development of heart‐rate modulating drugs. Abstract The sinoatrial node (SAN) is the normal pacemaker of the mammalian heart.  Over several decades, a large amount of data on the ionic mechanisms underlying the spontaneous electrical activity of SAN pacemaker cells has been obtained, mostly in experiments on single cells isolated from rabbit SAN. This wealth of data has allowed the development of mathematical models of the electrical activity of rabbit SAN pacemaker cells. The present study aimed to construct a comprehensive model of the electrical activity of a human SAN pacemaker cell using recently obtained electrophysiological data from human SAN pacemaker cells.  We based our model on the recent Severi–DiFrancesco model of a rabbit SAN pacemaker cell. The action potential and calcium transient of the resulting model are close to the experimentally recorded values. The model has a much smaller ‘funny current’ (I f) than do rabbit cells, although its modulatory role is highly similar. Changes in pacing rate upon the implementation of mutations associated with sinus node dysfunction agree with the clinical observations. This agreement holds for both loss‐of‐function and gain‐of‐function mutations in the HCN4, SCN5A and KCNQ1 genes, underlying ion channelopathies in I f, fast sodium current and slow delayed rectifier potassium current, respectively. We conclude that our human SAN cell model can be a useful tool in the design of experiments and the development of drugs that aim to modulate heart rate. PMID:28185290

Simple control-theoretic models of human steering activity in visually guided vehicle control

NASA Technical Reports Server (NTRS)

Hess, Ronald A.

1991-01-01

A simple control theoretic model of human steering or control activity in the lateral-directional control of vehicles such as automobiles and rotorcraft is discussed. The term 'control theoretic' is used to emphasize the fact that the model is derived from a consideration of well-known control system design principles as opposed to psychological theories regarding egomotion, etc. The model is employed to emphasize the 'closed-loop' nature of tasks involving the visually guided control of vehicles upon, or in close proximity to, the earth and to hypothesize how changes in vehicle dynamics can significantly alter the nature of the visual cues which a human might use in such tasks.

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.

Response repetition biases in human perceptual decisions are explained by activity decay in competitive attractor models

PubMed Central

Bonaiuto, James J; de Berker, Archy; Bestmann, Sven

2016-01-01

Animals and humans have a tendency to repeat recent choices, a phenomenon known as choice hysteresis. The mechanism for this choice bias remains unclear. Using an established, biophysically informed model of a competitive attractor network for decision making, we found that decaying tail activity from the previous trial caused choice hysteresis, especially during difficult trials, and accurately predicted human perceptual choices. In the model, choice variability could be directionally altered through amplification or dampening of post-trial activity decay through simulated depolarizing or hyperpolarizing network stimulation. An analogous intervention using transcranial direct current stimulation (tDCS) over left dorsolateral prefrontal cortex (dlPFC) yielded a close match between model predictions and experimental results: net soma depolarizing currents increased choice hysteresis, while hyperpolarizing currents suppressed it. Residual activity in competitive attractor networks within dlPFC may thus give rise to biases in perceptual choices, which can be directionally controlled through non-invasive brain stimulation. DOI: http://dx.doi.org/10.7554/eLife.20047.001 PMID:28005007

An adaptive Hidden Markov Model for activity recognition based on a wearable multi-sensor device

USDA-ARS?s Scientific Manuscript database

Human activity recognition is important in the study of personal health, wellness and lifestyle. In order to acquire human activity information from the personal space, many wearable multi-sensor devices have been developed. In this paper, a novel technique for automatic activity recognition based o...

Evidence for Model-based Computations in the Human Amygdala during Pavlovian Conditioning

PubMed Central

Prévost, Charlotte; McNamee, Daniel; Jessup, Ryan K.; Bossaerts, Peter; O'Doherty, John P.

2013-01-01

Contemporary computational accounts of instrumental conditioning have emphasized a role for a model-based system in which values are computed with reference to a rich model of the structure of the world, and a model-free system in which values are updated without encoding such structure. Much less studied is the possibility of a similar distinction operating at the level of Pavlovian conditioning. In the present study, we scanned human participants while they participated in a Pavlovian conditioning task with a simple structure while measuring activity in the human amygdala using a high-resolution fMRI protocol. After fitting a model-based algorithm and a variety of model-free algorithms to the fMRI data, we found evidence for the superiority of a model-based algorithm in accounting for activity in the amygdala compared to the model-free counterparts. These findings support an important role for model-based algorithms in describing the processes underpinning Pavlovian conditioning, as well as providing evidence of a role for the human amygdala in model-based inference. PMID:23436990

The Influence of Neck Muscle Activation on Head and Neck Injuries of Occupants in Frontal Impacts.

PubMed

Li, Fan; Lu, Ronggui; Hu, Wei; Li, Honggeng; Hu, Shiping; Hu, Jiangzhong; Wang, Haibin; Xie, He

2018-01-01

The aim of the present paper was to study the influence of neck muscle activation on head and neck injuries of vehicle occupants in frontal impacts. A mixed dummy-human finite element model was developed to simulate a frontal impact. The head-neck part of a Hybrid III dummy model was replaced by a well-validated head-neck FE model with passive and active muscle characteristics. The mixed dummy-human FE model was validated by 15 G frontal volunteer tests conducted in the Naval Biodynamics Laboratory. The effects of neck muscle activation on the head dynamic responses and neck injuries of occupants in three frontal impact intensities, low speed (10 km/h), medium speed (30 km/h), and high speed (50 km/h), were studied. The results showed that the mixed dummy-human FE model has good biofidelity. The activation of neck muscles can not only lower the head resultant acceleration under different impact intensities and the head angular acceleration in medium- and high-speed impacts, thereby reducing the risks of head injury, but also protect the neck from injury in low-speed impacts.

DEVELOPING MEANINGFUL COHORTS FOR HUMAN EXPOSURE MODELS

EPA Science Inventory

This paper summarizes numerous statistical analyses focused on the U.S. Environmental Protection Agency's Consolidated Human Activity Database (CHAD), used by many exposure modelers as the basis for data on what people do and where they spend their time. In doing so, modelers ...

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.

Human activity discrimination for maritime application

NASA Astrophysics Data System (ADS)

Boettcher, Evelyn; Deaver, Dawne M.; Krapels, Keith

2008-04-01

The US Army RDECOM CERDEC Night Vision and Electronic Sensors Directorate (NVESD) is investigating how motion affects the target acquisition model (NVThermIP) sensor performance estimates. This paper looks specifically at estimating sensor performance for the task of discriminating human activities on watercraft, and was sponsored by the Office of Naval Research (ONR). Traditionally, sensor models were calibrated using still images. While that approach is sufficient for static targets, video allows one to use motion cues to aid in discerning the type of human activity more quickly and accurately. This, in turn, will affect estimated sensor performance and these effects are measured in order to calibrate current target acquisition models for this task. The study employed an eleven alternative forced choice (11AFC) human perception experiment to measure the task difficulty of discriminating unique human activities on watercrafts. A mid-wave infrared camera was used to collect video at night. A description of the construction of this experiment is given, including: the data collection, image processing, perception testing and how contrast was defined for video. These results are applicable to evaluate sensor field performance for Anti-Terrorism and Force Protection (AT/FP) tasks for the U.S. Navy.

Patch-occupancy models indicate human activity as major determinant of forest elephant Loxodonta cyclotis seasonal distribution in an industrial corridor in Gabon

USGS Publications Warehouse

Buij, R.; McShea, W.J.; Campbell, P.; Lee, M.E.; Dallmeier, F.; Guimondou, S.; Mackaga, L.; Guisseougou, N.; Mboumba, S.; Hines, J.E.; Nichols, J.D.; Alonso, A.

2007-01-01

The importance of human activity and ecological features in influencing African forest elephant ranging behaviour was investigated in the Rabi-Ndogo corridor of the Gamba Complex of Protected Areas in southwest Gabon. Locations in a wide geographical area with a range of environmental variables were selected for patch-occupancy surveys using elephant dung to assess seasonal presence and absence of elephants. Patch-occupancy procedures allowed for covariate modelling evaluating hypotheses for both occupancy in relation to human activity and ecological features, and detection probability in relation to vegetation density. The best fitting models for old and fresh dung data sets indicate that (1) detection probability for elephant dung is negatively related to the relative density of the vegetation, and (2) human activity, such as presence and infrastructure, are more closely associated with elephant distribution patterns than are ecological features, such as the presence of wetlands and preferred fresh fruit. Our findings emphasize the sensitivity of elephants to human disturbance, in this case infrastructure development associated with gas and oil production. Patch-occupancy methodology offers a viable alternative to current transect protocols for monitoring programs with multiple covariates.

Integrating Human Factors into Crew Exploration Vehicle (CEV) Design

NASA Technical Reports Server (NTRS)

Whitmore, Mihriban; Holden, Kritina; Baggerman, Susan; Campbell, Paul

2007-01-01

The purpose of this design process is to apply Human Engineering (HE) requirements and guidelines to hardware/software and to provide HE design, analysis and evaluation of crew interfaces. The topics include: 1) Background/Purpose; 2) HE Activities; 3) CASE STUDY: Net Habitable Volume (NHV) Study; 4) CASE STUDY: Human Modeling Approach; 5) CASE STUDY: Human Modeling Results; 6) CASE STUDY: Human Modeling Conclusions; 7) CASE STUDY: Human-in-the-Loop Evaluation Approach; 8) CASE STUDY: Unsuited Evaluation Results; 9) CASE STUDY: Suited Evaluation Results; 10) CASE STUDY: Human-in-the-Loop Evaluation Conclusions; 11) Near-Term Plan; and 12) In Conclusion

Statistical Properties of Longitudinal Time-Activity Data for Use in Human Exposure Modeling

EPA Science Inventory

Understanding the longitudinal properties of the time spent in different locations and activities is important in characterizing human exposure to pollutants. The results of a four-season longitudinal time-activity diary study in eight working adults are presented, with the goal ...

Cancer Prevention by Tocopherols and Tea Polyphenols

PubMed Central

Yang, Chung S.; Li, Guangxun; Yang, Zhihong; Guan, Fei; Chen, Amber; Ju, Jihyeung

2013-01-01

Tocopherols (vitamin E) and tea polyphenols have been reported to have cancer preventive activities. Large-scale human trials with high doses of alpha-tocopherol, however, have produced disappointing results. This review presents data showing that γ- and δ-tocopherols inhibit colon, lung, mammary and prostate carcinogenesis in animal models, whereas α-tocopherol is ineffective in animal and human studies. Possible mechanisms of action are discussed. A broad cancer preventive activity of green tea polyphenols has been demonstrated in animal models, and many mechanisms have been proposed. The cancer preventive activity of green tea in humans, however, has not been conclusively demonstrated and remains to be further investigated. PMID:23403075

Anti-inflammatory effects of physical activity in relationship to improved cognitive status in humans and mouse models of Alzheimer's disease.

PubMed

Stranahan, Alexis M; Martin, Bronwen; Maudsley, Stuart

2012-01-01

Physical activity has been correlated with a reduced incidence of cognitive decline and Alzheimer's disease in human populations. Although data from intervention-based randomized trials is scarce, there is some indication that exercise may confer protection against age-related deficits in cognitive function. Data from animal models suggests that exercise, in the form of voluntary wheel running, is associated with reduced amyloid deposition and enhanced clearance of amyloid beta, the major constituent of plaques in Alzheimer's disease. Treadmill exercise has also been shown to ameliorate the accumulation of phosphorylated tau, an essential component of neurofibrillary tangles in Alzheimer's models. A common therapeutic theme arising from studies of exercise-induced neuroprotection in human populations and in animal models involves reduced inflammation in the central nervous system. In this respect, physical activity may promote neuronal resilience by reducing inflammation.

Cytochrome P450 Activity in Ex Vivo Cornea Models and a Human Cornea Construct.

PubMed

Kölln, Christian; Reichl, Stephan

2016-07-01

The pharmacokinetic behaviors of novel ophthalmic drugs are often preliminarily investigated in preclinical studies using ex vivo animal cornea or corneal cell culture models. During transcorneal passage, topically applied drugs may be affected by drug metabolizing enzymes. The knowledge regarding the functional expression of metabolic enzymes in corneal tissue is marginal; thus, the aim of this study was to investigate cytochrome P450 activity in an organotypic three-dimensional human cornea construct and to compare it with porcine and rabbit corneas, which are commonly used ex vivo cornea models. The total cytochrome P450 activity was determined by measuring the transformation of 7-ethoxycoumarin. Furthermore, the expression of the cytochrome P450 enzyme 2D6 (CYP2D6) was investigated at the protein level using immunohistochemistry and western blotting. CYP2D6 activity measurements were performed using a d-luciferin-based assay. In summary, similar levels of the total cytochrome P450 activity were identified in all 3 cornea models. The protein expression of CYP2D6 was confirmed in the human cornea construct and porcine cornea, whereas the signals in the rabbit cornea were weak. The analysis of the CYP2D6 activity indicated similar values for the human cornea construct and porcine cornea; however, a distinctly lower activity was observed in the rabbit cornea. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Modeling activity recognition of multi resident using label combination of multi label classification in smart home

NASA Astrophysics Data System (ADS)

Mohamed, Raihani; Perumal, Thinagaran; Sulaiman, Md Nasir; Mustapha, Norwati; Zainudin, M. N. Shah

2017-10-01

Pertaining to the human centric concern and non-obtrusive way, the ambient sensor type technology has been selected, accepted and embedded in the environment in resilient style. Human activities, everyday are gradually becoming complex and thus complicate the inferences of activities when it involving the multi resident in the same smart environment. Current works solutions focus on separate model between the resident, activities and interactions. Some study use data association and extra auxiliary of graphical nodes to model human tracking information in an environment and some produce separate framework to incorporate the auxiliary for interaction feature model. Thus, recognizing the activities and which resident perform the activity at the same time in the smart home are vital for the smart home development and future applications. This paper will cater the above issue by considering the simplification and efficient method using the multi label classification framework. This effort eliminates time consuming and simplifies a lot of pre-processing tasks comparing with previous approach. Applications to the multi resident multi label learning in smart home problems shows the LC (Label Combination) using Decision Tree (DT) as base classifier can tackle the above problems.

Human Capital Investment and the Gender Division of Labor in a Brawn-Based Economy

PubMed Central

Pitt, Mark M.; Rosenzweig, Mark R.; Hassan, Nazmul

2013-01-01

We use a model of human capital investment and activity choice to explain facts describing gender differentials in the levels and returns to human capital investments. These include the higher return to and level of schooling, the small effect of healthiness on wages, and the large effect of healthiness on schooling for females relative to males. The model incorporates gender differences in the level and responsiveness of brawn to nutrition in a Roy-economy setting in which activities reward skill and brawn differentially. Empirical evidence from rural Bangladesh provides support for the model and the importance of the distribution of brawn. PMID:25152536

Functional human antibody CDR fusions as long-acting therapeutic endocrine agonists.

PubMed

Liu, Tao; Zhang, Yong; Liu, Yan; Wang, Ying; Jia, Haiqun; Kang, Mingchao; Luo, Xiaozhou; Caballero, Dawna; Gonzalez, Jose; Sherwood, Lance; Nunez, Vanessa; Wang, Danling; Woods, Ashley; Schultz, Peter G; Wang, Feng

2015-02-03

On the basis of the 3D structure of a bovine antibody with a well-folded, ultralong complementarity-determining region (CDR), we have developed a versatile approach for generating human or humanized antibody agonists with excellent pharmacological properties. Using human growth hormone (hGH) and human leptin (hLeptin) as model proteins, we have demonstrated that functional human antibody CDR fusions can be efficiently engineered by grafting the native hormones into different CDRs of the humanized antibody Herceptin. The resulting Herceptin CDR fusion proteins were expressed in good yields in mammalian cells and retain comparable in vitro biological activity to the native hormones. Pharmacological studies in rodents indicated a 20- to 100-fold increase in plasma circulating half-life for these antibody agonists and significantly extended in vivo activities in the GH-deficient rat model and leptin-deficient obese mouse model for the hGH and hLeptin antibody fusions, respectively. These results illustrate the utility of antibody CDR fusions as a general and versatile strategy for generating long-acting protein therapeutics.

High-resolution Continental Scale Land Surface Model incorporating Land-water Management in United States

NASA Astrophysics Data System (ADS)

Shin, S.; Pokhrel, Y. N.

2016-12-01

Land surface models have been used to assess water resources sustainability under changing Earth environment and increasing human water needs. Overwhelming observational records indicate that human activities have ubiquitous and pertinent effects on the hydrologic cycle; however, they have been crudely represented in large scale land surface models. In this study, we enhance an integrated continental-scale land hydrology model named Leaf-Hydro-Flood to better represent land-water management. The model is implemented at high resolution (5km grids) over the continental US. Surface water and groundwater are withdrawn based on actual practices. Newly added irrigation, water diversion, and dam operation schemes allow better simulations of stream flows, evapotranspiration, and infiltration. Results of various hydrologic fluxes and stores from two sets of simulation (one with and the other without human activities) are compared over a range of river basin and aquifer scales. The improved simulations of land hydrology have potential to build consistent modeling framework for human-water-climate interactions.

ANALYSIS OF DISCRIMINATING FACTORS IN HUMAN ACTIVITIES THAT AFFECT EXPOSURE

EPA Science Inventory

Accurately modeling exposure to particulate matter (PM) and other pollutants ultimately involves the utilization of human location-activity databases to assist in understanding the potential variability of microenvironmental exposures. This paper critically considers and stati...

The Sustainability Cycle and Loop: models for a more unified understanding of sustainability.

PubMed

Hay, Laura; Duffy, Alex; Whitfield, R I

2014-01-15

In spite of the considerable research on sustainability, reports suggest that we are barely any closer to a more sustainable society. As such, there is an urgent need to improve the effectiveness of human efforts towards sustainability. A clearer and more unified understanding of sustainability among different people and sectors could help to facilitate this. This paper presents the results of an inductive literature investigation, aiming to develop models to explain the nature of sustainability in the Earth system, and how humans can effectively strive for it. The major contributions are two general and complementary models, that may be applied in any context to provide a common basis for understanding sustainability: the Sustainability Cycle (S-Cycle), and the Sustainability Loop (S-Loop). Literature spanning multiple sectors is examined from the perspective of three concepts, emerging as significant in relation to our aim. Systems are shown to provide the context for human action towards sustainability, and the nature of the Earth system and its sub-systems is explored. Activities are outlined as a fundamental target that humans need to sustain, since they produce the entities both needed and desired by society. The basic behaviour of activities operating in the Earth system is outlined. Finally, knowledge is positioned as the driver of human action towards sustainability, and the key components of knowledge involved are examined. The S-Cycle and S-Loop models are developed via a process of induction from the reviewed literature. The S-Cycle describes the operation of activities in a system from the perspective of sustainability. The sustainability of activities in a system depends upon the availability of resources, and the availability of resources depends upon the rate that activities consume and produce them. Humans may intervene in these dynamics via an iterative process of interpretation and action, described in the S-Loop model. The models are briefly applied to a system described in the literature. It is shown that the S-Loop may be used to guide efforts towards sustainability in a particular system of interest, by prescribing the basic activities involved. The S-Cycle may be applied complementary to the S-Loop, to support the interpretation of activity behaviour described in the latter. Given their general nature, the models provide the basis for a more unified understanding of sustainability. It is hoped that their use may go some way towards improving the effectiveness of human action towards sustainability. Copyright © 2013 Elsevier Ltd. All rights reserved.

Modeling large-scale human alteration of land surface hydrology and climate

NASA Astrophysics Data System (ADS)

Pokhrel, Yadu N.; Felfelani, Farshid; Shin, Sanghoon; Yamada, Tomohito J.; Satoh, Yusuke

2017-12-01

Rapidly expanding human activities have profoundly affected various biophysical and biogeochemical processes of the Earth system over a broad range of scales, and freshwater systems are now amongst the most extensively altered ecosystems. In this study, we examine the human-induced changes in land surface water and energy balances and the associated climate impacts using a coupled hydrological-climate model framework which also simulates the impacts of human activities on the water cycle. We present three sets of analyses using the results from two model versions—one with and the other without considering human activities; both versions are run in offline and coupled mode resulting in a series of four experiments in total. First, we examine climate and human-induced changes in regional water balance focusing on the widely debated issue of the desiccation of the Aral Sea in central Asia. Then, we discuss the changes in surface temperature as a result of changes in land surface energy balance due to irrigation over global and regional scales. Finally, we examine the global and regional climate impacts of increased atmospheric water vapor content due to irrigation. Results indicate that the direct anthropogenic alteration of river flow in the Aral Sea basin resulted in the loss of 510 km3 of water during the latter half of the twentieth century which explains about half of the total loss of water from the sea. Results of irrigation-induced changes in surface energy balance suggest a significant surface cooling of up to 3.3 K over 1° grids in highly irrigated areas but a negligible change in land surface temperature when averaged over sufficiently large global regions. Results from the coupled model indicate a substantial change in 2 m air temperature and outgoing longwave radiation due to irrigation, highlighting the non-local (regional and global) implications of irrigation. These results provide important insights on the direct human alteration of land surface water and energy balances, highlighting the need to incorporate human activities such as irrigation into the framework of global climate models and Earth system models for better prediction of future changes under increasing human influence and continuing global climate change.

Assessing the response of runoff to climate change and human activities for a typical basin in the Northern Taihang Mountain, China

NASA Astrophysics Data System (ADS)

Wang, Jinfeng; Gao, Yanchuan; Wang, Sheng

2018-04-01

Climate change and human activities are the two main factors on runoff change. Quantifying the contribution of climate change and human activities on runoff change is important for water resources planning and management. In this study, the variation trend and abrupt change point of hydro-meteorological factors during 1960-2012 were detected by using the Mann-Kendall test and Pettitt change-point statistics. Then the runoff was simulated by SWAT model. The contribution of climate change and human activities on runoff change was calculated based on the SWAT model and the elasticity coefficient method. The results showed that in contrast to the increasing trend for annual temperature, the significant decreasing trends were detected for annual runoff and precipitation, with an abrupt change point in 1982. The simulated results of SWAT had good consistency with observed ones, and the values of R2 and E_{NS} all exceeded 0.75. The two methods used for assessing the contribution of climate change and human activities on runoff reduction yielded consistent results. The contribution of climate change (precipitation reduction and temperature rise) was {˜ }37.5%, while the contribution of human activities (the increase of economic forest and built-up land, hydrologic projects) was {˜ }62.5%.

A pairwise maximum entropy model accurately describes resting-state human brain networks

PubMed Central

Watanabe, Takamitsu; Hirose, Satoshi; Wada, Hiroyuki; Imai, Yoshio; Machida, Toru; Shirouzu, Ichiro; Konishi, Seiki; Miyashita, Yasushi; Masuda, Naoki

2013-01-01

The resting-state human brain networks underlie fundamental cognitive functions and consist of complex interactions among brain regions. However, the level of complexity of the resting-state networks has not been quantified, which has prevented comprehensive descriptions of the brain activity as an integrative system. Here, we address this issue by demonstrating that a pairwise maximum entropy model, which takes into account region-specific activity rates and pairwise interactions, can be robustly and accurately fitted to resting-state human brain activities obtained by functional magnetic resonance imaging. Furthermore, to validate the approximation of the resting-state networks by the pairwise maximum entropy model, we show that the functional interactions estimated by the pairwise maximum entropy model reflect anatomical connexions more accurately than the conventional functional connectivity method. These findings indicate that a relatively simple statistical model not only captures the structure of the resting-state networks but also provides a possible method to derive physiological information about various large-scale brain networks. PMID:23340410

Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models.

PubMed

Lin, Jie; Sampath, Deepak; Nannini, Michelle A; Lee, Brian B; Degtyarev, Michael; Oeh, Jason; Savage, Heidi; Guan, Zhengyu; Hong, Rebecca; Kassees, Robert; Lee, Leslie B; Risom, Tyler; Gross, Stefan; Liederer, Bianca M; Koeppen, Hartmut; Skelton, Nicholas J; Wallin, Jeffrey J; Belvin, Marcia; Punnoose, Elizabeth; Friedman, Lori S; Lin, Kui

2013-04-01

We describe the preclinical pharmacology and antitumor activity of GDC-0068, a novel highly selective ATP-competitive pan-Akt inhibitor currently in clinical trials for the treatment of human cancers. The effect of GDC-0068 on Akt signaling was characterized using specific biomarkers of the Akt pathway, and response to GDC-0068 was evaluated in human cancer cell lines and xenograft models with various genetic backgrounds, either as a single agent or in combination with chemotherapeutic agents. GDC-0068 blocked Akt signaling both in cultured human cancer cell lines and in tumor xenograft models as evidenced by dose-dependent decrease in phosphorylation of downstream targets. Inhibition of Akt activity by GDC-0068 resulted in blockade of cell-cycle progression and reduced viability of cancer cell lines. Markers of Akt activation, including high-basal phospho-Akt levels, PTEN loss, and PIK3CA kinase domain mutations, correlate with sensitivity to GDC-0068. Isogenic PTEN knockout also sensitized MCF10A cells to GDC-0068. In multiple tumor xenograft models, oral administration of GDC-0068 resulted in antitumor activity ranging from tumor growth delay to regression. Consistent with the role of Akt in a survival pathway, GDC-0068 also enhanced antitumor activity of classic chemotherapeutic agents. GDC-0068 is a highly selective, orally bioavailable Akt kinase inhibitor that shows pharmacodynamic inhibition of Akt signaling and robust antitumor activity in human cancer cells in vitro and in vivo. Our preclinical data provide a strong mechanistic rationale to evaluate GDC-0068 in cancers with activated Akt signaling. ©2012 AACR.

Agent Based Modeling of Collaboration and Work Practices Onboard the International Space Station

NASA Technical Reports Server (NTRS)

Acquisti, Alessandro; Sierhuis, Maarten; Clancey, William J.; Bradshaw, Jeffrey M.; Shaffo, Mike (Technical Monitor)

2002-01-01

The International Space Station is one the most complex projects ever, with numerous interdependent constraints affecting productivity and crew safety. This requires planning years before crew expeditions, and the use of sophisticated scheduling tools. Human work practices, however, are difficult to study and represent within traditional planning tools. We present an agent-based model and simulation of the activities and work practices of astronauts onboard the ISS based on an agent-oriented approach. The model represents 'a day in the life' of the ISS crew and is developed in Brahms, an agent-oriented, activity-based language used to model knowledge in situated action and learning in human activities.

Mathematical Modelling of Liner Piston Maintenance Activity using Field Data to Minimize Overhauling Time and Human Energy Consumption

NASA Astrophysics Data System (ADS)

Belkhode, Pramod Namdeorao

2017-06-01

Field data based model is proposed to reduce the overhauling time and human energy consumed in liner piston maintenance activity so as to increase the productivity of liner piston maintenance activity. The independent variables affecting the phenomenon such as anthropometric parameters of workers (Eastman Kodak Co. Ltd in Section VIA Appendix-A: Anthropometric Data. Ergonomic Design for People at Work, Van Nostrans Reinhold, New York, 1), workers parameters, specification of liner piston data, specification of tools used in liner piston maintenance activity, specification of solvents, axial clearance of big end bearing and bolt elongation, workstation data (Eastman Kodak Co. Ltd in Work Place Ergonomic Design for People at Work, Van Nostrans Reinhold, New York, 2) and extraneous variables, namely, temperature, humidity at workplace, illumination at workplace and noise at workplace (Eastman Kodak Co. Ltd in Chapter V Environment Ergonomic Design for People at Work, Van Nostrans Reinhold, New York, 3) are taken into account. The model is formulated for dependent variables of liner piston maintenance activity to minimize the overhauling time and human energy consumption so as to improve the productivity of liner piston maintenance activity. The developed model can predict the performance of liner piston maintenance activity which involves man and machine system (Schenck in Theories of Engineering Experimentation, Mc-Graw Hill, New York 4). The model is then optimized by optimization technique and the sensitivity analysis of the model has also been estimated.

Training Classifiers with Shadow Features for Sensor-Based Human Activity Recognition.

PubMed

Fong, Simon; Song, Wei; Cho, Kyungeun; Wong, Raymond; Wong, Kelvin K L

2017-02-27

In this paper, a novel training/testing process for building/using a classification model based on human activity recognition (HAR) is proposed. Traditionally, HAR has been accomplished by a classifier that learns the activities of a person by training with skeletal data obtained from a motion sensor, such as Microsoft Kinect. These skeletal data are the spatial coordinates (x, y, z) of different parts of the human body. The numeric information forms time series, temporal records of movement sequences that can be used for training a classifier. In addition to the spatial features that describe current positions in the skeletal data, new features called 'shadow features' are used to improve the supervised learning efficacy of the classifier. Shadow features are inferred from the dynamics of body movements, and thereby modelling the underlying momentum of the performed activities. They provide extra dimensions of information for characterising activities in the classification process, and thereby significantly improve the classification accuracy. Two cases of HAR are tested using a classification model trained with shadow features: one is by using wearable sensor and the other is by a Kinect-based remote sensor. Our experiments can demonstrate the advantages of the new method, which will have an impact on human activity detection research.

Training Classifiers with Shadow Features for Sensor-Based Human Activity Recognition

PubMed Central

Fong, Simon; Song, Wei; Cho, Kyungeun; Wong, Raymond; Wong, Kelvin K. L.

2017-01-01

In this paper, a novel training/testing process for building/using a classification model based on human activity recognition (HAR) is proposed. Traditionally, HAR has been accomplished by a classifier that learns the activities of a person by training with skeletal data obtained from a motion sensor, such as Microsoft Kinect. These skeletal data are the spatial coordinates (x, y, z) of different parts of the human body. The numeric information forms time series, temporal records of movement sequences that can be used for training a classifier. In addition to the spatial features that describe current positions in the skeletal data, new features called ‘shadow features’ are used to improve the supervised learning efficacy of the classifier. Shadow features are inferred from the dynamics of body movements, and thereby modelling the underlying momentum of the performed activities. They provide extra dimensions of information for characterising activities in the classification process, and thereby significantly improve the classification accuracy. Two cases of HAR are tested using a classification model trained with shadow features: one is by using wearable sensor and the other is by a Kinect-based remote sensor. Our experiments can demonstrate the advantages of the new method, which will have an impact on human activity detection research. PMID:28264470

Synthesis, QSAR, and Molecular Dynamics Simulation of Amidino-substituted Benzimidazoles as Dipeptidyl Peptidase III Inhibitors.

PubMed

Rastija, Vesna; Agić, Dejan; Tomiš, Sanja; Nikolič, Sonja; Hranjec, Marijana; Grace, Karminski-Zamola; Abramić, Marija

2015-01-01

A molecular modeling study is performed on series of benzimidazol-based inhibitors of human dipeptidyl peptidase III (DPP III). An eight novel compounds were synthesized in excellent yields using green chemistry approach. This study is aimed to elucidate the structural features of benzimidazole derivatives required for antagonism of human DPP III activity using Quantitative Structure-Activity Relationship (QSAR) analysis, and to understand the mechanism of one of the most potent inhibitor binding into the active site of this enzyme, by molecular dynamics (MD) simulations. The best model obtained includes S3K and RDF045m descriptors which have explained 89.4 % of inhibitory activity. Depicted moiety for strong inhibition activity matches to the structure of most potent compound. MD simulation has revealed importance of imidazolinyl and phenyl groups in the mechanism of binding into the active site of human DPP III.

Culture models of human mammary epithelial cell transformation

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

Stampfer, Martha R.; Yaswen, Paul

2000-11-10

Human pre-malignant breast diseases, particularly ductal carcinoma in situ (DCIS)3 already display several of the aberrant phenotypes found in primary breast cancers, including chromosomal abnormalities, telomerase activity, inactivation of the p53 gene and overexpression of some oncogenes. Efforts to model early breast carcinogenesis in human cell cultures have largely involved studies in vitro transformation of normal finite lifespan human mammary epithelial cells (HMEC) to immortality and malignancy. We present a model of HMEC immortal transformation consistent with the know in vivo data. This model includes a recently described, presumably epigenetic process, termed conversion, which occurs in cells that have overcomemore » stringent replicative senescence and are thus able to maintain proliferation with critically short telomeres. The conversion process involves reactivation of telomerase activity, and acquisition of good uniform growth in the absence and presence of TFGB. We propose th at overcoming the proliferative constraints set by senescence, and undergoing conversion, represent key rate-limiting steps in human breast carcinogenesis, and occur during early stage breast cancer progression.« less

Xenobiotica-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models.

PubMed

Oesch, F; Fabian, E; Landsiedel, Robert

2018-06-18

Studies on the metabolic fate of medical drugs, skin care products, cosmetics and other chemicals intentionally or accidently applied to the human skin have become increasingly important in order to ascertain pharmacological effectiveness and to avoid toxicities. The use of freshly excised human skin for experimental investigations meets with ethical and practical limitations. Hence information on xenobiotic-metabolizing enzymes (XME) in the experimental systems available for pertinent studies compared with native human skin has become crucial. This review collects available information of which-taken with great caution because of the still very limited data-the most salient points are: in the skin of all animal species and skin-derived in vitro systems considered in this review cytochrome P450 (CYP)-dependent monooxygenase activities (largely responsible for initiating xenobiotica metabolism in the organ which provides most of the xenobiotica metabolism of the mammalian organism, the liver) are very low to undetectable. Quite likely other oxidative enzymes [e.g. flavin monooxygenase, COX (cooxidation by prostaglandin synthase)] will turn out to be much more important for the oxidative xenobiotic metabolism in the skin. Moreover, conjugating enzyme activities such as glutathione transferases and glucuronosyltransferases are much higher than the oxidative CYP activities. Since these conjugating enzymes are predominantly detoxifying, the skin appears to be predominantly protected against CYP-generated reactive metabolites. The following recommendations for the use of experimental animal species or human skin in vitro models may tentatively be derived from the information available to date: for dermal absorption and for skin irritation esterase activity is of special importance which in pig skin, some human cell lines and reconstructed skin models appears reasonably close to native human skin. With respect to genotoxicity and sensitization reactive-metabolite-reducing XME in primary human keratinocytes and several reconstructed human skin models appear reasonably close to human skin. For a more detailed delineation and discussion of the severe limitations see the Conclusions section in the end of this review.

Orthogonal use of a human tRNA synthetase active site to achieve multi-functionality

PubMed Central

Zhou, Quansheng; Kapoor, Mili; Guo, Min; Belani, Rajesh; Xu, Xiaoling; Kiosses, William B.; Hanan, Melanie; Park, Chulho; Armour, Eva; Do, Minh-Ha; Nangle, Leslie A.; Schimmel, Paul; Yang, Xiang-Lei

2011-01-01

Protein multi-functionality is an emerging explanation for the complexity of higher organisms. In this regard, while aminoacyl tRNA synthetases catalyze amino acid activation for protein synthesis, some also act in pathways for inflammation, angiogenesis, and apoptosis. How multiple functions evolved and their relationship to the active site is not clear. Here structural modeling analysis, mutagenesis, and cell-based functional studies show that the potent angiostatic, natural fragment of human TrpRS associates via Trp side chains that protrude from the cognate cellular receptor VE-cadherin. Modeling indicates that (I prefer the way it was because the conclusion was reached not only by modeling, but more so by experimental studies.)VE-cadherin Trp side chains fit into the Trp-specific active site of the synthetase. Thus, specific side chains of the receptor mimic (?) amino acid substrates and expand the functionality of the active site of the synthetase. We propose that orthogonal use of the same active site may be a general way to develop multi-functionality of human tRNA synthetases and other proteins. PMID:20010843

A Novel In Vitro Model for Studying Quiescence and Activation of Primary Isolated Human Myoblasts

PubMed Central

Sellathurai, Jeeva; Cheedipudi, Sirisha; Dhawan, Jyotsna; Schrøder, Henrik Daa

2013-01-01

Skeletal muscle stem cells, satellite cells, are normally quiescent but become activated upon muscle injury. Recruitment of resident satellite cells may be a useful strategy for treatment of muscle disorders, but little is known about gene expression in quiescent human satellite cells or the mechanisms involved in their early activation. We have developed a method to induce quiescence in purified primary human myoblasts isolated from healthy individuals. Analysis of the resting state showed absence of BrdU incorporation and lack of KI67 expression, as well as the extended kinetics during synchronous reactivation into the cell cycle, confirming arrest in the G0 phase. Reactivation studies showed that the majority (>95%) of the G0 arrested cells were able to re-enter the cell cycle, confirming reversibility of arrest. Furthermore, a panel of important myogenic factors showed expression patterns similar to those reported for mouse satellite cells in G0, reactivated and differentiated cultures, supporting the applicability of the human model. In addition, gene expression profiling showed that a large number of genes (4598) were differentially expressed in cells activated from G0 compared to long term exponentially proliferating cultures normally used for in vitro studies. Human myoblasts cultured through many passages inevitably consist of a mixture of proliferating and non-proliferating cells, while cells activated from G0 are in a synchronously proliferating phase, and therefore may be a better model for in vivo proliferating satellite cells. Furthermore, the temporal propagation of proliferation in these synchronized cultures resembles the pattern seen in vivo during regeneration. We therefore present this culture model as a useful and novel condition for molecular analysis of quiescence and reactivation of human myoblasts. PMID:23717533

Active imaging system performance model for target acquisition

NASA Astrophysics Data System (ADS)

Espinola, Richard L.; Teaney, Brian; Nguyen, Quang; Jacobs, Eddie L.; Halford, Carl E.; Tofsted, David H.

2007-04-01

The U.S. Army RDECOM CERDEC Night Vision & Electronic Sensors Directorate has developed a laser-range-gated imaging system performance model for the detection, recognition, and identification of vehicle targets. The model is based on the established US Army RDECOM CERDEC NVESD sensor performance models of the human system response through an imaging system. The Java-based model, called NVLRG, accounts for the effect of active illumination, atmospheric attenuation, and turbulence effects relevant to LRG imagers, such as speckle and scintillation, and for the critical sensor and display components. This model can be used to assess the performance of recently proposed active SWIR systems through various trade studies. This paper will describe the NVLRG model in detail, discuss the validation of recent model components, present initial trade study results, and outline plans to validate and calibrate the end-to-end model with field data through human perception testing.

Comparison of human exposure model estimates of PM2.5 exposure variability using fine-scale CMAQ simulations from the Baltimore DISCOVER-AQ evaluation

EPA Science Inventory

Human exposure models estimate population distributions of exposure to air pollutants by combining ambient (outdoor) concentration data with human activity patterns to account for the time people spend in different locations (e.g., outdoors, indoors, in vehicles) and the various ...

Kinetic modeling of benzodiazepine receptor binding with PET and high specific activity [(11)C]Iomazenil in healthy human subjects.

PubMed

Bremner, J D; Horti, A; Staib, L H; Zea-Ponce, Y; Soufer, R; Charney, D S; Baldwin, R

2000-01-01

Quantitation of the PET benzodiazepine receptor antagonist, [(11)C]Iomazenil, using low specific activity radioligand was recently described. The purpose of this study was to quantitate benzodiazepine receptor binding in human subjects using PET and high specific activity [(11)C]Iomazenil. Six healthy human subjects underwent PET imaging following a bolus injection of high specific activity (>100 Ci/mmol) [(11)C]iomazenil. Arterial samples were collected at multiple time points after injection for measurement of unmetabolized total and nonprotein-bound parent compound in plasma. Time activity curves of radioligand concentration in brain and plasma were analyzed using two and three compartment model. Kinetic rate constants of transfer of radioligand between plasma, nonspecifically bound brain tissue, and specifically bound brain tissue compartments were fitted to the model. Values for fitted kinetic rate constants were used in the calculation of measures of benzodiazepine receptor binding, including binding potential (the ratio of receptor density to affinity), and product of BP and the fraction of free nonprotein-bound parent compound (V(3)'). Use of the three compartment model improved the goodness of fit in comparison to the two compartment model. Values for kinetic rate constants and measures of benzodiazepine receptor binding, including BP and V(3)', were similar to results obtained with the SPECT radioligand [(123)I]iomazenil, and a prior report with low specific activity [(11)C]Iomazenil. Kinetic modeling using the three compartment model with PET and high specific activity [(11)C]Iomazenil provides a reliable measure of benzodiazepine receptor binding. Synapse 35:68-77, 2000. Published 2000 Wiley-Liss, Inc.

Ex Vivo Expanded Human Regulatory T Cells Can Prolong Survival of a Human Islet Allograft in a Humanized Mouse Model

PubMed Central

Wu, Douglas C.; Hester, Joanna; Nadig, Satish N.; Zhang, Wei; Trzonkowski, Piotr; Gray, Derek; Hughes, Stephen; Johnson, Paul; Wood, Kathryn J.

2013-01-01

Background Human regulatory T cells (Treg) offer an attractive adjunctive therapy to reduce current reliance on lifelong, nonspecific immunosuppression after transplantation. Here, we evaluated the ability of ex vivo expanded human Treg to prevent the rejection of islets of Langerhans in a humanized mouse model and examined the mechanisms involved. Methods We engrafted human pancreatic islets of Langerhans into the renal subcapsular space of immunodeficient BALB/c.rag2−/−.cγ−/− mice, previously rendered diabetic via injection of the β-cell toxin streptozocin. After the establishment of stable euglycemia, mice were reconstituted with allogeneic human peripheral blood mononuclear cells (PBMC) and the resultant alloreactive response studied. Ex vivo expanded CD25highCD4+ human Treg, which expressed FoxP3, CTLA-4, and CD62L and remained CD127low, were then cotransferred together with human PBMC and islet allografts and monitored for evidence of rejection. Results Human islets transplanted into diabetic immunodeficient mice reversed diabetes but were rejected rapidly after the mice were reconstituted with allogeneic human PBMC. Cotransfer of purified, ex vivo expanded human Treg prolonged islet allograft survival resulting in the accumulation of Treg in the peripheral lymphoid tissue and suppression of proliferation and interferon-γ production by T cells. In vitro, Treg suppressed activation of signal transducers and activators of transcription and inhibited the effector differentiation of responder T cells. Conclusions Ex vivo expanded Treg retain regulatory activity in vivo, can protect a human islet allograft from rejection by suppressing signal transducers and activators of transcription activation and inhibiting T-cell differentiation, and have clinical potential as an adjunctive cellular therapy. PMID:23917725

Requirements for psychological models to support design: Towards ecological task analysis

NASA Technical Reports Server (NTRS)

Kirlik, Alex

1991-01-01

Cognitive engineering is largely concerned with creating environmental designs to support skillful and effective human activity. A set of necessary conditions are proposed for psychological models capable of supporting this enterprise. An analysis of the psychological nature of the design product is used to identify a set of constraints that models must meet if they can usefully guide design. It is concluded that cognitive engineering requires models with resources for describing the integrated human-environment system, and that these models must be capable of describing the activities underlying fluent and effective interaction. These features are required in order to be able to predict the cognitive activity that will be required given various design concepts, and to design systems that promote the acquisition of fluent, skilled behavior. These necessary conditions suggest that an ecological approach can provide valuable resources for psychological modeling to support design. Relying heavily on concepts from Brunswik's and Gibson's ecological theories, ecological task analysis is proposed as a framework in which to predict the types of cognitive activity required to achieve productive behavior, and to suggest how interfaces can be manipulated to alleviate certain types of cognitive demands. The framework is described in terms, and illustrated with an example from the previous research on modeling skilled human-environment interaction.

Design strategies for human & earth systems modeling to meet emerging multi-scale decision support needs

NASA Astrophysics Data System (ADS)

Spak, S.; Pooley, M.

2012-12-01

The next generation of coupled human and earth systems models promises immense potential and grand challenges as they transition toward new roles as core tools for defining and living within planetary boundaries. New frontiers in community model development include not only computational, organizational, and geophysical process questions, but also the twin objectives of more meaningfully integrating the human dimension and extending applicability to informing policy decisions on a range of new and interconnected issues. We approach these challenges by posing key policy questions that require more comprehensive coupled human and geophysical models, identify necessary model and organizational processes and outputs, and work backwards to determine design criteria in response to these needs. We find that modular community earth system model design must: * seamlessly scale in space (global to urban) and time (nowcasting to paleo-studies) and fully coupled on all component systems * automatically differentiate to provide complete coupled forward and adjoint models for sensitivity studies, optimization applications, and 4DVAR assimilation across Earth and human observing systems * incorporate diagnostic tools to quantify uncertainty in couplings, and in how human activity affects them * integrate accessible community development and application with JIT-compilation, cloud computing, game-oriented interfaces, and crowd-sourced problem-solving We outline accessible near-term objectives toward these goals, and describe attempts to incorporate these design objectives in recent pilot activities using atmosphere-land-ocean-biosphere-human models (WRF-Chem, IBIS, UrbanSim) at urban and regional scales for policy applications in climate, energy, and air quality.

Opinion formation in a social network: The role of human activity

NASA Astrophysics Data System (ADS)

Grabowski, Andrzej

2009-03-01

The model of opinion formation in human population based on social impact theory is investigated numerically. On the basis of a database received from the on-line game server, we examine the structure of social network and human dynamics. We calculate the activity of individuals, i.e. the relative time devoted daily to interactions with others in the artificial society. We study the influence of correlation between the activity of an individual and its connectivity on the process of opinion formation. We find that such correlations have a significant influence on the temperature of the phase transition and the effect of the mass media, modeled as an external stimulation acting on the social network.

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.

Combining Regional- and Local-Scale Air Quality Models with Exposure Models for Use in Environmental Health Studies

EPA Science Inventory

Population-based human exposure models predict the distribution of personal exposures to pollutants of outdoor origin using a variety of inputs, including: air pollution concentrations; human activity patterns, such as the amount of time spent outdoors vs. indoors, commuting, wal...

MSEE: Stochastic Cognitive Linguistic Behavior Models for Semantic Sensing

DTIC Science & Technology

2013-09-01

recognition, a Gaussian Process Dynamic Model with Social Network Analysis (GPDM-SNA) for a small human group action recognition, an extended GPDM-SNA...44  3.2. Small Human Group Activity Modeling Based on Gaussian Process Dynamic Model and Social Network Analysis (SN-GPDM...51  Approved for public release; distribution unlimited. 3 3.2.3. Gaussian Process Dynamical Model and

Context in Models of Human-Machine Systems

NASA Technical Reports Server (NTRS)

Callantine, Todd J.; Null, Cynthia H. (Technical Monitor)

1998-01-01

All human-machine systems models represent context. This paper proposes a theory of context through which models may be usefully related and integrated for design. The paper presents examples of context representation in various models, describes an application to developing models for the Crew Activity Tracking System (CATS), and advances context as a foundation for integrated design of complex dynamic systems.

Hippocampal Morphology in a Rat Model of Depression: The Effects of Physical Activity

PubMed Central

Sierakowiak, Adam; Mattsson, Anna; Gómez-Galán, Marta; Feminía, Teresa; Graae, Lisette; Aski, Sahar Nikkhou; Damberg, Peter; Lindskog, Mia; Brené, Stefan; Åberg, Elin

2015-01-01

Accumulating in vivo and ex vivo evidences show that humans suffering from depression have decreased hippocampal volume and altered spine density. Moreover, physical activity has an antidepressant effect in humans and in animal models, but to what extent physical activity can affect hippocampal volume and spine numbers in a model for depression is not known. In this study we analyzed whether physical activity affects hippocampal volume and spine density by analyzing a rodent genetic model of depression, Flinders Sensitive Line Rats (FSL), with Magnetic Resonance Imaging (MRI) and ex vivo Golgi staining. We found that physical activity in the form of voluntary wheel running during 5 weeks increased hippocampal volume. Moreover, runners also had larger numbers of thin spines in the dentate gyrus. Our findings support that voluntary wheel running, which is antidepressive in FSL rats, is associated with increased hippocampal volume and spine numbers. PMID:25674191

Hippocampal morphology in a rat model of depression: the effects of physical activity.

PubMed

Sierakowiak, Adam; Mattsson, Anna; Gómez-Galán, Marta; Feminía, Teresa; Graae, Lisette; Aski, Sahar Nikkhou; Damberg, Peter; Lindskog, Mia; Brené, Stefan; Åberg, Elin

2014-01-01

Accumulating in vivo and ex vivo evidences show that humans suffering from depression have decreased hippocampal volume and altered spine density. Moreover, physical activity has an antidepressant effect in humans and in animal models, but to what extent physical activity can affect hippocampal volume and spine numbers in a model for depression is not known. In this study we analyzed whether physical activity affects hippocampal volume and spine density by analyzing a rodent genetic model of depression, Flinders Sensitive Line Rats (FSL), with Magnetic Resonance Imaging (MRI) and ex vivo Golgi staining. We found that physical activity in the form of voluntary wheel running during 5 weeks increased hippocampal volume. Moreover, runners also had larger numbers of thin spines in the dentate gyrus. Our findings support that voluntary wheel running, which is antidepressive in FSL rats, is associated with increased hippocampal volume and spine numbers.

Mouse Model of Human Hereditary Pancreatitis

DTIC Science & Technology

2015-09-01

constructed and tested. The primary structure of the trypsinogen activation peptide in mouse T7 trypsinogen is shown. Positions mutated are indicated. 1...trypsinogen designed to increase autoactivation (spontaneous conversion to active trypsin). All mutations targeted the so-called activation peptide , a...mutations, as we previously seen in studies on human cationic trypsinogen. A peculiarity of the trypsinogen activation peptide is the 5

Decoding Spontaneous Emotional States in the Human Brain

PubMed Central

Kragel, Philip A.; Knodt, Annchen R.; Hariri, Ahmad R.; LaBar, Kevin S.

2016-01-01

Pattern classification of human brain activity provides unique insight into the neural underpinnings of diverse mental states. These multivariate tools have recently been used within the field of affective neuroscience to classify distributed patterns of brain activation evoked during emotion induction procedures. Here we assess whether neural models developed to discriminate among distinct emotion categories exhibit predictive validity in the absence of exteroceptive emotional stimulation. In two experiments, we show that spontaneous fluctuations in human resting-state brain activity can be decoded into categories of experience delineating unique emotional states that exhibit spatiotemporal coherence, covary with individual differences in mood and personality traits, and predict on-line, self-reported feelings. These findings validate objective, brain-based models of emotion and show how emotional states dynamically emerge from the activity of separable neural systems. PMID:27627738

The efficacy and pharmacokinetics of brincidofovir for the treatment of lethal rabbitpox virus infection: a model of smallpox disease.

PubMed

Trost, Lawrence C; Rose, Michelle L; Khouri, Jody; Keilholz, Laurie; Long, James; Godin, Stephen J; Foster, Scott A

2015-05-01

Brincidofovir (BCV) has broad-spectrum in vitro activity against dsDNA viruses, including smallpox, and is being developed as a treatment for smallpox as well as infections caused by other dsDNA viruses. BCV has previously been shown to be active in multiple animal models of smallpox. Here we present the results of a randomized, blinded, placebo-controlled study of the efficacy and pharmacokinetics of a novel, "humanized" regimen of BCV for treatment of New Zealand White rabbits infected with a highly lethal inoculum of rabbitpox virus, a well characterized model of smallpox. Compared with placebo, a dose-dependent increase in survival was observed in all BCV-treatment groups. Concentrations of cidofovir diphosphate (CDV-PP), the active antiviral, in rabbit peripheral blood mononuclear cells (PBMCs) were determined for comparison to those produced in humans at the dose proposed for treatment of smallpox. CDV-PP exposure in PBMCs from rabbits given BCV scaled to human exposures at the dose proposed for treatment of smallpox, which is also currently under evaluation for other indications. The results of this study demonstrate the activity of BCV in the rabbitpox model of smallpox and the feasibility of scaling doses efficacious in the model to a proposed human dose and regimen for treatment of smallpox. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

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.

Predicting human activities in sequences of actions in RGB-D videos

NASA Astrophysics Data System (ADS)

Jardim, David; Nunes, Luís.; Dias, Miguel

2017-03-01

In our daily activities we perform prediction or anticipation when interacting with other humans or with objects. Prediction of human activity made by computers has several potential applications: surveillance systems, human computer interfaces, sports video analysis, human-robot-collaboration, games and health-care. We propose a system capable of recognizing and predicting human actions using supervised classifiers trained with automatically labeled data evaluated in our human activity RGB-D dataset (recorded with a Kinect sensor) and using only the position of the main skeleton joints to extract features. Using conditional random fields (CRFs) to model the sequential nature of actions in a sequence has been used before, but where other approaches try to predict an outcome or anticipate ahead in time (seconds), we try to predict what will be the next action of a subject. Our results show an activity prediction accuracy of 89.9% using an automatically labeled dataset.

To react or not to react? Intrinsic stochasticity of human control in virtual stick balancing

PubMed Central

Zgonnikov, Arkady; Lubashevsky, Ihor; Kanemoto, Shigeru; Miyazawa, Toru; Suzuki, Takashi

2014-01-01

Understanding how humans control unstable systems is central to many research problems, with applications ranging from quiet standing to aircraft landing. Increasingly, much evidence appears in favour of event-driven control hypothesis: human operators only start actively controlling the system when the discrepancy between the current and desired system states becomes large enough. The event-driven models based on the concept of threshold can explain many features of the experimentally observed dynamics. However, much still remains unclear about the dynamics of human-controlled systems, which likely indicates that humans use more intricate control mechanisms. This paper argues that control activation in humans may be not threshold-driven, but instead intrinsically stochastic, noise-driven. Specifically, we suggest that control activation stems from stochastic interplay between the operator's need to keep the controlled system near the goal state, on the one hand, and the tendency to postpone interrupting the system dynamics, on the other hand. We propose a model capturing this interplay and show that it matches the experimental data on human balancing of virtual overdamped stick. Our results illuminate that the noise-driven activation mechanism plays a crucial role at least in the considered task, and, hypothetically, in a broad range of human-controlled processes. PMID:25056217

Therapeutic effects of autologous lymphocytes activated with trastuzumab for xenograft mouse models of human breast cancer.

PubMed

Nakagawa, Shinichiro; Matsuoka, Yusuke; Ichihara, Hideaki; Yoshida, Hitoji; Yoshida, Kenshi; Ueoka, Ryuichi

2013-01-01

Trastuzumab (TTZ) is molecular targeted drug used for metastatic breast cancer patients overexpressing human epidermal growth factor receptor 2 (HER2). Therapeutic effects of lymphocytes activated with TTZ (TTZ-LAK) using xenograft mouse models of human breast cancer (MDA-MB-453) cells were examined in vivo. Remarkable reduction of tumor volume in a xenograft mouse models intravenously treated with TTZ-LAK cells after the subcutaneously inoculated of MDA-MB-453 cells was verified in vivo. The migration of TTZ-LAK cells in tumor of mouse models subcutaneously inoculated MDA-MB-453 cells was observed on the basis of histological analysis using immunostaining with CD-3. Induction of apoptosis in tumor of xenograft mice treated with TTZ-LAK cells was observed in micrographs using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) method. It was noteworthy that the therapeutic effects of TTZ-LAK cells along with apoptosis were obtained for xenograft mouse models of human breast tumor in vivo.

Decoding the Semantic Content of Natural Movies from Human Brain Activity

PubMed Central

Huth, Alexander G.; Lee, Tyler; Nishimoto, Shinji; Bilenko, Natalia Y.; Vu, An T.; Gallant, Jack L.

2016-01-01

One crucial test for any quantitative model of the brain is to show that the model can be used to accurately decode information from evoked brain activity. Several recent neuroimaging studies have decoded the structure or semantic content of static visual images from human brain activity. Here we present a decoding algorithm that makes it possible to decode detailed information about the object and action categories present in natural movies from human brain activity signals measured by functional MRI. Decoding is accomplished using a hierarchical logistic regression (HLR) model that is based on labels that were manually assigned from the WordNet semantic taxonomy. This model makes it possible to simultaneously decode information about both specific and general categories, while respecting the relationships between them. Our results show that we can decode the presence of many object and action categories from averaged blood-oxygen level-dependent (BOLD) responses with a high degree of accuracy (area under the ROC curve > 0.9). Furthermore, we used this framework to test whether semantic relationships defined in the WordNet taxonomy are represented the same way in the human brain. This analysis showed that hierarchical relationships between general categories and atypical examples, such as organism and plant, did not seem to be reflected in representations measured by BOLD fMRI. PMID:27781035

Human psychophysics and rodent spinal neurones exhibit peripheral and central mechanisms of inflammatory pain in the UVB and UVB heat rekindling models.

PubMed

O'Neill, Jessica; Sikandar, Shafaq; McMahon, Stephen B; Dickenson, Anthony H

2015-09-01

Translational research is key to bridging the gaps between preclinical findings and the patients, and a translational model of inflammatory pain will ideally induce both peripheral and central sensitisation, more effectively mimicking clinical pathophysiology in some chronic inflammatory conditions. We conducted a parallel investigation of two models of inflammatory pain, using ultraviolet B (UVB) irradiation alone and UVB irradiation with heat rekindling. We used rodent electrophysiology and human quantitative sensory testing to characterise nociceptive processing in the peripheral and central nervous systems in both models. In both species, UVB irradiation produces peripheral sensitisation measured as augmented evoked activity of rat dorsal horn neurones and increased perceptual responses of human subjects to mechanical and thermal stimuli. In both species, UVB with heat rekindling produces central sensitisation. UVB irradiation alone and UVB with heat rekindling are translational models of inflammation that produce peripheral and central sensitisation, respectively. The predictive value of laboratory models for human pain processing is crucial for improving translational research. The discrepancy between peripheral and central mechanisms of pain is an important consideration for drug targets, and here we describe two models of inflammatory pain that involve ultraviolet B (UVB) irradiation, which can employ peripheral and central sensitisation to produce mechanical and thermal hyperalgesia in rats and humans. We use electrophysiology in rats to measure the mechanically- and thermally-evoked activity of rat spinal neurones and quantitative sensory testing to assess human psychophysical responses to mechanical and thermal stimulation in a model of UVB irradiation and in a model of UVB irradiation with heat rekindling. Our results demonstrate peripheral sensitisation in both species driven by UVB irradiation, with a clear mechanical and thermal hypersensitivity of rat dorsal horn neurones and enhanced perceptual responses of human subjects to both mechanical and thermal stimulation. Additional heat rekindling produces markers of central sensitisation in both species, including enhanced receptive field sizes. Importantly, we also showed a correlation in the evoked activity of rat spinal neurones to human thermal pain thresholds. The parallel results in rats and humans validate the translational use of both models and the potential for such models for preclinical assessment of prospective analgesics in inflammatory pain states. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Chimeric mice transplanted with human hepatocytes as a model for prediction of human drug metabolism and pharmacokinetics.

PubMed

Sanoh, Seigo; Ohta, Shigeru

2014-03-01

Preclinical studies in animal models are used routinely during drug development, but species differences of pharmacokinetics (PK) between animals and humans have to be taken into account in interpreting the results. Human hepatocytes are also widely used to examine metabolic activities mediated by cytochrome P450 (P450) and other enzymes, but such in vitro metabolic studies also have limitations. Recently, chimeric mice with humanized liver (h-chimeric mice), generated by transplantation of human donor hepatocytes, have been developed as a model for the prediction of metabolism and PK in humans, using both in vitro and in vivo approaches. The expression of human-specific metabolic enzymes and metabolic activities was confirmed in humanized liver of h-chimeric mice with high replacement ratios, and several reports indicate that the profiles of P450 and non-P450 metabolism in these mice adequately reflect those in humans. Further, the combined use of h-chimeric mice and r-chimeric mice, in which endogenous hepatocytes are replaced with rat hepatocytes, is a promising approach for evaluation of species differences in drug metabolism. Recent work has shown that data obtained in h-chimeric mice enable the semi-quantitative prediction of not only metabolites, but also PK parameters, such as hepatic clearance, of drug candidates in humans, although some limitations remain because of differences in the metabolic activities, hepatic blood flow and liver structure between humans and mice. In addition, fresh h-hepatocytes can be isolated reproducibly from h-chimeric mice for metabolic studies. Copyright © 2013 John Wiley & Sons, Ltd.

Development of a landscape integrity model framework to support regional conservation planning.

PubMed

Walston, Leroy J; Hartmann, Heidi M

2018-01-01

Land managers increasingly rely upon landscape assessments to understand the status of natural resources and identify conservation priorities. Many of these landscape planning efforts rely on geospatial models that characterize the ecological integrity of the landscape. These general models utilize measures of habitat disturbance and human activity to map indices of ecological integrity. We built upon these modeling frameworks by developing a Landscape Integrity Index (LII) model using geospatial datasets of the human footprint, as well as incorporation of other indicators of ecological integrity such as biodiversity and vegetation departure. Our LII model serves as a general indicator of ecological integrity in a regional context of human activity, biodiversity, and change in habitat composition. We also discuss the application of the LII framework in two related coarse-filter landscape conservation approaches to expand the size and connectedness of protected areas as regional mitigation for anticipated land-use changes.

Development of a landscape integrity model framework to support regional conservation planning

PubMed Central

Hartmann, Heidi M.

2018-01-01

Land managers increasingly rely upon landscape assessments to understand the status of natural resources and identify conservation priorities. Many of these landscape planning efforts rely on geospatial models that characterize the ecological integrity of the landscape. These general models utilize measures of habitat disturbance and human activity to map indices of ecological integrity. We built upon these modeling frameworks by developing a Landscape Integrity Index (LII) model using geospatial datasets of the human footprint, as well as incorporation of other indicators of ecological integrity such as biodiversity and vegetation departure. Our LII model serves as a general indicator of ecological integrity in a regional context of human activity, biodiversity, and change in habitat composition. We also discuss the application of the LII framework in two related coarse-filter landscape conservation approaches to expand the size and connectedness of protected areas as regional mitigation for anticipated land-use changes. PMID:29614093

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

PubMed

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

2017-03-13

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

Humanized mouse lines and their application for prediction of human drug metabolism and toxicological risk assessment

PubMed Central

Cheung, Connie; Gonzalez, Frank J

2008-01-01

Cytochrome P450s (P450s) are important enzymes involved in the metabolism of xenobiotics, particularly clinically used drugs, and are also responsible for metabolic activation of chemical carcinogens and toxins. Many xenobiotics can activate nuclear receptors that in turn induce the expression of genes encoding xenobiotic metabolizing enzymes and drug transporters. Marked species differences in the expression and regulation of cytochromes P450 and xenobiotic nuclear receptors exist. Thus obtaining reliable rodent models to accurately reflect human drug and carcinogen metabolism is severely limited. Humanized transgenic mice were developed in an effort to create more reliable in vivo systems to study and predict human responses to xenobiotics. Human P450s or human xenobiotic-activated nuclear receptors were introduced directly or replaced the corresponding mouse gene, thus creating “humanized” transgenic mice. Mice expressing human CYP1A1/CYP1A2, CYP2E1, CYP2D6, CYP3A4, CY3A7, PXR, PPARα were generated and characterized. These humanized mouse models offers a broad utility in the evaluation and prediction of toxicological risk that may aid in the development of safer drugs. PMID:18682571

Discussion of Source Reconstruction Models Using 3D MCG Data

NASA Astrophysics Data System (ADS)

Melis, Massimo De; Uchikawa, Yoshinori

In this study we performed the source reconstruction of magnetocardiographic signals generated by the human heart activity to localize the site of origin of the heart activation. The localizations were performed in a four compartment model of the human volume conductor. The analyses were conducted on normal subjects and on a subject affected by the Wolff-Parkinson-White syndrome. Different models of the source activation were used to evaluate whether a general model of the current source can be applied in the study of the cardiac inverse problem. The data analyses were repeated using normal and vector component data of the MCG. The results show that a distributed source model has the better accuracy in performing the source reconstructions, and that 3D MCG data allow finding smaller differences between the different source models.

Ex vivo model of meningococcal bacteremia using human blood for measuring vaccine-induced serum passive protective activity.

PubMed

Plested, Joyce S; Welsch, Jo Anne; Granoff, Dan M

2009-06-01

The binding of complement factor H (fH) to meningococci was recently found to be specific for human fH. Therefore, passive protective antibody activity measured in animal models of meningococcal bacteremia may overestimate protection in humans, since in the absence of bound fH, complement activation is not downregulated. We developed an ex vivo model of meningococcal bacteremia using nonimmune human blood to measure the passive protective activity of stored sera from 36 adults who had been immunized with an investigational meningococcal multicomponent recombinant protein vaccine. Before immunization, human complement-mediated serum bactericidal activity (SBA) titers of > or = 1:4 against group B strains H44/76, NZ98/254, and S3032 were present in 19, 11, and 8% of subjects, respectively; these proportions increased to 97, 22, and 36%, respectively, 1 month after dose 3 (P < 0.01 for H44/76 and S3032). Against the two SBA-resistant strains, NZ98/254 and S3032, passive protective titers of > or = 1:4 were present in 11 and 42% of sera before immunization, respectively, and these proportions increased to 61 and 94% after immunization (P < 0.001 for each strain). Most of the sera with SBA titers of <1:4 and passive protective activity showed a level of killing in the whole-blood assay (>1 to 2 log(10) decreases in CFU/ml during a 90-min incubation) similar to that of sera with SBA titers of > or = 1:4. In conclusion, passive protective activity was 2.6- to 2.8-fold more frequent than SBA after immunization. The ability of SBA-negative sera to kill Neisseria meningitidis in human blood where fH is bound to the bacteria provides further evidence that SBA titers of > or = 1:4 measured with human complement may underestimate meningococcal immunity.

Combining Chimeric Mice with Humanized Liver, Mass Spectrometry, and Physiologically-Based Pharmacokinetic Modeling in Toxicology.

PubMed

Yamazaki, Hiroshi; Suemizu, Hiroshi; Mitsui, Marina; Shimizu, Makiko; Guengerich, F Peter

2016-12-19

Species differences exist in terms of drug oxidation activities, which are mediated mainly by cytochrome P450 (P450) enzymes. To overcome the problem of species extrapolation, transchromosomic mice containing a human P450 3A cluster or chimeric mice transplanted with human hepatocytes have been introduced into the human toxicology research area. In this review, drug metabolism and disposition mediated by humanized livers in chimeric mice are summarized in terms of biliary/urinary excretions of phthalate and bisphenol A and plasma clearances of the human cocktail probe drugs caffeine, warfarin, omeprazole, metoprolol, and midazolam. Simulation of human plasma concentrations of the teratogen thalidomide and its human metabolites is possible with a simplified physiologically based pharmacokinetic model based on data obtained in chimeric mice, in accordance with reported clinical thalidomide concentrations. In addition, in vivo nonspecific hepatic protein binding parameters of metabolically activated 14 C-drug candidate and hepatotoxic medicines in humanized liver mice can be analyzed by accelerator mass spectrometry and are useful for predictions in humans.

The anti-tumour activity of rLj-RGD4, an RGD toxin protein from Lampetra japonica, on human laryngeal squamous carcinoma Hep-2 cells in nude mice.

PubMed

Shao, Fangyu; Lv, Mei; Zheng, Yuanyuan; Jiang, Junshu; Wang, Yue; Lv, Li; Wang, Jihong

2015-12-01

The objective of this study is to investigate the antiproliferative activity and mechanism of integrin-binding rLj-RGD4 in a Hep-2 human laryngeal carcinoma-bearing nude mouse model. Human laryngeal squamous carcinoma cells (Hep-2) were inoculated subcutaneously into the axilla of nude mice to generate a Hep-2 human laryngeal carcinoma-bearing nude mouse model. When the Hep-2 xenograft model was successfully established, the animals were randomly separated into five groups. Three groups were treated with different dosages of rLj-RGD4. Cisplatin was administered to the positive control group, and normal saline (NaCl) was administered to the negative control group for 3 weeks. The body weights and the survival of the nude mice were evaluated, and the volumes and weights of the solid tumours were measured. The mechanism underlying rLj-RGD4 inhibition of tumour growth in transplanted Hep-2 human laryngeal carcinoma-bearing nude mice was evaluated by haematoxylin-eosin (HE) staining, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL), measurement of intratumoural microvessel density (MVD), Western blotting, and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The tumour volumes and weights of the treatment groups were reduced compared with the model group, and survival times were improved by rLj-RGD4 treatment in Hep-2 human laryngeal carcinoma-bearing nude mice. The number of apoptotic Hep-2 human cells and intratumoural MVD significantly decreased after the administration of rLj-RGD4. In the xenograft tissue of animals treated with rLj-RGD4, FAK, PI3K, and Akt expression was unaltered, whereas P-FAK, P-PI3K, Bcl-2, P-Akt, and VEGF levels were down-regulated. In addition, activated caspase-3, activated caspase-9, and Bax levels were up-regulated. rLj-RGD4 exhibits potent in vivo activity and inhibits the growth of transplanted Hep-2 human laryngeal carcinoma cells in a nude mouse model. Thus, these results indicate that the recombinant RGD toxin protein rLj-RGD4 may serve as a potent clinical therapy for human laryngeal squamous carcinoma. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

FXR activation by obeticholic acid or nonsteroidal agonists induces a human-like lipoprotein cholesterol change in mice with humanized chimeric liver.

PubMed

Papazyan, Romeo; Liu, Xueqing; Liu, Jingwen; Dong, Bin; Plummer, Emily M; Lewis, Ronald D; Roth, Jonathan D; Young, Mark A

2018-06-01

Obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist that regulates bile acid and lipid metabolism. FXR activation induces distinct changes in circulating cholesterol among animal models and humans. The mechanistic basis of these effects has been elusive because of difficulties in studying lipoprotein homeostasis in mice, which predominantly package circulating cholesterol in HDLs. Here, we tested the effects of OCA in chimeric mice whose livers are mostly composed (≥80%) of human hepatocytes. Chimeric mice exhibited a human-like ratio of serum LDL cholesterol (LDL-C) to HDL cholesterol (HDL-C) at baseline. OCA treatment in chimeric mice increased circulating LDL-C and decreased circulating HDL-C levels, demonstrating that these mice closely model the cholesterol effects of FXR activation in humans. Mechanistically, OCA treatment increased hepatic cholesterol in chimeric mice but not in control mice. This increase correlated with decreased SREBP-2 activity and target gene expression, including a significant reduction in LDL receptor protein. Cotreatment with atorvastatin reduced total cholesterol, rescued LDL receptor protein levels, and normalized serum LDL-C. Treatment with two clinically relevant nonsteroidal FXR agonists elicited similar lipoprotein and hepatic changes in chimeric mice, suggesting that the increase in circulating LDL-C is a class effect of FXR activation.

Human-induced shifts in geomorphic process rates: An example of landslide activity following forest cover change.

NASA Astrophysics Data System (ADS)

Guns, Marie; Balthazar, Vincent; Vanacker, Veerle

2013-04-01

Mountain regions present unique challenges and opportunities to land use change research. Very few, if any, mountain ecosystems remain unaffected by human impact. Based on the exemplary evidence from local case studies, it is not yet possible to have an overall assessment of the extent and impact of human activities on mountain erosion as mountain regions are typically characterized by rapid changes in geomorphic, cryospheric, climatic, hydrologic, ecological and socio-economic conditions over relatively short distances. Here, we present a conceptual model that allows evaluating human-induced shifts in geomorphic process rates. The basic idea behind this model is that the magnitude-frequency distribution of geomorphic processes is dependent on the intensity of human disturbance. The conceptual model is here applied for characterising landslide activity following forest cover change. We selected a tropical Andean catchment with a deforestation rate of 1.4% over the last 45 years. Landslide inventories were established based on historical aerial photographs (1963, 1977, and 1989) and very high-resolution satellite images (2010). Statistical analyses show that the total number of landslides is rising, and that they are increasingly associated with human disturbances (deforestation, road construction). This is particularly the case for shallow landslides that become more frequent after clearcutting. As the human-induced shifts in landslide activity are significant for the low-magnitude events only, the total impact on geomorphic process rates is rather limited in this particular area. This work shows that including information on the magnitude-frequency of geomorphic events before, during and after human disturbances offers new possibilities to quantify the complex response of geomorphic processes to human disturbances.

Contractile activity of human skeletal muscle cells prevents insulin resistance by inhibiting pro-inflammatory signalling pathways.

PubMed

Lambernd, S; Taube, A; Schober, A; Platzbecker, B; Görgens, S W; Schlich, R; Jeruschke, K; Weiss, J; Eckardt, K; Eckel, J

2012-04-01

Obesity is closely associated with muscle insulin resistance and is a major risk factor for the pathogenesis of type 2 diabetes. Regular physical activity not only prevents obesity, but also considerably improves insulin sensitivity and skeletal muscle metabolism. We sought to establish and characterise an in vitro model of human skeletal muscle contraction, with a view to directly studying the signalling pathways and mechanisms that are involved in the beneficial effects of muscle activity. Contracting human skeletal muscle cell cultures were established by applying electrical pulse stimulation. To induce insulin resistance, skeletal muscle cells were incubated with human adipocyte-derived conditioned medium, monocyte chemotactic protein (MCP)-1 and chemerin. Similarly to in exercising skeletal muscle in vivo, electrical pulse stimulation induced contractile activity in human skeletal muscle cells, combined with the formation of sarcomeres, activation of AMP-activated protein kinase (AMPK) and increased IL-6 secretion. Insulin-stimulated glucose uptake was substantially elevated in contracting cells compared with control. The incubation of skeletal muscle cells with adipocyte-conditioned media, chemerin and MCP-1 significantly reduced the insulin-stimulated phosphorylation of Akt. This effect was abrogated by concomitant pulse stimulation of the cells. Additionally, pro-inflammatory signalling by adipocyte-derived factors was completely prevented by electrical pulse stimulation of the myotubes. We showed that the effects of electrical pulse stimulation on skeletal muscle cells were similar to the effect of exercise on skeletal muscle in vivo in terms of enhanced AMPK activation and IL-6 secretion. In our model, muscle contractile activity eliminates insulin resistance by blocking pro-inflammatory signalling pathways. This novel model therefore provides a unique tool for investigating the molecular mechanisms that mediate the beneficial effects of muscle contraction.

Implementation and validation of the extended Hill-type muscle model with robust routing capabilities in LS-DYNA for active human body models.

PubMed

Kleinbach, Christian; Martynenko, Oleksandr; Promies, Janik; Haeufle, Daniel F B; Fehr, Jörg; Schmitt, Syn

2017-09-02

In the state of the art finite element AHBMs for car crash analysis in the LS-DYNA software material named *MAT_MUSCLE (*MAT_156) is used for active muscles modeling. It has three elements in parallel configuration, which has several major drawbacks: restraint approximation of the physical reality, complicated parameterization and absence of the integrated activation dynamics. This study presents implementation of the extended four element Hill-type muscle model with serial damping and eccentric force-velocity relation including [Formula: see text] dependent activation dynamics and internal method for physiological muscle routing. Proposed model was implemented into the general-purpose finite element (FE) simulation software LSDYNA as a user material for truss elements. This material model is verified and validated with three different sets of mammalian experimental data, taken from the literature. It is compared to the *MAT_MUSCLE (*MAT_156) Hill-type muscle model already existing in LS-DYNA, which is currently used in finite element human body models (HBMs). An application example with an arm model extracted from the FE ViVA OpenHBM is given, taking into account physiological muscle paths. The simulation results show better material model accuracy, calculation robustness and improved muscle routing capability compared to *MAT_156. The FORTRAN source code for the user material subroutine dyn21.f and the muscle parameters for all simulations, conducted in the study, are given at https://zenodo.org/record/826209 under an open source license. This enables a quick application of the proposed material model in LS-DYNA, especially in active human body models (AHBMs) for applications in automotive safety.

Double dynamic scaling in human communication dynamics

NASA Astrophysics Data System (ADS)

Wang, Shengfeng; Feng, Xin; Wu, Ye; Xiao, Jinhua

2017-05-01

In the last decades, human behavior has been deeply understanding owing to the huge quantities data of human behavior available for study. The main finding in human dynamics shows that temporal processes consist of high-activity bursty intervals alternating with long low-activity periods. A model, assuming the initiator of bursty follow a Poisson process, is widely used in the modeling of human behavior. Here, we provide further evidence for the hypothesis that different bursty intervals are independent. Furthermore, we introduce a special threshold to quantitatively distinguish the time scales of complex dynamics based on the hypothesis. Our results suggest that human communication behavior is a composite process of double dynamics with midrange memory length. The method for calculating memory length would enhance the performance of many sequence-dependent systems, such as server operation and topic identification.

Consolidated Human Activity Database (CHAD) for use in human exposure and health studies and predictive models

EPA Pesticide Factsheets

EPA scientists have compiled detailed data on human behavior from 22 separate exposure and time-use studies into CHAD. The database includes more than 54,000 individual study days of detailed human behavior.

Interaction studies reveal specific recognition of an anti-inflammatory polyphosphorhydrazone dendrimer by human monocytes

NASA Astrophysics Data System (ADS)

Ledall, Jérémy; Fruchon, Séverine; Garzoni, Matteo; Pavan, Giovanni M.; Caminade, Anne-Marie; Turrin, Cédric-Olivier; Blanzat, Muriel; Poupot, Rémy

2015-10-01

Dendrimers are nano-materials with perfectly defined structure and size, and multivalency properties that confer substantial advantages for biomedical applications. Previous work has shown that phosphorus-based polyphosphorhydrazone (PPH) dendrimers capped with azabisphosphonate (ABP) end groups have immuno-modulatory and anti-inflammatory properties leading to efficient therapeutic control of inflammatory diseases in animal models. These properties are mainly prompted through activation of monocytes. Here, we disclose new insights into the molecular mechanisms underlying the anti-inflammatory activation of human monocytes by ABP-capped PPH dendrimers. Following an interdisciplinary approach, we have characterized the physicochemical and biological behavior of the lead ABP dendrimer with model and cell membranes, and compared this experimental set of data to predictive computational modelling studies. The behavior of the ABP dendrimer was compared to the one of an isosteric analog dendrimer capped with twelve azabiscarboxylate (ABC) end groups instead of twelve ABP end groups. The ABC dendrimer displayed no biological activity on human monocytes, therefore it was considered as a negative control. In detail, we show that the ABP dendrimer can bind both non-specifically and specifically to the membrane of human monocytes. The specific binding leads to the internalization of the ABP dendrimer by human monocytes. On the contrary, the ABC dendrimer only interacts non-specifically with human monocytes and is not internalized. These data indicate that the bioactive ABP dendrimer is recognized by specific receptor(s) at the surface of human monocytes.Dendrimers are nano-materials with perfectly defined structure and size, and multivalency properties that confer substantial advantages for biomedical applications. Previous work has shown that phosphorus-based polyphosphorhydrazone (PPH) dendrimers capped with azabisphosphonate (ABP) end groups have immuno-modulatory and anti-inflammatory properties leading to efficient therapeutic control of inflammatory diseases in animal models. These properties are mainly prompted through activation of monocytes. Here, we disclose new insights into the molecular mechanisms underlying the anti-inflammatory activation of human monocytes by ABP-capped PPH dendrimers. Following an interdisciplinary approach, we have characterized the physicochemical and biological behavior of the lead ABP dendrimer with model and cell membranes, and compared this experimental set of data to predictive computational modelling studies. The behavior of the ABP dendrimer was compared to the one of an isosteric analog dendrimer capped with twelve azabiscarboxylate (ABC) end groups instead of twelve ABP end groups. The ABC dendrimer displayed no biological activity on human monocytes, therefore it was considered as a negative control. In detail, we show that the ABP dendrimer can bind both non-specifically and specifically to the membrane of human monocytes. The specific binding leads to the internalization of the ABP dendrimer by human monocytes. On the contrary, the ABC dendrimer only interacts non-specifically with human monocytes and is not internalized. These data indicate that the bioactive ABP dendrimer is recognized by specific receptor(s) at the surface of human monocytes. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr03884g

Investigating the American Time Use Survey from an exposure modeling perspective.

PubMed

George, Barbara Jane; McCurdy, Thomas

2011-01-01

This paper describes an evaluation of the US Bureau of Labor Statistics' American Time Use Survey (ATUS) for potential use in modeling human exposures to environmental pollutants. The ATUS is a large, on-going, cross-sectional survey of where Americans spend time and what activities they undertake in those locations. The data are reported as a series of sequential activities over a 24-h time period--a "diary day"--starting at 0400 hours. Between 12,000 and 13,000 surveys are obtained each year and the Bureau has plans to continue ATUS for the foreseeable future. The ATUS already has about 73,000 diary days of data, more than twice as many as that which currently exists in the US Environmental Protection Agency's (EPA) "Consolidated Human Activity Database" (CHAD) that the Agency uses for exposure modeling purposes. There are limitations for using ATUS in modeling human exposures to environmental pollutants. The ATUS does not report the location for a number of activities regarded as "personal." For 2006, personal activities with missing location information totaled 572 min/day, on average, for survey participants: about 40% of their day. Another limitation is that ATUS does not distinguish between indoor and outdoor activities at home, two of the traditional locational demarcations used in human exposure modeling. This lack of information affects exposure estimates to both indoor and outdoor air pollutants and potentially affects non-dietary ingestion estimates for children, which can vary widely depending on whether or not a child is indoors. Finally, a detailed analysis of the work travel activity in a subsample from ATUS 2006 indicates that the coding scheme is not fully consistent with a CHAD-based exposure modeling approach. For ATUS respondents in this subsample who reported work as an activity, roughly 48% of their days were missing work travel at one or both ends of the work shift or reported within work-shift travel inconsistently. An extensive effort would be needed to recode work travel data from ATUS for EPA's exposure modeling purposes.

A case for human systems neuroscience.

PubMed

Gardner, J L

2015-06-18

Can the human brain itself serve as a model for a systems neuroscience approach to understanding the human brain? After all, how the brain is able to create the richness and complexity of human behavior is still largely mysterious. What better choice to study that complexity than to study it in humans? However, measurements of brain activity typically need to be made non-invasively which puts severe constraints on what can be learned about the internal workings of the brain. Our approach has been to use a combination of psychophysics in which we can use human behavioral flexibility to make quantitative measurements of behavior and link those through computational models to measurements of cortical activity through magnetic resonance imaging. In particular, we have tested various computational hypotheses about what neural mechanisms could account for behavioral enhancement with spatial attention (Pestilli et al., 2011). Resting both on quantitative measurements and considerations of what is known through animal models, we concluded that weighting of sensory signals by the magnitude of their response is a neural mechanism for efficient selection of sensory signals and consequent improvements in behavioral performance with attention. While animal models have many technical advantages over studying the brain in humans, we believe that human systems neuroscience should endeavor to validate, replicate and extend basic knowledge learned from animal model systems and thus form a bridge to understanding how the brain creates the complex and rich cognitive capacities of humans. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Orthotopic mouse models for the preclinical and translational study of targeted therapies against metastatic human thyroid carcinoma with BRAFV600E or wild-type BRAF

PubMed Central

Antonello, ZA; Nucera, C

2015-01-01

Molecular signature of advanced and metastatic thyroid carcinoma involves deregulation of multiple fundamental pathways activated in the tumor microenvironment. They include BRAFV600E and AKT that affect tumor initiation, progression and metastasis. Human thyroid cancer orthotopic mouse models are based on human cell lines that generally harbor genetic alterations found in human thyroid cancers. They can reproduce in vivo and in situ (into the thyroid) many features of aggressive and refractory human advanced thyroid carcinomas, including local invasion and metastasis. Humanized orthotopic mouse models seem to be ideal and commonly used for preclinical and translational studies of compounds and therapies not only because they may mimic key aspects of human diseases (e.g. metastasis), but also for their reproducibility. In addition, they might provide the possibility to evaluate systemic effects of treatments. So far, human thyroid cancer in vivo models were mainly used to test single compounds, non selective and selective. Despite the greater antitumor activity and lower toxicity obtained with different selective drugs in respect to non-selective ones, most of them are only able to delay disease progression, which ultimately could restart with similar aggressive behavior. Aggressive thyroid tumors (for example, anaplastic or poorly differentiated thyroid carcinoma) carry several complex genetic alterations that are likely cooperating to promote disease progression and might confer resistance to single-compound approaches. Orthotopic models of human thyroid cancer also hold the potential to be good models for testing novel combinatorial therapies. In this article, we will summarize results on preclinical testing of selective and nonselective single compounds in orthotopic mouse models based on validated human thyroid cancer cell lines harboring the BRAFV600E mutation or with wild-type BRAF. Furthermore, we will discuss the potential use of this model also for combinatorial approaches, which are expected to take place in the upcoming human thyroid cancer basic and clinical research. PMID:24362526

Alternative complement pathway activation increases mortality in a model of burn injury in mice.

PubMed Central

Gelfand, J A; Donelan, M; Hawiger, A; Burke, J F

1982-01-01

We have studied the role of the complement system in burn injury in an experimental model in mice. A 25% body surface area, full-thickness scald wound was produced in anesthetized animals. Massive activation of the alternative complement pathway, but not the classical pathway, was seen. This activation was associated with the generation of neutrophil aggregating activity in the plasma, neutrophil aggregates in the lungs, increased pulmonary vascular permeability, and increased lung edema formation. Decomplementation with cobra venom factor (CVF) or genetic C5 deficiency diminished these pathologic changes, and CVF pretreatment substantially reduced burn mortality in the first 24 h. Preliminary data show that human burn patients have a similar pattern of complement activation involving predominantly the alternative pathway, indicating the possible relevance of the murine model to human disease. Images PMID:7174787

Advances and perspectives in in vitro human gut fermentation modeling.

PubMed

Payne, Amanda N; Zihler, Annina; Chassard, Christophe; Lacroix, Christophe

2012-01-01

The gut microbiota is a highly specialized organ containing host-specific assemblages of microbes whereby metabolic activity directly impacts human health and disease. In vitro gut fermentation models present an unmatched opportunity of performing studies frequently challenged in humans and animals owing to ethical concerns. Multidisciplinary systems biology analyses supported by '-omics' platforms remain widely neglected in the field of in vitro gut fermentation modeling but are key to advancing the significance of these models. Model-driven experimentation using a combination of in vitro gut fermentation and in vitro human cell models represent an advanced approach in identifying complex host-microbe interactions and niches central to gut fermentation processes. The aim of this review is to highlight the advances and challenges exhibited by in vitro human gut fermentation modeling. Copyright © 2011 Elsevier Ltd. All rights reserved.

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.

DEMONSTRATION OF HUMAN EXPOSURE TOOLS

EPA Science Inventory

The Human Exposure and Atmospheric Sciences Division (HEASD) of the National Exposure Research Laboratory (NERL) conducts research on exposure measurements, human activity patterns, exposure and dose models, and cumulative exposures critical for the Agency to make scientificall...

Chemical form of selenium affects its uptake, transport and glutathione peroxidase activity in the human intestinal Caco-2 cell model

USDA-ARS?s Scientific Manuscript database

Determining the effect of selenium (Se) chemical form on uptake and transport in human intestinal cells is critical to assess Se bioavailability. In the present study, we measured the uptake and transport of various Se compounds in the human intestinal Caco-2 cell model. We found that two sources...

Meganucleases Revolutionize the Production of Genetically Engineered Pigs for the Study of Human Diseases.

PubMed

Redel, Bethany K; Prather, Randall S

2016-04-01

Animal models of human diseases are critically necessary for developing an in-depth knowledge of disease development and progression. In addition, animal models are vital to the development of potential treatments or even cures for human diseases. Pigs are exceptional models as their size, physiology, and genetics are closer to that of humans than rodents. In this review, we discuss the use of pigs in human translational research and the evolving technology that has increased the efficiency of genetically engineering pigs. With the emergence of the clustered, regularly interspaced, short palindromic repeat (CRISPR)/CRISPR-associated (Cas) protein 9 system technology, the cost and time it takes to genetically engineer pigs has markedly decreased. We will also discuss the use of another meganuclease, the transcription activator-like effector nucleases , to produce pigs with severe combined immunodeficiency by developing targeted modifications of the recombination activating gene 2 (RAG2).RAG2mutant pigs may become excellent animals to facilitate the development of xenotransplantation, regenerative medicine, and tumor biology. The use of pig biomedical models is vital for furthering the knowledge of, and for treating human, diseases. © The Author(s) 2015.

UWB pulse propagation into human tissues

NASA Astrophysics Data System (ADS)

Cavagnaro, Marta; Pittella, Erika; Pisa, Stefano

2013-12-01

In this paper the propagation of a UWB pulse into a layered model of the human body is studied to characterize absorption and reflection of the UWB signal due to the different body tissues. Several time behaviours for the incident UWB pulse are considered and compared with reference to the feasibility of breath and heartbeat activity monitoring. Results show that if the UWB source is placed far from the human body, the reflection coming from the interface between air and skin can be used to detect the respiratory activity. On the contrary, if the UWB source is placed close to the human body, a small reflection due to the interface between the posterior lung wall and the bone, which is well distanced in time from the reflections due to the first layers of the body model, can be used to detect lung and heart changes associated with the cardio-respiratory activity.

Activation status of the Pregnane X Receptor (PXR) influences Vemurafenib availability in humanized mouse models

PubMed Central

MacLeod, A. Kenneth; McLaughlin, Lesley A.; Henderson, Colin J.; Wolf, C. Roland

2015-01-01

Vemurafenib is a revolutionary treatment for melanoma, but the magnitude of therapeutic response is highly variable and the rapid acquisition of resistance is frequent. Here, we examined how vemurafenib disposition, particularly through cytochrome P450-mediated oxidation pathways, could potentially influence these outcomes using a panel of knockout and transgenic humanized mouse models. We identified CYP3A4 as the major enzyme involved in the metabolism of vemurafenib in in vitro assays with human liver microsomes. However, mice expressing human CYP3A4 did not process vemurafenib to a greater extent than CYP3A4 null animals, suggesting that other pregnane X receptor (PXR)-regulated pathways may contribute more significantly to vemurafenib metabolism in vivo. Activation of PXR, but not of the closely related constitutive androstane receptor (CAR), profoundly reduced circulating levels of vemurafenib in humanized mice. This effect was independent of CYP3A4 and was negated by co-treatment with the drug efflux transporter inhibitor, elacridar. Finally, vemurafenib strongly induced PXR activity in vitro, but only weakly induced PXR in vivo. Taken together, our findings demonstrate that vemurafenib is unlikely to exhibit a clinically significant interaction with CYP3A4, but that modulation of bioavailability through PXR-mediated regulation of drug transporters (for example by other drugs) has the potential to markedly influence systemic exposure and thereby therapeutic outcomes. Activation status of the Pregnane X Receptor (PXR) influences Vemurafenib availability in humanized mouse models. PMID:26363009

Changes in river water temperature between 1980 and 2012 in Yongan watershed, eastern China: Magnitude, drivers and models

NASA Astrophysics Data System (ADS)

Chen, Dingjiang; Hu, Minpeng; Guo, Yi; Dahlgren, Randy A.

2016-02-01

Climate warming is expected to have major impacts on river water quality, water column/hyporheic zone biogeochemistry and aquatic ecosystems. A quantitative understanding of spatio-temporal air (Ta) and water (Tw) temperature dynamics is required to guide river management and to facilitate adaptations to climate change. This study determined the magnitude, drivers and models for increasing Tw in three river segments of the Yongan watershed in eastern China. Over the 1980-2012 period, Tw in the watershed increased by 0.029-0.046 °C yr-1 due to a ∼0.050 °C yr-1 increase of Ta and changes in local human activities (e.g., increasing developed land and population density and decreasing forest area). A standardized multiple regression model was developed for predicting annual Tw (R2 = 0.88-0.91) and identifying/partitioning the impact of the principal drivers on increasing Tw:Ta (76 ± 1%), local human activities (14 ± 2%), and water discharge (10 ± 1%). After normalizing water discharge, climate warming and local human activities were estimated to contribute 81-95% and 5-19% of the observed rising Tw, respectively. Models forecast a 0.32-1.76 °C increase in Tw by 2050 compared with the 2000-2012 baseline condition based on four future scenarios. Heterogeneity of warming rates existed across seasons and river segments, with the lower flow river and dry season demonstrating a more pronounced response to climate warming and human activities. Rising Tw due to changes in climate, local human activities and hydrology has a considerable potential to aggravate river water quality degradation and coastal water eutrophication in summer. Thus it should be carefully considered in developing watershed management strategies in response to climate change.

Augmentation of Antitumor Immunity by Human and Mouse CAR T Cells Secreting IL-18.

PubMed

Hu, Biliang; Ren, Jiangtao; Luo, Yanping; Keith, Brian; Young, Regina M; Scholler, John; Zhao, Yangbing; June, Carl H

2017-09-26

The effects of transgenically encoded human and mouse IL-18 on T cell proliferation and its application in boosting chimeric antigen receptor (CAR) T cells are presented. Robust enhancement of proliferation of IL-18-secreting human T cells occurred in a xenograft model, and this was dependent on TCR and IL-18R signaling. IL-18 augmented IFN-γ secretion and proliferation of T cells activated by the endogenous TCR. TCR-deficient, human IL-18-expressing CD19 CAR T cells exhibited enhanced proliferation and antitumor activity in the xenograft model. Antigen-propelled activation of cytokine helper ensemble (APACHE) CAR T cells displayed inducible expression of IL-18 and enhanced antitumor immunity. In an intact mouse tumor model, CD19-IL-18 CAR T cells induced deeper B cell aplasia, significantly enhanced CAR T cell proliferation, and effectively augmented antitumor effects in mice with B16F10 melanoma. These findings point to a strategy to develop universal CAR T cells for patients with solid tumors. Copyright © 2017. Published by Elsevier Inc.

Space Life Sciences Directorate's Position on the Physiological Effects of Exposing the Crewmemeber to Low-Voltage Electrical Hazards During Extravehicular Activity

NASA Technical Reports Server (NTRS)

Hamilton, Douglas; Kramer, Leonard; Mikatarian, Ron; Polk, James; Duncan, Michael; Koontz, Steven

2010-01-01

The models predict that, for low voltage exposures in the space suit, physiologically active current could be conducted across the crew member causing catastrophic hazards. Future work with Naval Health Research Center Detachment Directed Energy Bio-effects Laboratory is being proposed to analyze additional current paths across the human torso and upper limbs. These models may need to be verified with human studies.

Impacts of human activity modes and climate on heavy metal "spread" in groundwater are biased.

PubMed

Chen, Ming; Qin, Xiaosheng; Zeng, Guangming; Li, Jian

2016-06-01

Groundwater quality deterioration has attracted world-wide concerns due to its importance for human water supply. Although more and more studies have shown that human activities and climate are changing the groundwater status, an investigation on how different groundwater heavy metals respond to human activity modes (e.g. mining, waste disposal, agriculture, sewage effluent and complex activity) in a varying climate has been lacking. Here, for each of six heavy metals (i.e. Fe, Zn, Mn, Pb, Cd and Cu) in groundwater, we use >330 data points together with mixed-effect models to indicate that (i) human activity modes significantly influence the Cu and Mn but not Zn, Fe, Pb and Cd levels, and (ii) annual mean temperature (AMT) only significantly influences Cu and Pb levels, while annual precipitation (AP) only significantly affects Fe, Cu and Mn levels. Given these differences, we suggest that the impacts of human activity modes and climate on heavy metal "spread" in groundwater are biased. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pharmacologic inhibition of MEK signaling prevents growth of canine hemangiosarcoma.

PubMed

Andersen, Nicholas J; Nickoloff, Brian J; Dykema, Karl J; Boguslawski, Elissa A; Krivochenitser, Roman I; Froman, Roe E; Dawes, Michelle J; Baker, Laurence H; Thomas, Dafydd G; Kamstock, Debra A; Kitchell, Barbara E; Furge, Kyle A; Duesbery, Nicholas S

2013-09-01

Angiosarcoma is a rare neoplasm of endothelial origin that has limited treatment options and poor five-year survival. As a model for human angiosarcoma, we studied primary cells and tumorgrafts derived from canine hemangiosarcoma (HSA), which is also an endothelial malignancy with similar presentation and histology. Primary cells isolated from HSA showed constitutive extracellular signal-regulated kinase (ERK) activation. The mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor CI-1040 reduced ERK activation and the viability of primary cells derived from visceral, cutaneous, and cardiac HSA in vitro. HSA-derived primary cells were also sensitive to sorafenib, an inhibitor of B-Raf and multireceptor tyrosine kinases. In vivo, CI-1040 or PD0325901 decreased the growth of cutaneous cell-derived xenografts and cardiac-derived tumorgrafts. Sorafenib decreased tumor size in both in vivo models, although cardiac tumorgrafts were more sensitive. In human angiosarcoma, we noted that 50% of tumors stained positively for phosphorylated ERK1/2 and that the expression of several MEK-responsive transcription factors was upregulated. Our data showed that MEK signaling is essential for the growth of HSA in vitro and in vivo and provided evidence that the same pathways are activated in human angiosarcoma. This indicates that MEK inhibitors may form part of an effective therapeutic strategy for the treatment of canine HSA or human angiosarcoma, and it highlights the use of spontaneous canine cancers as a model of human disease.

*Combining regional - and local-scale air quality models with exposure models for use in environmental health studies - Title changed from Linking air quality and exposure models for use in environmental health studies

EPA Science Inventory

Population-based human exposure models predict the distribution of personal exposures to pollutants of outdoor origin using a variety of inputs, including air pollution concentrations; human activity patterns, such as the amount of time spent outdoors versus indoors, commuting, w...

A dual-loop model of the human controller

NASA Technical Reports Server (NTRS)

Hess, R. A.

1977-01-01

A representative model of the human controller in single-axis compensatory tracking tasks that exhibits an internal feedback loop which is not evident in single-loop models now in common use is presented. This hypothetical inner-loop involves a neuromuscular command signal derived from the time rate of change of controlled element output which is due to control activity. It is not contended that the single-loop human controller models now in use are incorrect, but that they contain an implicit but important internal loop closure, which, if explicitly considered, can account for a good deal of the adaptive nature of the human controller in a systematic manner.

Modeling Liver-Related Adverse Effects of Drugs Using kNN QSAR Method

PubMed Central

Rodgers, Amie D.; Zhu, Hao; Fourches, Dennis; Rusyn, Ivan; Tropsha, Alexander

2010-01-01

Adverse effects of drugs (AEDs) continue to be a major cause of drug withdrawals both in development and post-marketing. While liver-related AEDs are a major concern for drug safety, there are few in silico models for predicting human liver toxicity for drug candidates. We have applied the Quantitative Structure Activity Relationship (QSAR) approach to model liver AEDs. In this study, we aimed to construct a QSAR model capable of binary classification (active vs. inactive) of drugs for liver AEDs based on chemical structure. To build QSAR models, we have employed an FDA spontaneous reporting database of human liver AEDs (elevations in activity of serum liver enzymes), which contains data on approximately 500 approved drugs. Approximately 200 compounds with wide clinical data coverage, structural similarity and balanced (40/60) active/inactive ratio were selected for modeling and divided into multiple training/test and external validation sets. QSAR models were developed using the k nearest neighbor method and validated using external datasets. Models with high sensitivity (>73%) and specificity (>94%) for prediction of liver AEDs in external validation sets were developed. To test applicability of the models, three chemical databases (World Drug Index, Prestwick Chemical Library, and Biowisdom Liver Intelligence Module) were screened in silico and the validity of predictions was determined, where possible, by comparing model-based classification with assertions in publicly available literature. Validated QSAR models of liver AEDs based on the data from the FDA spontaneous reporting system can be employed as sensitive and specific predictors of AEDs in pre-clinical screening of drug candidates for potential hepatotoxicity in humans. PMID:20192250

Operator function modeling: Cognitive task analysis, modeling and intelligent aiding in supervisory control systems

NASA Technical Reports Server (NTRS)

Mitchell, Christine M.

1990-01-01

The design, implementation, and empirical evaluation of task-analytic models and intelligent aids for operators in the control of complex dynamic systems, specifically aerospace systems, are studied. Three related activities are included: (1) the models of operator decision making in complex and predominantly automated space systems were used and developed; (2) the Operator Function Model (OFM) was used to represent operator activities; and (3) Operator Function Model Expert System (OFMspert), a stand-alone knowledge-based system was developed, that interacts with a human operator in a manner similar to a human assistant in the control of aerospace systems. OFMspert is an architecture for an operator's assistant that uses the OFM as its system and operator knowledge base and a blackboard paradigm of problem solving to dynamically generate expectations about upcoming operator activities and interpreting actual operator actions. An experiment validated the OFMspert's intent inferencing capability and showed that it inferred the intentions of operators in ways comparable to both a human expert and operators themselves. OFMspert was also augmented with control capabilities. An interface allowed the operator to interact with OFMspert, delegating as much or as little control responsibility as the operator chose. With its design based on the OFM, OFMspert's control capabilities were available at multiple levels of abstraction and allowed the operator a great deal of discretion over the amount and level of delegated control. An experiment showed that overall system performance was comparable for teams consisting of two human operators versus a human operator and OFMspert team.

Anatomically realistic multiscale models of normal and abnormal gastrointestinal electrical activity

PubMed Central

Cheng, Leo K; Komuro, Rie; Austin, Travis M; Buist, Martin L; Pullan, Andrew J

2007-01-01

One of the major aims of the International Union of Physiological Sciences (IUPS) Physiome Project is to develop multiscale mathematical and computer models that can be used to help understand human health. We present here a small facet of this broad plan that applies to the gastrointestinal system. Specifically, we present an anatomically and physiologically based modelling framework that is capable of simulating normal and pathological electrical activity within the stomach and small intestine. The continuum models used within this framework have been created using anatomical information derived from common medical imaging modalities and data from the Visible Human Project. These models explicitly incorporate the various smooth muscle layers and networks of interstitial cells of Cajal (ICC) that are known to exist within the walls of the stomach and small bowel. Electrical activity within individual ICCs and smooth muscle cells is simulated using a previously published simplified representation of the cell level electrical activity. This simulated cell level activity is incorporated into a bidomain representation of the tissue, allowing electrical activity of the entire stomach or intestine to be simulated in the anatomically derived models. This electrical modelling framework successfully replicates many of the qualitative features of the slow wave activity within the stomach and intestine and has also been used to investigate activity associated with functional uncoupling of the stomach. PMID:17457969

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.

Campaign datasets for Observations and Modeling of the Green Ocean Amazon (GOAMAZON)

DOE Data Explorer

Martin,Scot; Mei,Fan; Alexander,Lizabeth; Artaxo,Paulo; Barbosa,Henrique; Bartholomew,Mary Jane; Biscaro,Thiago; Buseck,Peter; Chand,Duli; Comstock,Jennifer; Dubey,Manvendra; Godstein,Allen; Guenther,Alex; Hubbe,John; Jardine,Kolby; Jimenez,Jose-Luis; Kim,Saewung; Kuang,Chongai; Laskin,Alexander; Long,Chuck; Paralovo,Sarah; Petaja,Tuukka; Powers,Heath; Schumacher,Courtney; Sedlacek,Arthur; Senum,Gunnar; Smith,James; Shilling,John; Springston,Stephen; Thayer,Mitchell; Tomlinson,Jason; Wang,Jian; Xie,Shaocheng

2016-05-30

The hydrologic cycle of the Amazon Basin is one of the primary heat engines of the Southern Hemisphere. Any accurate climate model must succeed in a good description of the Basin, both in its natural state and in states perturbed by regional and global human activities. At the present time, however, tropical deep convection in a natural state is poorly understood and modeled, with insufficient observational data sets for model constraint. Furthermore, future climate scenarios resulting from human activities globally show the possible drying and the eventual possible conversion of rain forest to savanna in response to global climate change. Based on our current state of knowledge, the governing conditions of this catastrophic change are not defined. Human activities locally, including the economic development activities that are growing the population and the industry within the Basin, also have the potential to shift regional climate, most immediately by an increment in aerosol number and mass concentrations, and the shift is across the range of values to which cloud properties are most sensitive. The ARM Climate Research Facility in the Amazon Basin seeks to understand aerosol and cloud life cycles, particularly the susceptibility to cloud aerosol precipitation interactions, within the Amazon Basin.

Muscle short-range stiffness can be used to estimate the endpoint stiffness of the human arm

PubMed Central

Hu, Xiao; Murray, Wendy M.

2011-01-01

The mechanical properties of the human arm are regulated to maintain stability across many tasks. The static mechanics of the arm can be characterized by estimates of endpoint stiffness, considered especially relevant for the maintenance of posture. At a fixed posture, endpoint stiffness can be regulated by changes in muscle activation, but which activation-dependent muscle properties contribute to this global measure of limb mechanics remains unclear. We evaluated the role of muscle properties in the regulation of endpoint stiffness by incorporating scalable models of muscle stiffness into a three-dimensional musculoskeletal model of the human arm. Two classes of muscle models were tested: one characterizing short-range stiffness and two estimating stiffness from the slope of the force-length curve. All models were compared with previously collected experimental data describing how endpoint stiffness varies with changes in voluntary force. Importantly, muscle properties were not fit to the experimental data but scaled only by the geometry of individual muscles in the model. We found that force-dependent variations in endpoint stiffness were accurately described by the short-range stiffness of active arm muscles. Over the wide range of evaluated arm postures and voluntary forces, the musculoskeletal model incorporating short-range stiffness accounted for 98 ± 2, 91 ± 4, and 82 ± 12% of the variance in stiffness orientation, shape, and area, respectively, across all simulated subjects. In contrast, estimates based on muscle force-length curves were less accurate in all measures, especially stiffness area. These results suggest that muscle short-range stiffness is a major contributor to endpoint stiffness of the human arm. Furthermore, the developed model provides an important tool for assessing how the nervous system may regulate endpoint stiffness via changes in muscle activation. PMID:21289133

Biological Tools to Study the Effects of Environmental Contaminants at the Feto–Maternal Interface

PubMed Central

Mannelli, Chiara; Ietta, Francesca; Avanzati, Anna Maria; Skarzynski, Dariusz

2015-01-01

The identification of reproductive toxicants is a major scientific challenge for human health. Prenatal life is the most vulnerable and important time span of human development. For obvious ethical reasons, in vivo models cannot be used in human pregnancy, and animal models do not perfectly reflect human physiology. This review describes the in vitro test models representative of the human feto–maternal interface and the effects of environmental chemicals with estrogen-like activity, mainly bisphenol A and para-nonylphenol, with a particular emphasis on the effects at low, nontoxic doses similar to concentrations commonly detected in the population. PMID:26740808

Human Centered Hardware Modeling and Collaboration

NASA Technical Reports Server (NTRS)

Stambolian Damon; Lawrence, Brad; Stelges, Katrine; Henderson, Gena

2013-01-01

In order to collaborate engineering designs among NASA Centers and customers, to in clude hardware and human activities from multiple remote locations, live human-centered modeling and collaboration across several sites has been successfully facilitated by Kennedy Space Center. The focus of this paper includes innovative a pproaches to engineering design analyses and training, along with research being conducted to apply new technologies for tracking, immersing, and evaluating humans as well as rocket, vehic le, component, or faci lity hardware utilizing high resolution cameras, motion tracking, ergonomic analysis, biomedical monitoring, wor k instruction integration, head-mounted displays, and other innovative human-system integration modeling, simulation, and collaboration applications.

The Cool and Belkin Faceted Classification of Information Interactions Revisited

ERIC Educational Resources Information Center

Huvila, Isto

2010-01-01

Introduction: The complexity of human information activity is a challenge for both practice and research in information sciences and information management. Literature presents a wealth of approaches to analytically structure and make sense of human information activity including a faceted classification model of information interactions published…

Structure and dynamics of zymogen human blood coagulation factor X.

PubMed

Venkateswarlu, Divi; Perera, Lalith; Darden, Tom; Pedersen, Lee G

2002-03-01

The solution structure and dynamics of the human coagulation factor X (FX) have been investigated to understand the key structural elements in the zymogenic form that participates in the activation process. The model was constructed based on the 2.3-A-resolution x-ray crystallographic structure of active-site inhibited human FXa (PDB:1XKA). The missing gamma-carboxyglutamic acid (GLA) and part of epidermal growth factor 1 (EGF1) domains of the light chain were modeled based on the template of GLA-EGF1 domains of the tissue factor (TF)-bound FVIIa structure (PDB:1DAN). The activation peptide and other missing segments of FX were introduced using homology modeling. The full calcium-bound model of FX was subjected to 6.2 ns of molecular dynamics simulation in aqueous medium using the AMBER6.0 package. We observed significant reorientation of the serine-protease (SP) domain upon activation leading to a compact multi-domain structure. The solution structure of zymogen appears to be in a well-extended conformation with the distance between the calcium ions in the GLA domain and the catalytic residues estimated to be approximately 95 A in contrast to approximately 83 A in the activated form. The latter is in close agreement with fluorescence studies on FXa. The S1-specificity residues near the catalytic triad show significant differences between the zymogen and activated structures.

Mechanisms of anaphylaxis in human low-affinity IgG receptor locus knock-in mice.

PubMed

Gillis, Caitlin M; Jönsson, Friederike; Mancardi, David A; Tu, Naxin; Beutier, Héloïse; Van Rooijen, Nico; Macdonald, Lynn E; Murphy, Andrew J; Bruhns, Pierre

2017-04-01

Anaphylaxis can proceed through distinct IgE- or IgG-dependent pathways, which have been investigated in various mouse models. We developed a novel mouse strain in which the human low-affinity IgG receptor locus, comprising both activating (hFcγRIIA, hFcγRIIIA, and hFcγRIIIB) and inhibitory (hFcγRIIB) hFcγR genes, has been inserted into the equivalent murine locus, corresponding to a locus swap. We sought to determine the capabilities of hFcγRs to induce systemic anaphylaxis and identify the cell types and mediators involved. hFcγR expression on mouse and human cells was compared to validate the model. Passive systemic anaphylaxis was induced by injection of heat-aggregated human intravenous immunoglobulin and active systemic anaphylaxis after immunization and challenge. Anaphylaxis severity was evaluated based on hypothermia and mortality. The contribution of receptors, mediators, or cell types was assessed based on receptor blockade or depletion. The human-to-mouse low-affinity FcγR locus swap engendered hFcγRIIA/IIB/IIIA/IIIB expression in mice comparable with that seen in human subjects. Knock-in mice were susceptible to passive and active anaphylaxis, accompanied by downregulation of both activating and inhibitory hFcγR expression on specific myeloid cells. The contribution of hFcγRIIA was predominant. Depletion of neutrophils protected against hypothermia and mortality. Basophils contributed to a lesser extent. Anaphylaxis was inhibited by platelet-activating factor receptor or histamine receptor 1 blockade. Low-affinity FcγR locus-switched mice represent an unprecedented model of cognate hFcγR expression. Importantly, IgG-related anaphylaxis proceeds within a native context of activating and inhibitory hFcγRs, indicating that, despite robust hFcγRIIB expression, activating signals can dominate to initiate a severe anaphylactic reaction. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

PREDICTING POPULATION EXPOSURES TO PM: THE IMPORTANCE OF MICROENVIRONMENTAL CONCENTRATIONS AND HUMAN ACTIVITIES

EPA Science Inventory

The Stochastic Human Exposure and Dose Simulation (SHEDS) models being developed by the US EPA/NERL use a probabilistic approach to predict population exposures to pollutants. The SHEDS model for particulate matter (SHEDS-PM) estimates the population distribution of PM exposure...

On the Modeling of Electrical Effects Experienced by Space Explorers During Extra Vehicular Activities: Intracorporal Currents, Resistances, and Electric Fields

NASA Technical Reports Server (NTRS)

Cela, Carlos J.; Loizos, Kyle; Lazzi, Gianluca; Hamilton, Douglas; Lee, Raphael C.

2011-01-01

Recent research has shown that space explorers engaged in Extra Vehicular Activities (EVAs) may be exposed, under certain conditions, to undesired electrical currents. This work focuses on determining whether these undesired induced electrical currents could be responsible for involuntary neuromuscular activity in the subjects, possibly caused by either large diameter peripheral nerve activation or reflex activity from cutaneous afferent stimulation. An efficient multiresolution variant of the admittance method along with a millimeter-resolution model of a male human body were used to calculate induced electric fields, resistance between contact electrodes used to simulate the potential exposure condition, and currents induced in the human body model. Results show that, under realistic exposure conditions using a 15V source, current density magnitudes and total current injected are well above previously reported startle reaction thresholds. This indicates that, under the considered conditions, the subjects could experience involuntary motor response.

Active Learning of Classification Models with Likert-Scale Feedback.

PubMed

Xue, Yanbing; Hauskrecht, Milos

2017-01-01

Annotation of classification data by humans can be a time-consuming and tedious process. Finding ways of reducing the annotation effort is critical for building the classification models in practice and for applying them to a variety of classification tasks. In this paper, we develop a new active learning framework that combines two strategies to reduce the annotation effort. First, it relies on label uncertainty information obtained from the human in terms of the Likert-scale feedback. Second, it uses active learning to annotate examples with the greatest expected change. We propose a Bayesian approach to calculate the expectation and an incremental SVM solver to reduce the time complexity of the solvers. We show the combination of our active learning strategy and the Likert-scale feedback can learn classification models more rapidly and with a smaller number of labeled instances than methods that rely on either Likert-scale labels or active learning alone.

Active Learning of Classification Models with Likert-Scale Feedback

PubMed Central

Xue, Yanbing; Hauskrecht, Milos

2017-01-01

Annotation of classification data by humans can be a time-consuming and tedious process. Finding ways of reducing the annotation effort is critical for building the classification models in practice and for applying them to a variety of classification tasks. In this paper, we develop a new active learning framework that combines two strategies to reduce the annotation effort. First, it relies on label uncertainty information obtained from the human in terms of the Likert-scale feedback. Second, it uses active learning to annotate examples with the greatest expected change. We propose a Bayesian approach to calculate the expectation and an incremental SVM solver to reduce the time complexity of the solvers. We show the combination of our active learning strategy and the Likert-scale feedback can learn classification models more rapidly and with a smaller number of labeled instances than methods that rely on either Likert-scale labels or active learning alone. PMID:28979827

High Efficiency Latency and Activation of Herpes Simplex Virus in Human Cells

NASA Astrophysics Data System (ADS)

Wigdahl, Brian L.; Scheck, Adrienne C.; de Clercq, Erik; Rapp, Fred

1982-09-01

Herpes simplex virus (HSV) exists in humans in a latent form that can be activated. To characterize the molecular basis of the cell-virus interactions and to analyze the state of the latent HSV genome, an in vitro model system was established. In this system a large fraction of the latently infected cells contain an HSV genome that can be activated. Cell survival was reduced minimally after repression of high multiplicity HSV type 1 (HSV-1) infection of human fibroblast cells with (E)-5-(2-bromovinyl)-2'-deoxyuridine in combination with human leukocyte interferon (IFN-α ). A minimum of 1 to 3 percent of the surviving cells contained an HSV genome that could be activated either by human cytomegalovirus superinfection or reduction in incubation temperature.

Three-dimensional quantitative structure-activity relationship study on anti-cancer activity of 3,4-dihydroquinazoline derivatives against human lung cancer A549 cells

NASA Astrophysics Data System (ADS)

Cho, Sehyeon; Choi, Min Ji; Kim, Minju; Lee, Sunhoe; Lee, Jinsung; Lee, Seok Joon; Cho, Haelim; Lee, Kyung-Tae; Lee, Jae Yeol

2015-03-01

A series of 3,4-dihydroquinazoline derivatives with anti-cancer activities against human lung cancer A549 cells were subjected to three-dimensional quantitative structure-activity relationship (3D-QSAR) studies using the comparative molecular similarity indices analysis (CoMSIA) approaches. The most potent compound, 1 was used to align the molecules. As a result, the best prediction was obtained with CoMSIA combined the steric, electrostatic, hydrophobic, hydrogen bond donor, and hydrogen bond acceptor fields (q2 = 0.720, r2 = 0.897). This model was validated by an external test set of 6 compounds giving satisfactory predictive r2 value of 0.923 as well as the scrambling stability test. This model would guide the design of potent 3,4-dihydroquinazoline derivatives as anti-cancer agent for the treatment of human lung cancer.

Rehabilitation Strategies after Spinal Cord Injury: Inquiry into the Mechanisms of Success and Failure

PubMed Central

Murray, Marion; Lemay, Michel A.

2017-01-01

Abstract Body-weight supported locomotor training (BWST) promotes recovery of load-bearing stepping in lower mammals, but its efficacy in individuals with a spinal cord injury (SCI) is limited and highly dependent on injury severity. While animal models with complete spinal transections recover stepping with step-training, motor complete SCI individuals do not, despite similarly intensive training. In this review, we examine the significant differences between humans and animal models that may explain this discrepancy in the results obtained with BWST. We also summarize the known effects of SCI and locomotor training on the muscular, motoneuronal, interneuronal, and supraspinal systems in human and non-human models of SCI and address the potential causes for failure to translate to the clinic. The evidence points to a deficiency in neuronal activation as the mechanism of failure, rather than muscular insufficiency. While motoneuronal and interneuronal systems cannot be directly probed in humans, the changes brought upon by step-training in SCI animal models suggest a beneficial re-organization of the systems’ responsiveness to descending and afferent feedback that support locomotor recovery. The literature on partial lesions in humans and animal models clearly demonstrate a greater dependency on supraspinal input to the lumbar cord in humans than in non-human mammals for locomotion. Recent results with epidural stimulation that activates the lumbar interneuronal networks and/or increases the overall excitability of the locomotor centers suggest that these centers are much more dependent on the supraspinal tonic drive in humans. Sensory feedback shapes the locomotor output in animal models but does not appear to be sufficient to drive it in humans. PMID:27762657

A Qualitative Model of Human Interaction with Complex Dynamic Systems

NASA Technical Reports Server (NTRS)

Hess, Ronald A.

1987-01-01

A qualitative model describing human interaction with complex dynamic systems is developed. The model is hierarchical in nature and consists of three parts: a behavior generator, an internal model, and a sensory information processor. The behavior generator is responsible for action decomposition, turning higher level goals or missions into physical action at the human-machine interface. The internal model is an internal representation of the environment which the human is assumed to possess and is divided into four submodel categories. The sensory information processor is responsible for sensory composition. All three parts of the model act in consort to allow anticipatory behavior on the part of the human in goal-directed interaction with dynamic systems. Human workload and error are interpreted in this framework, and the familiar example of an automobile commute is used to illustrate the nature of the activity in the three model elements. Finally, with the qualitative model as a guide, verbal protocols from a manned simulation study of a helicopter instrument landing task are analyzed with particular emphasis on the effect of automation on human-machine performance.

A qualitative model of human interaction with complex dynamic systems

NASA Technical Reports Server (NTRS)

Hess, Ronald A.

1987-01-01

A qualitative model describing human interaction with complex dynamic systems is developed. The model is hierarchical in nature and consists of three parts: a behavior generator, an internal model, and a sensory information processor. The behavior generator is responsible for action decomposition, turning higher level goals or missions into physical action at the human-machine interface. The internal model is an internal representation of the environment which the human is assumed to possess and is divided into four submodel categories. The sensory information processor is responsible for sensory composition. All three parts of the model act in consort to allow anticipatory behavior on the part of the human in goal-directed interaction with dynamic systems. Human workload and error are interpreted in this framework, and the familiar example of an automobile commute is used to illustrate the nature of the activity in the three model elements. Finally, with the qualitative model as a guide, verbal protocols from a manned simulation study of a helicopter instrument landing task are analyzed with particular emphasis on the effect of automation on human-machine performance.

MicroRNA-9 Inhibits NLRP3 Inflammasome Activation in Human Atherosclerosis Inflammation Cell Models through the JAK1/STAT Signaling Pathway.

PubMed

Wang, Yue; Han, Zhihua; Fan, Yuqi; Zhang, Junfeng; Chen, Kan; Gao, Lin; Zeng, Huasu; Cao, Jiatian; Wang, Changqian

2017-01-01

MicroRNA-9 (miR-9) is involved in inflammatory reaction in atherosclerosis; however, its function and regulatory mechanisms remain unclear. We aimed to uncover the exact roles of miR-9 and downstream signaling pathways using in vitro human atherosclerosis models. We used oxidized low-density lipoprotein (oxLDL)-stimulated human THP-1 derived macrophages, oxLDL-stimulated human primary peripheral blood monocytes and lipopolysaccharides (LPS) or Alum-stimulated human THP-1 derived macrophages as in vitro atherosclerosis inflammation models. Transient transfection of over-expression vectors, small interference RNAs (siRNAs) or antisense oligonucleotides was used to regulate intracellular protein or miR-9 levels. Cell responses and signal transduction were detected by multiple assays including Western blotting, enzyme-linked immunosorbent assay (ELISA) and luciferase reporter assay. MiR-9 inhibited while anti-miR-9 antisense oligonucleotides induced interleukin-1 beta (IL-1β) and NLRP3 inflammasome activation in all in vitro models. Janus kinase 1 (JAK1) and matrix metalloproteinase 13 (MMP-13) were identified as the target genes of miR-9. In oxLDL-stimulated human THP-1 derived macrophages, knockdown of JAK1 by siRNA blocked the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and mimicked the effects of miR-9. In the same model, JAK1 knockdown blocked the phosphorylation of NF-κB p65 in the nuclei and the phosphorylation of NF-κB IκBα in the cytoplasm. Our study demonstrated that miR-9 could inhibit activation of the NLRP3 inflammasome and attenuate atherosclerosis-related inflammation, likely through the JAK1/STAT1 signaling pathway. Therefore, miR-9 may serve as a potential therapeutic target for atherosclerosis. © 2017 The Author(s)Published by S. Karger AG, Basel.

A Three-Dimensional Human Atrial Model with Fiber Orientation. Electrograms and Arrhythmic Activation Patterns Relationship

PubMed Central

Tobón, Catalina; Ruiz-Villa, Carlos A.; Heidenreich, Elvio; Romero, Lucia; Hornero, Fernando; Saiz, Javier

2013-01-01

The most common sustained cardiac arrhythmias in humans are atrial tachyarrhythmias, mainly atrial fibrillation. Areas of complex fractionated atrial electrograms and high dominant frequency have been proposed as critical regions for maintaining atrial fibrillation; however, there is a paucity of data on the relationship between the characteristics of electrograms and the propagation pattern underlying them. In this study, a realistic 3D computer model of the human atria has been developed to investigate this relationship. The model includes a realistic geometry with fiber orientation, anisotropic conductivity and electrophysiological heterogeneity. We simulated different tachyarrhythmic episodes applying both transient and continuous ectopic activity. Electrograms and their dominant frequency and organization index values were calculated over the entire atrial surface. Our simulations show electrograms with simple potentials, with little or no cycle length variations, narrow frequency peaks and high organization index values during stable and regular activity as the observed in atrial flutter, atrial tachycardia (except in areas of conduction block) and in areas closer to ectopic activity during focal atrial fibrillation. By contrast, cycle length variations and polymorphic electrograms with single, double and fragmented potentials were observed in areas of irregular and unstable activity during atrial fibrillation episodes. Our results also show: 1) electrograms with potentials without negative deflection related to spiral or curved wavefronts that pass over the recording point and move away, 2) potentials with a much greater proportion of positive deflection than negative in areas of wave collisions, 3) double potentials related with wave fragmentations or blocking lines and 4) fragmented electrograms associated with pivot points. Our model is the first human atrial model with realistic fiber orientation used to investigate the relationship between different atrial arrhythmic propagation patterns and the electrograms observed at more than 43000 points on the atrial surface. PMID:23408928

Structural insight of dopamine β-hydroxylase, a drug target for complex traits, and functional significance of exonic single nucleotide polymorphisms.

PubMed

Kapoor, Abhijeet; Shandilya, Manish; Kundu, Suman

2011-01-01

Human dopamine β-hydroxylase (DBH) is an important therapeutic target for complex traits. Several single nucleotide polymorphisms (SNPs) have also been identified in DBH with potential adverse physiological effect. However, difficulty in obtaining diffractable crystals and lack of a suitable template for modeling the protein has ensured that neither crystallographic three-dimensional structure nor computational model for the enzyme is available to aid rational drug design, prediction of functional significance of SNPs or analytical protein engineering. Adequate biochemical information regarding human DBH, structural coordinates for peptidylglycine alpha-hydroxylating monooxygenase and computational data from a partial model of rat DBH were used along with logical manual intervention in a novel way to build an in silico model of human DBH. The model provides structural insight into the active site, metal coordination, subunit interface, substrate recognition and inhibitor binding. It reveals that DOMON domain potentially promotes tetramerization, while substrate dopamine and a potential therapeutic inhibitor nepicastat are stabilized in the active site through multiple hydrogen bonding. Functional significance of several exonic SNPs could be described from a structural analysis of the model. The model confirms that SNP resulting in Ala318Ser or Leu317Pro mutation may not influence enzyme activity, while Gly482Arg might actually do so being in the proximity of the active site. Arg549Cys may cause abnormal oligomerization through non-native disulfide bond formation. Other SNPs like Glu181, Glu250, Lys239 and Asp290 could potentially inhibit tetramerization thus affecting function. The first three-dimensional model of full-length human DBH protein was obtained in a novel manner with a set of experimental data as guideline for consistency of in silico prediction. Preliminary physicochemical tests validated the model. The model confirms, rationalizes and provides structural basis for several biochemical data and claims testable hypotheses regarding function. It provides a reasonable template for drug design as well.

Humanized Mouse Model of Skin Inflammation Is Characterized by Disturbed Keratinocyte Differentiation and Influx of IL-17A Producing T Cells

PubMed Central

de Oliveira, Vivian L.; Keijsers, Romy R. M. C.; van de Kerkhof, Peter C. M.; Seyger, Marieke M. B.; Fasse, Esther; Svensson, Lars; Latta, Markus; Norsgaard, Hanne; Labuda, Tord; Hupkens, Pieter; van Erp, Piet E. J.; Joosten, Irma; Koenen, Hans J. P. M.

2012-01-01

Humanized mouse models offer a challenging possibility to study human cell function in vivo. In the huPBL-SCID-huSkin allograft model human skin is transplanted onto immunodeficient mice and allowed to heal. Thereafter allogeneic human peripheral blood mononuclear cells are infused intra peritoneally to induce T cell mediated inflammation and microvessel destruction of the human skin. This model has great potential for in vivo study of human immune cells in (skin) inflammatory processes and for preclinical screening of systemically administered immunomodulating agents. Here we studied the inflammatory skin response of human keratinocytes and human T cells and the concomitant systemic human T cell response. As new findings in the inflamed human skin of the huPBL-SCID-huSkin model we here identified: 1. Parameters of dermal pathology that enable precise quantification of the local skin inflammatory response exemplified by acanthosis, increased expression of human β-defensin-2, Elafin, K16, Ki67 and reduced expression of K10 by microscopy and immunohistochemistry. 2. Induction of human cytokines and chemokines using quantitative real-time PCR. 3. Influx of inflammation associated IL-17A-producing human CD4+ and CD8+ T cells as well as immunoregulatory CD4+Foxp3+ cells using immunohistochemistry and -fluorescence, suggesting that active immune regulation is taking place locally in the inflamed skin. 4. Systemic responses that revealed activated and proliferating human CD4+ and CD8+ T cells that acquired homing marker expression of CD62L and CLA. Finally, we demonstrated the value of the newly identified parameters by showing significant changes upon systemic treatment with the T cell inhibitory agents cyclosporine-A and rapamycin. In summary, here we equipped the huPBL-SCID-huSkin humanized mouse model with relevant tools not only to quantify the inflammatory dermal response, but also to monitor the peripheral immune status. This combined approach will gain our understanding of the dermal immunopathology in humans and benefit the development of novel therapeutics for controlling inflammatory skin diseases. PMID:23094018

Human Resource Planning: Challenges for Industrial/Organizational Psychologists.

ERIC Educational Resources Information Center

Jackson, Susan E.; Schuler, Randall S.

1990-01-01

Describes activities that industrial/organizational psychologists engage in as they seek to improve the competitiveness of organizations through effective human resource planning. Presents a model for describing human resource short-term, intermediate-term, and long-term planning. (JS)

Epstein-Barr virus latency switch in human B-cells: a physico-chemical model.

PubMed

Werner, Maria; Ernberg, Ingemar; Zou, Jiezhi; Almqvist, Jenny; Aurell, Erik

2007-08-31

The Epstein-Barr virus is widespread in all human populations and is strongly associated with human disease, ranging from infectious mononucleosis to cancer. In infected cells the virus can adopt several different latency programs, affecting the cells' behaviour. Experimental results indicate that a specific genetic switch between viral latency programs, reprograms human B-cells between proliferative and resting states. Each of these two latency programs makes use of a different viral promoter, Cp and Qp, respectively. The hypothesis tested in this study is that this genetic switch is controlled by both human and viral transcription factors; Oct-2 and EBNA-1. We build a physico-chemical model to investigate quantitatively the dynamical properties of the promoter regulation and experimentally examine protein level variations between the two latency programs. Our experimental results display significant differences in EBNA-1 and Oct-2 levels between resting and proliferating programs. With the model we identify two stable latency programs, corresponding to a resting and proliferating cell. The two programs differ in robustness and transcriptional activity. The proliferating state is markedly more stable, with a very high transcriptional activity from its viral promoter. We predict the promoter activities to be mutually exclusive in the two different programs, and our relative promoter activities correlate well with experimental data. Transitions between programs can be induced, by affecting the protein levels of our transcription factors. Simulated time scales are in line with experimental results. We show that fundamental properties of the Epstein-Barr virus involvement in latent infection, with implications for tumor biology, can be modelled and understood mathematically. We conclude that EBNA-1 and Oct-2 regulation of Cp and Qp is sufficient to establish mutually exclusive expression patterns. Moreover, the modelled genetic control predict both mono- and bistable behavior and a considerable difference in transition dynamics, based on program stability and promoter activities. Both these phenomena we hope can be further investigated experimentally, to increase the understanding of this important switch. Our results also stress the importance of the little known regulation of human transcription factor Oct-2.

A model for the control mode man-computer interface dialogue

NASA Technical Reports Server (NTRS)

Chafin, R. L.

1981-01-01

A four stage model is presented for the control mode man-computer interface dialogue. It consists of context development, semantic development syntactic development, and command execution. Each stage is discussed in terms of the operator skill levels (naive, novice, competent, and expert) and pertinent human factors issues. These issues are human problem solving, human memory, and schemata. The execution stage is discussed in terms of the operators typing skills. This model provides an understanding of the human process in command mode activity for computer systems and a foundation for relating system characteristics to operator characteristics.

A novel human model of the neurodegenerative disease GM1 gangliosidosis using induced pluripotent stem cells demonstrates inflammasome activation.

PubMed

Son, Mi-Young; Kwak, Jae Eun; Seol, Binna; Lee, Da Yong; Jeon, Hyejin; Cho, Yee Sook

2015-09-01

GM1 gangliosidosis (GM1) is an inherited neurodegenerative disorder caused by mutations in the lysosomal β-galactosidase (β-gal) gene. Insufficient β-gal activity leads to abnormal accumulation of GM1 gangliosides in tissues, particularly in the central nervous system, resulting in progressive neurodegeneration. Here, we report an in vitro human GM1 model, based on induced pluripotent stem cell (iPSC) technology. Neural progenitor cells differentiated from GM1 patient-derived iPSCs (GM1-NPCs) recapitulated the biochemical and molecular phenotypes of GM1, including defective β-gal activity and increased lysosomes. Importantly, the characterization of GM1-NPCs established that GM1 is significantly associated with the activation of inflammasomes, which play a critical role in the pathogenesis of various neurodegenerative diseases. Specific inflammasome inhibitors potently alleviated the disease-related phenotypes of GM1-NPCs in vitro and in vivo. Our data demonstrate that GM1-NPCs are a valuable in vitro human GM1 model and suggest that inflammasome activation is a novel target pathway for GM1 drug development. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Human activity recognition based on feature selection in smart home using back-propagation algorithm.

PubMed

Fang, Hongqing; He, Lei; Si, Hao; Liu, Peng; Xie, Xiaolei

2014-09-01

In this paper, Back-propagation(BP) algorithm has been used to train the feed forward neural network for human activity recognition in smart home environments, and inter-class distance method for feature selection of observed motion sensor events is discussed and tested. And then, the human activity recognition performances of neural network using BP algorithm have been evaluated and compared with other probabilistic algorithms: Naïve Bayes(NB) classifier and Hidden Markov Model(HMM). The results show that different feature datasets yield different activity recognition accuracy. The selection of unsuitable feature datasets increases the computational complexity and degrades the activity recognition accuracy. Furthermore, neural network using BP algorithm has relatively better human activity recognition performances than NB classifier and HMM. Copyright © 2014 ISA. Published by Elsevier Ltd. All rights reserved.

Dynamics of circulating gamma delta T cell activity in an immunocompetent mouse model of high-grade glioma

USDA-ARS?s Scientific Manuscript database

Human gamma delta T cells are potent effectors against glioma cell lines in vitro and in human/mouse xenograft models of glioblastoma, however, this effect has not been investigated in an immunocompetent mouse model. In this report, we established GL261 intracranial gliomas in syngeneic WT C57BL/6 m...

Cultivating Curiosity: Integrating Hybrid Teaching in Courses in Human Behavior in the Social Environment

ERIC Educational Resources Information Center

Rodriguez-Keyes, Elizabeth; Schneider, Dana A.

2013-01-01

This study illustrates an experience of implementing a hybrid model for teaching human behavior in the social environment in an urban university setting. Developing a hybrid model in a BSW program arose out of a desire to reach students in a different way. Designed to promote curiosity and active learning, this particular hybrid model has students…

The Isolation and Characterization of Human Prostate Cancer Stem Cells

DTIC Science & Technology

2012-02-01

established cell lines and primary patient samples) with human prostate fibroblasts hold promise as models of tumor initiation/cancer stem cell activity...We continue to optimize and validate our in vitro model of prostate cancer initiation to facilitate cancer stem cell discovery as well as drug targeting.

A Review on Human Activity Recognition Using Vision-Based Method.

PubMed

Zhang, Shugang; Wei, Zhiqiang; Nie, Jie; Huang, Lei; Wang, Shuang; Li, Zhen

2017-01-01

Human activity recognition (HAR) aims to recognize activities from a series of observations on the actions of subjects and the environmental conditions. The vision-based HAR research is the basis of many applications including video surveillance, health care, and human-computer interaction (HCI). This review highlights the advances of state-of-the-art activity recognition approaches, especially for the activity representation and classification methods. For the representation methods, we sort out a chronological research trajectory from global representations to local representations, and recent depth-based representations. For the classification methods, we conform to the categorization of template-based methods, discriminative models, and generative models and review several prevalent methods. Next, representative and available datasets are introduced. Aiming to provide an overview of those methods and a convenient way of comparing them, we classify existing literatures with a detailed taxonomy including representation and classification methods, as well as the datasets they used. Finally, we investigate the directions for future research.

A Review on Human Activity Recognition Using Vision-Based Method

PubMed Central

Nie, Jie

2017-01-01

Human activity recognition (HAR) aims to recognize activities from a series of observations on the actions of subjects and the environmental conditions. The vision-based HAR research is the basis of many applications including video surveillance, health care, and human-computer interaction (HCI). This review highlights the advances of state-of-the-art activity recognition approaches, especially for the activity representation and classification methods. For the representation methods, we sort out a chronological research trajectory from global representations to local representations, and recent depth-based representations. For the classification methods, we conform to the categorization of template-based methods, discriminative models, and generative models and review several prevalent methods. Next, representative and available datasets are introduced. Aiming to provide an overview of those methods and a convenient way of comparing them, we classify existing literatures with a detailed taxonomy including representation and classification methods, as well as the datasets they used. Finally, we investigate the directions for future research. PMID:29065585

Native Electrophoresis-Coupled Activity Assays Reveal Catalytically-Active Protein Aggregates of Escherichia coli β-Glucuronidase

PubMed Central

Burchett, Gina G.; Folsom, Charles G.; Lane, Kimberly T.

2015-01-01

β-glucuronidase is found as a functional homotetramer in a variety of organisms, including humans and other animals, as well as a number of bacteria. This enzyme is important in these organisms, catalyzing the hydrolytic removal of a glucuronide moiety from substrate molecules. This process serves to break down sugar conjugates in animals and provide sugars for metabolism in bacteria. While β-glucuronidase is primarily found as a homotetramer, previous studies have indicated that the human form of the protein is also catalytically active as a dimer. Here we present evidence for not only an active dimer of the E. coli form of the protein, but also for several larger active complexes, including an octomer and a 16-mer. Additionally, we propose a model for the structures of these large complexes, based on computationally-derived molecular modeling studies. These structures may have application in the study of human disease, as several diseases have been associated with the aggregation of proteins. PMID:26121040

Native Electrophoresis-Coupled Activity Assays Reveal Catalytically-Active Protein Aggregates of Escherichia coli β-Glucuronidase.

PubMed

Burchett, Gina G; Folsom, Charles G; Lane, Kimberly T

2015-01-01

β-glucuronidase is found as a functional homotetramer in a variety of organisms, including humans and other animals, as well as a number of bacteria. This enzyme is important in these organisms, catalyzing the hydrolytic removal of a glucuronide moiety from substrate molecules. This process serves to break down sugar conjugates in animals and provide sugars for metabolism in bacteria. While β-glucuronidase is primarily found as a homotetramer, previous studies have indicated that the human form of the protein is also catalytically active as a dimer. Here we present evidence for not only an active dimer of the E. coli form of the protein, but also for several larger active complexes, including an octomer and a 16-mer. Additionally, we propose a model for the structures of these large complexes, based on computationally-derived molecular modeling studies. These structures may have application in the study of human disease, as several diseases have been associated with the aggregation of proteins.

A reverse-translational study of dysfunctional exploration in psychiatric disorders: from mice to men.

PubMed

Perry, William; Minassian, Arpi; Paulus, Martin P; Young, Jared W; Kincaid, Meegin J; Ferguson, Eliza J; Henry, Brook L; Zhuang, Xiaoxi; Masten, Virginia L; Sharp, Richard F; Geyer, Mark A

2009-10-01

Bipolar mania and schizophrenia are recognized as separate disorders but share many commonalities, which raises the question of whether they are the same disorder on different ends of a continuum. The lack of distinct endophenotypes of bipolar mania and schizophrenia has complicated the development of animal models that are specific to these disorders. Exploration is fundamental to survival and is dysregulated in these 2 disorders. Although exploratory behavior in rodents has been widely studied, surprisingly little work has examined this critical function in humans. To quantify the exploratory behavior of individuals with bipolar mania and schizophrenia and to identify distinctive phenotypes of these illnesses. Static group comparison by the use of a novel human open field paradigm, the human Behavioral Pattern Monitor (BPM). Psychiatric hospital. Fifteen patients with bipolar mania and 16 patients with schizophrenia were compared with 26 healthy volunteers in the human BPM. The effects of amphetamine sulfate, the selective dopamine transporter inhibitor GBR12909, and the genetic knockdown of the dopamine transporter were compared with controls in the mouse BPM. The amount of motor activity, spatial patterns of activity, and exploration of novel stimuli were quantified in both the human and mouse BPMs. Patients with bipolar mania demonstrated a unique exploratory pattern, characterized by high motor activity and increased object exploration. Patients with schizophrenia did not show the expected habituation of motor activity. Selective genetic or pharmacologic inhibition of the dopamine transporter matched the mania phenotype better than the effects of amphetamine, which has been the criterion standard for animal models of mania. These findings validate the human open field paradigm and identify defining characteristics of bipolar mania that are distinct from those of schizophrenia. This cross-species study of exploration calls into question an accepted animal model of mania and should help to develop more accurate human and animal models, which are essential to the identification of the neurobiological underpinnings of neuropsychiatric disorders.

A reverse translational study of dysfunctional exploration in psychiatric disorders: from mice to men

PubMed Central

Perry, William; Minassian, Arpi; Paulus, Martin P.; Young, Jared W.; Kincaid, Meegin J.; Ferguson, Eliza J.; Henry, Brook L.; Zhuang, Xiaoxi; Masten, Virginia L.; Sharp, Richard F.; Geyer, Mark A.

2009-01-01

Context Bipolar mania and schizophrenia are recognized as separate disorders but share many commonalities, raising the question of whether they are in fact the same disorder on different ends of a continuum. The lack of distinct endophenotypes of bipolar mania and schizophrenia has complicated the development of animal models that are specific to these disorders. Exploration is fundamental to survival and is dysregulated in these two disorders. Although exploratory behavior in rodents has been widely studied, surprisingly little work has examined this critical function in humans. Objective We used a novel human open field paradigm, the human Behavioral Pattern Monitor (BPM), to quantify exploratory behavior of individuals with bipolar mania and schizophrenia and to identify distinctive phenotypes of these illnesses. Design Static group comparison. Setting Psychiatric hospital. Participants 15 bipolar mania and 16 schizophrenia subjects were compared to 26 healthy volunteers in the human BPM. The effects of amphetamine, the selective dopamine transporter (DAT) inhibitor GBR12909, and genetic knockdown of the DAT were compared to controls in the mouse BPM. Measures The amount of motor activity, spatial patterns of activity, and exploration of novel stimuli were quantified in both the human and mouse BPMs. Results Bipolar manic subjects demonstrated a unique exploratory pattern, characterized by high motor activity and increased object exploration. Schizophrenia subjects did not show the expected habituation of motor activity. Selective genetic or pharmacological inhibition of the DAT matched the mania phenotype better than the “gold standard” model of mania (amphetamine). Conclusion These findings validate the human open field paradigm and identify defining characteristics of bipolar mania that are distinct from schizophrenia. This cross-species study of exploration calls into question an accepted animal model of mania and should help to develop more accurate human and animal models, which are essential to identify neurobiological underpinnings of neuropsychiatric disorders. PMID:19805697

Joint object and action recognition via fusion of partially observable surveillance imagery data

NASA Astrophysics Data System (ADS)

Shirkhodaie, Amir; Chan, Alex L.

2017-05-01

Partially observable group activities (POGA) occurring in confined spaces are epitomized by their limited observability of the objects and actions involved. In many POGA scenarios, different objects are being used by human operators for the conduct of various operations. In this paper, we describe the ontology of such as POGA in the context of In-Vehicle Group Activity (IVGA) recognition. Initially, we describe the virtue of ontology modeling in the context of IVGA and show how such an ontology and a priori knowledge about the classes of in-vehicle activities can be fused for inference of human actions that consequentially leads to understanding of human activity inside the confined space of a vehicle. In this paper, we treat the problem of "action-object" as a duality problem. We postulate a correlation between observed human actions and the object that is being utilized within those actions, and conversely, if an object being handled is recognized, we may be able to expect a number of actions that are likely to be performed on that object. In this study, we use partially observable human postural sequences to recognition actions. Inspired by convolutional neural networks (CNNs) learning capability, we present an architecture design using a new CNN model to learn "action-object" perception from surveillance videos. In this study, we apply a sequential Deep Hidden Markov Model (DHMM) as a post-processor to CNN to decode realized observations into recognized actions and activities. To generate the needed imagery data set for the training and testing of these new methods, we use the IRIS virtual simulation software to generate high-fidelity and dynamic animated scenarios that depict in-vehicle group activities under different operational contexts. The results of our comparative investigation are discussed and presented in detail.

Characterization of Acid Sphingomyelinase Activity in Human Cerebrospinal Fluid

PubMed Central

Mühle, Christiane; Huttner, Hagen B.; Walter, Silke; Reichel, Martin; Canneva, Fabio; Lewczuk, Piotr; Gulbins, Erich; Kornhuber, Johannes

2013-01-01

Background As a key enzyme in sphingolipid metabolism, acid sphingomyelinase (ASM) is involved in the regulation of cell fate and signaling via hydrolysis of sphingomyelin to form ceramide. While increased activity of the lysosomal form has been associated with various pathological conditions, there are few studies on secretory ASM limited only to cell models, plasma or serum. Methods An optimized assay based on a fluorescent substrate was applied to measure the ASM activity in cerebrospinal fluid (CSF) collected from mice and from 42 patients who were classified as controls based on normal routine CSF values. Results We have detected ASM activity in human CSF, established a sensitive quantitative assay and characterized the enzyme’s properties. The enzyme resembles plasmatic ASM including protein stability and Zn2+-dependence but the assays differ considerably in the optimal detergent concentration. Significantly increased activities in the CSF of ASM transgenic mice and undetectable levels in ASM knock-out mice prove that the measured ASM activity originates from the ASM-encoding gene SMPD1. CSF localized ASM activities were comparable to corresponding serum ASM levels at their respective optimal reaction conditions, but no correlation was observed. The large variance in ASM activity was independent of sex, age or analyzed routine CSF parameters. Conclusions Human and mouse CSF contain detectable levels of secretory ASM, which are unrelated to serum ASM activities. Further investigations in humans and in animal models will help to elucidate the role of this enzyme in human disease and to assess its value as a potential biomarker for disease type, severity, progress or therapeutic success. PMID:23658784

Amphetamine increases activity but not exploration in humans and mice

PubMed Central

Minassian, Arpi; Young, Jared W.; Cope, Zackary A.; Henry, Brook L.; Geyer, Mark A.; Perry, William

2015-01-01

Rationale Cross-species quantification of physiological behavior enables a better understanding of the biological systems underlying neuropsychiatric diseases such as Bipolar Disorder (BD). Cardinal symptoms of manic BD include increased motor activity and goal-directed behavior, thought to be related to increased catecholamine activity, potentially selective to dopamine homeostatic dysregulation. Objectives The objective of this study was to test whether acute administration of amphetamine, a norepinephrine/dopamine transporter inhibitor and dopamine releaser, would replicate the profile of activity and exploration observed in both humans with manic BD and mouse models of mania. Methods Healthy volunteers with no psychiatric history were randomized to a one-time dose of placebo (n=25), 10 mg d-amphetamine (n=18), or 20 mg amphetamine (n=23). 80 mice were administered one of 4 doses of d-amphetamine or vehicle. Humans and mice were tested in the Behavioral Pattern Monitor (BPM), which quantifies motor activity, exploratory behavior, and spatial patterns of behavior. Results In humans, the 20-mg dose of amphetamine increased motor activity as measured by acceleration without marked effects on exploration or spatial patterns of activity. In mice, amphetamine increased activity, decreased specific exploration, and caused straighter, one-dimensional movements in a dose-dependent manner. Conclusions Consistent with mice, amphetamine increased motoric activity in humans without increasing exploration. Given that BD patients exhibit heightened exploration, these data further emphasize the limitation of amphetamine-induced hyperactivity as a suitable model for BD. Further, these studies highlight the utility of cross-species physiological paradigms in validating biological mechanisms of psychiatric diseases. PMID:26449721

Active site mutant transgene confers tolerance to human β-glucuronidase without affecting the phenotype of MPS VII mice

PubMed Central

Sly, William S.; Vogler, Carole; Grubb, Jeffrey H.; Zhou, Mi; Jiang, Jinxing; Zhou, Xiao Yan; Tomatsu, Shunji; Bi, Yanhua; Snella, Elizabeth M.

2001-01-01

Mucopolysaccharidosis type VII (MPS VII; Sly syndrome) is an autosomal recessive lysosomal storage disorder due to an inherited deficiency of β-glucuronidase. A naturally occurring mouse model for this disease was discovered at The Jackson Laboratory and shown to be due to homozygosity for a 1-bp deletion in exon 10 of the gus gene. The murine model MPS VII (gusmps/mps) has been very well characterized and used extensively to evaluate experimental strategies for lysosomal storage diseases, including bone marrow transplantation, enzyme replacement therapy, and gene therapy. To enhance the value of this model for enzyme and gene therapy, we produced a transgenic mouse expressing the human β-glucuronidase cDNA with an amino acid substitution at the active site nucleophile (E540A) and bred it onto the MPS VII (gusmps/mps) background. We demonstrate here that the mutant mice bearing the active site mutant human transgene retain the clinical, morphological, biochemical, and histopathological characteristics of the original MPS VII (gusmps/mps) mouse. However, they are now tolerant to immune challenge with human β-glucuronidase. This “tolerant MPS VII mouse model” should be useful for preclinical trials evaluating the effectiveness of enzyme and/or gene therapy with the human gene products likely to be administered to human patients with MPS VII. PMID:11226217

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

Human thrombomodulin knock-in mice reveal differential effects of human thrombomodulin on thrombosis and atherosclerosis.

PubMed

Raife, Thomas J; Dwyre, Denis M; Stevens, Jeff W; Erger, Rochelle A; Leo, Lorie; Wilson, Katina M; Fernández, Jose A; Wilder, Jennifer; Kim, Hyung-Suk; Griffin, John H; Maeda, Nobuyo; Lentz, Steven R

2011-11-01

We sought to develop a murine model to examine the antithrombotic and antiinflammatory functions of human thrombomodulin in vivo. Knock-in mice that express human thrombomodulin from the murine thrombomodulin gene locus were generated. Compared with wild-type mice, human thrombomodulin knock-in mice exhibited decreased protein C activation in the aorta (P<0.01) and lung (P<0.001). Activation of endogenous protein C following infusion of thrombin was decreased by 90% in knock-in mice compared with wild-type mice (P<0.05). Carotid artery thrombosis induced by photochemical injury occurred more rapidly in knock-in mice (12±3 minutes) than in wild-type mice (31±6 minutes; P<0.05). No differences in serum cytokine levels were detected between knock-in and wild-type mice after injection of endotoxin. When crossed with apolipoprotein E-deficient mice and fed a Western diet, knock-in mice had a further decrease in protein C activation but did not exhibit increased atherosclerosis. Expression of human thrombomodulin in place of murine thrombomodulin produces viable mice with a prothrombotic phenotype but unaltered responses to systemic inflammatory or atherogenic stimuli. This humanized animal model will be useful for investigating the function of human thrombomodulin under pathophysiological conditions in vivo.

Modeling the epidemiological history of plague in Central Asia: Palaeoclimatic forcing on a disease system over the past millennium

PubMed Central

2010-01-01

Background Human cases of plague (Yersinia pestis) infection originate, ultimately, in the bacterium's wildlife host populations. The epidemiological dynamics of the wildlife reservoir therefore determine the abundance, distribution and evolution of the pathogen, which in turn shape the frequency, distribution and virulence of human cases. Earlier studies have shown clear evidence of climatic forcing on contemporary plague abundance in rodents and humans. Results We find that high-resolution palaeoclimatic indices correlate with plague prevalence and population density in a major plague host species, the great gerbil (Rhombomys opimus), over 1949-1995. Climate-driven models trained on these data predict independent data on human plague cases in early 20th-century Kazakhstan from 1904-1948, suggesting a consistent impact of climate on large-scale wildlife reservoir dynamics influencing human epidemics. Extending the models further back in time, we also find correspondence between their predictions and qualitative records of plague epidemics over the past 1500 years. Conclusions Central Asian climate fluctuations appear to have had significant influences on regional human plague frequency in the first part of the 20th century, and probably over the past 1500 years. This first attempt at ecoepidemiological reconstruction of historical disease activity may shed some light on how long-term plague epidemiology interacts with human activity. As plague activity in Central Asia seems to have followed climate fluctuations over the past centuries, we may expect global warming to have an impact upon future plague epidemiology, probably sustaining or increasing plague activity in the region, at least in the rodent reservoirs, in the coming decades. See commentary: http://www.biomedcentral.com/1741-7007/8/108 PMID:20799946

Modeling the epidemiological history of plague in Central Asia: palaeoclimatic forcing on a disease system over the past millennium.

PubMed

Kausrud, Kyrre Linné; Begon, Mike; Ari, Tamara Ben; Viljugrein, Hildegunn; Esper, Jan; Büntgen, Ulf; Leirs, Herwig; Junge, Claudia; Yang, Bao; Yang, Meixue; Xu, Lei; Stenseth, Nils Chr

2010-08-27

Human cases of plague (Yersinia pestis) infection originate, ultimately, in the bacterium's wildlife host populations. The epidemiological dynamics of the wildlife reservoir therefore determine the abundance, distribution and evolution of the pathogen, which in turn shape the frequency, distribution and virulence of human cases. Earlier studies have shown clear evidence of climatic forcing on contemporary plague abundance in rodents and humans. We find that high-resolution palaeoclimatic indices correlate with plague prevalence and population density in a major plague host species, the great gerbil (Rhombomys opimus), over 1949-1995. Climate-driven models trained on these data predict independent data on human plague cases in early 20th-century Kazakhstan from 1904-1948, suggesting a consistent impact of climate on large-scale wildlife reservoir dynamics influencing human epidemics. Extending the models further back in time, we also find correspondence between their predictions and qualitative records of plague epidemics over the past 1500 years. Central Asian climate fluctuations appear to have had significant influences on regional human plague frequency in the first part of the 20th century, and probably over the past 1500 years. This first attempt at ecoepidemiological reconstruction of historical disease activity may shed some light on how long-term plague epidemiology interacts with human activity. As plague activity in Central Asia seems to have followed climate fluctuations over the past centuries, we may expect global warming to have an impact upon future plague epidemiology, probably sustaining or increasing plague activity in the region, at least in the rodent reservoirs, in the coming decades.See commentary: http://www.biomedcentral.com/1741-7007/8/108.

A Biologically Constrained, Mathematical Model of Cortical Wave Propagation Preceding Seizure Termination

PubMed Central

González-Ramírez, Laura R.; Ahmed, Omar J.; Cash, Sydney S.; Wayne, C. Eugene; Kramer, Mark A.

2015-01-01

Epilepsy—the condition of recurrent, unprovoked seizures—manifests in brain voltage activity with characteristic spatiotemporal patterns. These patterns include stereotyped semi-rhythmic activity produced by aggregate neuronal populations, and organized spatiotemporal phenomena, including waves. To assess these spatiotemporal patterns, we develop a mathematical model consistent with the observed neuronal population activity and determine analytically the parameter configurations that support traveling wave solutions. We then utilize high-density local field potential data recorded in vivo from human cortex preceding seizure termination from three patients to constrain the model parameters, and propose basic mechanisms that contribute to the observed traveling waves. We conclude that a relatively simple and abstract mathematical model consisting of localized interactions between excitatory cells with slow adaptation captures the quantitative features of wave propagation observed in the human local field potential preceding seizure termination. PMID:25689136

Interaction studies reveal specific recognition of an anti-inflammatory polyphosphorhydrazone dendrimer by human monocytes.

PubMed

Ledall, Jérémy; Fruchon, Séverine; Garzoni, Matteo; Pavan, Giovanni M; Caminade, Anne-Marie; Turrin, Cédric-Olivier; Blanzat, Muriel; Poupot, Rémy

2015-11-14

Dendrimers are nano-materials with perfectly defined structure and size, and multivalency properties that confer substantial advantages for biomedical applications. Previous work has shown that phosphorus-based polyphosphorhydrazone (PPH) dendrimers capped with azabisphosphonate (ABP) end groups have immuno-modulatory and anti-inflammatory properties leading to efficient therapeutic control of inflammatory diseases in animal models. These properties are mainly prompted through activation of monocytes. Here, we disclose new insights into the molecular mechanisms underlying the anti-inflammatory activation of human monocytes by ABP-capped PPH dendrimers. Following an interdisciplinary approach, we have characterized the physicochemical and biological behavior of the lead ABP dendrimer with model and cell membranes, and compared this experimental set of data to predictive computational modelling studies. The behavior of the ABP dendrimer was compared to the one of an isosteric analog dendrimer capped with twelve azabiscarboxylate (ABC) end groups instead of twelve ABP end groups. The ABC dendrimer displayed no biological activity on human monocytes, therefore it was considered as a negative control. In detail, we show that the ABP dendrimer can bind both non-specifically and specifically to the membrane of human monocytes. The specific binding leads to the internalization of the ABP dendrimer by human monocytes. On the contrary, the ABC dendrimer only interacts non-specifically with human monocytes and is not internalized. These data indicate that the bioactive ABP dendrimer is recognized by specific receptor(s) at the surface of human monocytes.

Quantifying the relative contribution of climate and human impacts on streamflow at seasonal scale

NASA Astrophysics Data System (ADS)

Xin, Z.; Zhang, L.; Li, Y.; Zhang, C.

2017-12-01

Both climate change and human activities have induced changes to hydrology. The quantification of their impacts on streamflow is a challenge, especially at the seasonal scale due to seasonality of climate and human impacts, i.e., water use for irrigation and water storage and release due to reservoir operation. In this study, the decomposition method based on the Budyko hypothesis is extended to the seasonal scale and is used to quantify the climate and human impacts on annual and seasonal streamflow changes. The results are further compared and verified with those simulated by the hydrological method of abcd model. Data are split into two periods (1953-1974 and 1975-2005) to quantify the change. Three seasons, including wet, dry and irrigation seasons are defined by introducing the monthly aridity index. In general, results showed a satisfactory agreement between the Budyko decomposition method and abcd model. Both climate change and human activities were found to induce a decrease in streamflow at the annual scale, with 67% of the change contributed by human activities. At the seasonal scale, the human-induced contribution to the reduced stream flow was 64% and 73% for dry and wet seasons, respectively; whereas in the irrigation season, the impact of human activities on reducing the streamflow was more pronounced (180%) since the climate contributes to increased streamflow. In addition, the quantification results were analyzed for each month in the wet season to reveal the effects of intense precipitation and reservoir operation rules during flood season.

Immunocompetent syngeneic cotton rat tumor models for the assessment of replication-competent oncolytic adenovirus

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

Steel, Jason C.; Morrison, Brian J.; Mannan, Poonam

Oncolytic adenoviruses as a treatment for cancer have demonstrated limited clinical activity. Contributing to this may be the relevance of preclinical animal models used to study these agents. Syngeneic mouse tumor models are generally non-permissive for adenoviral replication, whereas human tumor xenograft models exhibit attenuated immune responses to the vector. The cotton rat (Sigmodon hispidus) is susceptible to human adenovirus infection, permissive for viral replication and exhibits similar inflammatory pathology to humans with adenovirus replicating in the lungs, respiratory passages and cornea. We evaluated three transplantable tumorigenic cotton rat cell lines, CCRT, LCRT and VCRT as models for the studymore » of oncolytic adenoviruses. All three cells lines were readily infected with adenovirus type-5-based vectors and exhibited high levels of transgene expression. The cell lines supported viral replication demonstrated by the induction of cytopathogenic effect (CPE) in tissue culture, increase in virus particle numbers and assembly of virions seen on transmission electron microscopy. In vivo, LCRT and VCRT tumors demonstrated delayed growth after injection with replicating adenovirus. No in vivo antitumor activity was seen in CCRT tumors despite in vitro oncolysis. Adenovirus was also rapidly cleared from the CCRT tumors compared to LCRT and VCRT tumors. The effect observed with the different cotton rat tumor cell lines mimics the variable results of human clinical trials highlighting the potential relevance of this model for assessing the activity and toxicity of oncolytic adenoviruses.« less

Modelling of the Human Knee Joint Supported by Active Orthosis

NASA Astrophysics Data System (ADS)

Musalimov, V.; Monahov, Y.; Tamre, M.; Rõbak, D.; Sivitski, A.; Aryassov, G.; Penkov, I.

2018-02-01

The article discusses motion of a healthy knee joint in the sagittal plane and motion of an injured knee joint supported by an active orthosis. A kinematic scheme of a mechanism for the simulation of a knee joint motion is developed and motion of healthy and injured knee joints are modelled in Matlab. Angles between links, which simulate the femur and tibia are controlled by Simulink block of Model predictive control (MPC). The results of simulation have been compared with several samples of real motion of the human knee joint obtained from motion capture systems. On the basis of these analyses and also of the analysis of the forces in human lower limbs created at motion, an active smart orthosis is developed. The orthosis design was optimized to achieve an energy saving system with sufficient anatomy, necessary reliability, easy exploitation and low cost. With the orthosis it is possible to unload the knee joint, and also partially or fully compensate muscle forces required for the bending of the lower limb.

Perspectives on Systems Modeling of Human Peripheral Blood Mononuclear Cells

PubMed Central

Sen, Partho; Kemppainen, Esko; Orešič, Matej

2018-01-01

Human peripheral blood mononuclear cells (PBMCs) are the key drivers of the immune responses. These cells undergo activation, proliferation and differentiation into various subsets. During these processes they initiate metabolic reprogramming, which is coordinated by specific gene and protein activities. PBMCs as a model system have been widely used to study metabolic and autoimmune diseases. Herein we review various omics and systems-based approaches such as transcriptomics, epigenomics, proteomics, and metabolomics as applied to PBMCs, particularly T helper subsets, that unveiled disease markers and the underlying mechanisms. We also discuss and emphasize several aspects of T cell metabolic modeling in healthy and disease states using genome-scale metabolic models. PMID:29376056

Contributions of the Model of Modelling Diagram to the Learning of Ionic Bonding: Analysis of a Case Study

ERIC Educational Resources Information Center

Mendonca, Paula Cristina Cardoso; Justi, Rosaria

2011-01-01

Current proposals for science education recognise the importance of students' involvement in activities aimed at favouring the understanding of science as a human, dynamic and non-linear construct. Modelling-based teaching is one of the alternatives through which to address such issues. Modelling-based teaching activities for ionic bonding were…

Effect of intermittent feedback control on robustness of human-like postural control system

NASA Astrophysics Data System (ADS)

Tanabe, Hiroko; Fujii, Keisuke; Suzuki, Yasuyuki; Kouzaki, Motoki

2016-03-01

Humans have to acquire postural robustness to maintain stability against internal and external perturbations. Human standing has been recently modelled using an intermittent feedback control. However, the causality inside of the closed-loop postural control system associated with the neural control strategy is still unknown. Here, we examined the effect of intermittent feedback control on postural robustness and of changes in active/passive components on joint coordinative structure. We implemented computer simulation of a quadruple inverted pendulum that is mechanically close to human tiptoe standing. We simulated three pairs of joint viscoelasticity and three choices of neural control strategies for each joint: intermittent, continuous, or passive control. We examined postural robustness for each parameter set by analysing the region of active feedback gain. We found intermittent control at the hip joint was necessary for model stabilisation and model parameters affected the robustness of the pendulum. Joint sways of the pendulum model were partially smaller than or similar to those of experimental data. In conclusion, intermittent feedback control was necessary for the stabilisation of the quadruple inverted pendulum. Also, postural robustness of human-like multi-link standing would be achieved by both passive joint viscoelasticity and neural joint control strategies.

Effect of intermittent feedback control on robustness of human-like postural control system.

PubMed

Tanabe, Hiroko; Fujii, Keisuke; Suzuki, Yasuyuki; Kouzaki, Motoki

2016-03-02

Humans have to acquire postural robustness to maintain stability against internal and external perturbations. Human standing has been recently modelled using an intermittent feedback control. However, the causality inside of the closed-loop postural control system associated with the neural control strategy is still unknown. Here, we examined the effect of intermittent feedback control on postural robustness and of changes in active/passive components on joint coordinative structure. We implemented computer simulation of a quadruple inverted pendulum that is mechanically close to human tiptoe standing. We simulated three pairs of joint viscoelasticity and three choices of neural control strategies for each joint: intermittent, continuous, or passive control. We examined postural robustness for each parameter set by analysing the region of active feedback gain. We found intermittent control at the hip joint was necessary for model stabilisation and model parameters affected the robustness of the pendulum. Joint sways of the pendulum model were partially smaller than or similar to those of experimental data. In conclusion, intermittent feedback control was necessary for the stabilisation of the quadruple inverted pendulum. Also, postural robustness of human-like multi-link standing would be achieved by both passive joint viscoelasticity and neural joint control strategies.

Effect of intermittent feedback control on robustness of human-like postural control system

PubMed Central

Tanabe, Hiroko; Fujii, Keisuke; Suzuki, Yasuyuki; Kouzaki, Motoki

2016-01-01

Humans have to acquire postural robustness to maintain stability against internal and external perturbations. Human standing has been recently modelled using an intermittent feedback control. However, the causality inside of the closed-loop postural control system associated with the neural control strategy is still unknown. Here, we examined the effect of intermittent feedback control on postural robustness and of changes in active/passive components on joint coordinative structure. We implemented computer simulation of a quadruple inverted pendulum that is mechanically close to human tiptoe standing. We simulated three pairs of joint viscoelasticity and three choices of neural control strategies for each joint: intermittent, continuous, or passive control. We examined postural robustness for each parameter set by analysing the region of active feedback gain. We found intermittent control at the hip joint was necessary for model stabilisation and model parameters affected the robustness of the pendulum. Joint sways of the pendulum model were partially smaller than or similar to those of experimental data. In conclusion, intermittent feedback control was necessary for the stabilisation of the quadruple inverted pendulum. Also, postural robustness of human-like multi-link standing would be achieved by both passive joint viscoelasticity and neural joint control strategies. PMID:26931281

Subthalamic nucleus detects unnatural android movement.

PubMed

Ikeda, Takashi; Hirata, Masayuki; Kasaki, Masashi; Alimardani, Maryam; Matsushita, Kojiro; Yamamoto, Tomoyuki; Nishio, Shuichi; Ishiguro, Hiroshi

2017-12-19

An android, i.e., a realistic humanoid robot with human-like capabilities, may induce an uncanny feeling in human observers. The uncanny feeling about an android has two main causes: its appearance and movement. The uncanny feeling about an android increases when its appearance is almost human-like but its movement is not fully natural or comparable to human movement. Even if an android has human-like flexible joints, its slightly jerky movements cause a human observer to detect subtle unnaturalness in them. However, the neural mechanism underlying the detection of unnatural movements remains unclear. We conducted an fMRI experiment to compare the observation of an android and the observation of a human on which the android is modelled, and we found differences in the activation pattern of the brain regions that are responsible for the production of smooth and natural movement. More specifically, we found that the visual observation of the android, compared with that of the human model, caused greater activation in the subthalamic nucleus (STN). When the android's slightly jerky movements are visually observed, the STN detects their subtle unnaturalness. This finding suggests that the detection of unnatural movements is attributed to an error signal resulting from a mismatch between a visual input and an internal model for smooth movement.

Monkey liver cytochrome P450 2C19 is involved in R- and S-warfarin 7-hydroxylation.

PubMed

Hosoi, Yoshio; Uno, Yasuhiro; Murayama, Norie; Fujino, Hideki; Shukuya, Mitsunori; Iwasaki, Kazuhide; Shimizu, Makiko; Utoh, Masahiro; Yamazaki, Hiroshi

2012-12-15

Cynomolgus monkeys are widely used as primate models in preclinical studies. However, some differences are occasionally seen between monkeys and humans in the activities of cytochrome P450 enzymes. R- and S-warfarin are model substrates for stereoselective oxidation in humans. In this current research, the activities of monkey liver microsomes and 14 recombinantly expressed monkey cytochrome P450 enzymes were analyzed with respect to R- and S-warfarin 6- and 7-hydroxylation. Monkey liver microsomes efficiently mediated both R- and S-warfarin 7-hydroxylation, in contrast to human liver microsomes, which preferentially catalyzed S-warfarin 7-hydroxylation. R-Warfarin 7-hydroxylation activities in monkey liver microsomes were not inhibited by α-naphthoflavone or ketoconazole, and were roughly correlated with P450 2C19 levels and flurbiprofen 4-hydroxylation activities in microsomes from 20 monkey livers. In contrast, S-warfarin 7-hydroxylation activities were not correlated with the four marker drug oxidation activities used. Among the 14 recombinantly expressed monkey P450 enzymes tested, P450 2C19 had the highest activities for R- and S-warfarin 7-hydroxylations. Monkey P450 3A4 and 3A5 slowly mediated R- and S-warfarin 6-hydroxylations. Kinetic analysis revealed that monkey P450 2C19 had high V(max) and low K(m) values for R-warfarin 7-hydroxylation, comparable to those for monkey liver microsomes. Monkey P450 2C19 also mediated S-warfarin 7-hydroxylation with V(max) and V(max)/K(m) values comparable to those for recombinant human P450 2C9. R-warfarin could dock favorably into monkey P450 2C19 modeled. These results collectively suggest high activities for monkey liver P450 2C19 toward R- and S-warfarin 6- and 7-hydroxylation in contrast to the saturation kinetics of human P450 2C9-mediated S-warfarin 7-hydroxylation. Copyright © 2012 Elsevier Inc. All rights reserved.

Preconditioning electromyographic data for an upper extremity model using neural networks

NASA Technical Reports Server (NTRS)

Roberson, D. J.; Fernjallah, M.; Barr, R. E.; Gonzalez, R. V.

1994-01-01

A back propagation neural network has been employed to precondition the electromyographic signal (EMG) that drives a computational model of the human upper extremity. This model is used to determine the complex relationship between EMG and muscle activation, and generates an optimal muscle activation scheme that simulates the actual activation. While the experimental and model predicted results of the ballistic muscle movement are very similar, the activation function between the start and the finish is not. This neural network preconditions the signal in an attempt to more closely model the actual activation function over the entire course of the muscle movement.

Overview of past, ongoing and future efforts of the integrated modeling of global change for Northern Eurasia

NASA Astrophysics Data System (ADS)

Monier, Erwan; Kicklighter, David; Sokolov, Andrei; Zhuang, Qianlai; Melillo, Jerry; Reilly, John

2016-04-01

Northern Eurasia is both a major player in the global carbon budget (it includes roughly 70% of the Earth's boreal forest and more than two-thirds of the Earth's permafrost) and a region that has experienced dramatic climate change (increase in temperature, growing season length, floods and droughts) over the past century. Northern Eurasia has also undergone significant land-use change, both driven by human activity (including deforestation, expansion of agricultural lands and urbanization) and natural disturbances (such as wildfires and insect outbreaks). These large environmental and socioeconomic impacts have major implications for the carbon cycle in the region. Northern Eurasia is made up of a diverse set of ecosystems that range from tundra to forests, with significant areas of croplands and pastures as well as deserts, with major urban areas. As such, it represents a complex system with substantial challenges for the modeling community. In this presentation, we provide an overview of past, ongoing and possible future efforts of the integrated modeling of global change for Northern Eurasia. We review the variety of existing modeling approaches to investigate specific components of Earth system dynamics in the region. While there are a limited number of studies that try to integrate various aspects of the Earth system (through scale, teleconnections or processes), we point out that there are few systematic analyses of the various feedbacks within the Earth system (between components, regions or scale). As a result, there is a lack of knowledge of the relative importance of such feedbacks, and it is unclear how policy relevant current studies are that fail to account for these feedbacks. We review the role of Earth system models, and their advantages/limitations compared to detailed single component models. We further introduce the human activity system (global trade, economic models, demographic model and so on), the need for coupled human/earth system models and Integrated Assessment Models (IAMs), a suite of models that couple human activity models to Earth System Models. Finally, we conclude the presentation with examples of emerging issues that require a representation of the coupled human/earth system models.

Hydrolysis of pyrethroids by human and rat tissues: Examination of intestinal, liver and serum carboxylesterases

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

Crow, J. Allen; Borazjani, Abdolsamad; Potter, Philip M.

2007-05-15

Hydrolytic metabolism of pyrethroid insecticides in humans is one of the major catabolic pathways that clear these compounds from the body. Rodent models are often used to determine the disposition and clearance rates of these esterified compounds. In this study the distribution and activities of esterases that catalyze pyrethroid metabolism have been investigated in vitro using several human and rat tissues, including small intestine, liver and serum. The major esterase in human intestine is carboxylesterase 2 (hCE2). We found that the pyrethroid trans-permethrin is effectively hydrolyzed by a sample of pooled human intestinal microsomes (5 individuals), while deltamethrin and bioresmethrinmore » are not. This result correlates well with the substrate specificity of recombinant hCE2 enzyme. In contrast, a sample of pooled rat intestinal microsomes (5 animals) hydrolyze trans-permethrin 4.5-fold slower than the sample of human intestinal microsomes. Furthermore, it is demonstrated that pooled samples of cytosol from human or rat liver are {approx} 2-fold less hydrolytically active (normalized per mg protein) than the corresponding microsomal fraction toward pyrethroid substrates; however, the cytosolic fractions do have significant amounts ({approx} 40%) of the total esteratic activity. Moreover, a 6-fold interindividual variation in carboxylesterase 1 protein expression in human hepatic cytosols was observed. Human serum was shown to lack pyrethroid hydrolytic activity, but rat serum has hydrolytic activity that is attributed to a single CE isozyme. We purified the serum CE enzyme to homogeneity to determine its contribution to pyrethroid metabolism in the rat. Both trans-permethrin and bioresmethrin were effectively cleaved by this serum CE, but deltamethrin, esfenvalerate, alpha-cypermethrin and cis-permethrin were slowly hydrolyzed. Lastly, two model lipase enzymes were examined for their ability to hydrolyze pyrethroids. However, no hydrolysis products could be detected. Together, these results demonstrate that extrahepatic esterolytic metabolism of specific pyrethroids may be significant. Moreover, hepatic cytosolic and microsomal hydrolytic metabolism should each be considered during the development of pharmacokinetic models that predict the disposition of pyrethroids and other esterified compounds.« less

Immunomodulatory activity of a plant extract containing human papillomavirus 16-E7 protein in human monocyte-derived dendritic cells.

PubMed

Di Bonito, P; Grasso, F; Mangino, G; Massa, S; Illiano, E; Franconi, R; Fanales-Belasio, E; Falchi, M; Affabris, E; Giorgi, C

2009-01-01

This study reports the immunomodulatory activity on human monocyte derived dendritic cells (MDDCs) of a vaccine preparation shown to be effective against an HPV16-related tumour in an animal model. The vaccine is composed of extract from Nicotiana benthamiana leaves containing HPV16 E7 protein expressed by a potato virus X-derived vector (NbPVX-E7). The effect of the extract was evaluated on MDDC differentiation and maturation by monitoring the phenotypic expression of specific markers. The results show that NbPVX-E7 does not induce monocyte differentiation to dendritic cells, but does induce MDDC maturation. Plant extract does not influence MDDC-uptake of E7-FITC while it significantly improves the Ovalbumin-FITC uptake, considered as a model antigen. Importantly, NbPVX-E7-pulsed MDDCs/PBMCs are able to prime human blood-derived lymphocytes from healthy individuals to induce HPV16 E7-specific cytotoxic activity. This is a propaedeutic study for a possible use of E7-containing plant extract in human immunotherapy of HPV-related lesions.

Divide and Conquer-Based 1D CNN Human Activity Recognition Using Test Data Sharpening †

PubMed Central

Yoon, Sang Min

2018-01-01

Human Activity Recognition (HAR) aims to identify the actions performed by humans using signals collected from various sensors embedded in mobile devices. In recent years, deep learning techniques have further improved HAR performance on several benchmark datasets. In this paper, we propose one-dimensional Convolutional Neural Network (1D CNN) for HAR that employs a divide and conquer-based classifier learning coupled with test data sharpening. Our approach leverages a two-stage learning of multiple 1D CNN models; we first build a binary classifier for recognizing abstract activities, and then build two multi-class 1D CNN models for recognizing individual activities. We then introduce test data sharpening during prediction phase to further improve the activity recognition accuracy. While there have been numerous researches exploring the benefits of activity signal denoising for HAR, few researches have examined the effect of test data sharpening for HAR. We evaluate the effectiveness of our approach on two popular HAR benchmark datasets, and show that our approach outperforms both the two-stage 1D CNN-only method and other state of the art approaches. PMID:29614767

Divide and Conquer-Based 1D CNN Human Activity Recognition Using Test Data Sharpening.

PubMed

Cho, Heeryon; Yoon, Sang Min

2018-04-01

Human Activity Recognition (HAR) aims to identify the actions performed by humans using signals collected from various sensors embedded in mobile devices. In recent years, deep learning techniques have further improved HAR performance on several benchmark datasets. In this paper, we propose one-dimensional Convolutional Neural Network (1D CNN) for HAR that employs a divide and conquer-based classifier learning coupled with test data sharpening. Our approach leverages a two-stage learning of multiple 1D CNN models; we first build a binary classifier for recognizing abstract activities, and then build two multi-class 1D CNN models for recognizing individual activities. We then introduce test data sharpening during prediction phase to further improve the activity recognition accuracy. While there have been numerous researches exploring the benefits of activity signal denoising for HAR, few researches have examined the effect of test data sharpening for HAR. We evaluate the effectiveness of our approach on two popular HAR benchmark datasets, and show that our approach outperforms both the two-stage 1D CNN-only method and other state of the art approaches.

Dual Modifications of α-Galactosylceramide Synergize to Promote Activation of Human Invariant Natural Killer T Cells and Stimulate Anti-tumor Immunity.

PubMed

Chennamadhavuni, Divya; Saavedra-Avila, Noemi Alejandra; Carreño, Leandro J; Guberman-Pfeffer, Matthew J; Arora, Pooja; Yongqing, Tang; Koay, Hui-Fern; Godfrey, Dale I; Keshipeddy, Santosh; Richardson, Stewart K; Sundararaj, Srinivasan; Lo, Jae Ho; Wen, Xiangshu; Gascón, José A; Yuan, Weiming; Rossjohn, Jamie; Le Nours, Jérôme; Porcelli, Steven A; Howell, Amy R

2018-05-17

Glycosylceramides that activate CD1d-restricted invariant natural killer T (iNKT) cells have potential therapeutic applications for augmenting immune responses against cancer and infections. Previous studies using mouse models identified sphinganine variants of α-galactosylceramide as promising iNKT cell activators that stimulate cytokine responses with a strongly proinflammatory bias. However, the activities of sphinganine variants in mice have generally not translated well to studies of human iNKT cell responses. Here, we show that strongly proinflammatory and anti-tumor iNKT cell responses were achieved in mice by a variant of α-galactosylceramide that combines a sphinganine base with a hydrocinnamoyl ester on C6″ of the sugar. Importantly, the activities observed with this variant were largely preserved for human iNKT cell responses. Structural and in silico modeling studies provided a mechanistic basis for these findings and suggested basic principles for capturing useful properties of sphinganine analogs of synthetic iNKT cell activators in the design of immunotherapeutic agents. Copyright © 2018 Elsevier Ltd. All rights reserved.

On inclusion of water resource management in Earth system models - Part 1: Problem definition and representation of water demand

NASA Astrophysics Data System (ADS)

Nazemi, A.; Wheater, H. S.

2015-01-01

Human activities have caused various changes to the Earth system, and hence the interconnections between human activities and the Earth system should be recognized and reflected in models that simulate Earth system processes. One key anthropogenic activity is water resource management, which determines the dynamics of human-water interactions in time and space and controls human livelihoods and economy, including energy and food production. There are immediate needs to include water resource management in Earth system models. First, the extent of human water requirements is increasing rapidly at the global scale and it is crucial to analyze the possible imbalance between water demands and supply under various scenarios of climate change and across various temporal and spatial scales. Second, recent observations show that human-water interactions, manifested through water resource management, can substantially alter the terrestrial water cycle, affect land-atmospheric feedbacks and may further interact with climate and contribute to sea-level change. Due to the importance of water resource management in determining the future of the global water and climate cycles, the World Climate Research Program's Global Energy and Water Exchanges project (WRCP-GEWEX) has recently identified gaps in describing human-water interactions as one of the grand challenges in Earth system modeling (GEWEX, 2012). Here, we divide water resource management into two interdependent elements, related firstly to water demand and secondly to water supply and allocation. In this paper, we survey the current literature on how various components of water demand have been included in large-scale models, in particular land surface and global hydrological models. Issues of water supply and allocation are addressed in a companion paper. The available algorithms to represent the dominant demands are classified based on the demand type, mode of simulation and underlying modeling assumptions. We discuss the pros and cons of available algorithms, address various sources of uncertainty and highlight limitations in current applications. We conclude that current capability of large-scale models to represent human water demands is rather limited, particularly with respect to future projections and coupled land-atmospheric simulations. To fill these gaps, the available models, algorithms and data for representing various water demands should be systematically tested, intercompared and improved. In particular, human water demands should be considered in conjunction with water supply and allocation, particularly in the face of water scarcity and unknown future climate.

Discovery of potent peptide-mimetic antagonists for the human thrombin receptor, protease-activated receptor-1 (PAR-1).

PubMed

Maryanoff, Bruce E; Zhang, Han-Cheng; Andrade-Gordon, Patricia; Derian, Claudia K

2003-03-01

Protease-activated receptors (PARs) represent a unique family of seven-transmembrane G-protein-coupled receptors, which are enzymatically cleaved to expose a new extracellular N-terminus that acts as a tethered activating ligand. PAR-1 is cleaved and activated by the serine protease alpha-thrombin, is expressed in various tissues (e.g. platelets and vascular cells), and is involved in cellular responses associated with hemostasis, proliferation, and tissue injury. By using a de novo design approach, we have discovered a series of potent heterocycle-based peptide-miimetic antagonists of PAR-1, exemplified by advanced leads RWJ-56110 (22) and RWJ-58259 (32). These compounds are potent, selective PAR-1 antagonists, devoid of PAR-1 agonist and thrombin inhibitory activity: they bind to PAR-1, interfere with calcium mobilization and cellular functions associated with PAR-1, and do not affect PAR-2, PAR-3, or PAR-4. RWJ-56110 was determined to be a direct inhibitor of PAR-1 activation and internalization, without affecting PAR-1 N-terminal cleavage. At high concentrations of alpha-thrombin, RWJ-56110 fully blocked activation responses in human vascular cells, but not in human platelets; whereas, at high concentrations of TRAP-6, RWJ-56110 blocked activation responses in both cell types. This result is consistent with the presence of another thrombin receptor on human platelets, namely PAR-4. RWJ-56110 and RWJ-58259 clearly interrupt the binding of a tethered ligand to its receptor. RWJ-58259 demonstrated antirestenotic activity in a rat balloon angioplasty model and antithrombotic activity in a cynomolgus monkey arterial injury model. Such PAR-1 antagonists should not only serve as useful tools to delineate the physiological and pathophysiological roles of PAR-1, but also may have therapeutic potential for treating thrombosis and restenosis in humans.

Aegeline inspired synthesis of novel β3-AR agonist improves insulin sensitivity in vitro and in vivo models of insulin resistance.

PubMed

Rajan, Sujith; Satish, Sabbu; Shankar, Kripa; Pandeti, Sukanya; Varshney, Salil; Srivastava, Ankita; Kumar, Durgesh; Gupta, Abhishek; Gupta, Sanchita; Choudhary, Rakhi; Balaramnavar, Vishal M; Narender, Tadigoppula; Gaikwad, Anil N

2018-03-07

In our drug discovery program of natural product, earlier we have reported Aegeline that is N-acylated-1-amino-2- alcohol, which was isolated from the leaves of Aeglemarmelos showed anti-hyperlipidemic activity for which the QSAR studies predicted the compound to be the β3-AR agonist, but the mechanism of its action was not elucidated. In our present study, we have evaluated the β3-AR activity of novel N-acyl-1-amino-3-arylopropanol synthetic mimics of aegeline and its beneficial effect in insulin resistance. In this study, we have proposed the novel pharmacophore model using reported molecules for antihyperlipidemic activity. The reported pharmacophore features were also compared with the newly developed pharmacophore model for the observed biological activity. Based on 3D pharmacophore modeling of known β3AR agonist, we screened 20 synthetic derivatives of Aegeline from the literature. From these, the top scoring compound 10C was used for further studies. The in-slico result was further validated in HEK293T cells co-trransfected with human β3-AR and CRE-Luciferase reporter plasmid for β3-AR activity.The most active compound was selected and β3-AR activity was further validated in white and brown adipocytes differentiated from human mesenchymal stem cells (hMSCs). Insulin resistance model developed in hMSC derived adipocytes was used to study the insulin sensitizing property. 8 week HFD fed C57BL6 mice was given 50 mg/Kg of the selected compound and metabolic phenotyping was done to evaluate its anti-diabetic effect. As predicted by in-silico 3D pharmacophore modeling, the compound 10C was found to be the most active and specific β3-AR agonist with EC 50 value of 447 nM. The compound 10C activated β3AR pathway, induced lipolysis, fatty acid oxidation and increased oxygen consumption rate (OCR) in human adipocytes. Compound 10C induced expression of brown adipocytes specific markers and reverted chronic insulin induced insulin resistance in white adipocytes. The compound 10C also improved insulin sensitivity and glucose tolerance in 8 week HFD fed C57BL6 mice. This study enlightens the use of in vitro insulin resistance model close to human physiology to elucidates the insulin sensitizing activity of the compound 10C and edifies the use of β3AR agonist as therapeutic interventions for insulin resistance and type 2 diabetes. Copyright © 2018. Published by Elsevier Inc.

Human innate responses and adjuvant activity of TLR ligands in vivo in mice reconstituted with a human immune system.

PubMed

Cheng, Liang; Zhang, Zheng; Li, Guangming; Li, Feng; Wang, Li; Zhang, Liguo; Zurawski, Sandra M; Zurawski, Gerard; Levy, Yves; Su, Lishan

2017-10-27

TLR ligands (TLR-Ls) represent a class of novel vaccine adjuvants. However, their immunologic effects in humans remain poorly defined in vivo. Using a humanized mouse model with a functional human immune system, we investigated how different TLR-Ls stimulated human innate immune response in vivo and their applications as vaccine adjuvants for enhancing human cellular immune response. We found that splenocytes from humanized mice showed identical responses to various TLR-Ls as human PBMCs in vitro. To our surprise, various TLR-Ls stimulated human cytokines and chemokines differently in vivo compared to that in vitro. For example, CpG-A was most efficient to induce IFN-α production in vitro. In contrast, CpG-B, R848 and Poly I:C stimulated much more IFN-α than CpG-A in vivo. Importantly, the human innate immune response to specific TLR-Ls in humanized mice was different from that reported in C57BL/6 mice, but similar to that reported in nonhuman primates. Furthermore, we found that different TLR-Ls distinctively activated and mobilized human plasmacytoid dendritic cells (pDCs), myeloid DCs (mDCs) and monocytes in different organs. Finally, we showed that, as adjuvants, CpG-B, R848 and Poly I:C can all enhance antigen specific CD4 + T cell response, while only R848 and Poly I:C induced CD8 + cytotoxic T cells response to a CD40-targeting HIV vaccine in humanized mice, correlated with their ability to activate human mDCs but not pDCs. We conclude that humanized mice serve as a highly relevant model to evaluate and rank the human immunologic effects of novel adjuvants in vivo prior to testing in humans. Copyright © 2017 Elsevier Ltd. All rights reserved.

Genetic programs expressed in resting and IL-4 alternatively activated mouse and human macrophages: similarities and differences.

PubMed

Martinez, Fernando O; Helming, Laura; Milde, Ronny; Varin, Audrey; Melgert, Barbro N; Draijer, Christina; Thomas, Benjamin; Fabbri, Marco; Crawshaw, Anjali; Ho, Ling Pei; Ten Hacken, Nick H; Cobos Jiménez, Viviana; Kootstra, Neeltje A; Hamann, Jörg; Greaves, David R; Locati, Massimo; Mantovani, Alberto; Gordon, Siamon

2013-02-28

The molecular repertoire of macrophages in health and disease can provide novel biomarkers for diagnosis, prognosis, and treatment. Th2-IL-4–activated macrophages (M2) have been associated with important diseases in mice, yet no specific markers are available for their detection in human tissues. Although mouse models are widely used for macrophage research, translation to the human can be problematic and the human macrophage system remains poorly described. In the present study, we analyzed and compared the transcriptome and proteome of human and murine macrophages under resting conditions (M0) and after IL-4 activation (M2). We provide a resource for tools enabling macrophage detection in human tissues by identifying a set of 87 macrophage-related genes. Furthermore, we extend current understanding of M2 activation in different species and identify Transglutaminase 2 as a conserved M2 marker that is highly expressed by human macrophages and monocytes in the prototypic Th2 pathology asthma.

Insights into the O-Acetylation Reaction of Hydroxylated Heterocyclic Amines by Human Arylamine N-Acetyltransferases: A Computational Study

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

Lau, E Y; Felton, J S; Lightstone, F C

2006-06-06

A computational study was performed to better understand the differences between human arylamine N-acetyltransferase (NAT) 1 and 2. Homology models were constructed from available crystal structures and comparisons of the active site residues 125, 127, and 129 for these two enzymes provide insight into observed substrate differences. The NAT2 model provided a basis for understanding how some of the common mutations may affect the structure of the protein. Molecular dynamics simulations of the human NAT models and the template structure (NAT from Mycobacterium smegmatis) were performed and showed the models to be stable and reasonable. Docking studies of hydroxylated heterocyclicmore » amines in the models of NAT1 and NAT2 probed the differences exhibited by these two proteins with mutagenic agents. The hydroxylated heterocyclic amines were only able to fit into the NAT2 active site, and an alternative binding site by the P-loop was found using our models and will be discussed. Additionally, quantum mechanical calculations were performed to study the O-acetylation reaction of the hydroxylated heterocyclic amines N-OH MeIQx and N-OH PhIP. This study has given us insight into why there are substrate differences among isoenzymes and explains some of the polymorphic activity differences.« less

Dynamic Socialized Gaussian Process Models for Human Behavior Prediction in a Health Social Network

PubMed Central

Shen, Yelong; Phan, NhatHai; Xiao, Xiao; Jin, Ruoming; Sun, Junfeng; Piniewski, Brigitte; Kil, David; Dou, Dejing

2016-01-01

Modeling and predicting human behaviors, such as the level and intensity of physical activity, is a key to preventing the cascade of obesity and helping spread healthy behaviors in a social network. In our conference paper, we have developed a social influence model, named Socialized Gaussian Process (SGP), for socialized human behavior modeling. Instead of explicitly modeling social influence as individuals' behaviors influenced by their friends' previous behaviors, SGP models the dynamic social correlation as the result of social influence. The SGP model naturally incorporates personal behavior factor and social correlation factor (i.e., the homophily principle: Friends tend to perform similar behaviors) into a unified model. And it models the social influence factor (i.e., an individual's behavior can be affected by his/her friends) implicitly in dynamic social correlation schemes. The detailed experimental evaluation has shown the SGP model achieves better prediction accuracy compared with most of baseline methods. However, a Socialized Random Forest model may perform better at the beginning compared with the SGP model. One of the main reasons is the dynamic social correlation function is purely based on the users' sequential behaviors without considering other physical activity-related features. To address this issue, we further propose a novel “multi-feature SGP model” (mfSGP) which improves the SGP model by using multiple physical activity-related features in the dynamic social correlation learning. Extensive experimental results illustrate that the mfSGP model clearly outperforms all other models in terms of prediction accuracy and running time. PMID:27746515

Human-induced Terrestrial Water Storage Change: A Global Analysis using Hydrological Models and GRACE

NASA Astrophysics Data System (ADS)

Felfelani, F.; Pokhrel, Y. N.

2016-12-01

Hydrological models and data derived from the Gravity Recovery and Climate Experiment (GRACE) satellite mission are used to study terrestrial water storage (TWS) change; however, both have disadvantages that necessitate the integrated use of them. While GRACE doesn't disintegrate the vertical storage into its components, most models do not account for human activities. Here we use two Land Surface Models (LSMs), i.e., HiGW-MAT and PCRGLOBWB that fully couple natural and human drivers of changes in water cycle, explicitly simulating the changes in various TWS compartments. We first evaluate the models performance with GRACE observations. Then, we quantify the human footprint over global river basins located in different geographic and climate regions. To quantify human impacts, a new framework is proposed based on the GRACE observations (representing both climate variability and human activities) together with the natural simulation of LSMs using water budget equation (P-ET-R; P for precipitation, ET for evapotranspiration, and R for runoff). Finally, we examine the uncertainty in TWS simulations arising from the uncertainties in forcing data. Results indicate that, in snow-dominated regions, PCRGLOBWB generally fails to reproduce neither the interannual variability of observed TWS nor the seasonal cycle, while HiGW-MAT model shows significantly better results. In basins with human signatures, PCRGLOBWB generally shows better agreement with GRACE compared to HiGW-MAT. It is found that HiGW-MAT tends to overestimate groundwater depletion in basins with human impacts (e.g., Amudarya, Colorado, Euphrates and Indus), which results in larger negative interannual TWS trend compared to GRACE. Euphrates and Ganges river basins experience the highest human-induced TWS deficit rates (2.08 cm/yr and 1.94 cm/yr, respectively) during the simulation period of 2002-2010. Uncertainty analysis of results from the same model but with different forcing data suggests a high standard deviation in the order of 10 cm/yr.

Toxicity challenges in environmental chemicals: Prediction of human plasma protein binding through quantitative structure-activity relationship (QSAR) models (2016 IVIVE Workshop Proceedings)

EPA Science Inventory

Physiologically based pharmacokinetic (PBPK) models bridge the gap between in vitro assays and in vivo effects by accounting for the adsorption, distribution, metabolism, and excretion of xenobiotics, which is especially useful in the assessment of human toxicity. Quantitative st...

Human serum activates CIDEB-mediated lipid droplet enlargement in hepatoma cells

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

Singaravelu, Ragunath; National Research Council of Canada, Ottawa, Ontario K1A 0R6; Lyn, Rodney K.

Highlights: •Human serum induced differentiation of hepatoma cells increases cellular lipid droplet (LD) size. •The observed increase in LD size correlates with increased PGC-1α and CIDEB expression. •Induction of CIDEB expression correlates with rescue of VLDL secretion and loss of ADRP. •siRNA knockdown of CIDEB impairs the human serum mediated increase in LD size. •This system represents a cost-efficient model to study CIDEB’s role in lipid biology. -- Abstract: Human hepatocytes constitutively express the lipid droplet (LD) associated protein cell death-inducing DFFA-like effector B (CIDEB). CIDEB mediates LD fusion, as well as very-low-density lipoprotein (VLDL) maturation. However, there are limitedmore » cell culture models readily available to study CIDEB’s role in these biological processes, as hepatoma cell lines express negligible levels of CIDEB. Recent work has highlighted the ability of human serum to differentiate hepatoma cells. Herein, we demonstrate that culturing Huh7.5 cells in media supplemented with human serum activates CIDEB expression. This activation occurs through the induced expression of PGC-1α, a positive transcriptional regulator of CIDEB. Coherent anti-Stokes Raman scattering (CARS) microscopy revealed a correlation between CIDEB levels and LD size in human serum treated Huh7.5 cells. Human serum treatment also resulted in a rapid decrease in the levels of adipose differentiation-related protein (ADRP). Furthermore, individual overexpression of CIDEB was sufficient to down-regulate ADRP protein levels. siRNA knockdown of CIDEB revealed that the human serum mediated increase in LD size was CIDEB-dependent. Overall, our work highlights CIDEB’s role in LD fusion, and presents a new model system to study the PGC-1α/CIDEB pathway’s role in LD dynamics and the VLDL pathway.« less

Bridging the gap between computation and clinical biology: validation of cable theory in humans

PubMed Central

Finlay, Malcolm C.; Xu, Lei; Taggart, Peter; Hanson, Ben; Lambiase, Pier D.

2013-01-01

Introduction: Computerized simulations of cardiac activity have significantly contributed to our understanding of cardiac electrophysiology, but techniques of simulations based on patient-acquired data remain in their infancy. We sought to integrate data acquired from human electrophysiological studies into patient-specific models, and validated this approach by testing whether electrophysiological responses to sequential premature stimuli could be predicted in a quantitatively accurate manner. Methods: Eleven patients with structurally normal hearts underwent electrophysiological studies. Semi-automated analysis was used to reconstruct activation and repolarization dynamics for each electrode. This S2 extrastimuli data was used to inform individualized models of cardiac conduction, including a novel derivation of conduction velocity restitution. Activation dynamics of multiple premature extrastimuli were then predicted from this model and compared against measured patient data as well as data derived from the ten-Tusscher cell-ionic model. Results: Activation dynamics following a premature S3 were significantly different from those after an S2. Patient specific models demonstrated accurate prediction of the S3 activation wave, (Pearson's R2 = 0.90, median error 4%). Examination of the modeled conduction dynamics allowed inferences into the spatial dispersion of activation delay. Further validation was performed against data from the ten-Tusscher cell-ionic model, with our model accurately recapitulating predictions of repolarization times (R2 = 0.99). Conclusions: Simulations based on clinically acquired data can be used to successfully predict complex activation patterns following sequential extrastimuli. Such modeling techniques may be useful as a method of incorporation of clinical data into predictive models. PMID:24027527

A HUMAN FACTORS META MODEL FOR U.S. NUCLEAR POWER PLANT CONTROL ROOM MODERNIZATION

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

Joe, Jeffrey C.

Over the last several years, the United States (U.S.) Department of Energy (DOE) has sponsored human factors research and development (R&D) and human factors engineering (HFE) activities through its Light Water Reactor Sustainability (LWRS) program to modernize the main control rooms (MCR) of commercial nuclear power plants (NPP). Idaho National Laboratory (INL), in partnership with numerous commercial nuclear utilities, has conducted some of this R&D to enable the life extension of NPPs (i.e., provide the technical basis for the long-term reliability, productivity, safety, and security of U.S. NPPs). From these activities performed to date, a human factors meta model formore » U.S. NPP control room modernization can now be formulated. This paper discusses this emergent HFE meta model for NPP control room modernization, with the goal of providing an integrated high level roadmap and guidance on how to perform human factors R&D and HFE for those in the U.S. nuclear industry that are engaging in the process of upgrading their MCRs.« less

Molecular modeling and analysis of human and plant endo-β-N-acetyl- glucosaminidases for mutations effects on function

PubMed Central

Choragudi, Shechinah Felice; Veeramachaneni, Ganesh Kumar; Raman, BV; JS, Bondili

2014-01-01

Endo- β-N-acetylgucosaminidases (ENGases) are the enzymes that catalyze both hydrolysis and transglycosylation reactions. It is of interest to study ENGases because of their ability to synthesize glycopeptides. Homology models of Human, Arabidopsis thaliana and Sorghum ENGases were developed and their active sites marked based on information available from Arthrobacter protophormiae (PDB ID: 3FHQ) ENGase. Further, these models were docked with the natural substrate GlcNAc-Asn and the inhibitor Man3GlcNAc-thiazoline. The catalytic triad of Asn, Glu and Tyr (N171, E173 and Y205 of bacteria) were found to be conserved across the phyla. The crucial Y299F mutation showing 3 times higher transglycosylation activity than in wild type Endo-A is known. The hydrolytic activity remained unchanged in bacteria, while the transglycosylation activity increased. This Y to F change is found to be naturally evolved and should be attributing higher transglycosylation rates in human and Arabidopsis thaliana ENGases. Ligand interactions Ligplots revealed the interaction of amino acids with hydrophobic side chains and polar uncharged side chain amino acids. Thus, structure based molecular model-ligand interactions provide insights into the catalytic mechanism of ENGases and assist in the rational engineering of ENGases. PMID:25258486

Molecular modeling and analysis of human and plant endo-β-N-acetyl- glucosaminidases for mutations effects on function.

PubMed

Choragudi, Shechinah Felice; Veeramachaneni, Ganesh Kumar; Raman, Bv; Js, Bondili

2014-01-01

Endo- β-N-acetylgucosaminidases (ENGases) are the enzymes that catalyze both hydrolysis and transglycosylation reactions. It is of interest to study ENGases because of their ability to synthesize glycopeptides. Homology models of Human, Arabidopsis thaliana and Sorghum ENGases were developed and their active sites marked based on information available from Arthrobacter protophormiae (PDB ID: 3FHQ) ENGase. Further, these models were docked with the natural substrate GlcNAc-Asn and the inhibitor Man3GlcNAc-thiazoline. The catalytic triad of Asn, Glu and Tyr (N171, E173 and Y205 of bacteria) were found to be conserved across the phyla. The crucial Y299F mutation showing 3 times higher transglycosylation activity than in wild type Endo-A is known. The hydrolytic activity remained unchanged in bacteria, while the transglycosylation activity increased. This Y to F change is found to be naturally evolved and should be attributing higher transglycosylation rates in human and Arabidopsis thaliana ENGases. Ligand interactions Ligplots revealed the interaction of amino acids with hydrophobic side chains and polar uncharged side chain amino acids. Thus, structure based molecular model-ligand interactions provide insights into the catalytic mechanism of ENGases and assist in the rational engineering of ENGases.

Development and Validation of the Total HUman Model for Safety (THUMS) Toward Further Understanding of Occupant Injury Mechanisms in Precrash and During Crash.

PubMed

Iwamoto, Masami; Nakahira, Yuko; Kimpara, Hideyuki

2015-01-01

Active safety devices such as automatic emergency brake (AEB) and precrash seat belt have the potential to accomplish further reduction in the number of the fatalities due to automotive accidents. However, their effectiveness should be investigated by more accurate estimations of their interaction with human bodies. Computational human body models are suitable for investigation, especially considering muscular tone effects on occupant motions and injury outcomes. However, the conventional modeling approaches such as multibody models and detailed finite element (FE) models have advantages and disadvantages in computational costs and injury predictions considering muscular tone effects. The objective of this study is to develop and validate a human body FE model with whole body muscles, which can be used for the detailed investigation of interaction between human bodies and vehicular structures including some safety devices precrash and during a crash with relatively low computational costs. In this study, we developed a human body FE model called THUMS (Total HUman Model for Safety) with a body size of 50th percentile adult male (AM50) and a sitting posture. The model has anatomical structures of bones, ligaments, muscles, brain, and internal organs. The total number of elements is 281,260, which would realize relatively low computational costs. Deformable material models were assigned to all body parts. The muscle-tendon complexes were modeled by truss elements with Hill-type muscle material and seat belt elements with tension-only material. The THUMS was validated against 35 series of cadaver or volunteer test data on frontal, lateral, and rear impacts. Model validations for 15 series of cadaver test data associated with frontal impacts are presented in this article. The THUMS with a vehicle sled model was applied to investigate effects of muscle activations on occupant kinematics and injury outcomes in specific frontal impact situations with AEB. In the validations using 5 series of cadaver test data, force-time curves predicted by the THUMS were quantitatively evaluated using correlation and analysis (CORA), which showed good or acceptable agreement with cadaver test data in most cases. The investigation of muscular effects showed that muscle activation levels and timing had significant effects on occupant kinematics and injury outcomes. Although further studies on accident injury reconstruction are needed, the THUMS has the potential for predictions of occupant kinematics and injury outcomes considering muscular tone effects with relatively low computational costs.

Does solar activity affect human happiness?

NASA Astrophysics Data System (ADS)

Kristoufek, Ladislav

2018-03-01

We investigate the direct influence of solar activity (represented by sunspot numbers) on human happiness (represented by the Twitter-based Happiness Index). We construct four models controlling for various statistical and dynamic effects of the analyzed series. The final model gives promising results. First, there is a statistically significant negative influence of solar activity on happiness which holds even after controlling for the other factors. Second, the final model, which is still rather simple, explains around 75% of variance of the Happiness Index. Third, our control variables contribute significantly as well: happiness is higher in no sunspots days, happiness is strongly persistent, there are strong intra-week cycles and happiness peaks during holidays. Our results strongly contribute to the topical literature and they provide evidence of unique utility of the online data.

The Human Central Pattern Generator for Locomotion.

PubMed

Minassian, Karen; Hofstoetter, Ursula S; Dzeladini, Florin; Guertin, Pierre A; Ijspeert, Auke

2017-03-01

The ability of dedicated spinal circuits, referred to as central pattern generators (CPGs), to produce the basic rhythm and neural activation patterns underlying locomotion can be demonstrated under specific experimental conditions in reduced animal preparations. The existence of CPGs in humans is a matter of debate. Equally elusive is the contribution of CPGs to normal bipedal locomotion. To address these points, we focus on human studies that utilized spinal cord stimulation or pharmacological neuromodulation to generate rhythmic activity in individuals with spinal cord injury, and on neuromechanical modeling of human locomotion. In the absence of volitional motor control and step-specific sensory feedback, the human lumbar spinal cord can produce rhythmic muscle activation patterns that closely resemble CPG-induced neural activity of the isolated animal spinal cord. In this sense, CPGs in humans can be defined by the activity they produce. During normal locomotion, CPGs could contribute to the activation patterns during specific phases of the step cycle and simplify supraspinal control of step cycle frequency as a feedforward component to achieve a targeted speed. Determining how the human CPGs operate will be essential to advance the theory of neural control of locomotion and develop new locomotor neurorehabilitation paradigms.

Multiagent Modeling and Simulation in Human-Robot Mission Operations Work System Design

NASA Technical Reports Server (NTRS)

Sierhuis, Maarten; Clancey, William J.; Sims, Michael H.; Shafto, Michael (Technical Monitor)

2001-01-01

This paper describes a collaborative multiagent modeling and simulation approach for designing work systems. The Brahms environment is used to model mission operations for a semi-autonomous robot mission to the Moon at the work practice level. It shows the impact of human-decision making on the activities and energy consumption of a robot. A collaborative work systems design methodology is described that allows informal models, created with users and stakeholders, to be used as input to the development of formal computational models.

Human and mouse homo-oligomeric meprin A metalloendopeptidase: substrate and inhibitor specificities.

PubMed

Bylander, John E; Bertenshaw, Greg P; Matters, Gail L; Hubbard, Simon J; Bond, Judith S

2007-11-01

Meprin metalloproteinases have been implicated in the susceptibility to and progression of diabetic nephropathy and inflammatory bowel diseases. Our studies with experimental models of these diseases in mice are congruent with the conclusion that meprins modulate the inflammatory responses and tissue damage. To determine whether the mouse and human enzymes differ, recombinant forms of meprin A from the two species were compared with respect to structure, substrates and inhibitors. Human homo-oligomeric meprin A formed oligomers ranging from 950,000 to 1,500,000 Da vs. 900,000 Da for mouse meprin A. Human and mouse meprin A exhibited similar activity against azocasein, fibronectin, collagen IV, and peptides such as parathyroid hormone, ghrelin, and gastrin-releasing peptide. The human enzyme had lower activity against gelatin, bradykinin, alpha-melanocyte-stimulating hormone and neurotensin, and higher activity against secretin and orcokinin. Human meprin A showed a preference for acidic residues in the P1' position of the substrate, unlike mouse meprin A. Several metalloproteinase inhibitors had IC(50) values in the nanomolar range, but potency ranged from similar values to a difference of several orders of magnitude for meprins from the two species. This work provides valuable data to improve predictability for human systems based on meprin functions in mouse models.

How Object, Situation and Personality Shape Human Attitude in Learning: An Activity Perspective and a Multilevel Modeling Approach

ERIC Educational Resources Information Center

Sun, Jun

2009-01-01

Based on Activity Theory, this article examines attitude formation in human learning as shaped by the experiences of individual learners with various learning objects in particular learning contexts. It hypothesizes that a learner's object-related perceptions, personality traits and situational perceptions may have different relationships with the…

A dynamic model for generating actuator specifications for small arms barrel active stabilization

NASA Astrophysics Data System (ADS)

Pathak, Anupam; Brei, Diann; Luntz, Jonathan; Lavigna, Chris

2006-03-01

Due to stresses encountered in combat, it is known that soldier marksmanship noticeably decreases regardless of prior training. Active stabilization systems in small arms have potential to address this problem to increase soldier survivability and mission effectiveness. The key to success is proper actuator design, but this is highly dependent on proper specification which is challenging due to the human/weapon interaction. This paper presents a generic analytical dynamic model which is capable of defining the necessary actuation specifications for a wide range of small arms platforms. The model is unique because it captures the human interface--shoulder and arm--that introduces the jitter disturbance in addition to the geometry, inertial properties and active stabilization stiffness of the small arms platform. Because no data to date is available for actual shooter-induced disturbance in field conditions, a method is given using the model to back-solve from measured shooting range variability data the disturbance amplitude information relative to the input source (arm or shoulder). As examples of the applicability of the model to various small arms systems, two different weapon systems were investigated: the M24 sniper weapon and the M16 assault rifle. In both cases, model based simulations provided valuable insight into impact on the actuation specifications (force, displacement, phase, frequency) due to the interplay of the human-weapon-active stabilization interface including the effect of shooter-disturbance frequency, disturbance location (shoulder vs. arm), and system parameters (stiffness, barrel rotation).

Spontaneous appetence for wheel-running: a model of dependency on physical activity in rat.

PubMed

Ferreira, Anthony; Lamarque, Stéphanie; Boyer, Patrice; Perez-Diaz, Fernando; Jouvent, Roland; Cohen-Salmon, Charles

2006-12-01

According to human observations of a syndrome of physical activity dependence and its consequences, we tried to examine if running activity in a free activity paradigm, where rats had a free access to activity wheel, may present a valuable animal model for physical activity dependence and most generally to behavioral dependence. The pertinence of reactivity to novelty, a well-known pharmacological dependence predictor was also tested. Given the close linkage observed in human between physical activity and drugs use and abuse, the influence of free activity in activity wheels on reactivity to amphetamine injection and reactivity to novelty were also assessed. It appeared that (1) free access to wheel may be used as a valuable model for physical activity addiction, (2) two populations differing in activity amount also differed in dependence to wheel-running. (3) Reactivity to novelty did not appeared as a predictive factor for physical activity dependence (4) activity modified novelty reactivity and (5) subjects who exhibited a high appetence to wheel-running, presented a strong reactivity to amphetamine. These results propose a model of dependency on physical activity without any pharmacological intervention, and demonstrate the existence of individual differences in the development of this addiction. In addition, these data highlight the development of a likely vulnerability to pharmacological addiction after intense and sustained physical activity, as also described in man. This model could therefore prove pertinent for studying behavioral dependencies and the underlying neurobiological mechanisms. These results may influence the way psychiatrists view behavioral dependencies and phenomena such as doping in sport or addiction to sport itself.

Incorporating Anthropogenic Influences into Fire Probability Models: Effects of Human Activity and Climate Change on Fire Activity in California.

PubMed

Mann, Michael L; Batllori, Enric; Moritz, Max A; Waller, Eric K; Berck, Peter; Flint, Alan L; Flint, Lorraine E; Dolfi, Emmalee

2016-01-01

The costly interactions between humans and wildfires throughout California demonstrate the need to understand the relationships between them, especially in the face of a changing climate and expanding human communities. Although a number of statistical and process-based wildfire models exist for California, there is enormous uncertainty about the location and number of future fires, with previously published estimates of increases ranging from nine to fifty-three percent by the end of the century. Our goal is to assess the role of climate and anthropogenic influences on the state's fire regimes from 1975 to 2050. We develop an empirical model that integrates estimates of biophysical indicators relevant to plant communities and anthropogenic influences at each forecast time step. Historically, we find that anthropogenic influences account for up to fifty percent of explanatory power in the model. We also find that the total area burned is likely to increase, with burned area expected to increase by 2.2 and 5.0 percent by 2050 under climatic bookends (PCM and GFDL climate models, respectively). Our two climate models show considerable agreement, but due to potential shifts in rainfall patterns, substantial uncertainty remains for the semiarid inland deserts and coastal areas of the south. Given the strength of human-related variables in some regions, however, it is clear that comprehensive projections of future fire activity should include both anthropogenic and biophysical influences. Previous findings of substantially increased numbers of fires and burned area for California may be tied to omitted variable bias from the exclusion of human influences. The omission of anthropogenic variables in our model would overstate the importance of climatic ones by at least 24%. As such, the failure to include anthropogenic effects in many models likely overstates the response of wildfire to climatic change.

Incorporating Anthropogenic Influences into Fire Probability Models: Effects of Human Activity and Climate Change on Fire Activity in California

PubMed Central

Batllori, Enric; Moritz, Max A.; Waller, Eric K.; Berck, Peter; Flint, Alan L.; Flint, Lorraine E.; Dolfi, Emmalee

2016-01-01

The costly interactions between humans and wildfires throughout California demonstrate the need to understand the relationships between them, especially in the face of a changing climate and expanding human communities. Although a number of statistical and process-based wildfire models exist for California, there is enormous uncertainty about the location and number of future fires, with previously published estimates of increases ranging from nine to fifty-three percent by the end of the century. Our goal is to assess the role of climate and anthropogenic influences on the state’s fire regimes from 1975 to 2050. We develop an empirical model that integrates estimates of biophysical indicators relevant to plant communities and anthropogenic influences at each forecast time step. Historically, we find that anthropogenic influences account for up to fifty percent of explanatory power in the model. We also find that the total area burned is likely to increase, with burned area expected to increase by 2.2 and 5.0 percent by 2050 under climatic bookends (PCM and GFDL climate models, respectively). Our two climate models show considerable agreement, but due to potential shifts in rainfall patterns, substantial uncertainty remains for the semiarid inland deserts and coastal areas of the south. Given the strength of human-related variables in some regions, however, it is clear that comprehensive projections of future fire activity should include both anthropogenic and biophysical influences. Previous findings of substantially increased numbers of fires and burned area for California may be tied to omitted variable bias from the exclusion of human influences. The omission of anthropogenic variables in our model would overstate the importance of climatic ones by at least 24%. As such, the failure to include anthropogenic effects in many models likely overstates the response of wildfire to climatic change. PMID:27124597

Dynamic response and transfer function of social systems: A neuro-inspired model of collective human activity patterns.

PubMed

Lymperopoulos, Ilias N

2017-10-01

The interaction of social networks with the external environment gives rise to non-stationary activity patterns reflecting the temporal structure and strength of exogenous influences that drive social dynamical processes far from an equilibrium state. Following a neuro-inspired approach, based on the dynamics of a passive neuronal membrane, and the firing rate dynamics of single neurons and neuronal populations, we build a state-of-the-art model of the collective social response to exogenous interventions. In this regard, we analyze online activity patterns with a view to determining the transfer function of social systems, that is, the dynamic relationship between external influences and the resulting activity. To this end, first we estimate the impulse response (Green's function) of collective activity, and then we show that the convolution of the impulse response with a time-varying external influence field accurately reproduces empirical activity patterns. To capture the dynamics of collective activity when the generating process is in a state of statistical equilibrium, we incorporate into the model a noisy input convolved with the impulse response function, thus precisely reproducing the fluctuations of stationary collective activity around a resting value. The outstanding goodness-of-fit of the model results to empirical observations, indicates that the model explains human activity patterns generated by time-dependent external influences in various socio-economic contexts. The proposed model can be used for inferring the temporal structure and strength of external influences, as well as the inertia of collective social activity. Furthermore, it can potentially predict social activity patterns. Copyright © 2017 Elsevier Ltd. All rights reserved.

Uncovering the mystery of opposite circadian rhythms between mouse and human leukocytes in humanized mice.

PubMed

Zhao, Yue; Liu, Min; Chan, Xue Ying; Tan, Sue Yee; Subramaniam, Sharrada; Fan, Yong; Loh, Eva; Chang, Kenneth Tou En; Tan, Thiam Chye; Chen, Qingfeng

2017-11-02

Many immune parameters show circadian rhythms during the 24-hour day in mammals. The most striking circadian oscillation is the number of circulating immune cells that display an opposite rhythm between humans and mice. The physiological roles and mechanisms of circadian variations in mouse leukocytes are well studied, whereas for humans they remain unclear because of the lack of a proper model. In this study, we found that consistent with their natural host species, mouse and human circulating leukocytes exhibited opposite circadian oscillations in humanized mice. This cyclic pattern of trafficking correlated well with the diurnal expression levels of C-X-C chemokine receptor 4, which were controlled by the intracellular hypoxia-inducible factor 1α/aryl hydrocarbon receptor nuclear translocator-like heterodimer. Furthermore, we also discovered that p38 mitogen-activated protein kinases/mitogen-activated 2 had opposite effects between mice and humans in generating intracellular reactive oxygen species, which subsequently regulated HIF-1α expression. In conclusion, we propose humanized mice as a robust model for human circadian studies and reveal insights on a novel molecular clock network in the human circadian rhythm. © 2017 by The American Society of Hematology.

Exact Solution of the Gyration Radius of an Individual's Trajectory for a Simplified Human Regular Mobility Model

NASA Astrophysics Data System (ADS)

Yan, Xiao-Yong; Han, Xiao-Pu; Zhou, Tao; Wang, Bing-Hong

2011-12-01

We propose a simplified human regular mobility model to simulate an individual's daily travel with three sequential activities: commuting to workplace, going to do leisure activities and returning home. With the assumption that the individual has a constant travel speed and inferior limit of time at home and in work, we prove that the daily moving area of an individual is an ellipse, and finally obtain an exact solution of the gyration radius. The analytical solution captures the empirical observation well.

Unified underpinning of human mobility in the real world and cyberspace

NASA Astrophysics Data System (ADS)

Zhao, Yi-Ming; Zeng, An; Yan, Xiao-Yong; Wang, Wen-Xu; Lai, Ying-Cheng

2016-05-01

Human movements in the real world and in cyberspace affect not only dynamical processes such as epidemic spreading and information diffusion but also social and economical activities such as urban planning and personalized recommendation in online shopping. Despite recent efforts in characterizing and modeling human behaviors in both the real and cyber worlds, the fundamental dynamics underlying human mobility have not been well understood. We develop a minimal, memory-based random walk model in limited space for reproducing, with a single parameter, the key statistical behaviors characterizing human movements in both cases. The model is validated using relatively big data from mobile phone and online commerce, suggesting memory-based random walk dynamics as the unified underpinning for human mobility, regardless of whether it occurs in the real world or in cyberspace.

Towards the Verification of Human-Robot Teams

NASA Technical Reports Server (NTRS)

Fisher, Michael; Pearce, Edward; Wooldridge, Mike; Sierhuis, Maarten; Visser, Willem; Bordini, Rafael H.

2005-01-01

Human-Agent collaboration is increasingly important. Not only do high-profile activities such as NASA missions to Mars intend to employ such teams, but our everyday activities involving interaction with computational devices falls into this category. In many of these scenarios, we are expected to trust that the agents will do what we expect and that the agents and humans will work together as expected. But how can we be sure? In this paper, we bring together previous work on the verification of multi-agent systems with work on the modelling of human-agent teamwork. Specifically, we target human-robot teamwork. This paper provides an outline of the way we are using formal verification techniques in order to analyse such collaborative activities. A particular application is the analysis of human-robot teams intended for use in future space exploration.

Physical environment virtualization for human activities recognition

NASA Astrophysics Data System (ADS)

Poshtkar, Azin; Elangovan, Vinayak; Shirkhodaie, Amir; Chan, Alex; Hu, Shuowen

2015-05-01

Human activity recognition research relies heavily on extensive datasets to verify and validate performance of activity recognition algorithms. However, obtaining real datasets are expensive and highly time consuming. A physics-based virtual simulation can accelerate the development of context based human activity recognition algorithms and techniques by generating relevant training and testing videos simulating diverse operational scenarios. In this paper, we discuss in detail the requisite capabilities of a virtual environment to aid as a test bed for evaluating and enhancing activity recognition algorithms. To demonstrate the numerous advantages of virtual environment development, a newly developed virtual environment simulation modeling (VESM) environment is presented here to generate calibrated multisource imagery datasets suitable for development and testing of recognition algorithms for context-based human activities. The VESM environment serves as a versatile test bed to generate a vast amount of realistic data for training and testing of sensor processing algorithms. To demonstrate the effectiveness of VESM environment, we present various simulated scenarios and processed results to infer proper semantic annotations from the high fidelity imagery data for human-vehicle activity recognition under different operational contexts.

Bridging the Gap between Human Judgment and Automated Reasoning in Predictive Analytics

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

Sanfilippo, Antonio P.; Riensche, Roderick M.; Unwin, Stephen D.

2010-06-07

Events occur daily that impact the health, security and sustainable growth of our society. If we are to address the challenges that emerge from these events, anticipatory reasoning has to become an everyday activity. Strong advances have been made in using integrated modeling for analysis and decision making. However, a wider impact of predictive analytics is currently hindered by the lack of systematic methods for integrating predictive inferences from computer models with human judgment. In this paper, we present a predictive analytics approach that supports anticipatory analysis and decision-making through a concerted reasoning effort that interleaves human judgment and automatedmore » inferences. We describe a systematic methodology for integrating modeling algorithms within a serious gaming environment in which role-playing by human agents provides updates to model nodes and the ensuing model outcomes in turn influence the behavior of the human players. The approach ensures a strong functional partnership between human players and computer models while maintaining a high degree of independence and greatly facilitating the connection between model and game structures.« less

Molecular design of two sterol 14α-demethylase homology models and their interactions with the azole antifungals ketoconazole and bifonazole

NASA Astrophysics Data System (ADS)

Rupp, Bernd; Raub, Stephan; Marian, Christel; Höltje, Hans-Dieter

2005-03-01

Sterol 14α-demethylase (CYP51) is one of the known major targets for azole antifungals. Therapeutic side effects of these antifungals are based on interactions of the azoles with the human analogue enzyme. This study describes for the first time a comparison of a human CYP51 (HU-CYP51) homology model with a homology model of the fungal CYP51 of Candida albicans (CA-CYP51). Both models are constructed by using the crystal structure of Mycobacterium tuberculosis MT-CYP51 (PDB code: 1EA1). The binding mode of the azole ketoconazole is investigated in molecular dynamics simulations with the GROMACS force field. The usage of special parameters for the iron azole complex binding is necessary to obtain the correct complex geometry in the active site of the enzyme models. Based on the dynamics simulations it is possible to explain the enantioselectivity of the human enzyme and also to predict the binding mode of the isomers of ketoconazole in the active site of the fungal model.

Single-molecule FRET-Rosetta reveals RNA structural rearrangements during human telomerase catalysis

PubMed Central

Parks, Joseph W.; Kappel, Kalli; Das, Rhiju; Stone, Michael D.

2017-01-01

Maintenance of telomeres by telomerase permits continuous proliferation of rapidly dividing cells, including the majority of human cancers. Despite its direct biomedical significance, the architecture of the human telomerase complex remains unknown. Generating homogeneous telomerase samples has presented a significant barrier to developing improved structural models. Here we pair single-molecule Förster resonance energy transfer (smFRET) measurements with Rosetta modeling to map the conformations of the essential telomerase RNA core domain within the active ribonucleoprotein. FRET-guided modeling places the essential pseudoknot fold distal to the active site on a protein surface comprising the C-terminal element, a domain that shares structural homology with canonical polymerase thumb domains. An independently solved medium-resolution structure of Tetrahymena telomerase provides a blind test of our modeling methodology and sheds light on the structural homology of this domain across diverse organisms. Our smFRET-Rosetta models reveal nanometer-scale rearrangements within the RNA core domain during catalysis. Taken together, our FRET data and pseudoatomic molecular models permit us to propose a possible mechanism for how RNA core domain rearrangement is coupled to template hybrid elongation. PMID:28096444

Simulation of adaptive semi-active magnetorheological seat damper for vehicle occupant blast protection

NASA Astrophysics Data System (ADS)

Yoo, Jin-Hyeong; Murugan, Muthuvel; Wereley, Norman M.

2013-04-01

This study investigates a lumped-parameter human body model which includes lower leg in seated posture within a quarter-car model for blast injury assessment simulation. To simulate the shock acceleration of the vehicle, mine blast analysis was conducted on a generic land vehicle crew compartment (sand box) structure. For the purpose of simulating human body dynamics with non-linear parameters, a physical model of a lumped-parameter human body within a quarter car model was implemented using multi-body dynamic simulation software. For implementing the control scheme, a skyhook algorithm was made to work with the multi-body dynamic model by running a co-simulation with the control scheme software plug-in. The injury criteria and tolerance levels for the biomechanical effects are discussed for each of the identified vulnerable body regions, such as the relative head displacement and the neck bending moment. The desired objective of this analytical model development is to study the performance of adaptive semi-active magnetorheological damper that can be used for vehicle-occupant protection technology enhancements to the seat design in a mine-resistant military vehicle.

Targeting human Mas-related G protein-coupled receptor X1 to inhibit persistent pain

PubMed Central

Li, Zhe; Tseng, Pang-Yen; Tiwari, Vinod; Xu, Qian; He, Shao-Qiu; Wang, Yan; Zheng, Qin; Han, Liang; Wu, Zhiping; Blobaum, Anna L.; Cui, Yiyuan; Tiwari, Vineeta; Sun, Shuohao; Cheng, Yingying; Huang-Lionnet, Julie H. Y.; Geng, Yixun; Xiao, Bo; Peng, Junmin; Hopkins, Corey; Raja, Srinivasa N.; Guan, Yun; Dong, Xinzhong

2017-01-01

Human Mas-related G protein-coupled receptor X1 (MRGPRX1) is a promising target for pain inhibition, mainly because of its restricted expression in nociceptors within the peripheral nervous system. However, constrained by species differences across Mrgprs, drug candidates that activate MRGPRX1 do not activate rodent receptors, leaving no responsive animal model to test the effect on pain in vivo. Here, we generated a transgenic mouse line in which we replaced mouse Mrgprs with human MrgprX1. This humanized mouse allowed us to characterize an agonist [bovine adrenal medulla 8–22 (BAM8–22)] and a positive allosteric modulator (PAM), ML382, of MRGPRX1. Cellular studies suggested that ML382 enhances the ability of BAM8–22 to inhibit high-voltage-activated Ca2+ channels and attenuate spinal nociceptive transmission. Importantly, both BAM8–22 and ML382 effectively attenuated evoked, persistent, and spontaneous pain without causing obvious side effects. Notably, ML382 by itself attenuated both evoked pain hypersensitivity and spontaneous pain in MrgprX1 mice after nerve injury without acquiring coadministration of an exogenous agonist. Our findings suggest that humanized MrgprX1 mice provide a promising preclinical model and that activating MRGPRX1 is an effective way to treat persistent pain. PMID:28223516

Activation of mouse and human peroxisome proliferator-activated receptor alpha by perfluoroalkyl acids of different functional groups and chain lengths.

PubMed

Wolf, Cynthia J; Takacs, Margy L; Schmid, Judith E; Lau, Christopher; Abbott, Barbara D

2008-11-01

Perfluoroalkyl acids (PFAAs) are surfactants used in consumer products and persist in the environment. Some PFAAs elicit adverse effects on rodent development and survival. PFAAs can activate peroxisome proliferator-activated receptor alpha (PPARalpha) and may act via PPARalpha to produce some of their effects. This study evaluated the ability of numerous PFAAs to induce mouse and human PPARalpha activity in a transiently transfected COS-1 cell assay. COS-1 cells were transfected with either a mouse or human PPARalpha receptor-luciferase reporter plasmid. After 24 h, cells were exposed to either negative controls (water or dimethyl sulfoxide, 0.1%); positive control (WY-14643, PPARalpha agonist); perfluorooctanoic acid or perfluorononanoic acid at 0.5-100 microM; perfluorobutanoic acid, perfluorohexanoic acid, perfluorohexane sulfonate, or perfluorodecanoic acid (PFDA) at 5-100 microM; or perfluorobutane sulfonate or perfluorooctane sulfonate at 1-250 microM. After 24 h of exposure, luciferase activity from the plasmid was measured. Each PFAA activated both mouse and human PPARalpha in a concentration-dependent fashion, except PFDA with human PPARalpha. Activation of PPARalpha by PFAA carboxylates was positively correlated with carbon chain length, up to C9. PPARalpha activity was higher in response to carboxylates compared to sulfonates. Activation of mouse PPARalpha was generally higher compared to that of human PPARalpha. We conclude that, in general, (1) PFAAs of increasing carbon backbone chain lengths induce increasing activity of the mouse and human PPARalpha with a few exceptions, (2) PFAA carboxylates are stronger activators of mouse and human PPARalpha than PFAA sulfonates, and (3) in most cases, the mouse PPARalpha appears to be more sensitive to PFAAs than the human PPARalpha in this model.

Altered fatty acid metabolism and reduced stearoyl-coenzyme a desaturase activity in asthma.

PubMed

Rodriguez-Perez, N; Schiavi, E; Frei, R; Ferstl, R; Wawrzyniak, P; Smolinska, S; Sokolowska, M; Sievi, N A; Kohler, M; Schmid-Grendelmeier, P; Michalovich, D; Simpson, K D; Hessel, E M; Jutel, M; Martin-Fontecha, M; Palomares, O; Akdis, C A; O'Mahony, L

2017-11-01

Fatty acids and lipid mediator signaling play an important role in the pathogenesis of asthma, yet this area remains largely underexplored. The aims of this study were (i) to examine fatty acid levels and their metabolism in obese and nonobese asthma patients and (ii) to determine the functional effects of altered fatty acid metabolism in experimental models. Medium- and long-chain fatty acid levels were quantified in serum from 161 human volunteers by LC/MS. Changes in stearoyl-coenzyme A desaturase (SCD) expression and activity were evaluated in the ovalbumin (OVA) and house dust mite (HDM) murine models. Primary human bronchial epithelial cells from asthma patients and controls were evaluated for SCD expression and activity. The serum desaturation index (an indirect measure of SCD) was significantly reduced in nonobese asthma patients and in the OVA murine model. SCD1 gene expression was significantly reduced within the lungs following OVA or HDM challenge. Inhibition of SCD in mice promoted airway hyper-responsiveness. SCD1 expression was suppressed in bronchial epithelial cells from asthma patients. IL-4 and IL-13 reduced epithelial cell SCD1 expression. Inhibition of SCD reduced surfactant protein C expression and suppressed rhinovirus-induced IP-10 secretion, which was associated with increased viral titers. This is the first study to demonstrate decreased fatty acid desaturase activity in humans with asthma. Experimental models in mice and human epithelial cells suggest that inhibition of desaturase activity leads to airway hyper-responsiveness and reduced antiviral defense. SCD may represent a new target for therapeutic intervention in asthma patients. © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

Atlas-guided volumetric diffuse optical tomography enhanced by generalized linear model analysis to image risk decision-making responses in young adults.

PubMed

Lin, Zi-Jing; Li, Lin; Cazzell, Mary; Liu, Hanli

2014-08-01

Diffuse optical tomography (DOT) is a variant of functional near infrared spectroscopy and has the capability of mapping or reconstructing three dimensional (3D) hemodynamic changes due to brain activity. Common methods used in DOT image analysis to define brain activation have limitations because the selection of activation period is relatively subjective. General linear model (GLM)-based analysis can overcome this limitation. In this study, we combine the atlas-guided 3D DOT image reconstruction with GLM-based analysis (i.e., voxel-wise GLM analysis) to investigate the brain activity that is associated with risk decision-making processes. Risk decision-making is an important cognitive process and thus is an essential topic in the field of neuroscience. The Balloon Analog Risk Task (BART) is a valid experimental model and has been commonly used to assess human risk-taking actions and tendencies while facing risks. We have used the BART paradigm with a blocked design to investigate brain activations in the prefrontal and frontal cortical areas during decision-making from 37 human participants (22 males and 15 females). Voxel-wise GLM analysis was performed after a human brain atlas template and a depth compensation algorithm were combined to form atlas-guided DOT images. In this work, we wish to demonstrate the excellence of using voxel-wise GLM analysis with DOT to image and study cognitive functions in response to risk decision-making. Results have shown significant hemodynamic changes in the dorsal lateral prefrontal cortex (DLPFC) during the active-choice mode and a different activation pattern between genders; these findings correlate well with published literature in functional magnetic resonance imaging (fMRI) and fNIRS studies. Copyright © 2014 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc.

Genetically Engineered Pig Models for Human Diseases

PubMed Central

Prather, Randall S.; Lorson, Monique; Ross, Jason W.; Whyte, Jeffrey J.; Walters, Eric

2015-01-01

Although pigs are used widely as models of human disease, their utility as models has been enhanced by genetic engineering. Initially, transgenes were added randomly to the genome, but with the application of homologous recombination, zinc finger nucleases, and transcription activator-like effector nuclease (TALEN) technologies, now most any genetic change that can be envisioned can be completed. To date these genetic modifications have resulted in animals that have the potential to provide new insights into human diseases for which a good animal model did not exist previously. These new animal models should provide the preclinical data for treatments that are developed for diseases such as Alzheimer's disease, cystic fibrosis, retinitis pigmentosa, spinal muscular atrophy, diabetes, and organ failure. These new models will help to uncover aspects and treatments of these diseases that were otherwise unattainable. The focus of this review is to describe genetically engineered pigs that have resulted in models of human diseases. PMID:25387017

Hand gesture recognition in confined spaces with partial observability and occultation constraints

NASA Astrophysics Data System (ADS)

Shirkhodaie, Amir; Chan, Alex; Hu, Shuowen

2016-05-01

Human activity detection and recognition capabilities have broad applications for military and homeland security. These tasks are very complicated, however, especially when multiple persons are performing concurrent activities in confined spaces that impose significant obstruction, occultation, and observability uncertainty. In this paper, our primary contribution is to present a dedicated taxonomy and kinematic ontology that are developed for in-vehicle group human activities (IVGA). Secondly, we describe a set of hand-observable patterns that represents certain IVGA examples. Thirdly, we propose two classifiers for hand gesture recognition and compare their performance individually and jointly. Finally, we present a variant of Hidden Markov Model for Bayesian tracking, recognition, and annotation of hand motions, which enables spatiotemporal inference to human group activity perception and understanding. To validate our approach, synthetic (graphical data from virtual environment) and real physical environment video imagery are employed to verify the performance of these hand gesture classifiers, while measuring their efficiency and effectiveness based on the proposed Hidden Markov Model for tracking and interpreting dynamic spatiotemporal IVGA scenarios.

Designing Anticancer Peptides by Constructive Machine Learning.

PubMed

Grisoni, Francesca; Neuhaus, Claudia S; Gabernet, Gisela; Müller, Alex T; Hiss, Jan A; Schneider, Gisbert

2018-04-21

Constructive (generative) machine learning enables the automated generation of novel chemical structures without the need for explicit molecular design rules. This study presents the experimental application of such a deep machine learning model to design membranolytic anticancer peptides (ACPs) de novo. A recurrent neural network with long short-term memory cells was trained on α-helical cationic amphipathic peptide sequences and then fine-tuned with 26 known ACPs by transfer learning. This optimized model was used to generate unique and novel amino acid sequences. Twelve of the peptides were synthesized and tested for their activity on MCF7 human breast adenocarcinoma cells and selectivity against human erythrocytes. Ten of these peptides were active against cancer cells. Six of the active peptides killed MCF7 cancer cells without affecting human erythrocytes with at least threefold selectivity. These results advocate constructive machine learning for the automated design of peptides with desired biological activities. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Evolutionary Design of Convolutional Neural Networks for Human Activity Recognition in Sensor-Rich Environments.

PubMed

Baldominos, Alejandro; Saez, Yago; Isasi, Pedro

2018-04-23

Human activity recognition is a challenging problem for context-aware systems and applications. It is gaining interest due to the ubiquity of different sensor sources, wearable smart objects, ambient sensors, etc. This task is usually approached as a supervised machine learning problem, where a label is to be predicted given some input data, such as the signals retrieved from different sensors. For tackling the human activity recognition problem in sensor network environments, in this paper we propose the use of deep learning (convolutional neural networks) to perform activity recognition using the publicly available OPPORTUNITY dataset. Instead of manually choosing a suitable topology, we will let an evolutionary algorithm design the optimal topology in order to maximize the classification F1 score. After that, we will also explore the performance of committees of the models resulting from the evolutionary process. Results analysis indicates that the proposed model was able to perform activity recognition within a heterogeneous sensor network environment, achieving very high accuracies when tested with new sensor data. Based on all conducted experiments, the proposed neuroevolutionary system has proved to be able to systematically find a classification model which is capable of outperforming previous results reported in the state-of-the-art, showing that this approach is useful and improves upon previously manually-designed architectures.

Evolutionary Design of Convolutional Neural Networks for Human Activity Recognition in Sensor-Rich Environments

PubMed Central

2018-01-01

Human activity recognition is a challenging problem for context-aware systems and applications. It is gaining interest due to the ubiquity of different sensor sources, wearable smart objects, ambient sensors, etc. This task is usually approached as a supervised machine learning problem, where a label is to be predicted given some input data, such as the signals retrieved from different sensors. For tackling the human activity recognition problem in sensor network environments, in this paper we propose the use of deep learning (convolutional neural networks) to perform activity recognition using the publicly available OPPORTUNITY dataset. Instead of manually choosing a suitable topology, we will let an evolutionary algorithm design the optimal topology in order to maximize the classification F1 score. After that, we will also explore the performance of committees of the models resulting from the evolutionary process. Results analysis indicates that the proposed model was able to perform activity recognition within a heterogeneous sensor network environment, achieving very high accuracies when tested with new sensor data. Based on all conducted experiments, the proposed neuroevolutionary system has proved to be able to systematically find a classification model which is capable of outperforming previous results reported in the state-of-the-art, showing that this approach is useful and improves upon previously manually-designed architectures. PMID:29690587

A novel framework for intelligent surveillance system based on abnormal human activity detection in academic environments.

PubMed

Al-Nawashi, Malek; Al-Hazaimeh, Obaida M; Saraee, Mohamad

2017-01-01

Abnormal activity detection plays a crucial role in surveillance applications, and a surveillance system that can perform robustly in an academic environment has become an urgent need. In this paper, we propose a novel framework for an automatic real-time video-based surveillance system which can simultaneously perform the tracking, semantic scene learning, and abnormality detection in an academic environment. To develop our system, we have divided the work into three phases: preprocessing phase, abnormal human activity detection phase, and content-based image retrieval phase. For motion object detection, we used the temporal-differencing algorithm and then located the motions region using the Gaussian function. Furthermore, the shape model based on OMEGA equation was used as a filter for the detected objects (i.e., human and non-human). For object activities analysis, we evaluated and analyzed the human activities of the detected objects. We classified the human activities into two groups: normal activities and abnormal activities based on the support vector machine. The machine then provides an automatic warning in case of abnormal human activities. It also embeds a method to retrieve the detected object from the database for object recognition and identification using content-based image retrieval. Finally, a software-based simulation using MATLAB was performed and the results of the conducted experiments showed an excellent surveillance system that can simultaneously perform the tracking, semantic scene learning, and abnormality detection in an academic environment with no human intervention.

Profiling Bioactivity of the ToxCast Chemical Library Using BioMAP Primary Human Cell Systems

EPA Science Inventory

The complexity of human biology has made prediction of health effects as a consequence of exposure to environmental chemicals especially challenging. Complex cell systems, such as the Biologically Multiplexed Activity Profiling (BioMAP) primary, human, cell-based disease models, ...

Pharmacokinetic parameters explain the therapeutic activity of antimicrobial agents in a silkworm infection model.

PubMed

Paudel, Atmika; Panthee, Suresh; Urai, Makoto; Hamamoto, Hiroshi; Ohwada, Tomohiko; Sekimizu, Kazuhisa

2018-01-25

Poor pharmacokinetic parameters are a major reason for the lack of therapeutic activity of some drug candidates. Determining the pharmacokinetic parameters of drug candidates at an early stage of development requires an inexpensive animal model with few associated ethical issues. In this study, we used the silkworm infection model to perform structure-activity relationship studies of an antimicrobial agent, GPI0039, a novel nitrofuran dichloro-benzyl ester, and successfully identified compound 5, a nitrothiophene dichloro-benzyl ester, as a potent antimicrobial agent with superior therapeutic activity in the silkworm infection model. Further, we compared the pharmacokinetic parameters of compound 5 with a nitrothiophene benzyl ester lacking chlorine, compound 7, that exerted similar antimicrobial activity but had less therapeutic activity in silkworms, and examined the metabolism of these antimicrobial agents in human liver fractions in vitro. Compound 5 had appropriate pharmacokinetic parameters, such as an adequate half-life, slow clearance, large area under the curve, low volume of distribution, and long mean residence time, compared with compound 7, and was slowly metabolized by human liver fractions. These findings suggest that the therapeutic effectiveness of an antimicrobial agent in the silkworms reflects appropriate pharmacokinetic properties.

An in vivo model of functional and vascularized human brain organoids.

PubMed

Mansour, Abed AlFatah; Gonçalves, J Tiago; Bloyd, Cooper W; Li, Hao; Fernandes, Sarah; Quang, Daphne; Johnston, Stephen; Parylak, Sarah L; Jin, Xin; Gage, Fred H

2018-06-01

Differentiation of human pluripotent stem cells to small brain-like structures known as brain organoids offers an unprecedented opportunity to model human brain development and disease. To provide a vascularized and functional in vivo model of brain organoids, we established a method for transplanting human brain organoids into the adult mouse brain. Organoid grafts showed progressive neuronal differentiation and maturation, gliogenesis, integration of microglia, and growth of axons to multiple regions of the host brain. In vivo two-photon imaging demonstrated functional neuronal networks and blood vessels in the grafts. Finally, in vivo extracellular recording combined with optogenetics revealed intragraft neuronal activity and suggested graft-to-host functional synaptic connectivity. This combination of human neural organoids and an in vivo physiological environment in the animal brain may facilitate disease modeling under physiological conditions.

Noscapinoids with anti-cancer activity against human acute lymphoblastic leukemia cells (CEM): a three dimensional chemical space pharmacophore modeling and electronic feature analysis.

PubMed

Naik, Pradeep K; Santoshi, Seneha; Joshi, Harish C

2012-01-01

We have identified a new class of microtubule-binding compounds-noscapinoids-that alter microtubule dynamics at stoichiometric concentrations without affecting tubulin polymer mass. Noscapinoids show great promise as chemotherapeutic agents for the treatment of human cancers. To investigate the structural determinants of noscapinoids responsible for anti-cancer activity, we tested 36 structurally diverse noscapinoids in human acute lymphoblastic leukemia cells (CEM). The IC(50) values of these noscapinoids vary from 1.2 to 56.0 μM. Pharmacophore models of anti-cancer activity were generated that identify two hydrogen bond acceptors, two aromatic rings, two hydrophobic groups, and one positively charged group as essential structural features. Additionally, an atom-based quantitative structure-activity relationship (QSAR) model was developed that gave a statistically satisfying result (R(2) = 0.912, Q(2) = 0.908, Pearson R = 0.951) and effectively predicts the anti-cancer activity of training and test set compounds. The pharmacophore model presented here is well supported by electronic property analysis using density functional theory at B3LYP/3-21*G level. Molecular electrostatic potential, particularly localization of negative potential near oxygen atoms of the dimethoxy isobenzofuranone ring of active compounds, matched the hydrogen bond acceptor feature of the generated pharmacophore. Our results further reveal that all active compounds have smaller lowest unoccupied molecular orbital (LUMO) energies concentrated over the dimethoxy isobenzofuranone ring, azido group, and nitro group, which is indicative of the electron acceptor capacity of the compounds. Results obtained from this study will be useful in the efficient design and development of more active noscapinoids.

The human element in technology transfer

NASA Technical Reports Server (NTRS)

Peake, H. J.

1978-01-01

A transfer model composed of three roles and their linkages was considered. This model and a growing body of experience was analyzed to provide guidance in the human elements of technology transfer. For example, criteria for selection of technology transfer agents was described, and some needed working climate factors were known. These concepts were successfully applied to transfer activities.

COST 728 Project Report: Urbanization of Meteorological and Air Quality Models - Chapter 5 - Model Urbanization Strategy: Summaries, Recommendations and Requirements

EPA Science Inventory

The urban canopy (UC), the layer of the atmosphere between the ground and the top of the highest buildings, is the region where people live and human activities take place. Because of this importance (e.g., human health, preservation of buildings) significant efforts have been d...

Evidence Evaluation: Measure "Z" Corresponds to Human Utility Judgments Better than Measure "L" and Optimal-Experimental-Design Models

ERIC Educational Resources Information Center

Rusconi, Patrice; Marelli, Marco; D'Addario, Marco; Russo, Selena; Cherubini, Paolo

2014-01-01

Evidence evaluation is a crucial process in many human activities, spanning from medical diagnosis to impression formation. The present experiments investigated which, if any, normative model best conforms to people's intuition about the value of the obtained evidence. Psychologists, epistemologists, and philosophers of science have proposed…

PAL(TM) 2.0 Human Anatomy Software Tool Use in Community College Traditional and Online Anatomy Laboratory Classes: Student-Perceived Learning Benefits

ERIC Educational Resources Information Center

Kuyatt, Brian Lee

2012-01-01

Human anatomy courses, with laboratory, are curricular requirements in graduate medical, undergraduate nursing, and all allied health science programs. Anatomy laboratory courses engage students in hands-on activities, including human cadaver or mammalian dissection, supported by photos from textbooks, detailed plastic models or human anatomical…

Development of a new knock-in mouse model and evaluation of pharmacological activities of lusutrombopag, a novel, nonpeptidyl small-molecule agonist of the human thrombopoietin receptor c-Mpl.

PubMed

Yoshida, Hiroshi; Yamada, Hajime; Nogami, Wataru; Dohi, Keiji; Kurino-Yamada, Tomomi; Sugiyama, Koji; Takahashi, Koji; Gahara, Yoshinari; Kitaura, Motoji; Hasegawa, Minoru; Oshima, Itsuki; Kuwabara, Kenji

2018-03-01

Lusutrombopag (S-888711), an oral small-molecule thrombopoietin receptor (TPOR) agonist, has gained first approval as a drug to treat thrombocytopenia of chronic liver disease in patients undergoing elective invasive procedures in Japan. Preclinical studies were performed to evaluate its efficacy against megakaryopoiesis and thrombopoiesis. To investigate the proliferative activity and efficacy of megakaryocytic colony formation via human TPOR, lusutrombopag was applied to cultured human c-Mpl-expressing Ba/F3 (Ba/F3-hMpl) cells and human bone marrow-derived CD34-positive cells, respectively. Lusutrombopag caused a robust increase in Ba/F3-hMpl cells by activating pathways in a manner similar to that of thrombopoietin and induced colony-forming units-megakaryocyte and polyploid megakaryocytes in human CD34-positive cells. Because lusutrombopag has high species specificity for human TPOR, there was no suitable experimental animal model for drug evaluation, except for immunodeficient mouse-based xenograft models. Therefore, a novel genetically modified knock-in mouse, TPOR-Ki/Shi, was developed by replacing mouse Mpl with human-mouse chimera Mpl. In TPOR-Ki/Shi mice, lusutrombopag significantly increased circulating platelets in a dose-dependent manner during 21-day repeated oral administration. Histopathological study of the TPOR-Ki/Shi mice on day 22 also revealed a significant increase in megakaryocytes in the bone marrow. These results indicate that lusutrombopag acts on human TPOR to upregulate differentiation and proliferation of megakaryocytic cells, leading to platelet production. Copyright © 2018 ISEH – Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

Learning a Taxonomy of Predefined and Discovered Activity Patterns

PubMed Central

Krishnan, Narayanan; Cook, Diane J.; Wemlinger, Zachary

2013-01-01

Many intelligent systems that focus on the needs of a human require information about the activities that are being performed by the human. At the core of this capability is activity recognition. Activity recognition techniques have become robust but rarely scale to handle more than a few activities. They also rarely learn from more than one smart home data set because of inherent differences between labeling techniques. In this paper we investigate a data-driven approach to creating an activity taxonomy from sensor data found in disparate smart home datasets. We investigate how the resulting taxonomy can help analyze the relationship between classes of activities. We also analyze how the taxonomy can be used to scale activity recognition to a large number of activity classes and training datasets. We describe our approach and evaluate it on 34 smart home datasets. The results of the evaluation indicate that the hierarchical modeling can reduce training time while maintaining accuracy of the learned model. PMID:25302084

Toxicity challenges in environmental chemicals: Prediction of human plasma protein binding through quantitative structure-activity relationship (QSAR) models

EPA Science Inventory

The present study explores the merit of utilizing available pharmaceutical data to construct a quantitative structure-activity relationship (QSAR) for prediction of the fraction of a chemical unbound to plasma protein (Fub) in environmentally relevant compounds. Independent model...

PD-1 blockade enhances elotuzumab efficacy in mouse tumor models

PubMed Central

Jhatakia, Amy; Kearney, Alper Y.; Brender, Ty; Maurer, Mark; Henning, Karla; Jenkins, Misty R.; Rogers, Amy J.; Neeson, Paul J.; Korman, Alan J.; Robbins, Michael D.; Graziano, Robert F.

2017-01-01

Elotuzumab, a humanized monoclonal antibody that binds human signaling lymphocytic activation molecule F7 (hSLAMF7) on myeloma cells, was developed to treat patients with multiple myeloma (MM). Elotuzumab has a dual mechanism of action that includes the direct activation of natural killer (NK) cells and the induction of NK cell–mediated antibody-dependent cellular cytotoxicity. This study aimed to characterize the effects of elotuzumab on NK cells in vitro and in patients with MM and to determine whether elotuzumab antitumor activity was improved by programmed death receptor-1 (PD-1) blockade. Elotuzumab promoted NK cell activation when added to a coculture of human NK cells and SLAMF7-expressing myeloma cells. An increased frequency of activated NK cells was observed in bone marrow aspirates from elotuzumab-treated patients. In mouse tumor models expressing hSLAMF7, maximal antitumor efficacy of a murine immunoglobulin G2a version of elotuzumab (elotuzumab-g2a) required both Fcγ receptor–expressing NK cells and CD8+ T cells and was significantly enhanced by coadministration of anti–PD-1 antibody. In these mouse models, elotuzumab-g2a and anti–PD-1 combination treatment promoted tumor-infiltrating NK and CD8+ T-cell activation, as well as increased intratumoral cytokine and chemokine release. These observations support the rationale for clinical investigation of elotuzumab/anti–PD-1 combination therapy in patients with MM. PMID:29296719

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

Unraveling dynamics of human physical activity patterns in chronic pain conditions

NASA Astrophysics Data System (ADS)

Paraschiv-Ionescu, Anisoara; Buchser, Eric; Aminian, Kamiar

2013-06-01

Chronic pain is a complex disabling experience that negatively affects the cognitive, affective and physical functions as well as behavior. Although the interaction between chronic pain and physical functioning is a well-accepted paradigm in clinical research, the understanding of how pain affects individuals' daily life behavior remains a challenging task. Here we develop a methodological framework allowing to objectively document disruptive pain related interferences on real-life physical activity. The results reveal that meaningful information is contained in the temporal dynamics of activity patterns and an analytical model based on the theory of bivariate point processes can be used to describe physical activity behavior. The model parameters capture the dynamic interdependence between periods and events and determine a `signature' of activity pattern. The study is likely to contribute to the clinical understanding of complex pain/disease-related behaviors and establish a unified mathematical framework to quantify the complex dynamics of various human activities.

Non-Markovian character in human mobility: Online and offline.

PubMed

Zhao, Zhi-Dan; Cai, Shi-Min; Lu, Yang

2015-06-01

The dynamics of human mobility characterizes the trajectories that humans follow during their daily activities and is the foundation of processes from epidemic spreading to traffic prediction and information recommendation. In this paper, we investigate a massive data set of human activity, including both online behavior of browsing websites and offline one of visiting towers based mobile terminations. The non-Markovian character observed from both online and offline cases is suggested by the scaling law in the distribution of dwelling time at individual and collective levels, respectively. Furthermore, we argue that the lower entropy and higher predictability in human mobility for both online and offline cases may originate from this non-Markovian character. However, the distributions of individual entropy and predictability show the different degrees of non-Markovian character between online and offline cases. To account for non-Markovian character in human mobility, we apply a protype model with three basic ingredients, namely, preferential return, inertial effect, and exploration to reproduce the dynamic process of online and offline human mobilities. The simulations show that the model has an ability to obtain characters much closer to empirical observations.

Human factors systems approach to healthcare quality and patient safety

PubMed Central

Carayon, Pascale; Wetterneck, Tosha B.; Rivera-Rodriguez, A. Joy; Hundt, Ann Schoofs; Hoonakker, Peter; Holden, Richard; Gurses, Ayse P.

2013-01-01

Human factors systems approaches are critical for improving healthcare quality and patient safety. The SEIPS (Systems Engineering Initiative for Patient Safety) model of work system and patient safety is a human factors systems approach that has been successfully applied in healthcare research and practice. Several research and practical applications of the SEIPS model are described. Important implications of the SEIPS model for healthcare system and process redesign are highlighted. Principles for redesigning healthcare systems using the SEIPS model are described. Balancing the work system and encouraging the active and adaptive role of workers are key principles for improving healthcare quality and patient safety. PMID:23845724

Interest-Driven Model for Human Dynamics

NASA Astrophysics Data System (ADS)

Shang, Ming-Sheng; Chen, Guan-Xiong; Dai, Shuang-Xing; Wang, Bing-Hong; Zhou, Tao

2010-04-01

Empirical observations indicate that the interevent time distribution of human actions exhibits heavy-tailed features. The queuing model based on task priorities is to some extent successful in explaining the origin of such heavy tails, however, it cannot explain all the temporal statistics of human behavior especially for the daily entertainments. We propose an interest-driven model, which can reproduce the power-law distribution of interevent time. The exponent can be analytically obtained and is in good accordance with the simulations. This model well explains the observed relationship between activities and power-law exponents, as reported recently for web-based behavior and the instant message communications.

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.

Coupling of the Models of Human Physiology and Thermal Comfort

NASA Astrophysics Data System (ADS)

Pokorny, J.; Jicha, M.

2013-04-01

A coupled model of human physiology and thermal comfort was developed in Dymola/Modelica. A coupling combines a modified Tanabe model of human physiology and thermal comfort model developed by Zhang. The Coupled model allows predicting the thermal sensation and comfort of both local and overall from local boundary conditions representing ambient and personal factors. The aim of this study was to compare prediction of the Coupled model with the Fiala model prediction and experimental data. Validation data were taken from the literature, mainly from the validation manual of software Theseus-FE [1]. In the paper validation of the model for very light physical activities (1 met) indoor environment with temperatures from 12 °C up to 48 °C is presented. The Coupled model predicts mean skin temperature for cold, neutral and warm environment well. However prediction of core temperature in cold environment is inaccurate and very affected by ambient temperature. Evaluation of thermal comfort in warm environment is supplemented by skin wettedness prediction. The Coupled model is designed for non-uniform and transient environmental conditions; it is also suitable simulation of thermal comfort in vehicles cabins. The usage of the model is limited for very light physical activities up to 1.2 met only.

Petri Net computational modelling of Langerhans cell Interferon Regulatory Factor Network predicts their role in T cell activation.

PubMed

Polak, Marta E; Ung, Chuin Ying; Masapust, Joanna; Freeman, Tom C; Ardern-Jones, Michael R

2017-04-06

Langerhans cells (LCs) are able to orchestrate adaptive immune responses in the skin by interpreting the microenvironmental context in which they encounter foreign substances, but the regulatory basis for this has not been established. Utilising systems immunology approaches combining in silico modelling of a reconstructed gene regulatory network (GRN) with in vitro validation of the predictions, we sought to determine the mechanisms of regulation of immune responses in human primary LCs. The key role of Interferon regulatory factors (IRFs) as controllers of the human Langerhans cell response to epidermal cytokines was revealed by whole transcriptome analysis. Applying Boolean logic we assembled a Petri net-based model of the IRF-GRN which provides molecular pathway predictions for the induction of different transcriptional programmes in LCs. In silico simulations performed after model parameterisation with transcription factor expression values predicted that human LC activation of antigen-specific CD8 T cells would be differentially regulated by epidermal cytokine induction of specific IRF-controlled pathways. This was confirmed by in vitro measurement of IFN-γ production by activated T cells. As a proof of concept, this approach shows that stochastic modelling of a specific immune networks renders transcriptome data valuable for the prediction of functional outcomes of immune responses.

Rapamycin inhibits anal carcinogenesis in two preclinical animal models.

PubMed

Stelzer, Marie K; Pitot, Henry C; Liem, Amy; Lee, Denis; Kennedy, Gregory D; Lambert, Paul F

2010-12-01

The incidence of anal cancer is increasing especially among HIV-infected persons in the HAART era. Treatment of this cancer is based upon traditional chemoradiotherapeutic approaches, which are associated with high morbidity and of limited effectiveness for patients with high-grade disease. The mammalian target of rapamycin (mTOR) pathway has been implicated in several human cancers, and is being investigated as a potential therapeutic target. In archival human anal cancers, we observed mTOR pathway activation. To assess response of anal cancer to mTOR inhibition, we utilized two newly developed mouse models, one in which anal cancers are induced to arise in HPV16 transgenic mice and the second a human anal cancer xenograft model. Using the transgenic mouse model, we assessed the preventative effect of rapamycin on neoplastic disease. We saw significant changes in the overall incidence of tumors, and tumor growth rate was also reduced. Using both the transgenic mouse and human anal xenograft mouse models, we studied the therapeutic effect of rapamycin on preexisting anal cancer. Rapamycin was found to significantly slow, if not stop, the growth of both mouse and human anal cancers. As has been seen in other cancers, rapamycin treatment led to an activation of the MAPK pathway. These results provide us cause to pursue further the evaluation of rapamycin as a therapeutic agent in the control of anal cancer. ©2010 AACR.

Human Temporal Cortical Single Neuron Activity During Working Memory Maintenance

PubMed Central

Zamora, Leona; Corina, David; Ojemann, George

2016-01-01

The Working Memory model of human memory, first introduced by Baddeley and Hitch (1974), has been one of the most influential psychological constructs in cognitive psychology and human neuroscience. However the neuronal correlates of core components of this model have yet to be fully elucidated. Here we present data from two studies where human temporal cortical single neuron activity was recorded during tasks differentially affecting the maintenance component of verbal working memory. In Study One we vary the presence or absence of distracting items for the entire period of memory storage. In Study Two we vary the duration of storage so that distractors filled all, or only one-third of the time the memory was stored. Extracellular single neuron recordings were obtained from 36 subjects undergoing awake temporal lobe resections for epilepsy, 25 in Study one, 11 in Study two. Recordings were obtained from a total of 166 lateral temporal cortex neurons during performance of one of these two tasks, 86 study one, 80 study two. Significant changes in activity with distractor manipulation were present in 74 of these neurons (45%), 38 Study one, 36 Study two. In 48 (65%) of those there was increased activity during the period when distracting items were absent, 26 Study One, 22 Study Two. The magnitude of this increase was greater for Study One, 47.6%, than Study Two, 8.1%, paralleling the reduction in memory errors in the absence of distracters, for Study One of 70.3%, Study Two 26.3% These findings establish that human lateral temporal cortex is part of the neural system for working memory, with activity during maintenance of that memory that parallels performance, suggesting it represents active rehearsal. In 31 of these neurons (65%) this activity was an extension of that during working memory encoding that differed significantly from the neural processes recorded during overt and silent language tasks without a recent memory component, 17 Study one, 14 Study two. Contrary to the Baddeley model, that activity during verbal working memory maintenance often represented activity specific to working memory rather than speech or language. PMID:27059210

Functional Connectivity Mapping in the Animal Model: Principles and Applications of Resting-State fMRI

PubMed Central

Gorges, Martin; Roselli, Francesco; Müller, Hans-Peter; Ludolph, Albert C.; Rasche, Volker; Kassubek, Jan

2017-01-01

“Resting-state” fMRI has substantially contributed to the understanding of human and non-human functional brain organization by the analysis of correlated patterns in spontaneous activity within dedicated brain systems. Spontaneous neural activity is indirectly measured from the blood oxygenation level-dependent signal as acquired by echo planar imaging, when subjects quietly “resting” in the scanner. Animal models including disease or knockout models allow a broad spectrum of experimental manipulations not applicable in humans. The non-invasive fMRI approach provides a promising tool for cross-species comparative investigations. This review focuses on the principles of “resting-state” functional connectivity analysis and its applications to living animals. The translational aspect from in vivo animal models toward clinical applications in humans is emphasized. We introduce the fMRI-based investigation of the non-human brain’s hemodynamics, the methodological issues in the data postprocessing, and the functional data interpretation from different abstraction levels. The longer term goal of integrating fMRI connectivity data with structural connectomes obtained with tracing and optical imaging approaches is presented and will allow the interrogation of fMRI data in terms of directional flow of information and may identify the structural underpinnings of observed functional connectivity patterns. PMID:28539914

The use of team-based, guided inquiry learning to overcome educational disadvantages in learning human physiology: a structural equation model.

PubMed

Rathner, Joseph A; Byrne, Graeme

2014-09-01

The study of human bioscience is viewed as a crucial curriculum in allied health. Nevertheless, bioscience (and particularly physiology) is notoriously difficult for undergraduates, particularly academically disadvantaged students. So endemic are the high failure rates (particularly in nursing) that it has come to be known as "the human bioscience problem." In the present report, we describe the outcomes for individual success in studying first-year human physiology in a subject that emphasises team-based active learning as the major pedagogy for mastering subject learning outcomes. Structural equation modeling was used to develop a model of the impact team learning had on individual performance. Modeling was consistent with the idea that students with similar academic abilities (as determined by tertiary entrance rank) were advantaged (scored higher on individual assessment items) by working in strong teams (teams that scored higher in team-based assessments). Analysis of covariance revealed that students who studied the subject with active learning as the major mode of learning activities outperformed students who studied the subject using the traditional didactic teaching format (lectures and tutorials, P = 0.000). After adjustment for tertiary entrance rank (via analysis of covariance) on two individual tests (the final exam and a late-semester in-class test), individual student grades improved by 8% (95% confidence interval: 6-10%) and 12% (95% confidence interval: 10-14%) when students engaged in team-based active learning. These data quantitatively support the notion that weaker students working in strong teams can overcome their educational disadvantages. Copyright © 2014 The American Physiological Society.

The use of team-based, guided inquiry learning to overcome educational disadvantages in learning human physiology: a structural equation model

PubMed Central

Byrne, Graeme

2014-01-01

The study of human bioscience is viewed as a crucial curriculum in allied health. Nevertheless, bioscience (and particularly physiology) is notoriously difficult for undergraduates, particularly academically disadvantaged students. So endemic are the high failure rates (particularly in nursing) that it has come to be known as “the human bioscience problem.” In the present report, we describe the outcomes for individual success in studying first-year human physiology in a subject that emphasises team-based active learning as the major pedagogy for mastering subject learning outcomes. Structural equation modeling was used to develop a model of the impact team learning had on individual performance. Modeling was consistent with the idea that students with similar academic abilities (as determined by tertiary entrance rank) were advantaged (scored higher on individual assessment items) by working in strong teams (teams that scored higher in team-based assessments). Analysis of covariance revealed that students who studied the subject with active learning as the major mode of learning activities outperformed students who studied the subject using the traditional didactic teaching format (lectures and tutorials, P = 0.000). After adjustment for tertiary entrance rank (via analysis of covariance) on two individual tests (the final exam and a late-semester in-class test), individual student grades improved by 8% (95% confidence interval: 6–10%) and 12% (95% confidence interval: 10–14%) when students engaged in team-based active learning. These data quantitatively support the notion that weaker students working in strong teams can overcome their educational disadvantages. PMID:25179611

Capsaicin Displays Anti-Proliferative Activity against Human Small Cell Lung Cancer in Cell Culture and Nude Mice Models via the E2F Pathway

PubMed Central

Hardman, W. Elaine; Luo, Haitao; Chen, Yi C.; Carpenter, A. Betts; Lau, Jamie K.; Dasgupta, Piyali

2010-01-01

Background Small cell lung cancer (SCLC) is characterized by rapid progression and low survival rates. Therefore, novel therapeutic agents are urgently needed for this disease. Capsaicin, the active ingredient of chilli peppers, displays anti-proliferative activity in prostate and epidermoid cancer in vitro. However, the anti-proliferative activity of capsaicin has not been studied in human SCLCs. The present manuscript fills this void of knowledge and explores the anti-proliferative effect of capsaicin in SCLC in vitro and in vivo. Methodology/Principal Findings BrdU assays and PCNA ELISAs showed that capsaicin displays robust anti-proliferative activity in four human SCLC cell lines. Furthermore, capsaicin potently suppressed the growth of H69 human SCLC tumors in vivo as ascertained by CAM assays and nude mice models. The second part of our study attempted to provide insight into molecular mechanisms underlying the anti-proliferative activity of capsaicin. We found that the anti-proliferative activity of capsaicin is correlated with a decrease in the expression of E2F-responsive proliferative genes like cyclin E, thymidylate synthase, cdc25A and cdc6, both at mRNA and protein levels. The transcription factor E2F4 mediated the anti-proliferative activity of capsaicin. Ablation of E2F4 levels by siRNA methodology suppressed capsaicin-induced G1 arrest. ChIP assays demonstrated that capsaicin caused the recruitment of E2F4 and p130 on E2F-responsive proliferative promoters, thereby inhibiting cell proliferation. Conclusions/Significance Our findings suggest that the anti-proliferative effects of capsaicin could be useful in the therapy of human SCLCs. PMID:20421925

Historical trends and the long-term changes of the hydrological cycle components in a Mediterranean river basin.

PubMed

Mentzafou, A; Wagner, S; Dimitriou, E

2018-04-29

Identifying the historical hydrometeorological trends in a river basin is necessary for understanding the dominant interactions between climate, human activities and local hydromorphological conditions. Estimating the hydrological reference conditions in a river is also crucial for estimating accurately the impacts from human water related activities and design appropriate water management schemes. In this effort, the output of a regional past climate model was used, covering the period from 1660 to 1990, in combination with a dynamic, spatially distributed, hydrologic model to estimate the past and recent trends in the main hydrologic parameters such as overland flow, water storages and evapotranspiration, in a Mediterranean river basin. The simulated past hydrologic conditions (1660-1960) were compared with the current hydrologic regime (1960-1990), to assess the magnitude of human and natural impacts on the identified hydrologic trends. The hydrological components of the recent period of 2008-2016 were also examined in relation to the impact of human activities. The estimated long-term trends of the hydrologic parameters were partially assigned to varying atmospheric forcing due to volcanic activity combined with spontaneous meteorological fluctuations. Copyright © 2018. Published by Elsevier B.V.

Identifying and modeling the structural discontinuities of human interactions

NASA Astrophysics Data System (ADS)

Grauwin, Sebastian; Szell, Michael; Sobolevsky, Stanislav; Hövel, Philipp; Simini, Filippo; Vanhoof, Maarten; Smoreda, Zbigniew; Barabási, Albert-László; Ratti, Carlo

2017-04-01

The idea of a hierarchical spatial organization of society lies at the core of seminal theories in human geography that have strongly influenced our understanding of social organization. Along the same line, the recent availability of large-scale human mobility and communication data has offered novel quantitative insights hinting at a strong geographical confinement of human interactions within neighboring regions, extending to local levels within countries. However, models of human interaction largely ignore this effect. Here, we analyze several country-wide networks of telephone calls - both, mobile and landline - and in either case uncover a systematic decrease of communication induced by borders which we identify as the missing variable in state-of-the-art models. Using this empirical evidence, we propose an alternative modeling framework that naturally stylizes the damping effect of borders. We show that this new notion substantially improves the predictive power of widely used interaction models. This increases our ability to understand, model and predict social activities and to plan the development of infrastructures across multiple scales.

Identifying and modeling the structural discontinuities of human interactions

PubMed Central

Grauwin, Sebastian; Szell, Michael; Sobolevsky, Stanislav; Hövel, Philipp; Simini, Filippo; Vanhoof, Maarten; Smoreda, Zbigniew; Barabási, Albert-László; Ratti, Carlo

2017-01-01

The idea of a hierarchical spatial organization of society lies at the core of seminal theories in human geography that have strongly influenced our understanding of social organization. Along the same line, the recent availability of large-scale human mobility and communication data has offered novel quantitative insights hinting at a strong geographical confinement of human interactions within neighboring regions, extending to local levels within countries. However, models of human interaction largely ignore this effect. Here, we analyze several country-wide networks of telephone calls - both, mobile and landline - and in either case uncover a systematic decrease of communication induced by borders which we identify as the missing variable in state-of-the-art models. Using this empirical evidence, we propose an alternative modeling framework that naturally stylizes the damping effect of borders. We show that this new notion substantially improves the predictive power of widely used interaction models. This increases our ability to understand, model and predict social activities and to plan the development of infrastructures across multiple scales. PMID:28443647

Identifying and modeling the structural discontinuities of human interactions.

PubMed

Grauwin, Sebastian; Szell, Michael; Sobolevsky, Stanislav; Hövel, Philipp; Simini, Filippo; Vanhoof, Maarten; Smoreda, Zbigniew; Barabási, Albert-László; Ratti, Carlo

2017-04-26

The idea of a hierarchical spatial organization of society lies at the core of seminal theories in human geography that have strongly influenced our understanding of social organization. Along the same line, the recent availability of large-scale human mobility and communication data has offered novel quantitative insights hinting at a strong geographical confinement of human interactions within neighboring regions, extending to local levels within countries. However, models of human interaction largely ignore this effect. Here, we analyze several country-wide networks of telephone calls - both, mobile and landline - and in either case uncover a systematic decrease of communication induced by borders which we identify as the missing variable in state-of-the-art models. Using this empirical evidence, we propose an alternative modeling framework that naturally stylizes the damping effect of borders. We show that this new notion substantially improves the predictive power of widely used interaction models. This increases our ability to understand, model and predict social activities and to plan the development of infrastructures across multiple scales.

Knowledge Management, Human Resource Management, and Higher Education: A Theoretical Model

ERIC Educational Resources Information Center

Brewer, Peggy D.; Brewer, Kristen L.

2010-01-01

Much has been written on the importance of knowledge management, the challenges facing organizations, and the important human resource management activities involved in assuring the acquisition and transfer of knowledge. Higher business education plays an important role in preparing students to assume the knowledge management and human resource…

To Live or to Die: Prosurvival Activity of PPARγ in Cancers

PubMed Central

Wang, Y. Lynn; Miao, Qi

2008-01-01

The role of PPARγ in tumorigenesis is controversial. In this article, we review and analyze literature from the past decade that highlights the potential proneoplastic activity of PPARγ. We discuss the following five aspects of the nuclear hormone receptor and its agonists: (1) relative expression of PPARγ in human tumor versus normal tissues; (2) receptor-dependent proneoplastic effects; (3) impact of PPARγ and its agonists on tumors in animal models; (4) clinical trials of thiazolidinediones (TZDs) in human malignancies; (5) TZDs as chemopreventive agents in epidemiology studies. The focus is placed on the most relevant in vivo animal models and human data. In vitro cell line studies are included only when the effects are shown to be dependent on the PPARγ receptor. PMID:18784849

Research study on neck injury lessening with active head restraint using human body FE model.

PubMed

Kitagawa, Yuichi; Yasuki, Tsuyoshi; Hasegawa, Junji

2008-12-01

The objective of this study is to examine the effectiveness of the active head restraint system in reducing neck injury risk of car occupants in low-speed rear impacts. A human body FE model "THUMS" was used to simulate head and neck kinematics of the occupant and to evaluate loading to the neck. Joint capsule strain was calculated to predict neck injury risk as well as NIC. The validity of the model was confirmed comparing its mechanical responses to those in human subjects in the literatures. Seat FE models were also prepared representing one with a fixed head restraint and the other one with an active head restraint system. The active head restraint system was designed to move the head restraint forward and upward when the lower unit was lower unit was loaded by the pelvis. Rear impact simulations were performed assuming a triangular acceleration pulse at a delta-V of 25 km/h. The model reproduced similar head and neck motions to those measured in the human volunteer test, except for active muscular responses. The calculated joint capsule strain also showed a good match with those of PMHS tests in the literature. A rear-impact simulation was conducted using the model with the fixed head restraint. The result revealed that NIC was strongly correlated with the relative acceleration between the head and the torso and that its maximum peak appeared when the head contacted the head restraint. It was also found that joint capsule strain grew in later timing synchronizing with the relative displacement. Another simulation with the active head restraint system showed that both NIC and joint capsule strain were lowered owing to the forward and upward motion of the head restraint. A close investigation of the vertebral motion indicated that the active head restraint reduced the magnitude of shear deformation in the facet joint, which contributed to the strain growth in the fixed head restraint case. Rear-impact simulations were conducted using a human body FE model, THUMS, representing an average-size male occupant. The cervical system including the facet joint capsules was incorporated to the model. The validity of the model was examined comparing its mechanical responses to those in the literature such as the whole body motion of the volunteer subject and the vertebral motion in the PMHS tests. Rear-impact simulations were conducted using the validated THUMS model and two prototype seat models; one had a fixed head restraint and the other one was equipped with an active head restraint system. The active head restraint system works moving the head restraint forward and upward when the lower unit is loaded by the pelvis. The head and neck kinematics and responses were analyzed from the simulation results. The force and acceleration rose at the pelvis first, followed by T1 and the head. The early timing of force rise and its magnitude indicated that the pelvis force was a good trigger for the active head restraint system. The results showed that the head was supported earlier in a case with the active head restraint system, and both NIC and joint capsule strain were lowered. The study also analyzed the mechanism of strain growth in the joint capsules. Relatively greater strain was observed in the direction of the facet joint surface, which was around 45 degrees inclined to the spinal column. The forward and upward motion of the active head restraint were aligned with the direction of the joint deformation and contributed to lower strain in the joint capsules. The results indicated that the active head restraint could help reduce the neck injury risk not only by supporting the head at an early timing but also through its trajectory stopping the joint deformation.

Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation.

PubMed

Sampaziotis, Fotios; de Brito, Miguel Cardoso; Madrigal, Pedro; Bertero, Alessandro; Saeb-Parsy, Kourosh; Soares, Filipa A C; Schrumpf, Elisabeth; Melum, Espen; Karlsen, Tom H; Bradley, J Andrew; Gelson, William Th; Davies, Susan; Baker, Alastair; Kaser, Arthur; Alexander, Graeme J; Hannan, Nicholas R F; Vallier, Ludovic

2015-08-01

The study of biliary disease has been constrained by a lack of primary human cholangiocytes. Here we present an efficient, serum-free protocol for directed differentiation of human induced pluripotent stem cells into cholangiocyte-like cells (CLCs). CLCs show functional characteristics of cholangiocytes, including bile acids transfer, alkaline phosphatase activity, γ-glutamyl-transpeptidase activity and physiological responses to secretin, somatostatin and vascular endothelial growth factor. We use CLCs to model in vitro key features of Alagille syndrome, polycystic liver disease and cystic fibrosis (CF)-associated cholangiopathy. Furthermore, we use CLCs generated from healthy individuals and patients with polycystic liver disease to reproduce the effects of the drugs verapamil and octreotide, and we show that the experimental CF drug VX809 rescues the disease phenotype of CF cholangiopathy in vitro. Our differentiation protocol will facilitate the study of biological mechanisms controlling biliary development, as well as disease modeling and drug screening.

Inter-species activity correlations reveal functional correspondences between monkey and human brain areas

PubMed Central

Mantini, Dante; Hasson, Uri; Betti, Viviana; Perrucci, Mauro G.; Romani, Gian Luca; Corbetta, Maurizio; Orban, Guy A.; Vanduffel, Wim

2012-01-01

Evolution-driven functional changes in the primate brain are typically assessed by aligning monkey and human activation maps using cortical surface expansion models. These models use putative homologous areas as registration landmarks, assuming they are functionally correspondent. In cases where functional changes have occurred in an area, this assumption prohibits to reveal whether other areas may have assumed lost functions. Here we describe a method to examine functional correspondences across species. Without making spatial assumptions, we assess similarities in sensory-driven functional magnetic resonance imaging responses between monkey (Macaca mulatta) and human brain areas by means of temporal correlation. Using natural vision data, we reveal regions for which functional processing has shifted to topologically divergent locations during evolution. We conclude that substantial evolution-driven functional reorganizations have occurred, not always consistent with cortical expansion processes. This novel framework for evaluating changes in functional architecture is crucial to building more accurate evolutionary models. PMID:22306809

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.

Understanding Substrate Selectivity of Human UDP-glucuronosyltransferases through QSAR modeling and analysis of homologous enzymes

PubMed Central

Dong, Dong; Ako, Roland; Hu, Ming; Wu, Baojian

2015-01-01

The UDP-glucuronosyltransferase (UGT) enzyme catalyzes the glucuronidation reaction which is a major metabolic and detoxification pathway in humans. Understanding the mechanisms for substrate recognition by UGT assumes great importance in an attempt to predict its contribution to xenobiotic/drug disposition in vivo. Spurred on by this interest, 2D/3D-quantitative structure activity relationships (QSAR) and pharmacophore models have been established in the absence of a complete mammalian UGT crystal structure. This review discusses the recent progress in modeling human UGT substrates including those with multiple sites of glucuronidation. A better understanding of UGT active site contributing to substrate selectivity (and regioselectivity) from the homologous enzymes (i.e., plant and bacterial UGTs, all belong to family 1 of glycosyltransferase (GT1)) is also highlighted, as these enzymes share a common catalytic mechanism and/or overlapping substrate selectivity. PMID:22385482

Coupling habitat suitability and ecosystem health with AEHRA to estimate E-flows under intensive human activities

NASA Astrophysics Data System (ADS)

Zhao, C. S.; Yang, S. T.; Zhang, H. T.; Liu, C. M.; Sun, Y.; Yang, Z. Y.; Zhang, Y.; Dong, B. E.; Lim, R. P.

2017-08-01

Sustaining adequate environmental flows (e-flows) is a key principle for maintaining river biodiversity and ecosystem health, and for supporting sustainable water resource management in basins under intensive human activities. But few methods could correctly relate river health to e-flows assessment at the catchment scale when they are applied to rivers highly impacted by human activities. An effective method is presented in this study to closely link river health to e-flows assessment for rivers at the catchment scale. Key fish species, as indicators of ecosystem health, were selected by using the foodweb model. A multi-species-based habitat suitability model (MHSI) was improved, and coupled with dominance of the key fish species as well as the Index of Biological Integrity (IBI) to enhance its accuracy in determining the fish-preferred key hydrologic habitat variables related to ecosystem health. Taking 5964 fish samples and concurrent hydrological habitat variables as the basis, the combination of key variables of flow-velocity and water-depth were determined and used to drive the Adapted Ecological Hydraulic Radius Approach (AEHRA) to study e-flows in a Chinese urban river impacted by intensive human activities. Results showed that upstream urbanization resulted in abnormal river-course geomorphology and consequently abnormal e-flows under intensive human activities. Selection of key species based on the foodweb and trophic levels of aquatic ecosystems can reflect a comprehensive requirement on e-flows of the whole aquatic ecosystem, which greatly increases its potential to be used as a guidance tool for rehabilitation of degraded ecosystems at large spatial scales. These findings have significant ramifications for catchment e-flows assessment under intensive human activities and for river ecohealth restoration in such rivers globally.

The relative role of climate change and human activities in the desertification process in Yulin region of northwest China.

PubMed

Wang, Tao; Sun, Jian-Guo; Han, Hui; Yan, Chang-Zhen

2012-12-01

To overcome the shortcoming of existing studies, this paper put forward a statistical vegetation-climate relationship model with integrated temporal and spatial characteristics. Based on this model, we quantitatively discriminated on the grid scale the relative role of climate change and human activities in the desertification dynamics from 1986 to 2000 in Yulin region. Yulin region's desertification development occurred mainly in the southern hilly and gully area and its reverse in the northwest sand and marsh area. This spatial pattern was especially evident and has never changed thoroughly. From the first time section (1986-1990) to the second (1991-1995), the desertification was developing as a whole, and either in the desertification development district or in the reverse district human activities' role was always occupying an overwhelmingly dominant position (they were 98.7% and 101.4%, respectively), the role of climate change was extremely slight. From the second time section (1991-1995) to the third (1996-2000), the desertification process was reaching a state of stability, in the desertification development district the role of climate change was nearly equivalent to that of human activities (they were 46.2% and 53.8% separately), and yet in the desertification reverse district, the role of human activities came up to 119.0%, the role of climate change amounted to -19.0%. In addition, the relative role of climate change and human activities possessed great spatial heterogeneity. The above conclusion rather coincides with the qualitative analysis in many literatures, which indicates that this method has certain rationality and can be utilized as a reference for the monitoring and studying of desertification in other areas.

Activation of human T cells in hypertension: Studies of Humanized Mice and Hypertensive Humans

PubMed Central

Itani, Hana A.; McMaster, William G.; Saleh, Mohamed A.; Nazarewicz, Rafal R.; Mikolajczyk, Tomasz P.; Kaszuba, Anna; Konior, Anna; Prejbisz, Aleksander; Januszewicz, Andrzej; Norlander, Allison E.; Chen, Wei; Bonami, Rachel H.; Marshall, Andrew F.; Poffenberger, Greg; Weyand, Cornelia M.; Madhur, Meena S.; Moore, Daniel J.; Harrison, David G.; Guzik, Tomasz J.

2016-01-01

Emerging evidence supports an important role for T cells in the genesis of hypertension. Because this work has predominantly been performed in experimental animals, we sought to determine whether human T cells are activated in hypertension. We employed a humanized mouse model in which the murine immune system is replaced by the human immune system. Angiotensin II increased systolic pressure to 162 mm Hg vs. 116 mm Hg for sham treated animals. Flow cytometry of thoracic lymph nodes, thoracic aorta and kidney revealed increased infiltration of human leukocytes (CD45+) and T lymphocytes (CD3+ and CD4+) in response to angiotensin II infusion. Interestingly, there was also an increase in the memory T cells (CD3+/CD45RO+) in the aortas and lymph nodes. Prevention of hypertension using hydralazine and hydrochlorothiazide prevented the accumulation of T cells in these tissues. Studies of isolated human T cells and monocytes indicated that angiotensin II had no direct effect on cytokine production by T cells or the ability of dendritic cells to drive T cell proliferation. We also observed an increase in circulating IL-17A producing CD4+ T cells and both CD4+ and CD8+ T cells that produce IFN-γ in hypertensive compared to normotensive humans. Thus, human T cells become activated and invade critical end-organ tissues in response to hypertension in a humanized mouse model. This response likely reflects the hypertensive milieu encountered in vivo and is not a direct effect of the hormone angiotensin II. PMID:27217403

Activation of Human T Cells in Hypertension: Studies of Humanized Mice and Hypertensive Humans.

PubMed

Itani, Hana A; McMaster, William G; Saleh, Mohamed A; Nazarewicz, Rafal R; Mikolajczyk, Tomasz P; Kaszuba, Anna M; Konior, Anna; Prejbisz, Aleksander; Januszewicz, Andrzej; Norlander, Allison E; Chen, Wei; Bonami, Rachel H; Marshall, Andrew F; Poffenberger, Greg; Weyand, Cornelia M; Madhur, Meena S; Moore, Daniel J; Harrison, David G; Guzik, Tomasz J

2016-07-01

Emerging evidence supports an important role for T cells in the genesis of hypertension. Because this work has predominantly been performed in experimental animals, we sought to determine whether human T cells are activated in hypertension. We used a humanized mouse model in which the murine immune system is replaced by the human immune system. Angiotensin II increased systolic pressure to 162 versus 116 mm Hg for sham-treated animals. Flow cytometry of thoracic lymph nodes, thoracic aorta, and kidney revealed increased infiltration of human leukocytes (CD45(+)) and T lymphocytes (CD3(+) and CD4(+)) in response to angiotensin II infusion. Interestingly, there was also an increase in the memory T cells (CD3(+)/CD45RO(+)) in the aortas and lymph nodes. Prevention of hypertension using hydralazine and hydrochlorothiazide prevented the accumulation of T cells in these tissues. Studies of isolated human T cells and monocytes indicated that angiotensin II had no direct effect on cytokine production by T cells or the ability of dendritic cells to drive T-cell proliferation. We also observed an increase in circulating interleukin-17A producing CD4(+) T cells and both CD4(+) and CD8(+) T cells that produce interferon-γ in hypertensive compared with normotensive humans. Thus, human T cells become activated and invade critical end-organ tissues in response to hypertension in a humanized mouse model. This response likely reflects the hypertensive milieu encountered in vivo and is not a direct effect of the hormone angiotensin II. © 2016 American Heart Association, Inc.

Human Immunodeficiency Virus Type 1 (HIV-1) Viral Protein R (Vpr)-Mediated Cell Cycle Arrest: An Analysis of Current Mechanistic Models

DTIC Science & Technology

2006-06-08

entices speculation on Vpr-mediated modulation of cellular stress responses. The major human small Hsp, HSP27 , represents an important point of...intersection for the two eukaryotic stress response mechanisms, i.e. HSF-mediated HSP expression induction and SAPK cascade activation. While HSP27 ...expression up-regulation requires HSF activation, functional activation of HSP27 requires MK2-catalyzed phosphorylation, and, therefore, p38 pathway

16(R)-hydroxyeicosatetraenoic acid, a novel cytochrome P450 product of arachidonic acid, suppresses activation of human polymorphonuclear leukocyte and reduces intracranial pressure in a rabbit model of thromboembolic stroke.

PubMed

Bednar, M M; Gross, C E; Russell, S R; Fuller, S P; Ahern, T P; Howard, D B; Falck, J R; Reddy, K M; Balazy, M

2000-12-01

Activated polymorphonuclear leukocytes (PMNs) have been suggested to contribute to the development of increased intracranial pressure (ICP). We recently demonstrated that human PMNs produce a novel cytochrome P450-derived arachidonic acid metabolite, 1 6(R)-hydroxyeicosatetraenoic acid [16(R)-HETE], that modulates their function. It was thus of interest to examine this novel mediator in an acute stroke model. 16-HETE was assessed initially in a variety of human PMN and platelet in vitro assays and subsequently in an established rabbit model of thromboembolic stroke. A total of 50 rabbits completed a randomized, blinded, four-arm study, receiving 16(R)-HETE, tissue plasminogen activator, both, or neither. Experiments were completed 7 hours after autologous clot embolization. The primary end point for efficacy was the suppression of increased ICP. In in vitro assays, 16(R)-HETE selectively inhibited human PMN adhesion and aggregation and leukotriene B4 synthesis. In the thromboembolic stroke model, animals that received 16(R)-HETE demonstrated significant suppression of increased ICP (7.7 +/- 1.2 to 13.1 +/- 2.7 mm Hg, baseline versus final 7-h time point, mean +/- standard error), compared with either the vehicle-treated group (7.7 +/- 0.9 to 15.8 +/- 2.6 mm Hg) or the tissue plasminogen activator-treated group (7.6 +/- 0.6 to 13.7 +/- 2.1 mm Hg). The group that received the combination of 16(R)-HETE plus tissue plasminogen activator demonstrated no significant change in ICP for the duration of the protocol (8.6 +/- 0.6 to 11.1 +/- 1.2 mm Hg). 16(R)-HETE suppresses the development of increased ICP in a rabbit model of thromboembolic stroke and may serve as a novel therapeutic strategy in ischemic and inflammatory pathophysiological states.

Human Activity Recognition from Body Sensor Data using Deep Learning.

PubMed

Hassan, Mohammad Mehedi; Huda, Shamsul; Uddin, Md Zia; Almogren, Ahmad; Alrubaian, Majed

2018-04-16

In recent years, human activity recognition from body sensor data or wearable sensor data has become a considerable research attention from academia and health industry. This research can be useful for various e-health applications such as monitoring elderly and physical impaired people at Smart home to improve their rehabilitation processes. However, it is not easy to accurately and automatically recognize physical human activity through wearable sensors due to the complexity and variety of body activities. In this paper, we address the human activity recognition problem as a classification problem using wearable body sensor data. In particular, we propose to utilize a Deep Belief Network (DBN) model for successful human activity recognition. First, we extract the important initial features from the raw body sensor data. Then, a kernel principal component analysis (KPCA) and linear discriminant analysis (LDA) are performed to further process the features and make them more robust to be useful for fast activity recognition. Finally, the DBN is trained by these features. Various experiments were performed on a real-world wearable sensor dataset to verify the effectiveness of the deep learning algorithm. The results show that the proposed DBN outperformed other algorithms and achieves satisfactory activity recognition performance.

A Reverse-Translational Approach to Bipolar Disorder: Rodent and human studies in the Behavioral Pattern Monitor

PubMed Central

Young, Jared W.; Minassian, Arpi; Paulus, Martin P.; Geyer, Mark A.; Perry, William

2007-01-01

Mania is the defining feature of Bipolar Disorder (BD). There has been limited progress in understanding the neurobiological underpinnings of BD mania and developing novel therapeutics, in part due to a paucity of relevant animal models with translational potential. Hyperactivity is a cardinal symptom of mania, traditionally measured in humans using observer-rated scales. Multivariate assessment of unconditioned locomotor behavior using the rat Behavioral Pattern Monitor (BPM) developed in our laboratory has shown that hyperactivity includes complex multifaceted behaviors. The BPM has been used to demonstrate differential effects of drugs on locomotor activity and exploratory behavior in rats. Studies of genetically engineered mice in a mouse BPM have confirmed its utility as a cross-species tool. In a “reverse-translational” approach to this work, we developed the human BPM to characterize motor activity in BD patients. Increased activity, object interactions, and altered locomotor patterns provide multidimensional phenotypes to model in the rodent BPM. This unique approach to modeling BD provides an opportunity to identify the neurobiology underlying BD mania and test novel antimanic agents. PMID:17706782

Development of a real time activity monitoring Android application utilizing SmartStep.

PubMed

Hegde, Nagaraj; Melanson, Edward; Sazonov, Edward

2016-08-01

Footwear based activity monitoring systems are becoming popular in academic research as well as consumer industry segments. In our previous work, we had presented developmental aspects of an insole based activity and gait monitoring system-SmartStep, which is a socially acceptable, fully wireless and versatile insole. The present work describes the development of an Android application that captures the SmartStep data wirelessly over Bluetooth Low energy (BLE), computes features on the received data, runs activity classification algorithms and provides real time feedback. The development of activity classification methods was based on the the data from a human study involving 4 participants. Participants were asked to perform activities of sitting, standing, walking, and cycling while they wore SmartStep insole system. Multinomial Logistic Discrimination (MLD) was utilized in the development of machine learning model for activity prediction. The resulting classification model was implemented in an Android Smartphone. The Android application was benchmarked for power consumption and CPU loading. Leave one out cross validation resulted in average accuracy of 96.9% during model training phase. The Android application for real time activity classification was tested on a human subject wearing SmartStep resulting in testing accuracy of 95.4%.

Past Holocene soil erosion modeling as a new way to decipher human-climate-environment interactions on natural geo-ecosystem over long time-scale.

NASA Astrophysics Data System (ADS)

Simonneau, Anaëlle; Di Giovanni, Christian; Chapron, Emmanuel

2017-04-01

Soil erosion is a global phenomenon dealing with both environmental, societal and economic issues. Soil erosion is also one of the key processes when it is a matter of Human-climate-environment interactions [1, 2] since if mechanical erosion of continental surfaces initially results from climatic forcing, it can be largely amplified by anthropogenic activities. Using multi-scalar datasets to model long-term (Holocene) erosion fluxes in contrasted areas, where human pressure is well documented by geoarchaeology, we address how landscape evolution, geomorphological processes, ecosystem response and human impacts have been connected over time. Beyond that, such interdisciplinary and integrative approach allow (1) to locally date, qualify, and in particular quantify, both climate variability (rainfall) and impacts of human activities on soils, and (2) to discuss of potential feedback mechanisms and the legacy of past socio-cultural systems on actual geo-ecosystems. Lacustrine sediment represents one of the more relevant natural archives in order to reconstruct environmental or climatic variability and human activities over the past thousand years. Over the last 50 years, the edges of lakes Paladru (low altitude site, 640 m a.s.l.) and Blanc Huez (high-altitude site, 2250 m a.s.l.), both located in Western French Alps and therefore sensitive to the same climatic influences, have been deeply studied by archaeologists who documented and dated periods of enhanced human pressures (agriculture, mining [3, 4]). In these two case-studies, we were therefore able to confront the specific calendars of local human activities with past landscape evolution (vegetation cover, 5) and soil erosion fluxes reconstituted from specific organic tracers quantified into the lacustrine sediments [3, 6]. Results demonstrated that, over the Holocene, climatic forcing, and more particularly glacial fluctuations, influenced human accessibility to high-altitude sites (lake Blanc Huez) and therefore regulated the anthropogenic impacts on the geo-ecosystem; whereas none feedback was identified at lower altitude (lake Paladru) at least after the Bronze Age period. Independent soil erosion modelling performed on the two sites add more information. Between 10,000 and 5500 cal years BP, annual rainfall estimations are the same for the two sites (around 300 mm per year), demonstrating that for both sites, soil erosion was only dependent of climate variability and rainfall intensity over this period. After 5500 cal years BP, the two models clearly differ, with a systematic overestimation of the sediment budget delivered into lake Paladru; and this time-interval matches the beginning of agricultural practices in the vicinity of this lake [3]. It suggests that human-induced soil erosion could be effective since the Neolithic period. Indeed, according to models, agrarian activities would explain up to 50% of soil erosion within the catchment area of lake Paladru between the Bronze Age and the Middle Age, suggesting that the actual geomorphology of the drainage basin is inherited from several millenary and not only from modern activities. [1] Dearing et al., 2006 [2] Ojima et al., 1994 [3] Simonneau et al., 2013, JAS [4] Garçon et al., 2012 [5] Doyen et al., 2016 [6] Simonneau et al., 2014, QSR

Prediction of Human Activity by Discovering Temporal Sequence Patterns.

PubMed

Li, Kang; Fu, Yun

2014-08-01

Early prediction of ongoing human activity has become more valuable in a large variety of time-critical applications. To build an effective representation for prediction, human activities can be characterized by a complex temporal composition of constituent simple actions and interacting objects. Different from early detection on short-duration simple actions, we propose a novel framework for long -duration complex activity prediction by discovering three key aspects of activity: Causality, Context-cue, and Predictability. The major contributions of our work include: (1) a general framework is proposed to systematically address the problem of complex activity prediction by mining temporal sequence patterns; (2) probabilistic suffix tree (PST) is introduced to model causal relationships between constituent actions, where both large and small order Markov dependencies between action units are captured; (3) the context-cue, especially interactive objects information, is modeled through sequential pattern mining (SPM), where a series of action and object co-occurrence are encoded as a complex symbolic sequence; (4) we also present a predictive accumulative function (PAF) to depict the predictability of each kind of activity. The effectiveness of our approach is evaluated on two experimental scenarios with two data sets for each: action-only prediction and context-aware prediction. Our method achieves superior performance for predicting global activity classes and local action units.

Essential role of TRPC6 channels in G2/M phase transition and development of human glioma.

PubMed

Ding, Xia; He, Zhuohao; Zhou, Kechun; Cheng, Ju; Yao, Hailan; Lu, Dongliang; Cai, Rong; Jin, Yening; Dong, Bin; Xu, Yinghui; Wang, Yizheng

2010-07-21

Patients with glioblastoma multiforme, the most aggressive form of glioma, have a median survival of approximately 12 months. Calcium (Ca(2+)) signaling plays an important role in cell proliferation, and some members of the Ca(2+)-permeable transient receptor potential canonical (TRPC) family of channel proteins have demonstrated a role in the proliferation of many types of cancer cells. In this study, we investigated the role of TRPC6 in cell cycle progression and in the development of human glioma. TRPC6 protein and mRNA expression were assessed in glioma (n = 33) and normal (n = 17) brain tissues from patients and in human glioma cell lines U251, U87, and T98G. Activation of TRPC6 channels was tested by platelet-derived growth factor-induced Ca(2+) imaging. The effect of inhibiting TRPC6 activity or expression using the dominant-negative mutant TRPC6 (DNC6) or RNA interference, respectively, was tested on cell growth, cell cycle progression, radiosensitization of glioma cells, and development of xenografted human gliomas in a mouse model. The green fluorescent protein (GFP) and wild-type TRPC6 (WTC6) were used as controls. Survival of mice bearing xenografted tumors in the GFP, DNC6, and WTC6 groups (n = 13, 15, and 13, respectively) was compared using Kaplan-Meier analysis. All statistical tests were two-sided. Functional TRPC6 was overexpressed in human glioma cells. Inhibition of TRPC6 activity or expression attenuated the increase in intracellular Ca(2+) by platelet-derived growth factor, suppressed cell growth and clonogenic ability, induced cell cycle arrest at the G2/M phase, and enhanced the antiproliferative effect of ionizing radiation. Cyclin-dependent kinase 1 activation and cell division cycle 25 homolog C expression regulated the cell cycle arrest. Inhibition of TRPC6 activity also reduced tumor volume in a subcutaneous mouse model of xenografted human tumors (P = .014 vs GFP; P < .001 vs WTC6) and increased mean survival in mice in an intracranial model (P < .001 vs GFP or WTC6). In this preclinical model, TRPC6 channels were essential for glioma development via regulation of G2/M phase transition. This study suggests that TRPC6 might be a new target for therapeutic intervention of human glioma.

Astaxanthin and withaferin A block paracrine cytokine interactions between UVB-exposed human keratinocytes and human melanocytes via the attenuation of endothelin-1 secretion and its downstream intracellular signaling.

PubMed

Niwano, Takao; Terazawa, Shuko; Nakajima, Hiroaki; Wakabayashi, Yuki; Imokawa, Genji

2015-06-01

Paracrine interactions between keratinocytes and melanocytes via cytokines play an essential role in regulating pigmentation in epidermal hyperpigmentary disorders. There is an urgent need for a human epidermal model in which melanogenic paracrine interactions between UVB-exposed keratinocytes and melanocytes can be precisely evaluated because human epidermal equivalents consisting of multilayered keratinocytes and melanocytes have significant limitations in this respect. To resolve this challenge, we established a co-culture system with cell inserts using human keratinocytes and human melanocytes that serves as an appropriate new model for UVB-induced hyperpigmentation. Using that new model, we examined the blocking effects of two natural chemicals, astaxanthin and withaferin A, on paracrine cytokine interactions between UVB-exposed keratinocytes and melanocytes and characterized their mechanisms of action. RT-PCR analysis showed that co-culture of human keratinocytes that had been exposed to UVB significantly stimulated human melanocytes to increase their expression of genes encoding microphthalmia-associated transcription factor, tyrosinase and tyrosinase-related protein 1. The catalytic activity of tyrosinase was also increased. ELISA assays revealed that UVB significantly increased the secretion of interleukin-1α, interleukin-6/8, granulocyte macrophage stimulatory factor and endothelin-1 but not α-melanocyte stimulating hormone. The addition of an endothelin-1 neutralizing antibody significantly abrogated the increase of tyrosinase activity. Post-irradiation treatment with astaxanthin or withaferin A significantly abolished the up-regulation of tyrosinase activity induced by UVB. Treatment with astaxanthin or withaferin A significantly reduced the increased levels of interleukin-1α, interleukin-6/8, granulocyte macrophage stimulatory factor and endothelin-1. Withaferin A but not astaxanthin also significantly abrogated the endothelin-1-stimulated activity of tyrosinase in melanocytes. Western blot analysis of intracellular signaling factors revealed that withaferin A but not astaxanthin significantly abolished the endothelin-1-stimulated phosphorylation of Raf-1, MEK, ERK, MITF and CREB in human melanocytes. These results demonstrate that this co-culture system is an appropriate model to characterize melanogenic paracrine interactions and that astaxanthin and withaferin A serve as potent inhibitors of those interactions. Their effects are caused not only by down-regulating the increased secretion of an intrinsic melanogenic cytokine, endothelin-1, by UVB-exposed human keratinocytes, but also by interrupting the endothelin-1-triggered downstream intracellular signaling between protein kinase C and Raf-1 in human melanocytes (only for withaferin A). Copyright © 2015 Elsevier Ltd. All rights reserved.

Microvesicating effects of sulfur mustard on an in vitro human skin model.

PubMed

Hayden, Patrick J; Petrali, John P; Stolper, Gina; Hamilton, Tracey A; Jackson, George R; Wertz, Philip W; Ito, Susumu; Smith, William J; Klausner, Mitchell

2009-10-01

Bis-(beta-chloroethyl) sulfide (SM) is a potent skin vesicant previously used for chemical warfare. Progress in determination of the mechanistic basis of SM pathology, and development of prophylactic and/or therapeutic countermeasures to SM exposure has been hampered by lack of physiologically relevant models of human skin. The current work evaluated a newly developed tissue engineered full-thickness human skin model in a completely in vitro approach to investigation of SM-induced dermal pathology. The model was first characterized with regard to overall morphology, lipid composition, basement membrane (BM) composition and ultrastructural features that are important targets of SM pathologic activity. Well-developed BM ultrastructural features were observed at the dermal-epidermal junction (DEJ), thus demonstrating successful resolution of a primary deficiency of models previously evaluated for SM studies. Studies were then conducted to evaluate histopathological effects of SM on the model. Good replication of in vivo effects was observed, including apoptosis of basal keratinocytes (KC) and microblister formation at the DEJ. Tissue engineered skin models with well-developed basement membrane structures thus appear to be useful tools for in vitro mechanistic studies of SM vesicant activity and development of preventive/therapeutic approaches for SM pathology.

Processing of social and monetary rewards in the human striatum.

PubMed

Izuma, Keise; Saito, Daisuke N; Sadato, Norihiro

2008-04-24

Despite an increasing focus on the neural basis of human decision making in neuroscience, relatively little attention has been paid to decision making in social settings. Moreover, although human social decision making has been explored in a social psychology context, few neural explanations for the observed findings have been considered. To bridge this gap and improve models of human social decision making, we investigated whether acquiring a good reputation, which is an important incentive in human social behaviors, activates the same reward circuitry as monetary rewards. In total, 19 subjects participated in functional magnetic resonance imaging (fMRI) experiments involving monetary and social rewards. The acquisition of one's good reputation robustly activated reward-related brain areas, notably the striatum, and these overlapped with the areas activated by monetary rewards. Our findings support the idea of a "common neural currency" for rewards and represent an important first step toward a neural explanation for complex human social behaviors.

Dosimetry of {sup 210}Po in humans, caribou, and wolves in northern Canada

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

Thomas, P.A.

1994-06-01

Effective doses from {sup 210}Po intake with caribou meat were determined for human residents in Baker Lake and Snowdrift in the Northwest Territories of Canada and compared to doses calculated from reported {sup 210}Po tissue activities in Alaskan and British residents. Effective doses were calculated to separate body tissues, using ICRP 60 human weighting factors and the ICRP 30 metabolic model for {sup 210}Po. Baker Lake and Alaskan effective doses were similar at 0.4 mSv y{sup {minus}1} and slightly higher than Snowdrift doses (0.3 mSv y{sup {minus}1}). Alaskan tissue activities indicated higher effective doses to liver, bone surfaces and redmore » marrow and lower doses to spleen than the {sup 210}Po metabolic model (ICRP 1979a) predicts. Effective doses to Baker Lake and Snowdrift caribou and wolves, calculated from tissue activities, ranged from 7-20 mSv y{sup {minus}1} using human weighting factors for comparison to human doses only. Effective doses to northern Canadians and wildlife were, respectively, 7-11% and 1.8-5 times an estimated human background of 4 mSv y{sup {minus}} from all sources. 51 refs., 2 figs., 9 tabs.« less

Lag threads organize the brain’s intrinsic activity

PubMed Central

Mitra, Anish; Snyder, Abraham Z.; Blazey, Tyler; Raichle, Marcus E.

2015-01-01

It has been widely reported that intrinsic brain activity, in a variety of animals including humans, is spatiotemporally structured. Specifically, propagated slow activity has been repeatedly demonstrated in animals. In human resting-state fMRI, spontaneous activity has been understood predominantly in terms of zero-lag temporal synchrony within widely distributed functional systems (resting-state networks). Here, we use resting-state fMRI from 1,376 normal, young adults to demonstrate that multiple, highly reproducible, temporal sequences of propagated activity, which we term “lag threads,” are present in the brain. Moreover, this propagated activity is largely unidirectional within conventionally understood resting-state networks. Modeling experiments show that resting-state networks naturally emerge as a consequence of shared patterns of propagation. An implication of these results is that common physiologic mechanisms may underlie spontaneous activity as imaged with fMRI in humans and slowly propagated activity as studied in animals. PMID:25825720

In vitro short-term exposure to air pollution PM{sub 2.5-0.3} induced cell cycle alterations and genetic instability in a human lung cell coculture model

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

Abbas, Imane; EA4492-UCEIV, Université du Littoral-Côte d’Opale, Dunkerque; Lebanese Atomic Energy Commission – CNRS, Beirut

Although its adverse health effects of air pollution particulate matter (PM2.5) are well-documented and often related to oxidative stress and pro-inflammatory response, recent evidence support the role of the remodeling of the airway epithelium involving the regulation of cell death processes. Hence, the overarching goals of the present study were to use an in vitro coculture model, based on human AM and L132 cells to study the possible alteration of TP53-RB gene signaling pathways (i.e. cell cycle phases, gene expression of TP53, BCL2, BAX, P21, CCND1, and RB, and protein concentrations of their active forms), and genetic instability (i.e. LOHmore » and/or MSI) in the PM{sub 2.5-0.3}-exposed coculture model. PM{sub 2.5-0.3} exposure of human AM from the coculture model induced marked cell cycle alterations after 24 h, as shown by increased numbers of L132 cells in subG1 and S+G2 cell cycle phases, indicating apoptosis and proliferation. Accordingly, activation of the TP53-RB gene signaling pathways after the coculture model exposure to PM{sub 2.5-0.3} was reported in the L132 cells. Exposure of human AM from the coculture model to PM{sub 2.5-0.3} resulted in MS alterations in 3p chromosome multiple critical regions in L132 cell population. Hence, in vitro short-term exposure of the coculture model to PM{sub 2.5-0.3} induced cell cycle alterations relying on the sequential occurrence of molecular abnormalities from TP53-RB gene signaling pathway activation and genetic instability. - Highlights: • Better knowledge on health adverse effects of air pollution PM{sub 2.5}. • Human alveolar macrophage and normal human epithelial lung cell coculture. • Molecular abnormalities from TP53-RB gene signaling pathway. • Loss of heterozygosity and microsatellite instability. • Pathologic changes in morphology and number of cells in relation to airway remodeling.« less

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

PubMed

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

2017-06-01

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

Prediction of Losartan-Active Carboxylic Acid Metabolite Exposure Following Losartan Administration Using Static and Physiologically Based Pharmacokinetic Models.

PubMed

Nguyen, Hoa Q; Lin, Jian; Kimoto, Emi; Callegari, Ernesto; Tse, Susanna; Obach, R Scott

2017-09-01

The aim of this study was to evaluate a strategy based on static and dynamic physiologically based pharmacokinetic (PBPK) modeling for the prediction of metabolite and parent drug area under the time-concentration curve ratio (AUC m /AUC p ) and their PK profiles in humans using in vitro data when active transport processes are involved in disposition. The strategy was applied to losartan and its pharmacologically active metabolite carboxylosartan as test compounds. Hepatobiliary transport including transport-mediated uptake, canilicular and basolateral efflux, and metabolic clearance estimates were obtained from in vitro studies using human liver microsomes and sandwich-cultured hepatocytes. Human renal clearance of carboxylosartan was estimated from dog renal clearance using allometric scaling approach. All clearance mechanisms were mechanistically incorporated in a static model to predict the relative exposure of carboxylosartan versus losartan (AUC m /AUC p ). The predicted AUC m /AUC p were consistent with the observed data following intravenous and oral administration of losartan. Moreover, the in vitro parameters were used as initial parameters in PBPK permeability-limited disposition models to predict the concentration-time profiles for both parent and its active metabolite after oral administration of losartan. The PBPK model was able to recover the plasma profiles of both losartan and carboxylosartan, further substantiating the validity of this approach. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Retro-binding thrombin active site inhibitors: identification of an orally active inhibitor of thrombin catalytic activity.

PubMed

Iwanowicz, Edwin J; Kimball, S David; Lin, James; Lau, Wan; Han, W-C; Wang, Tammy C; Roberts, Daniel G M; Schumacher, W A; Ogletree, Martin L; Seiler, Steven M

2002-11-04

A series of retro-binding inhibitors of human alpha-thrombin was prepared to elucidate structure-activity relationships (SAR) and optimize in vivo performance. Compounds 9 and 11, orally active inhibitors of thrombin catalytic activity, were identified to be efficacious in a thrombin-induced lethality model in mice.

Pharmacokinetics and Toxicology of a Fibroblast Activation Protein (FAP)-activated Prodrug in Murine Xenograft Models of Human Cancer

PubMed Central

Brennen, W. Nathaniel; Rosen, D. Marc; Chaux, Alcides; Netto, George J.; Isaacs, John T.; Denmeade, Samuel R.

2014-01-01

Background As carcinoma progresses, the stroma undergoes a variety of phenotypic changes, including the presence of carcinoma-associated fibroblasts (CAFs) that express fibroblast activation protein (FAP). FAP is a post-prolyl endopeptidase whose expression in a healthy adult is largely restricted to the cancer-associated stroma. FAP-targeted prodrugs with a 100-fold greater therapeutic window over the parent compound were previously generated. Methods Prodrugs and non-cleavable controls were incubated in the presence of FAP. Plasma and tumor half-lives (t1/2) of the full-length and active forms of the prodrugs were determined using LCMS. Biodistribution studies of prodrug activation were performed. Histopathological analysis of tissues from treated animals were compared to vehicle-treated controls. Toxicity and efficacy studies were performed in human breast (MDA-MB-231 and MCF-7) and prostate (LNCaP) cancer xenografts models. Results These FAP-activated prodrugs have a significantly slower clearance from tumor tissue than the circulation (~12 vs. ~4.5 hrs). Micromolar concentrations of active drug persist in the tumor. Active drug is detected in non-target tissues; however, histopathologic evaluation reveals no evidence of drug-induced toxicity. A FAP-activated prodrug (ERGETGP-S12ADT) inhibits tumor growth in multiple human breast and prostate cancer xenograft models. The anti-tumor effect is comparable to that observed with docetaxel, but results in significantly less toxicity. Conclusion FAP-activated prodrugs are a viable strategy for the management of prostate and other cancers. These prodrugs exhibit less toxicity than a commonly used chemotherapeutic agent. Further refinement of the FAP cleavage site for greater specificity may reduce prodrug activation in non-target tissues and enhance clinical benefit. PMID:25053236

Pharmacokinetics and toxicology of a fibroblast activation protein (FAP)-activated prodrug in murine xenograft models of human cancer.

PubMed

Brennen, W Nathaniel; Rosen, D Marc; Chaux, Alcides; Netto, George J; Isaacs, John T; Denmeade, Samuel R

2014-09-01

As carcinoma progresses, the stroma undergoes a variety of phenotypic changes, including the presence of carcinoma-associated fibroblasts (CAFs) that express fibroblast activation protein (FAP). FAP is a post-prolyl endopeptidase whose expression in a healthy adult is largely restricted to the cancer-associated stroma. FAP-targeted prodrugs with a 100-fold greater therapeutic window over the parent compound were previously generated. Prodrugs and non-cleavable controls were incubated in the presence of FAP. Plasma and tumor half-lives (t1/2) of the full-length and active forms of the prodrugs were determined using LCMS. Biodistribution studies of prodrug activation were performed. Histopathological analysis of tissues from treated animals were compared to vehicle-treated controls. Toxicity and efficacy studies were performed in human breast (MDA-MB-231 and MCF-7) and prostate (LNCaP) cancer xenografts models. These FAP-activated prodrugs have a significantly slower clearance from tumor tissue than the circulation (∼12 vs. ∼4.5 hr). Micromolar concentrations of active drug persist in the tumor. Active drug is detected in non-target tissues; however, histopathologic evaluation reveals no evidence of drug-induced toxicity. A FAP-activated prodrug (ERGETGP-S12ADT) inhibits tumor growth in multiple human breast and prostate cancer xenograft models. The anti-tumor effect is comparable to that observed with docetaxel, but results in significantly less toxicity. FAP-activated prodrugs are a viable strategy for the management of prostate and other cancers. These prodrugs exhibit less toxicity than a commonly used chemotherapeutic agent. Further refinement of the FAP cleavage site for greater specificity may reduce prodrug activation in non-target tissues and enhance clinical benefit. © 2014 Wiley Periodicals, Inc.

Hemolytic, anticancer and antigiardial activity of Palythoa caribaeorum venom.

PubMed

Lazcano-Pérez, Fernando; Zavala-Moreno, Ariana; Rufino-González, Yadira; Ponce-Macotela, Martha; García-Arredondo, Alejandro; Cuevas-Cruz, Miguel; Gómez-Manzo, Saúl; Marcial-Quino, Jaime; Arreguín-Lozano, Barbarín; Arreguín-Espinosa, Roberto

2018-01-01

Cnidarian venoms and extracts have shown a broad variety of biological activities including cytotoxic, antibacterial and antitumoral effects. Most of these studied extracts were obtained from sea anemones or jellyfish. The present study aimed to determine the toxic activity and assess the antitumor and antiparasitic potential of Palythoa caribaeorum venom by evaluating its in vitro toxicity on several models including human tumor cell lines and against the parasite Giardia intestinalis . The presence of cytolysins and vasoconstrictor activity of P. caribaeorum venom were determined by hemolysis, PLA 2 and isolated rat aortic ring assays, respectively. The cytotoxic effect was tested on HCT-15 (human colorectal adenocarcinoma), MCF-7 (human mammary adenocarcinoma), K562 (human chronic myelogenous leukemia), U251 (human glyoblastoma), PC-3 (human prostatic adenocarcinoma) and SKLU-1 (human lung adenocarcinoma). An in vivo toxicity assay was performed with crickets and the antiparasitic assay was performed against G. intestinalis at 24 h of incubation. P. caribaeorum venom produced hemolytic and PLA 2 activity and showed specific cytotoxicity against U251 and SKLU-1 cell lines, with approximately 50% growing inhibition. The venom was toxic to insects and showed activity against G. intestinalis in a dose-dependent manner by possibly altering its membrane osmotic equilibrium. These results suggest that P. caribaeorum venom contains compounds with potential therapeutic value against microorganisms and cancer.

Non-animal methodologies within biomedical research and toxicity testing.

PubMed

Knight, Andrew

2008-01-01

Laboratory animal models are limited by scientific constraints on human applicability, and increasing regulatory restrictions, driven by social concerns. Reliance on laboratory animals also incurs marked - and in some cases, prohibitive - logistical challenges, within high-throughput chemical testing programmes, such as those currently underway within Europe and the US. However, a range of non-animal methodologies is available within biomedical research and toxicity testing. These include: mechanisms to enhance the sharing and assessment of existing data prior to conducting further studies, and physicochemical evaluation and computerised modelling, including the use of structure-activity relationships and expert systems. Minimally-sentient animals from lower phylogenetic orders or early developmental vertebral stages may be used, as well as microorganisms and higher plants. A variety of tissue cultures, including immortalised cell lines, embryonic and adult stem cells, and organotypic cultures, are also available. In vitro assays utilising bacterial, yeast, protozoal, mammalian or human cell cultures exist for a wide range of toxic and other endpoints. These may be static or perfused, and may be used individually, or combined within test batteries. Human hepatocyte cultures and metabolic activation systems offer potential assessment of metabolite activity and organ-organ interaction. Microarray technology may allow genetic expression profiling, increasing the speed of toxin detection, well prior to more invasive endpoints. Enhanced human clinical trials utilising micro- dosing, staggered dosing, and more representative study populations and durations, as well as surrogate human tissues, advanced imaging modalities and human epidemiological, sociological and psycho- logical studies, may increase our understanding of illness aetiology and pathogenesis, and facilitate the development of safe and effective pharmacologic interventions. Particularly when human tissues are used, non-animal models may generate faster, cheaper results, more reliably predictive for humans, whilst yielding greater insights into human biochemical processes. Greater commitment to their development and implementation is necessary, however, to efficiently meet the needs of high-throughput chemical testing programmes, important emerging testing needs, and the ongoing development of human clinical interventions.

Production of MPS VII mouse (Gustm(hE540A·mE536A)Sly) doubly tolerant to human and mouse β-glucuronidase

PubMed Central

Tomatsu, Shunji; Orii, Koji O.; Vogler, Carole; Grubb, Jeffrey H.; Snella, Elizabeth M.; Gutierrez, Monica; Dieter, Tatiana; Holden, Christopher C.; Sukegawa, Kazuko; Orii, Tadao; Kondo, Naomi; Sly, William S.

2006-01-01

Mucopolysaccharidosis VII (MPS VII, Sly syndrome) is an autosomal recessive lysosomal storage disease caused by β-glucuronidase (GUS) deficiency. A naturally occurring mouse model of that disease has been very useful for studying experimental approaches to therapy. However, immune responses can complicate evaluation of the long-term benefits of enzyme replacement or gene therapy delivered to adult MPS VII mice. To make this model useful for studying the long-term effectiveness and side effects of experimental therapies delivered to adult mice, we developed a new MPS VII mouse model, which is tolerant to both human and murine GUS. To achieve this, we used homologous recombination to introduce simultaneously a human cDNA transgene expressing inactive human GUS into intron 9 of the murine Gus gene and a targeted active site mutation (E536A) into the adjacent exon 10. When the heterozygote products of germline transmission were bred to homozygosity, the homozygous mice expressed no GUS enzyme activity but expressed inactive human GUS protein highly and were tolerant to immune challenge with human enzyme. Expression of the mutant murine Gus gene was reduced to about 10% of normal levels, but the inactive murine GUS enzyme also conferred tolerance to murine GUS. This MPS VII mouse model should be useful to evaluate therapeutic responses in adult mice receiving repetitive doses of enzyme or mice receiving gene therapy as adults. Heterozygotes expressed only 9.5–26% of wild-type levels of murine GUS instead of the expected 50%, indicating a dominant-negative effect of the mutant enzyme monomers on the activity of GUS tetramers in different tissues. Corrective gene therapy in this model should provide high enough levels of expression of normal GUS monomers to overcome the dominant negative effect of mutant monomers on newly synthesized GUS tetramers in most tissues. PMID:12700165

Agonistic TAM-163 antibody targeting tyrosine kinase receptor-B: applying mechanistic modeling to enable preclinical to clinical translation and guide clinical trial design.

PubMed

Vugmeyster, Yulia; Rohde, Cynthia; Perreault, Mylene; Gimeno, Ruth E; Singh, Pratap

2013-01-01

TAM-163, an agonist monoclonal antibody targeting tyrosine receptor kinase-B (TrkB), is currently being investigated as a potential body weight modulatory agent in humans. To support the selection of the dose range for the first-in-human (FIH) trial of TAM-163, we conducted a mechanistic analysis of the pharmacokinetic (PK) and pharmacodynamic (PD) data (e.g., body weight gain) obtained in lean cynomolgus and obese rhesus monkeys following single doses ranging from 0.3 to 60 mg/kg. A target-mediated drug disposition (TMDD) model was used to describe the observed nonlinear PK and Emax approach was used to describe the observed dose-dependent PD effect. The TMDD model development was supported by the experimental determination of the binding affinity constant (9.4 nM) and internalization rate of the drug-target complex (2.08 h(-1)). These mechanistic analyses enabled linking of exposure, target (TrkB) coverage, and pharmacological activity (e.g., PD) in monkeys, and indicated that ≥ 38% target coverage (time-average) was required to achieve significant body weight gain in monkeys. Based on the scaling of the TMDD model from monkeys to humans and assuming similar relationship between the target coverage and pharmacological activity between monkey and humans, subcutaneous (SC) doses of 1 and 15 mg/kg in humans were projected to be the minimally and the fully pharmacologically active doses, respectively. Based on the minimal anticipated biological effect level (MABEL) approach for starting dose selection, the dose of 0.05 mg/kg (3 mg for a 60 kg human) SC was recommended as the starting dose for FIH trials, because at this dose level<10% target coverage was projected at Cmax (and all other time points). This study illustrates a rational mechanistic approach for the selection of FIH dose range for a therapeutic protein with a complex model of action.

The efficacy of 9-cis retinoic acid in experimental models of cancer.

PubMed

Gottardis, M M; Lamph, W W; Shalinsky, D R; Wellstein, A; Heyman, R A

1996-01-01

9-cis retinoic acid (9-cis RA) is a retinoid receptor pan-agonist that binds with high affinity to both retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Using a variety of in vivo and in vitro cancer models, we present experimental data that 9-cis RA has activity as a potential chemotherapeutic agent. Treatment of the human promyelocytic leukemia cell line HL-60 with 9-cis RA decreases cell proliferation, increases cell differentiation, and increases apoptosis. Induction of apoptosis correlates with an increase in tissue transglutaminase (type II) activity. In vivo, 9-cis RA induces complete tumor regression of an early passage human lip squamous cell carcinoma xenograft. Finally, 9-cis RA inhibits the anchorage-independent growth of the human breast cancer cell lines MCF-7 and LY2 (an antiestrogen-resistant MCF-7 variant). Transient co-transfection assays indicate that 9-cis RA inhibits estrogen receptor transcription of an ERE-tk-LUC reporter through RAR or RXR receptors. These data suggest that retinoid receptors can antagonize estrogen-dependent transcription and provides one possible mechanism for the inhibition of cell growth by 9-cis RA in breast cancer cell lines. In summary, these findings present evidence that 9-cis RA has a wide range of activities in human cancer models.

Uracil-DNA Glycosylase in Base Excision Repair and Adaptive Immunity

PubMed Central

Doseth, Berit; Visnes, Torkild; Wallenius, Anders; Ericsson, Ida; Sarno, Antonio; Pettersen, Henrik Sahlin; Flatberg, Arnar; Catterall, Tara; Slupphaug, Geir; Krokan, Hans E.; Kavli, Bodil

2011-01-01

Genomic uracil is a DNA lesion but also an essential key intermediate in adaptive immunity. In B cells, activation-induced cytidine deaminase deaminates cytosine to uracil (U:G mispairs) in Ig genes to initiate antibody maturation. Uracil-DNA glycosylases (UDGs) such as uracil N-glycosylase (UNG), single strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1), and thymine-DNA glycosylase remove uracil from DNA. Gene-targeted mouse models are extensively used to investigate the role of these enzymes in DNA repair and Ig diversification. However, possible species differences in uracil processing in humans and mice are yet not established. To address this, we analyzed UDG activities and quantities in human and mouse cell lines and in splenic B cells from Ung+/+ and Ung−/− backcrossed mice. Interestingly, human cells displayed ∼15-fold higher total uracil excision capacity due to higher levels of UNG. In contrast, SMUG1 activity was ∼8-fold higher in mouse cells, constituting ∼50% of the total U:G excision activity compared with less than 1% in human cells. In activated B cells, both UNG and SMUG1 activities were at levels comparable with those measured for mouse cell lines. Moreover, SMUG1 activity per cell was not down-regulated after activation. We therefore suggest that SMUG1 may work as a weak backup activity for UNG2 during class switch recombination in Ung−/− mice. Our results reveal significant species differences in genomic uracil processing. These findings should be taken into account when mouse models are used in studies of uracil DNA repair and adaptive immunity. PMID:21454529

Evaluation of the rotenone-induced activation of the Nrf2 pathway in a neuronal model derived from human induced pluripotent stem cells.

PubMed

Zagoura, Dimitra; Canovas-Jorda, David; Pistollato, Francesca; Bremer-Hoffmann, Susanne; Bal-Price, Anna

2017-06-01

Human induced pluripotent stem cells (hiPSCs) are considered as a powerful tool for drug and chemical screening and development of new in vitro testing strategies in the field of toxicology, including neurotoxicity evaluation. These cells are able to expand and efficiently differentiate into different types of neuronal and glial cells as well as peripheral neurons. These human cells-based neuronal models serve as test systems for mechanistic studies on different pathways involved in neurotoxicity. One of the well-known mechanisms that are activated by chemically-induced oxidative stress is the Nrf2 signaling pathway. Therefore, in the current study, we evaluated whether Nrf2 signaling machinery is expressed in human induced pluripotent stem cells (hiPSCs)-derived mixed neuronal/glial culture and if so whether it becomes activated by rotenone-induced oxidative stress mediated by complex I inhibition of mitochondrial respiration. Rotenone was found to induce the activation of Nrf2 signaling particularly at the highest tested concentration (100 nM), as shown by Nrf2 nuclear translocation and the up-regulation of the Nrf2-downstream antioxidant enzymes, NQO1 and SRXN1. Interestingly, exposure to rotenone also increased the number of astroglial cells in which Nrf2 activation may play an important role in neuroprotection. Moreover, rotenone caused cell death of dopaminergic neurons since a decreased percentage of tyrosine hydroxylase (TH + ) cells was observed. The obtained results suggest that hiPSC-derived mixed neuronal/glial culture could be a valuable in vitro human model for the establishment of neuronal specific assays in order to link Nrf2 pathway activation (biomarker of oxidative stress) with additional neuronal specific readouts that could be applied to in vitro neurotoxicity evaluation. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Anti-inflammatory and immunomodulatory effects of Aquaphilus dolomiae extract on in vitro models.

PubMed

Aries, Marie-Françoise; Hernandez-Pigeon, Hélène; Vaissière, Clémence; Delga, Hélène; Caruana, Antony; Lévêque, Marguerite; Bourrain, Muriel; Ravard Helffer, Katia; Chol, Bertrand; Nguyen, Thien; Bessou-Touya, Sandrine; Castex-Rizzi, Nathalie

2016-01-01

Atopic dermatitis (AD) is a common skin disease characterized by recurrent pruritic inflammatory skin lesions resulting from structural and immune defects of the skin barrier. Previous studies have shown the clinical efficacy of Avène thermal spring water in AD, and a new microorganism, Aquaphilus dolomiae was suspected to contribute to these unique properties. The present study evaluated the anti-inflammatory, antipruritic, and immunomodulatory properties of ES0, an original biological extract of A. dolomiae , in immune and inflammatory cell models in order to assess its potential use in the treatment of AD. An ES0 extract containing periplasmic and membrane proteins, peptides, lipopolysaccharides, and exopolysaccharides was obtained from A. dolomiae. The effects of the extract on pruritus and inflammatory mediators and immune mechanisms were evaluated by using various AD cell models and assays. In a keratinocyte model, ES0 inhibited the expression of the inflammatory mediators, thymic stromal lymphopoietin, interleukin (IL)-18, IL-4R, IL-8, monocyte chemoattractant protein-3, macrophage inflammatory protein-3α, and macrophage-derived chemokine and induced the expression of involucrin, which is involved in skin barrier keratinocyte terminal differentiation. In addition, ES0 inhibited protease-activated receptor-2 activation in HaCaT human keratinocytes stimulated by stratum corneum tryptic enzyme and T helper type (Th) 1, Th2, and Th17 cytokine production in Staphylococcal enterotoxin B-stimulated CD4+ lymphocytes. Lastly, ES0 markedly activated innate immunity through toll-like receptor (TLR) 2, TLR4, and TLR5 activation (in recombinant human embryonic kidney 293 cells) and through antimicrobial peptide induction (psoriasin, human beta-defensin-2, and cathelicidin), mainly through TLR5 activation (in normal human keratinocytes). Overall, these in vitro results confirm the marked regulatory activity of this A. dolomiae extract on inflammatory and immune responses, which may be of value by virtue of its potential as an adjunctive treatment of AD inflammatory and pruritic lesions.

1,25D3 enhances antitumor activity of gemcitabine and cisplatin in human bladder cancer models

PubMed Central

Ma, Yingyu; Yu, Wei-Dong; Trump, Donald L.; Johnson, Candace S.

2010-01-01

Background 1,25 dihydroxyvitamin D3 (1,25D3) potentiates the cytotoxic effects of several common chemotherapeutic agents. The combination of gemcitabine and cisplatin (GC) is a current standard chemotherapy regimen for bladder cancer. We investigated whether 1,25D3 could enhance the antitumor activity of GC in bladder cancer model systems. Methods Human bladder cancer T24 and UMUC3 cells were pretreated with 1,25D3 followed by GC. Apoptosis were assessed by annexin V staining. Caspase activation was examined by immunoblot analysis and substrate-based caspase activity assay. The cytotoxic effects were examined using MTT and in vitro clonogenic assay. p73 protein levels were assessed by immunoblot analysis. Knockdown of p73 was achieved by siRNA. The in vivo antitumor activity was assessed by in vivo excision clonogenic assay and tumor regrowth delay in the T24 xenograft model. Results 1,25D3 pretreatment enhanced GC-induced apoptosis and the activities of caspases- 8, 9 and 3 in T24 and UMUC3 cells. 1,25D3 synergistically reduced GC-suppressed surviving fraction in T24 cells. 1,25D3, gemcitabine, or cisplatin induced p73 accumulation, which was enhanced by GC or 1,25D3 and GC. p73 expression was lower in human primary bladder tumor tissue compared with adjacent normal tissue. Knockdown of p73 increased clonogenic capacity of T24 cells treated with 1,25D3, GC or 1,25D3 and GC. 1,25D3 and GC combination enhanced tumor regression compared with 1,25D3 or GC alone. Conclusions 1,25D3 potentiates GC-mediated growth inhibition in human bladder cancer models in vitro and in vivo, which involves p73 induction and apoptosis. PMID:20564622

Microenvironmental Regulation of Mammary Carcinogenesis

DTIC Science & Technology

2008-06-01

cells. These models share many of the hallmarks of multistage human breast cancer development including histological disease progression and immune cell... developed by Muller and colleagues20, represents a reasonable recapitulation of late-stage human breast cancer as determined by histological progression ...Annual Progress Report d. Develop a profile of proteolytic activities in normal and neoplastic mammary tissues from mouse models of mammary

Human Behaviour Representation in Constructive Modelling (Representation du comportement humain dans des modelisations creatives)

DTIC Science & Technology

2009-09-01

involved in R&T activities. RTO reports both to the Military Committee of NATO and to the Conference of National Armament Directors. It comprises a...4 11.5.3 Project Description 11-5 Chapter 12 – Technical Evaluation Report 12-1 12.1 Executive Summary 12-1 12.2 Introduction 12-2 12.3...modelling human factors has been slow over the past decade, other forums have been reporting a number of theoretical and applied papers on human behaviour

Combined monitoring, decision and control model for the human operator in a command and control desk

NASA Technical Reports Server (NTRS)

Muralidharan, R.; Baron, S.

1978-01-01

A report is given on the ongoing efforts to mode the human operator in the context of the task during the enroute/return phases in the ground based control of multiple flights of remotely piloted vehicles (RPV). The approach employed here uses models that have their analytical bases in control theory and in statistical estimation and decision theory. In particular, it draws heavily on the modes and the concepts of the optimal control model (OCM) of the human operator. The OCM is being extended into a combined monitoring, decision, and control model (DEMON) of the human operator by infusing decision theoretic notions that make it suitable for application to problems in which human control actions are infrequent and in which monitoring and decision-making are the operator's main activities. Some results obtained with a specialized version of DEMON for the RPV control problem are included.

Automation effects in a multiloop manual control system

NASA Technical Reports Server (NTRS)

Hess, R. A.; Mcnally, B. D.

1986-01-01

An experimental and analytical study was undertaken to investigate human interaction with a simple multiloop manual control system in which the human's activity was systematically varied by changing the level of automation. The system simulated was the longitudinal dynamics of a hovering helicopter. The automation-systems-stabilized vehicle responses from attitude to velocity to position and also provided for display automation in the form of a flight director. The control-loop structure resulting from the task definition can be considered a simple stereotype of a hierarchical control system. The experimental study was complemented by an analytical modeling effort which utilized simple crossover models of the human operator. It was shown that such models can be extended to the description of multiloop tasks involving preview and precognitive human operator behavior. The existence of time optimal manual control behavior was established for these tasks and the role which internal models may play in establishing human-machine performance was discussed.

Finite element modelling of human auditory periphery including a feed-forward amplification of the cochlea.

PubMed

Wang, Xuelin; Wang, Liling; Zhou, Jianjun; Hu, Yujin

2014-08-01

A three-dimensional finite element model is developed for the simulation of the sound transmission through the human auditory periphery consisting of the external ear canal, middle ear and cochlea. The cochlea is modelled as a straight duct divided into two fluid-filled scalae by the basilar membrane (BM) having an orthotropic material property with dimensional variation along its length. In particular, an active feed-forward mechanism is added into the passive cochlear model to represent the activity of the outer hair cells (OHCs). An iterative procedure is proposed for calculating the nonlinear response resulting from the active cochlea in the frequency domain. Results on the middle-ear transfer function, BM steady-state frequency response and intracochlear pressure are derived. A good match of the model predictions with experimental data from the literatures demonstrates the validity of the ear model for simulating sound pressure gain of middle ear, frequency to place map, cochlear sensitivity and compressive output for large intensity input. The current model featuring an active cochlea is able to correlate directly the sound stimulus in the ear canal with the vibration of BM and provides a tool to explore the mechanisms by which sound pressure in the ear canal is converted to a stimulus for the OHCs.

Reduced physical activity and risk of chronic disease: the biology behind the consequences.

PubMed

Booth, Frank W; Laye, Matthew J; Lees, Simon J; Rector, R Scott; Thyfault, John P

2008-03-01

This review focuses on three preserved, ancient, biological mechanisms (physical activity, insulin sensitivity, and fat storage). Genes in humans and rodents were selected in an environment of high physical activity that favored an optimization of aerobic metabolic pathways to conserve energy for a potential, future food deficiency. Today machines and other technologies have replaced much of the physical activity that selected optimal gene expression for energy metabolism. Distressingly, the negative by-product of a lack of ancient physical activity levels in our modern civilization is an increased risk of chronic disease. We have been employing a rodent wheel-lock model to approximate the reduction in physical activity in humans from the level under which genes were selected to a lower level observed in modern daily functioning. Thus far, two major changes have been identified when rats undertaking daily, natural voluntary running on wheels experience an abrupt cessation of the running (wheel lock model). First, insulin sensitivity in the epitrochlearis muscle of rats falls to sedentary values after 2 days of the cessation of running, confirming the decline to sedentary values in whole-body insulin sensitivity when physically active humans stop high levels of daily exercise. Second, visceral fat increases within 1 week after rats cease daily running, confirming the plasticity of human visceral fat. This review focuses on the supporting data for the aforementioned two outcomes. Our primary goal is to better understand how a physically inactive lifestyle initiates maladaptations that cause chronic disease.

Minocycline attenuates HIV-1 infection and suppresses chronic immune activation in humanized NOD/LtsZ-scidIL-2Rγnull mice

PubMed Central

Singh, Maneesh; Singh, Pratibha; Vaira, Dolores; Amand, Mathieu; Rahmouni, Souad; Moutschen, Michel

2014-01-01

More than a quarter of a century of research has established chronic immune activation and dysfunctional T cells as central features of chronic HIV infection and subsequent immunodeficiency. Consequently, the search for a new immunomodulatory therapy that could reduce immune activation and improve T-cell function has been increased. However, the lack of small animal models for in vivo HIV study has hampered progress. In the current study, we have investigated a model of cord blood haematopoietic progenitor cells (CB-HPCs) -transplanted humanized NOD/LtsZ-scidIL-2Rγnull mice in which progression of HIV infection is associated with widespread chronic immune activation and inflammation. Indeed, HIV infection in humanized NSG mice caused up-regulation of several T-cell immune activation markers such as CD38, HLA-DR, CD69 and co-receptor CCR5. T-cell exhaustion markers PD-1 and CTLA-4 were found to be significantly up-regulated on T cells. Moreover, increased plasmatic levels of lipopolysaccharide, sCD14 and interleukin-10 were also observed in infected mice. Treatment with minocycline resulted in a significant decrease of expression of cellular and plasma immune activation markers, inhibition of HIV replication and improved T-cell counts in HIV-infected humanized NSG mice. The study demonstrates that minocycline could be an effective, low-cost adjunctive treatment to regulate chronic immune activation and replication of HIV. PMID:24409837

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

In vivo bioluminescence imaging validation of a human biopsy-derived orthotopic mouse model of glioblastoma multiforme.

PubMed

Jarzabek, Monika A; Huszthy, Peter C; Skaftnesmo, Kai O; McCormack, Emmet; Dicker, Patrick; Prehn, Jochen H M; Bjerkvig, Rolf; Byrne, Annette T

2013-05-01

Glioblastoma multiforme (GBM), the most aggressive brain malignancy, is characterized by extensive cellular proliferation, angiogenesis, and single-cell infiltration into the brain. We have previously shown that a xenograft model based on serial xenotransplantation of human biopsy spheroids in immunodeficient rodents maintains the genotype and phenotype of the original patient tumor. The present work further extends this model for optical assessment of tumor engraftment and growth using bioluminescence imaging (BLI). A method for successful lentiviral transduction of the firefly luciferase gene into multicellular spheroids was developed and implemented to generate optically active patient tumor cells. Luciferase-expressing spheroids were injected into the brains of immunodeficient mice. BLI photon counts and tumor volumes from magnetic resonance imaging (MRI) were correlated. Luciferase-expressing tumors recapitulated the histopathologic hallmarks of human GBMs and showed proliferation rates and microvessel density counts similar to those of wild-type xenografts. Moreover, we detected widespread invasion of luciferase-positive tumor cells in the mouse brains. Herein we describe a novel optically active model of GBM that closely mimics human pathology with respect to invasion, angiogenesis, and proliferation indices. The model may thus be routinely used for the assessment of novel anti-GBM therapeutic approaches implementing well-established and cost-effective optical imaging strategies.

The Development of a High School Poetry Writing Program from Selected Writings of Erik Erikson, Kenneth Koch, and Theodore Roethke.

ERIC Educational Resources Information Center

Jacobs, Albert Luck, Jr.

In this study, a program for teaching poetry writing in secondary schools is derived from Kenneth Koch's and Theodore Roethke's ideas, and from Erik Erikson's model of adolescent human processes. A review of related literature defines three major approaches to the teaching of poetry writing: models, activities, and models and activities combined.…

Sporadic naturally occurring melanoma in dogs as a preclinical model for human melanoma

PubMed Central

Simpson, R Mark; Bastian, Boris C; Michael, Helen T; Webster, Joshua D; Prasad, Manju L; Conway, Catherine M; Prieto, Victor M; Gary, Joy M; Goldschmidt, Michael H; Esplin, D Glen; Smedley, Rebecca C; Piris, Adriano; Meuten, Donald J; Kiupel, Matti; Lee, Chyi-Chia R; Ward, Jerrold M; Dwyer, Jennifer E; Davis, Barbara J; Anver, Miriam R; Molinolo, Alfredo A; Hoover, Shelley B; Rodriguez-Canales, Jaime; Hewitt, Stephen M

2014-01-01

Melanoma represents a significant malignancy in humans and dogs. Different from genetically engineered models, sporadic canine melanocytic neoplasms share several characteristics with human disease that could make dogs a more relevant preclinical model. Canine melanomas rarely arise in sun-exposed sites. Most occur in the oral cavity, with a subset having intra-epithelial malignant melanocytes mimicking the in situ component of human mucosal melanoma. The spectrum of canine melanocytic neoplasia includes benign lesions with some analogy to nevi, as well as invasive primary melanoma, and widespread metastasis. Growing evidence of distinct subtypes in humans, differing in somatic and predisposing germ-line genetic alterations, cell of origin, epidemiology, relationship to ultraviolet radiation and progression from benign to malignant tumors, may also exist in dogs. Canine and human mucosal melanomas appear to harbor BRAF, NRAS, and c-kit mutations uncommonly, compared with human cutaneous melanomas, although both species share AKT and MAPK signaling activation. We conclude that there is significant overlap in the clinical and histopathological features of canine and human mucosal melanomas. This represents opportunity to explore canine oral cavity melanoma as a preclinical model. PMID:24128326

Cognitive Modeling of Learning Abilities: A Status Report of LAMP.

ERIC Educational Resources Information Center

Kyllonen, Patrick C.; Christal, Raymond E.

Research activities underway as part of the Air Force's Learning Abilities Measurement Program (LAMP) are described. A major objective of the program is to devise new models of the nature and organization of human abilities, that could be applied to improve personnel selection and classification systems. The activities of the project have been…

Human body contour data based activity recognition.

PubMed

Myagmarbayar, Nergui; Yuki, Yoshida; Imamoglu, Nevrez; Gonzalez, Jose; Otake, Mihoko; Yu, Wenwei

2013-01-01

This research work is aimed to develop autonomous bio-monitoring mobile robots, which are capable of tracking and measuring patients' motions, recognizing the patients' behavior based on observation data, and providing calling for medical personnel in emergency situations in home environment. The robots to be developed will bring about cost-effective, safe and easier at-home rehabilitation to most motor-function impaired patients (MIPs). In our previous research, a full framework was established towards this research goal. In this research, we aimed at improving the human activity recognition by using contour data of the tracked human subject extracted from the depth images as the signal source, instead of the lower limb joint angle data used in the previous research, which are more likely to be affected by the motion of the robot and human subjects. Several geometric parameters, such as, the ratio of height to weight of the tracked human subject, and distance (pixels) between centroid points of upper and lower parts of human body, were calculated from the contour data, and used as the features for the activity recognition. A Hidden Markov Model (HMM) is employed to classify different human activities from the features. Experimental results showed that the human activity recognition could be achieved with a high correct rate.

Influence of Human Activity Patterns, particle composition, and residential air exchange rates on modeled distributions of PM 2.5 exposure compared with central-site monitoring data

EPA Science Inventory

Central-site monitors do not account for factors such as outdoor-to-indoor transport and human activity patterns that influence personal exposures to ambient fine-particulate matter (PM_2.5). We describe and compare different ambient PM_2.5 exposure estimation...

Albumin nanocapsules containing fenretinide: pre-clinical evaluation of cytotoxic activity in experimental models of human non-small cell lung cancer.

PubMed

Pignatta, Sara; Orienti, Isabella; Falconi, Mirella; Teti, Gabriella; Arienti, Chiara; Medri, Laura; Zanoni, Michele; Carloni, Silvia; Zoli, Wainer; Amadori, Dino; Tesei, Anna

2015-02-01

The present study deals with the preparation of albumin nanocapsules containing fenretinide and their evaluation in experimental models of human non-small cell lung cancer. These nanocapsules showed enhanced antitumor activity with respect to free fenretinide due to the solubilization effect of albumin on the hydrophobic drug, known to improve bioavailability. The high expression of caveolin-1 on the A549 cell surface further enhanced the antitumor activity of the nanoencapsulated fenretinide. Caveolin-1 favored albumin uptake and improved the efficacy of the fenretinide-loaded albumin nanocapsules, especially in 3-D cultures where the densely packed 3-D structures impaired drug diffusibility and severely reduced the activity of the free drug. The efficacy of the fenretinide albumin nanocapsules was further confirmed in tumor xenograft models of A549 by the significant delay in tumor progression observed with respect to control after intravenous administration of the novel formulation. This study describes the preparation of fenretinide containing albumin nanocapsules and their evaluation in experimental models of non-small cell lung cancer, showing enhanced antitumor activity compared to free fenretinide. Copyright © 2015 Elsevier Inc. All rights reserved.

A Concentration Addition Model to Assess Activation of the Pregnane X Receptor (PXR) by Pesticide Mixtures Found in the French Diet

PubMed Central

de Sousa, Georges; Nawaz, Ahmad; Cravedi, Jean-Pierre; Rahmani, Roger

2014-01-01

French consumers are exposed to mixtures of pesticide residues in part through food consumption. As a xenosensor, the pregnane X receptor (hPXR) is activated by numerous pesticides, the combined effect of which is currently unknown. We examined the activation of hPXR by seven pesticide mixtures most likely found in the French diet and their individual components. The mixture's effect was estimated using the concentration addition (CA) model. PXR transactivation was measured by monitoring luciferase activity in hPXR/HepG2 cells and CYP3A4 expression in human hepatocytes. The three mixtures with the highest potency were evaluated using the CA model, at equimolar concentrations and at their relative proportion in the diet. The seven mixtures significantly activated hPXR and induced the expression of CYP3A4 in human hepatocytes. Of the 14 pesticides which constitute the three most active mixtures, four were found to be strong hPXR agonists, four medium, and six weak. Depending on the mixture and pesticide proportions, additive, greater than additive or less than additive effects between compounds were demonstrated. Predictions of the combined effects were obtained with both real-life and equimolar proportions at low concentrations. Pesticides act mostly additively to activate hPXR, when present in a mixture. Modulation of hPXR activation and its target genes induction may represent a risk factor contributing to exacerbate the physiological response of the hPXR signaling pathways and to explain some adverse effects in humans. PMID:25028461

A statistical model of the human core-temperature circadian rhythm

NASA Technical Reports Server (NTRS)

Brown, E. N.; Choe, Y.; Luithardt, H.; Czeisler, C. A.

2000-01-01

We formulate a statistical model of the human core-temperature circadian rhythm in which the circadian signal is modeled as a van der Pol oscillator, the thermoregulatory response is represented as a first-order autoregressive process, and the evoked effect of activity is modeled with a function specific for each circadian protocol. The new model directly links differential equation-based simulation models and harmonic regression analysis methods and permits statistical analysis of both static and dynamical properties of the circadian pacemaker from experimental data. We estimate the model parameters by using numerically efficient maximum likelihood algorithms and analyze human core-temperature data from forced desynchrony, free-run, and constant-routine protocols. By representing explicitly the dynamical effects of ambient light input to the human circadian pacemaker, the new model can estimate with high precision the correct intrinsic period of this oscillator ( approximately 24 h) from both free-run and forced desynchrony studies. Although the van der Pol model approximates well the dynamical features of the circadian pacemaker, the optimal dynamical model of the human biological clock may have a harmonic structure different from that of the van der Pol oscillator.

Constrained Total Energy Expenditure and Metabolic Adaptation to Physical Activity in Adult Humans.

PubMed

Pontzer, Herman; Durazo-Arvizu, Ramon; Dugas, Lara R; Plange-Rhule, Jacob; Bovet, Pascal; Forrester, Terrence E; Lambert, Estelle V; Cooper, Richard S; Schoeller, Dale A; Luke, Amy

2016-02-08

Current obesity prevention strategies recommend increasing daily physical activity, assuming that increased activity will lead to corresponding increases in total energy expenditure and prevent or reverse energy imbalance and weight gain [1-3]. Such Additive total energy expenditure models are supported by exercise intervention and accelerometry studies reporting positive correlations between physical activity and total energy expenditure [4] but are challenged by ecological studies in humans and other species showing that more active populations do not have higher total energy expenditure [5-8]. Here we tested a Constrained total energy expenditure model, in which total energy expenditure increases with physical activity at low activity levels but plateaus at higher activity levels as the body adapts to maintain total energy expenditure within a narrow range. We compared total energy expenditure, measured using doubly labeled water, against physical activity, measured using accelerometry, for a large (n = 332) sample of adults living in five populations [9]. After adjusting for body size and composition, total energy expenditure was positively correlated with physical activity, but the relationship was markedly stronger over the lower range of physical activity. For subjects in the upper range of physical activity, total energy expenditure plateaued, supporting a Constrained total energy expenditure model. Body fat percentage and activity intensity appear to modulate the metabolic response to physical activity. Models of energy balance employed in public health [1-3] should be revised to better reflect the constrained nature of total energy expenditure and the complex effects of physical activity on metabolic physiology. Copyright © 2016 Elsevier Ltd. All rights reserved.

Early Whole Blood Transcriptional Signatures Are Associated with Severity of Lung Inflammation in Cynomolgus Macaques with Mycobacterium tuberculosis Infection.

PubMed

Gideon, Hannah P; Skinner, Jason A; Baldwin, Nicole; Flynn, JoAnne L; Lin, Philana Ling

2016-12-15

Whole blood transcriptional profiling offers great diagnostic and prognostic potential. Although studies identified signatures for pulmonary tuberculosis (TB) and transcripts that predict the risk for developing active TB in humans, the early transcriptional changes immediately following Mycobacterium tuberculosis infection have not been evaluated. We evaluated the gene expression changes in the cynomolgus macaque model of TB, which recapitulates all clinical aspects of human M. tuberculosis infection, using a human microarray and analytics platform. We performed genome-wide blood transcriptional analysis on 38 macaques at 11 postinfection time points during the first 6 mo of M. tuberculosis infection. Of 6371 differentially expressed transcripts between preinfection and postinfection, the greatest change in transcriptional activity occurred 20-56 d postinfection, during which fluctuation of innate and adaptive immune response-related transcripts was observed. Modest transcriptional differences between active TB and latent infection were observed over the time course with substantial overlap. The pattern of module activity previously published for human active TB was similar in macaques with active disease. Blood transcript activity was highly correlated with lung inflammation (lung [ 18 F]fluorodeoxyglucose [FDG] avidity) measured by positron emission tomography and computed tomography at early time points postinfection. The differential signatures between animals with high and low lung FDG were stronger than between clinical outcomes. Analysis of preinfection signatures of macaques revealed that IFN signatures could influence eventual clinical outcomes and lung FDG avidity, even before infection. Our data support that transcriptional changes in the macaque model are translatable to human M. tuberculosis infection and offer important insights into early events of M. tuberculosis infection. Copyright © 2016 by The American Association of Immunologists, Inc.

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.

Simulation-Based Design for Wearable Robotic Systems: An Optimization Framework for Enhancing a Standing Long Jump.

PubMed

Ong, Carmichael F; Hicks, Jennifer L; Delp, Scott L

2016-05-01

Technologies that augment human performance are the focus of intensive research and development, driven by advances in wearable robotic systems. Success has been limited by the challenge of understanding human-robot interaction. To address this challenge, we developed an optimization framework to synthesize a realistic human standing long jump and used the framework to explore how simulated wearable robotic devices might enhance jump performance. A planar, five-segment, seven-degree-of-freedom model with physiological torque actuators, which have variable torque capacity depending on joint position and velocity, was used to represent human musculoskeletal dynamics. An active augmentation device was modeled as a torque actuator that could apply a single pulse of up to 100 Nm of extension torque. A passive design was modeled as rotational springs about each lower limb joint. Dynamic optimization searched for physiological and device actuation patterns to maximize jump distance. Optimization of the nominal case yielded a 2.27 m jump that captured salient kinematic and kinetic features of human jumps. When the active device was added to the ankle, knee, or hip, jump distance increased to between 2.49 and 2.52 m. Active augmentation of all three joints increased the jump distance to 3.10 m. The passive design increased jump distance to 3.32 m by adding torques of 135, 365, and 297 Nm to the ankle, knee, and hip, respectively. Dynamic optimization can be used to simulate a standing long jump and investigate human-robot interaction. Simulation can aid in the design of performance-enhancing technologies.

Serum thymulin in human zinc deficiency.

PubMed Central

Prasad, A S; Meftah, S; Abdallah, J; Kaplan, J; Brewer, G J; Bach, J F; Dardenne, M

1988-01-01

The activity of thymulin (a thymic hormone) is dependent on the presence of zinc in the molecule. We assayed serum thymulin activity in three models of mildly zinc-deficient (ZD) human subjects before and after zinc supplementation: (a) two human volunteers in whom a specific and mild zinc deficiency was induced by dietary means; (b) six mildly ZD adult sickle cell anemia (SCA) subjects; and (c) six mildly ZD adult non-SCA subjects. Their plasma zinc levels were normal and they showed no overt clinical manifestations of zinc deficiency. The diagnosis of mild zinc deficiency was based on the assay of zinc in lymphocytes, granulocytes, and platelets. Serum thymulin activity was decreased as a result of mild zinc deficiency and was corrected by in vivo and in vitro zinc supplementation, suggesting that this parameter was a sensitive indicator of zinc deficiency in humans. An increase in T101-, sIg-cells, decrease in T4+/T8+ ratio, and decreased IL 2 activity were observed in the experimental human model during the zinc depletion phase, all of which were corrected after repletion with zinc. Similar changes in lymphocyte subpopulation, correctable with zinc supplementation, were also observed in mildly ZD SCA subjects. Inasmuch as thymulin is known to induce intra- and extrathymic T cell differentiation, our studies provide a possible mechanism for the role of zinc on T cell functions. Images PMID:3262625

Glioma Invasiveness Responds Variably to Irradiation in a Co-Culture Model

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

Nakamura, Jean L.; Haas-Kogan, Daphne A.; Department of Neurological Surgery, University of California-San Francisco, San Francisco, CA

2007-11-01

Purpose: We developed a co-culture system to quantitate the growth and invasion of human malignant gliomas into a background of confluent normal human astrocytes, then used this assay to assess independently the effects of irradiating both cell types on glioma invasion. Methods and Materials: Enhanced green fluorescent protein (EGFP)-labeled immortalized human astrocytes, human malignant glioma cells, or transformed human astrocytes were focally plated onto a confluent layer of normal human astrocytes, and the invasiveness of EGFP-labeled cells was scored after 96 h. To address the consequences of irradiation on glioma invasion, the invasiveness of irradiated glioma cell lines and irradiatedmore » astrocytic backgrounds was assessed. Fluorescence-activated cell sorting was used to quantitate the total number of EGFP-labeled cells. Results: Growth in the co-culture assay consistently reflected transformation states of the plated cells. Immortalized, but untransformed human astrocytes failed even to establish growth on confluent normal human astrocytes. In contrast, all malignant human glioma cell lines and transformed human astrocytes demonstrated various degrees of infiltration into the astrocytic bed. Irradiation failed to alter the invasiveness of U87, A172, and U373. A 1-Gy dose slightly reduced the invasiveness of U251 MG by 75% (p < 0.05 by one-way analysis of variance and post hoc Neuman-Keuls), without reducing total cell numbers. Independently irradiating the human astrocytic bed did not alter the invasiveness of nonirradiated U251, whereas the matrix metalloproteinase (MMP) inhibitor GM6001 reduced U251 invasiveness in the co-culture assay. Conclusions: Growth in the co-culture assay reflects the transformation status and provides a useful in vitro model for assessing invasiveness. Human glioma invasiveness in the co-culture model responds variably to single low-dose fractions. MMP activity promotes invasiveness in the co-culture model. Reduced invasiveness in irradiated U251 appears to be mediated by MMP-independent mechanisms.« less

Spatial heterogeneity in human activities favors the persistence of wolves in agroecosystems.

PubMed

Ahmadi, Mohsen; López-Bao, José Vicente; Kaboli, Mohammad

2014-01-01

As human populations expand, there is increasing demand and pressure for land. Under this scenario, behavioural flexibility and adaptation become important processes leading to the persistence of large carnivores in human-dominated landscapes such as agroecosystems. A growing interest has recently emerged on the outcome of the coexistence between wolves and humans in these systems. It has been suggested that spatial heterogeneity in human activities would be a major environmental factor modulating vulnerability and persistence of this contentious species in agroecosystems. Here, we combined information from 35 den sites detected between 2011 and 2012 in agroecosystems of western Iran (Hamedan province), a set of environmental variables measured at landscape and fine spatial scales, and generalized linear models to identify patterns of den site selection by wolves in a highly-modified agroecosystem. On a landscape level, wolves selected a mixture of rangelands with scattered dry-farms on hillsides (showing a low human use) to locate their dens, avoiding areas with high densities of settlements and primary roads. On a fine spatial scale, wolves primarily excavated dens into the sides of elevated steep-slope hills with availability of water bodies in the vicinity of den sites, and wolves were relegated to dig in places with coarse-soil particles. Our results suggest that vulnerability of wolves in human-dominated landscapes could be compensated by the existence of spatial heterogeneity in human activities. Such heterogeneity would favor wolf persistence in agroecosystems favoring a land sharing model of coexistence between wolves and people.

Spatial Heterogeneity in Human Activities Favors the Persistence of Wolves in Agroecosystems

PubMed Central

Ahmadi, Mohsen; López-Bao, José Vicente; Kaboli, Mohammad

2014-01-01

As human populations expand, there is increasing demand and pressure for land. Under this scenario, behavioural flexibility and adaptation become important processes leading to the persistence of large carnivores in human-dominated landscapes such as agroecosystems. A growing interest has recently emerged on the outcome of the coexistence between wolves and humans in these systems. It has been suggested that spatial heterogeneity in human activities would be a major environmental factor modulating vulnerability and persistence of this contentious species in agroecosystems. Here, we combined information from 35 den sites detected between 2011 and 2012 in agroecosystems of western Iran (Hamedan province), a set of environmental variables measured at landscape and fine spatial scales, and generalized linear models to identify patterns of den site selection by wolves in a highly-modified agroecosystem. On a landscape level, wolves selected a mixture of rangelands with scattered dry-farms on hillsides (showing a low human use) to locate their dens, avoiding areas with high densities of settlements and primary roads. On a fine spatial scale, wolves primarily excavated dens into the sides of elevated steep-slope hills with availability of water bodies in the vicinity of den sites, and wolves were relegated to dig in places with coarse-soil particles. Our results suggest that vulnerability of wolves in human-dominated landscapes could be compensated by the existence of spatial heterogeneity in human activities. Such heterogeneity would favor wolf persistence in agroecosystems favoring a land sharing model of coexistence between wolves and people. PMID:25251567

Active and reactive behaviour in human mobility: the influence of attraction points on pedestrians

NASA Astrophysics Data System (ADS)

Gutiérrez-Roig, M.; Sagarra, O.; Oltra, A.; Palmer, J. R. B.; Bartumeus, F.; Díaz-Guilera, A.; Perelló, J.

2016-07-01

Human mobility is becoming an accessible field of study, thanks to the progress and availability of tracking technologies as a common feature of smart phones. We describe an example of a scalable experiment exploiting these circumstances at a public, outdoor fair in Barcelona (Spain). Participants were tracked while wandering through an open space with activity stands attracting their attention. We develop a general modelling framework based on Langevin dynamics, which allows us to test the influence of two distinct types of ingredients on mobility: reactive or context-dependent factors, modelled by means of a force field generated by attraction points in a given spatial configuration and active or inherent factors, modelled from intrinsic movement patterns of the subjects. The additive and constructive framework model accounts for some observed features. Starting with the simplest model (purely random walkers) as a reference, we progressively introduce different ingredients such as persistence, memory and perceptual landscape, aiming to untangle active and reactive contributions and quantify their respective relevance. The proposed approach may help in anticipating the spatial distribution of citizens in alternative scenarios and in improving the design of public events based on a facts-based approach.

Active and reactive behaviour in human mobility: the influence of attraction points on pedestrians

PubMed Central

Sagarra, O.; Oltra, A.; Palmer, J. R. B.; Bartumeus, F.; Díaz-Guilera, A.; Perelló, J.

2016-01-01

Human mobility is becoming an accessible field of study, thanks to the progress and availability of tracking technologies as a common feature of smart phones. We describe an example of a scalable experiment exploiting these circumstances at a public, outdoor fair in Barcelona (Spain). Participants were tracked while wandering through an open space with activity stands attracting their attention. We develop a general modelling framework based on Langevin dynamics, which allows us to test the influence of two distinct types of ingredients on mobility: reactive or context-dependent factors, modelled by means of a force field generated by attraction points in a given spatial configuration and active or inherent factors, modelled from intrinsic movement patterns of the subjects. The additive and constructive framework model accounts for some observed features. Starting with the simplest model (purely random walkers) as a reference, we progressively introduce different ingredients such as persistence, memory and perceptual landscape, aiming to untangle active and reactive contributions and quantify their respective relevance. The proposed approach may help in anticipating the spatial distribution of citizens in alternative scenarios and in improving the design of public events based on a facts-based approach. PMID:27493774

Chitosan derivatives targeting lipid bilayers: Synthesis, biological activity and interaction with model membranes.

PubMed

Martins, Danubia Batista; Nasário, Fábio Domingues; Silva-Gonçalves, Laiz Costa; de Oliveira Tiera, Vera Aparecida; Arcisio-Miranda, Manoel; Tiera, Marcio José; Dos Santos Cabrera, Marcia Perez

2018-02-01

The antimicrobial activity of chitosan and derivatives to human and plant pathogens represents a high-valued prospective market. Presently, two low molecular weight derivatives, endowed with hydrophobic and cationic character at different ratios were synthesized and characterized. They exhibit antimicrobial activity and increased performance in relation to the intermediate and starting compounds. However, just the derivative with higher cationic character showed cytotoxicity towards human cervical carcinoma cells. Considering cell membranes as targets, the mode of action was investigated through the interaction with model lipid vesicles mimicking bacterial, tumoral and erythrocyte membranes. Intense lytic activity and binding are demonstrated for both derivatives in anionic bilayers. The less charged compound exhibits slightly improved selectivity towards bacterial model membranes, suggesting that balancing its hydrophobic/hydrophilic character may improve efficiency. Observing the aggregation of vesicles, we hypothesize that the "charge cluster mechanism", ascribed to some antimicrobial peptides, could be applied to these chitosan derivatives. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

Activation of peroxisome proliferator-activated receptor-{alpha} enhances fatty acid oxidation in human adipocytes

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

Lee, Joo-Young; Hashizaki, Hikari; Goto, Tsuyoshi

2011-04-22

Highlights: {yields} PPAR{alpha} activation increased mRNA expression levels of adipocyte differentiation marker genes and GPDH activity in human adipocytes. {yields} PPAR{alpha} activation also increased insulin-dependent glucose uptake in human adipocytes. {yields} PPAR{alpha} activation did not affect lipid accumulation in human adipocytes. {yields} PPAR{alpha} activation increased fatty acid oxidation through induction of fatty acid oxidation-related genes in human adipocytes. -- Abstract: Peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}) is a key regulator for maintaining whole-body energy balance. However, the physiological functions of PPAR{alpha} in adipocytes have been unclarified. We examined the functions of PPAR{alpha} using human multipotent adipose tissue-derived stem cells as a humanmore » adipocyte model. Activation of PPAR{alpha} by GW7647, a potent PPAR{alpha} agonist, increased the mRNA expression levels of adipocyte differentiation marker genes such as PPAR{gamma}, adipocyte-specific fatty acid-binding protein, and lipoprotein lipase and increased both GPDH activity and insulin-dependent glucose uptake level. The findings indicate that PPAR{alpha} activation stimulates adipocyte differentiation. However, lipid accumulation was not changed, which is usually observed when PPAR{gamma} is activated. On the other hand, PPAR{alpha} activation by GW7647 treatment induced the mRNA expression of fatty acid oxidation-related genes such as CPT-1B and AOX in a PPAR{alpha}-dependent manner. Moreover, PPAR{alpha} activation increased the production of CO{sub 2} and acid soluble metabolites, which are products of fatty acid oxidation, and increased oxygen consumption rate in human adipocytes. The data indicate that activation of PPAR{alpha} stimulates both adipocyte differentiation and fatty acid oxidation in human adipocytes, suggesting that PPAR{alpha} agonists could improve insulin resistance without lipid accumulation in adipocytes. The expected effects of PPAR{alpha} activation are very valuable for managing diabetic conditions accompanied by obesity, because PPAR{gamma} agonists, usually used as antidiabetic drugs, induce excessive lipid accumulation in adipocytes in addition to improvement of insulin resistance.« less

Integrating modelling and smart sensors for environmental and human health

PubMed Central

Reis, Stefan; Seto, Edmund; Northcross, Amanda; Quinn, Nigel W.T.; Convertino, Matteo; Jones, Rod L.; Maier, Holger R.; Schlink, Uwe; Steinle, Susanne; Vieno, Massimo; Wimberly, Michael C.

2015-01-01

Sensors are becoming ubiquitous in everyday life, generating data at an unprecedented rate and scale. However, models that assess impacts of human activities on environmental and human health, have typically been developed in contexts where data scarcity is the norm. Models are essential tools to understand processes, identify relationships, associations and causality, formalize stakeholder mental models, and to quantify the effects of prevention and interventions. They can help to explain data, as well as inform the deployment and location of sensors by identifying hotspots and areas of interest where data collection may achieve the best results. We identify a paradigm shift in how the integration of models and sensors can contribute to harnessing ‘Big Data’ and, more importantly, make the vital step from ‘Big Data’ to ‘Big Information’. In this paper, we illustrate current developments and identify key research needs using human and environmental health challenges as an example. PMID:26644778

Human strength simulations for one and two-handed tasks in zero gravity

NASA Technical Reports Server (NTRS)

1972-01-01

A description is given of a three dimensional hand force capability model for the seated operator and a biomechanical model for analysis of symmetric sagittal plane activities. The models are used to simulate and study human strengths for one and two handed tasks in zero gravity. Specific conditions considered include: (1) one hand active, (2) both hands active but with different force directions on each, (3) body bracing situations provided by portable foot restraint when standing and lap belt when seated, (4) static or slow movement tasks with maximum length of 4 seconds and a minimum rest of 5 minutes between exertions, and (5) wide range of hand positions relative to either the feet or bisection of a line connecting the hip centers. Simulations were also made for shirt sleeved individuals and for the male population strengths with anthropometry matching that of astronauts.

Efficient generation of functional CFTR-expressing airway epithelial cells from human pluripotent stem cells.

PubMed

Wong, Amy P; Chin, Stephanie; Xia, Sunny; Garner, Jodi; Bear, Christine E; Rossant, Janet

2015-03-01

Airway epithelial cells are of great interest for research on lung development, regeneration and disease modeling. This protocol describes how to generate cystic fibrosis (CF) transmembrane conductance regulator protein (CFTR)-expressing airway epithelial cells from human pluripotent stem cells (PSCs). The stepwise approach from PSC culture to differentiation into progenitors and then mature epithelia with apical CFTR activity is outlined. Human PSCs that were inefficient at endoderm differentiation using our previous lung differentiation protocol were able to generate substantial lung progenitor cell populations. Augmented CFTR activity can be observed in all cultures as early as at 35 d of differentiation, and full maturation of the cells in air-liquid interface cultures occurs in <5 weeks. This protocol can be used for drug discovery, tissue regeneration or disease modeling.

Drug and Vaccine evaluation in the Human Aotus Plasmodium falciparum Model

DTIC Science & Technology

2011-05-01

and phenyl ring systems is anticipated to yield a valuable new antimalarial drug (33). The antimalarial activity and pharmacology of a series of...remains essentially unchanged since 1976, viz. to ascertain the antimalarial activity of drugs against P. falciparum and P. vivax in Aotus. The...Present data on the evaluation of potential antimalarial activity of drugs in the pre-clinical model of Aotus l. lemurinus (Panamanian night

Advancing coupled human-earth system models: The integrated Earth System Model Project

NASA Astrophysics Data System (ADS)

Thomson, A. M.; Edmonds, J. A.; Collins, W.; Thornton, P. E.; Hurtt, G. C.; Janetos, A. C.; Jones, A.; Mao, J.; Chini, L. P.; Calvin, K. V.; Bond-Lamberty, B. P.; Shi, X.

2012-12-01

As human and biogeophysical models develop, opportunities for connections between them evolve and can be used to advance our understanding of human-earth systems interaction in the context of a changing climate. One such integration is taking place with the Community Earth System Model (CESM) and the Global Change Assessment Model (GCAM). A multi-disciplinary, multi-institution team has succeeded in integrating the GCAM integrated assessment model of human activity into CESM to dynamically represent the feedbacks between changing climate and human decision making, in the context of greenhouse gas mitigation policies. The first applications of this capability have focused on the feedbacks between climate change impacts on terrestrial ecosystem productivity and human decisions affecting future land use change, which are in turn connected to human decisions about energy systems and bioenergy production. These experiments have been conducted in the context of the RCP4.5 scenario, one of four pathways of future radiative forcing being used in CMIP5, which constrains future human-induced greenhouse gas emissions from energy and land activities to stabilize radiative forcing at 4.5 W/m2 (~650 ppm CO2 -eq) by 2100. When this pathway is run in GCAM with the climate feedback on terrestrial productivity from CESM, there are implications for both the land use and energy system changes required for stabilization. Early findings indicate that traditional definitions of radiative forcing used in scenario development are missing a critical component of the biogeophysical consequences of land use change and their contribution to effective radiative forcing. Initial full coupling of the two global models has important implications for how climate impacts on terrestrial ecosystems changes the dynamics of future land use change for agriculture and forestry, particularly in the context of a climate mitigation policy designed to reduce emissions from land use as well as energy systems. While these initial experiments have relied on offline coupling methodologies, current and future experiments are utilizing a single model code developed to integrate GCAM into CESM as a component of the land model. This unique capability facilitates many new applications to scientific questions arising from human and biogeophysical systems interaction. Future developments will further integrate the energy system decisions and greenhouse gas emissions as simulated in GCAM with the appropriate climate and land system components of CESM.

Molecular characterization of human ABHD2 as TAG lipase and ester hydrolase

PubMed Central

M., Naresh Kumar; V.B.S.C., Thunuguntla; G.K., Veeramachaneni; B., Chandra Sekhar; Guntupalli, Swapna; J.S., Bondili

2016-01-01

Alterations in lipid metabolism have been progressively documented as a characteristic property of cancer cells. Though, human ABHD2 gene was found to be highly expressed in breast and lung cancers, its biochemical functionality is yet uncharacterized. In the present study we report, human ABHD2 as triacylglycerol (TAG) lipase along with ester hydrolysing capacity. Sequence analysis of ABHD2 revealed the presence of conserved motifs G205XS207XG209 and H120XXXXD125. Phylogenetic analysis showed homology to known lipases, Drosophila melanogaster CG3488. To evaluate the biochemical role, recombinant ABHD2 was expressed in Saccharomyces cerevisiae using pYES2/CT vector and His-tag purified protein showed TAG lipase activity. Ester hydrolase activity was confirmed with pNP acetate, butyrate and palmitate substrates respectively. Further, the ABHD2 homology model was built and the modelled protein was analysed based on the RMSD and root mean square fluctuation (RMSF) of the 100 ns simulation trajectory. Docking the acetate, butyrate and palmitate ligands with the model confirmed covalent binding of ligands with the Ser207 of the GXSXG motif. The model was validated with a mutant ABHD2 developed with alanine in place of Ser207 and the docking studies revealed loss of interaction between selected ligands and the mutant protein active site. Based on the above results, human ABHD2 was identified as a novel TAG lipase and ester hydrolase. PMID:27247428

Cancer Chemoprevention with Korean Angelica: Active Compounds, Pharmacokinetics, and Human Translational Considerations

PubMed Central

Lü, Junxuan; Zhang, Jinhui; Li, Li; Jiang, Cheng; Xing, Chengguo

2015-01-01

Angelica gigas Nakai (AGN) is a major medicinal herb used in Korea and several other Asian countries. Traditionally, its dried root has been used to treat anemia, pain, infection and articular rheumatism, most often through boiling in water to prepare the dosage forms. AGN extract or AGN-containing herbal mixtures are sold in the US and globally as dietary supplements for pain killing, memory enhancement and post-menopausal symptom relief. Decursin (D) and its isomer decursinol angelate (DA) are the major chemicals in the alcoholic extracts of the root of AGN. The anti-cancer activity of AGN alcoholic extract has been established in a number of animal cancer models, including a transgenic model of prostate carcinogenesis. Cell culture structure-activity studies have uncovered distinct cellular and molecular effects of D and DA vs. their pyranocoumarin core decursinol (DOH) with respect to cancer cells and those associated with their microenvironment. Pharmacokinetic (PK) study by us and others in rodent models indicated that DOH is the major and rapid in vivo first-pass liver metabolite of D and DA. Cognizant of metabolic differences among rodents and humans, we carried out a first-in-human PK study of D/DA to inform the translational relevance of efficacy and mechanism studies with rodent models. The combined use of vigorous animal tests and human PK studies can provide stronger scientific rationale to inform design and execution of translational studies to move AGN toward evidence-based herbal medicine. PMID:26623248

Molecular characterization of human ABHD2 as TAG lipase and ester hydrolase.

PubMed

M, Naresh Kumar; V B S C, Thunuguntla; G K, Veeramachaneni; B, Chandra Sekhar; Guntupalli, Swapna; J S, Bondili

2016-08-01

Alterations in lipid metabolism have been progressively documented as a characteristic property of cancer cells. Though, human ABHD2 gene was found to be highly expressed in breast and lung cancers, its biochemical functionality is yet uncharacterized. In the present study we report, human ABHD2 as triacylglycerol (TAG) lipase along with ester hydrolysing capacity. Sequence analysis of ABHD2 revealed the presence of conserved motifs G(205)XS(207)XG(209) and H(120)XXXXD(125) Phylogenetic analysis showed homology to known lipases, Drosophila melanogaster CG3488. To evaluate the biochemical role, recombinant ABHD2 was expressed in Saccharomyces cerevisiae using pYES2/CT vector and His-tag purified protein showed TAG lipase activity. Ester hydrolase activity was confirmed with pNP acetate, butyrate and palmitate substrates respectively. Further, the ABHD2 homology model was built and the modelled protein was analysed based on the RMSD and root mean square fluctuation (RMSF) of the 100 ns simulation trajectory. Docking the acetate, butyrate and palmitate ligands with the model confirmed covalent binding of ligands with the Ser(207) of the GXSXG motif. The model was validated with a mutant ABHD2 developed with alanine in place of Ser(207) and the docking studies revealed loss of interaction between selected ligands and the mutant protein active site. Based on the above results, human ABHD2 was identified as a novel TAG lipase and ester hydrolase. © 2016 The Author(s).

Cancer Chemoprevention with Korean Angelica: Active Compounds, Pharmacokinetics, and Human Translational Considerations.

PubMed

Lü, Junxuan; Zhang, Jinhui; Li, Li; Jiang, Cheng; Xing, Chengguo

2015-12-01

Angelica gigas Nakai (AGN) is a major medicinal herb used in Korea and several other Asian countries. Traditionally, its dried root has been used to treat anemia, pain, infection and articular rheumatism, most often through boiling in water to prepare the dosage forms. AGN extract or AGN-containing herbal mixtures are sold in the US and globally as dietary supplements for pain killing, memory enhancement and post-menopausal symptom relief. Decursin (D) and its isomer decursinol angelate (DA) are the major chemicals in the alcoholic extracts of the root of AGN. The anti-cancer activity of AGN alcoholic extract has been established in a number of animal cancer models, including a transgenic model of prostate carcinogenesis. Cell culture structure-activity studies have uncovered distinct cellular and molecular effects of D and DA vs. their pyranocoumarin core decursinol (DOH) with respect to cancer cells and those associated with their microenvironment. Pharmacokinetic (PK) study by us and others in rodent models indicated that DOH is the major and rapid in vivo first-pass liver metabolite of D and DA. Cognizant of metabolic differences among rodents and humans, we carried out a first-in-human PK study of D/DA to inform the translational relevance of efficacy and mechanism studies with rodent models. The combined use of vigorous animal tests and human PK studies can provide stronger scientific rationale to inform design and execution of translational studies to move AGN toward evidence-based herbal medicine.

On the origin of bursts and heavy tails in animal dynamics

NASA Astrophysics Data System (ADS)

Reynolds, A. M.

2011-01-01

Over recent years there has been an accumulation of evidence that many animal behaviours are characterised by common scale-invariant patterns of switching between two contrasting activities over a period of time. This is evidenced in mammalian wake-sleep patterns, in the intermittent stop-start locomotion of Drosophila fruit flies, and in the Lévy walk movement patterns of a diverse range of animals in which straight-line movements are punctuated by occasional turns. Here it is shown that these dynamics can be modelled by a stochastic variant of Barabási’s model [A.-L. Barabási, The origin of bursts and heavy tails in human dynamics, Nature 435 (2005) 207-211] for bursts and heavy tails in human dynamics. The new model captures a tension between two competing and conflicting activities. The durations of one type of activity are distributed according to an inverse-square power-law, mirroring the ubiquity of inverse-square power-law scaling seen in empirical data. The durations of the second type of activity follow exponential distributions with characteristic timescales that depend on species and metabolic rates. This again is a common feature of animal behaviour. Bursty human dynamics, on the other hand, are characterised by power-law distributions with scaling exponents close to -1 and -3/2.

Modeling the Impacts of Hydromodification (Conference paper)

EPA Science Inventory

Hydromodification is caused by anthropogenic activities driven by human population growth and resource consumption that alter watershed hydrologic responses. These activities include urbanization, channel modification, flow regulation by water impoundments, water withdrawal, and...

TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules.

PubMed

Liu, Qian; Sun, Jessica D; Wang, Jingli; Ahluwalia, Dharmendra; Baker, Amanda F; Cranmer, Lee D; Ferraro, Damien; Wang, Yan; Duan, Jian-Xin; Ammons, W Steve; Curd, John G; Matteucci, Mark D; Hart, Charles P

2012-06-01

Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity, different dosing sequences, and dosing regimens of TH-302 in combination with commonly used conventional chemotherapeutics were investigated in human tumor xenograft models. Seven chemotherapeutic drugs (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide) were tested in combination with TH-302 in eleven human xenograft models, including non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, fibrosarcoma, melanoma, and pancreatic cancer. The antitumor activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested. Administration of TH-302 2-8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity. TH-302 enhances the activity of a wide range of conventional anti-neoplastic agents in a broad panel of in vivo xenograft models. These data highlight in vivo effects of schedule and order of drug administration in regimen efficacy and toxicity and have relevance to the design of human regimens incorporating TH-302.

TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules

PubMed Central

Liu, Qian; Sun, Jessica D.; Wang, Jingli; Ahluwalia, Dharmendra; Baker, Amanda F.; Cranmer, Lee D.; Ferraro, Damien; Wang, Yan; Duan, Jian-Xin; Ammons, W. Steve; Curd, John G.; Matteucci, Mark D.

2014-01-01

Purpose Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity, different dosing sequences, and dosing regimens of TH-302 in combination with commonly used conventional chemotherapeutics were investigated in human tumor xenograft models. Methods Seven chemotherapeutic drugs (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide) were tested in combination with TH-302 in eleven human xenograft models, including non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, fibrosarcoma, melanoma, and pancreatic cancer. Results The antitumor activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested. Administration of TH-302 2–8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity. Conclusions TH-302 enhances the activity of a wide range of conventional anti-neoplastic agents in a broad panel of in vivo xenograft models. These data highlight in vivo effects of schedule and order of drug administration in regimen efficacy and toxicity and have relevance to the design of human regimens incorporating TH-302. PMID:22382881

Structure activity relationship modelling of milk protein-derived peptides with dipeptidyl peptidase IV (DPP-IV) inhibitory activity.

PubMed

Nongonierma, Alice B; FitzGerald, Richard J

2016-05-01

Quantitative structure activity type models were developed in an attempt to predict the key features of peptide sequences having dipeptidyl peptidase IV (DPP-IV) inhibitory activity. The models were then employed to help predict the potential of peptides, which are currently reported in the literature to be present in the intestinal tract of humans following milk/dairy product ingestion, to act as inhibitors of DPP-IV. Two models (z- and v-scale) for short (2-5 amino acid residues) bovine milk peptides, behaving as competitive inhibitors of DPP-IV, were developed. The z- and the v-scale models (p<0.05, R(2) of 0.829 and 0.815, respectively) were then applied to 56 milk protein-derived peptides previously reported in the literature to be found in the intestinal tract of humans which possessed a structural feature of DPP-IV inhibitory peptides (P at the N2 position). Ten of these peptides were synthetized and tested for their in vitro DPP-IV inhibitory properties. There was no agreement between the predicted and experimentally determined DPP-IV half maximal inhibitory concentrations (IC50) for the competitive peptide inhibitors. However, the ranking for DPP-IV inhibitory potency of the competitive peptide inhibitors was conserved. Furthermore, potent in vitro DPP-IV inhibitory activity was observed with two peptides, LPVPQ (IC50=43.8±8.8μM) and IPM (IC50=69.5±8.7μM). Peptides present within the gastrointestinal tract of human may have promise for the development of natural DPP-IV inhibitors for the management of serum glucose. Copyright © 2016 Elsevier Inc. All rights reserved.

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

Yang, Chung S., E-mail: csyang@rci.rutgers.edu; Lambert, Joshua D.; Ju Jihyeung

Tea made from the leaves of the plant Camellia sinensis is a popular beverage. The possible cancer-preventive activity of tea and tea polyphenols has been studied extensively. This article briefly reviews studies in animal models, cell lines, and possible relevance of these studies to the prevention of human cancer. The cancer-preventive activity of tea constituents have been demonstrated in many animal models including cancer of the skin, lung, oral cavity, esophagus, stomach, liver, pancreas, small intestine, colon, bladder, prostate, and mammary gland. The major active constituents are polyphenols, of which (-)-epigallocatechin-3-gallate (EGCG) is most abundant, most active, and most studied,more » and caffeine. The molecular mechanisms of the cancer-preventive action, however, are just beginning to be understood. Studies in cell lines led to the proposal of many mechanisms on the action of EGCG. However, mechanisms based on studies with very high concentrations of EGCG may not be relevant to cancer prevention in vivo. The autooxidation of EGCG in cell culture may also produce activities that do not occur in many internal organs. In contrast to the cancer prevention activity demonstrated in different animal models, no such conclusion can be convincingly drawn from epidemiological studies on tea consumption and human cancers. Even though the human data are inconclusive, tea constituents may still be used for the prevention of cancer at selected organ sites if sufficient concentrations of the agent can be delivered to these organs. Some interesting examples in this area are discussed.« less

Dual-loop model of the human controller

NASA Technical Reports Server (NTRS)

Hess, R. A.

1978-01-01

A dual-loop model of the human controller in single-axis compensatory tracking tasks is introduced. This model possesses an inner-loop closure that involves feeding back that portion of controlled element output rate that is due to control activity. A novel feature of the model is the explicit appearance of the human's internal representation of the manipulator-controlled element dynamics in the inner loop. The sensor inputs to the human controller are assumed to be system error and control force. The former can be sensed via visual, aural, or tactile displays, whereas the latter is assumed to be sensed in kinesthetic fashion. A set of general adaptive characteristics for the model is hypothesized, including a method for selecting simplified internal models of the manipulator-controlled element dynamics. It is demonstrated that the model can produce controller describing functions that closely approximate those measured in four laboratory tracking tasks in which the controlled element dynamics vary considerably in terms of ease of control. An empirically derived expression for the normalized injected error remnant spectrum is introduced.

The latest animal models of ovarian cancer for novel drug discovery.

PubMed

Magnotti, Elizabeth; Marasco, Wayne A

2018-03-01

Epithelial ovarian cancer is a heterogeneous disease classified into five subtypes, each with a different molecular profile. Most cases of ovarian cancer are diagnosed after metastasis of the primary tumor and are resistant to traditional platinum-based chemotherapeutics. Mouse models of ovarian cancer have been utilized to discern ovarian cancer tumorigenesis and the tumor's response to therapeutics. Areas covered: The authors provide a review of mouse models currently employed to understand ovarian cancer. This article focuses on advances in the development of orthotopic and patient-derived tumor xenograft (PDX) mouse models of ovarian cancer and discusses current humanized mouse models of ovarian cancer. Expert opinion: The authors suggest that humanized mouse models of ovarian cancer will provide new insight into the role of the human immune system in combating and augmenting ovarian cancer and aid in the development of novel therapeutics. Development of humanized mouse models will take advantage of the NSG and NSG-SGM3 strains of mice as well as new strains that are actively being derived.

Recent trends in digital human modeling and the concurrent issues that face human modeling approach

NASA Technical Reports Server (NTRS)

Rajulu, Sudhakar; Gonzalez, L. Javier; Margerum, Sarah; Clowers, Kurt; Moreny, Richard; Abercomby, Andrew; Velasquez, Luis

2006-01-01

Tremendous strides have been made in the recent years to digitally represent human beings in computer simulation models ranging from assembly plant maintenance operations to occupants getting in and out of vehicles to action movie scenarios. While some of these tools are being actively pursued by the engineering communities, there is still a lot of work that remains to be done for the newly planned planetary exploration missions. For example, certain unique and several common challenges are seen in developing computer generated suited human models for designing the next generation space vehicle. The purpose of this presentation is to discuss NASA s potential needs for better human models and to show also many of the inherent yet not too obvious pitfalls that still are left unresolved in this new arena of digital human modeling. As part of NASA s Habitability and Human Factors Branch, the Anthropometry and Biomechanics Facility has been engaged in studying the various facets of computer generated human physical performance models; for instance, it has been engaged in utilizing three-dimensional laser scan data along with three dimensional video based motion and reach data to gather suited anthropometric and shape and size information that are not available yet in the form of computer mannequins. Our goal is to bring in new approaches to deal with heavily clothed humans (such as, suited astronauts) and to overcome the current limitations of wrongly identifying humans (either real or virtual) as univariate percentiles. We are looking at whole-body posture based anthropometric models as a means to identify humans of significantly different shapes and sizes to arrive at mathematically sound computer models for analytical purposes.

Integrin activation controls metastasis in human breast cancer

NASA Astrophysics Data System (ADS)

Felding-Habermann, Brunhilde; O'Toole, Timothy E.; Smith, Jeffrey W.; Fransvea, Emilia; Ruggeri, Zaverio M.; Ginsberg, Mark H.; Hughes, Paul E.; Pampori, Nisar; Shattil, Sanford J.; Saven, Alan; Mueller, Barbara M.

2001-02-01

Metastasis is the primary cause of death in human breast cancer. Metastasis to bone, lungs, liver, and brain involves dissemination of breast cancer cells via the bloodstream and requires adhesion within the vasculature. Blood cell adhesion within the vasculature depends on integrins, a family of transmembrane adhesion receptors, and is regulated by integrin activation. Here we show that integrin v3 supports breast cancer cell attachment under blood flow conditions in an activation-dependent manner. Integrin v3 was found in two distinct functional states in human breast cancer cells. The activated, but not the nonactivated, state supported tumor cell arrest during blood flow through interaction with platelets. Importantly, activated αvβ3 was expressed by freshly isolated metastatic human breast cancer cells and variants of the MDA-MB 435 human breast cancer cell line, derived from mammary fat pad tumors or distant metastases in severe combined immunodeficient mice. Expression of constitutively activated mutant αvβ3D723R, but not αvβ3WT, in MDA-MB 435 cells strongly promoted metastasis in the mouse model. Thus breast cancer cells can exhibit a platelet-interactive and metastatic phenotype that is controlled by the activation of integrin αvβ3. Consequently, alterations within tumors that lead to the aberrant control of integrin activation are expected to adversely affect the course of human breast cancer.

Transfer Learning for Improved Audio-Based Human Activity Recognition.

PubMed

Ntalampiras, Stavros; Potamitis, Ilyas

2018-06-25

Human activities are accompanied by characteristic sound events, the processing of which might provide valuable information for automated human activity recognition. This paper presents a novel approach addressing the case where one or more human activities are associated with limited audio data, resulting in a potentially highly imbalanced dataset. Data augmentation is based on transfer learning; more specifically, the proposed method: (a) identifies the classes which are statistically close to the ones associated with limited data; (b) learns a multiple input, multiple output transformation; and (c) transforms the data of the closest classes so that it can be used for modeling the ones associated with limited data. Furthermore, the proposed framework includes a feature set extracted out of signal representations of diverse domains, i.e., temporal, spectral, and wavelet. Extensive experiments demonstrate the relevance of the proposed data augmentation approach under a variety of generative recognition schemes.

Some indazoles reduced the activity of human serum paraoxonase 1, an antioxidant enzyme: in vitro inhibition and molecular modeling studies.

PubMed

Alım, Zuhal; Kılıç, Deryanur; Demir, Yeliz

2018-05-09

Paraoxonase 1 (PON1: EC 3.1.8.1) is a vital antioxidant enzyme against mainly atherosclerosis and many other diseases associated with oxidative stress. Thus, studies related to PON1 have an important place in the pharmacology. In this study, we aimed to evaluate the in vitro inhibition effects of some indazoles on the activity of human PON1. PON1 was purified from human serum with a specific activity of 5000 U/mg and 13.50% yield by using simple chromatographic methods. The indazoles showed K i values in a range of 26.0 ± 3.00-111 ± 31.0 μM against hPON1. All these indazoles exhibited competitive inhibition. In addition, molecular docking studies were performed in order to assess the probable binding mechanisms into the active site of hPON1. Molecular modeling studies confirmed our results. Inhibition of PON1 by indazoles supplies a verification to further consideration of limitation dosage of indazole molecule groups as drug.

ARO/ARL Site Visit Project Review Presentation

DTIC Science & Technology

2012-07-01

hemodynamic activity. 7/11/2012 Challenges 10 complicated equipment gradient artifact BCG artifact How to combine the data? bias field auditory...noise 7/11/2012 11 A B C + + – – Our Solutions EEG+ BCG BCG 7/11/2012 12 (Goldman et al., Neuroimage 2009) Observing latent...Discrimination Results model human subjects Neurometric curve NOT optimized to match psychometric curve! human subjects model ( matrix word

Web-ware bioinformatical analysis and structure modelling of N-terminus of human multisynthetase complex auxiliary component protein p43.

PubMed

Deineko, Viktor

2006-01-01

Human multisynthetase complex auxiliary component, protein p43 is an endothelial monocyte-activating polypeptide II precursor. In this study, comprehensive sequence analysis of N-terminus has been performed to identify structural domains, motifs, sites of post-translation modification and other functionally important parameters. The spatial structure model of full-chain protein p43 is obtained.

Human Factors in the Design and Evaluation of Air Traffic Control Systems

DTIC Science & Technology

1995-04-01

the controller must filter through and decipher. Fortunately, some of this is done without the need for conscious attention ; fcr example, a clear...components of an information-processing model ? ...................... 166 5.3 ATTENTION ......................................... 172 0 5.3.1 What is...processing? support of our performance of daily activities, including our (,) job tasks. Two models of attention currently in use assume that human infor

Translational Animal Models of Atopic Dermatitis for Preclinical Studies



PubMed Central

Martel, Britta C.; Lovato, Paola; Bäumer, Wolfgang; Olivry, Thierry

2017-01-01

There is a medical need to develop new treatments for patients suffering from atopic dermatitis (AD). To improve the discovery and testing of novel treatments, relevant animal models for AD are needed. Generally, these animal models mimic different aspects of the pathophysiology of human AD, such as skin barrier defects and Th2 immune bias with additional Th1 and Th22, and in some populations Th17, activation. However, the pathomechanistic characterization and pharmacological validation of these animal models are generally incomplete. In this paper, we review animal models of AD in the context of preclinical use and their possible translation to the human disease. Most of these models use mice, but we will also critically evaluate dog models of AD, as increasing information on disease mechanism show their likely relevance for the human disease. PMID:28955179

Optimal estimator model for human spatial orientation

NASA Technical Reports Server (NTRS)

Borah, J.; Young, L. R.; Curry, R. E.

1979-01-01

A model is being developed to predict pilot dynamic spatial orientation in response to multisensory stimuli. Motion stimuli are first processed by dynamic models of the visual, vestibular, tactile, and proprioceptive sensors. Central nervous system function is then modeled as a steady-state Kalman filter which blends information from the various sensors to form an estimate of spatial orientation. Where necessary, this linear central estimator has been augmented with nonlinear elements to reflect more accurately some highly nonlinear human response characteristics. Computer implementation of the model has shown agreement with several important qualitative characteristics of human spatial orientation, and it is felt that with further modification and additional experimental data the model can be improved and extended. Possible means are described for extending the model to better represent the active pilot with varying skill and work load levels.

[Acetyl-11-keto-beta-boswellic acid and arsenic trioxide regulate the productions and activities of matrix metalloproteinases in human skin fibroblasts and human leukemia cell line THP-1].

PubMed

Liang, Ya-hui; Li, Ping; Zhao, Jing-xia; Liu, Xin; Huang, Qi-fu

2010-11-01

In order to reveal the treatment mechanism of Chinese medicine with the effect of activating blood and resolving putridity, we selected acetyl-11-keto-beta-boswellic acid (AKBA) and arsenic trioxide (ATO), the main monomeric components of frankincense and arsenolite which are two most commonly used Chinese medicine with effect of activating blood and resolving putridity. We combined AKBA and ATO as a compound, and explored its regulatory role in productions and activities of matrix metalloproteinase (MMP)-1, MMP-2 and MMP-9 in human skin fibroblasts (HSFbs) and human acute monocytic leukemia cell line THP-1 in inflammatory state. In order to simulate the inflammatory micro-environment of chronic wounds, we established 3 cell models: HSFb model activated by tumor necrosis factor-alpha (TNF-α), THP-1 cell model activated by phorbol-12-myristate-13-acetate (PMA) and HSFb-THP-1 cell coculture system. AKBA and ATO were cocultured with these cell models. Enzyme-linked immunosorbent assay (ELISA), gelatin zymography assay and reverse transcription-polymerase chain reaction (RT-PCR) were used to test the secretions, activities and mRNA expressions of MMP-1, MMP-2 and MMP-9. In the study of the regulatory mechanism of AKBA and ATO on MMPs, AKBA and ATO were cocultured with the cell models. ELISA was used to test the secretions of TNF-α and interleukin-1beta (IL-β) and Western blot was used to test the phosphorylation levels of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38 mitogen-activated proteinkinase (p38MAPK). Compound of AKBA and ATO inhibited MMP-1, MMP-2 and MMP-9 mRNA expressions, secretions and activities respectively in HSFbs and THP-1 cells in inflammatory state (P<0.05, P<0.01). Also compound of AKBA and ATO inhibited secretions of TNF-α and IL-1β in THP-1 cells and cell coculture system (P<0.01). It also decreased the phosphorylation of ERK1/2 and p38 MAPK in HSFbs and THP-1 cells (P<0.05, P<0.01). The combined use of AKBA and ATO which in line with the rule of activating blood and resolving putridity inhibits fibroblasts and inflammatory cells in producing MMPs in inflammatory state through inhibiting the release of inflammatory factors and MAPK cascade pathway.

Simulating Activities: Relating Motives, Deliberation and Attentive Coordination

NASA Technical Reports Server (NTRS)

Clancey, William J.; Clancy, Daniel (Technical Monitor)

2002-01-01

Activities are located behaviors, taking time, conceived as socially meaningful, and usually involving interaction with tools and the environment. In modeling human cognition as a form of problem solving (goal-directed search and operator sequencing), cognitive science researchers have not adequately studied "off-task" activities (e.g., waiting), non-intellectual motives (e.g., hunger), sustaining a goal state (e.g., playful interaction), and coupled perceptual-motor dynamics (e.g., following someone). These aspects of human behavior have been considered in bits and pieces in past research, identified as scripts, human factors, behavior settings, ensemble, flow experience, and situated action. More broadly, activity theory provides a comprehensive framework relating motives, goals, and operations. This paper ties these ideas together, using examples from work life in a Canadian High Arctic research station. The emphasis is on simulating human behavior as it naturally occurs, such that "working" is understood as an aspect of living. The result is a synthesis of previously unrelated analytic perspectives and a broader appreciation of the nature of human cognition. Simulating activities in this comprehensive way is useful for understanding work practice, promoting learning, and designing better tools, including human-robot systems.

Deep Recurrent Neural Networks for Human Activity Recognition

PubMed Central

Murad, Abdulmajid

2017-01-01

Adopting deep learning methods for human activity recognition has been effective in extracting discriminative features from raw input sequences acquired from body-worn sensors. Although human movements are encoded in a sequence of successive samples in time, typical machine learning methods perform recognition tasks without exploiting the temporal correlations between input data samples. Convolutional neural networks (CNNs) address this issue by using convolutions across a one-dimensional temporal sequence to capture dependencies among input data. However, the size of convolutional kernels restricts the captured range of dependencies between data samples. As a result, typical models are unadaptable to a wide range of activity-recognition configurations and require fixed-length input windows. In this paper, we propose the use of deep recurrent neural networks (DRNNs) for building recognition models that are capable of capturing long-range dependencies in variable-length input sequences. We present unidirectional, bidirectional, and cascaded architectures based on long short-term memory (LSTM) DRNNs and evaluate their effectiveness on miscellaneous benchmark datasets. Experimental results show that our proposed models outperform methods employing conventional machine learning, such as support vector machine (SVM) and k-nearest neighbors (KNN). Additionally, the proposed models yield better performance than other deep learning techniques, such as deep believe networks (DBNs) and CNNs. PMID:29113103

Deep Recurrent Neural Networks for Human Activity Recognition.

PubMed

Murad, Abdulmajid; Pyun, Jae-Young

2017-11-06

Adopting deep learning methods for human activity recognition has been effective in extracting discriminative features from raw input sequences acquired from body-worn sensors. Although human movements are encoded in a sequence of successive samples in time, typical machine learning methods perform recognition tasks without exploiting the temporal correlations between input data samples. Convolutional neural networks (CNNs) address this issue by using convolutions across a one-dimensional temporal sequence to capture dependencies among input data. However, the size of convolutional kernels restricts the captured range of dependencies between data samples. As a result, typical models are unadaptable to a wide range of activity-recognition configurations and require fixed-length input windows. In this paper, we propose the use of deep recurrent neural networks (DRNNs) for building recognition models that are capable of capturing long-range dependencies in variable-length input sequences. We present unidirectional, bidirectional, and cascaded architectures based on long short-term memory (LSTM) DRNNs and evaluate their effectiveness on miscellaneous benchmark datasets. Experimental results show that our proposed models outperform methods employing conventional machine learning, such as support vector machine (SVM) and k-nearest neighbors (KNN). Additionally, the proposed models yield better performance than other deep learning techniques, such as deep believe networks (DBNs) and CNNs.

Combining High-Speed Cameras and Stop-Motion Animation Software to Support Students' Modeling of Human Body Movement

NASA Astrophysics Data System (ADS)

Lee, Victor R.

2015-04-01

Biomechanics, and specifically the biomechanics associated with human movement, is a potentially rich backdrop against which educators can design innovative science teaching and learning activities. Moreover, the use of technologies associated with biomechanics research, such as high-speed cameras that can produce high-quality slow-motion video, can be deployed in such a way to support students' participation in practices of scientific modeling. As participants in classroom design experiment, fifteen fifth-grade students worked with high-speed cameras and stop-motion animation software (SAM Animation) over several days to produce dynamic models of motion and body movement. The designed series of learning activities involved iterative cycles of animation creation and critique and use of various depictive materials. Subsequent analysis of flipbooks of human jumping movements created by the students at the beginning and end of the unit revealed a significant improvement in both the epistemic fidelity of students' representations. Excerpts from classroom observations highlight the role that the teacher plays in supporting students' thoughtful reflection of and attention to slow-motion video. In total, this design and research intervention demonstrates that the combination of technologies, activities, and teacher support can lead to improvements in some of the foundations associated with students' modeling.

Multiview human activity recognition system based on spatiotemporal template for video surveillance system

NASA Astrophysics Data System (ADS)

Kushwaha, Alok Kumar Singh; Srivastava, Rajeev

2015-09-01

An efficient view invariant framework for the recognition of human activities from an input video sequence is presented. The proposed framework is composed of three consecutive modules: (i) detect and locate people by background subtraction, (ii) view invariant spatiotemporal template creation for different activities, (iii) and finally, template matching is performed for view invariant activity recognition. The foreground objects present in a scene are extracted using change detection and background modeling. The view invariant templates are constructed using the motion history images and object shape information for different human activities in a video sequence. For matching the spatiotemporal templates for various activities, the moment invariants and Mahalanobis distance are used. The proposed approach is tested successfully on our own viewpoint dataset, KTH action recognition dataset, i3DPost multiview dataset, MSR viewpoint action dataset, VideoWeb multiview dataset, and WVU multiview human action recognition dataset. From the experimental results and analysis over the chosen datasets, it is observed that the proposed framework is robust, flexible, and efficient with respect to multiple views activity recognition, scale, and phase variations.

Intensification of hydrological drought due to human activity in the middle reaches of the Yangtze River, China.

PubMed

Zhang, Dan; Zhang, Qi; Qiu, Jiaming; Bai, Peng; Liang, Kang; Li, Xianghu

2018-10-01

Hydrological extremes are changing under the impacts of environmental change, i.e., climate variation and human activity, which can substantially influence ecosystems and the living environment of humans in affected region. This study investigates the impacts of environmental change on hydrological drought in the middle reaches of the Yangtze River in China based on hydrological modelling. Change points for streamflow into two major lakes and a reservoir in the study area were detected in the late 1980s using the Mann-Kendall test. Streamflow simulation by a water balance model was performed, and the resulting Kling-Gupta efficiency value was >0.90. Hydrological drought events were identified based on the simulated streamflow under different scenarios. The results show that the hydrological drought occurrence was increased by precipitation, whereas the drought peak value was increased by potential evapotranspiration. The impacts of precipitation and potential evapotranspiration on drought severity and duration varied in the study area. However, hydrological drought was intensified by the influence of human activity, which increased the severity, duration and peak value of droughts. The dominant factor for hydrological drought severity is precipitation, followed by potential evapotranspiration and human activity. The impacts of climate variation and human activity on drought severity are larger than on drought duration. In addition, environmental change is shown to have an "accumulation effect" on hydrological drought, demonstrating that the indirect impacts of environmental change on hydrological drought are much larger than the direct impacts on streamflow. This study improves our understanding of the responses of hydrological extremes to environmental change, which is useful for the management of water resources and the prediction of hydrological disasters. Copyright © 2018 Elsevier B.V. All rights reserved.

Antagonizing Effects and Mechanisms of Afzelin against UVB-Induced Cell Damage

PubMed Central

Shin, Seoung Woo; Jung, Eunsun; Kim, Seungbeom; Kim, Jang-Hyun; Kim, Eui-Gyun; Lee, Jongsung; Park, Deokhoon

2013-01-01

Ultraviolet (UV) radiation induces DNA damage, oxidative stress, and inflammatory processes in human keratinocytes, resulting in skin inflammation, photoaging, and photocarcinogenesis. Adequate protection of skin against the harmful effects of UV irradiation is essential. Therefore, in this study, we investigated the protective effects of afzelin, one of the flavonoids, against UV irradiation in human keratinocytes and epidermal equivalent models. Spectrophotometric measurements revealed that the afzelin extinction maxima were in the UVB and UVA range, and UV transmission below 376 nm was <10%, indicating UV-absorbing activity of afzelin. In the phototoxicity assay using the 3T3 NRU phototoxicity test (3T3-NRU-PT), afzelin presented a tendency to no phototoxic potential. In addition, in order to investigate cellular functions of afzelin itself, cells were treated with afzelin after UVB irradiation. In human keratinocyte, afzelin effectively inhibited the UVB-mediated increase in lipid peroxidation and the formation of cyclobutane pyrimidine dimers. Afzelin also inhibited UVB-induced cell death in human keratinocytes by inhibiting intrinsic apoptotic signaling. Furthermore, afzelin showed inhibitory effects on UVB-induced release of pro-inflammatory mediators such as interleukin-6, tumor necrosis factor-α, and prostaglandin-E2 in human keratinocytes by interfering with the p38 kinase pathway. Using an epidermal equivalent model exposed to UVB radiation, anti-apoptotic activity of afzelin was also confirmed together with a photoprotective effect at the morphological level. Taken together, our results suggest that afzelin has several cellular activities such as DNA-protective, antioxidant, and anti-inflammatory as well as UV-absorbing activity and may protect human skin from UVB-induced damage by a combination of UV-absorbing and cellular activities. PMID:23626759

Frames, biases, and rational decision-making in the human brain.

PubMed

De Martino, Benedetto; Kumaran, Dharshan; Seymour, Ben; Dolan, Raymond J

2006-08-04

Human choices are remarkably susceptible to the manner in which options are presented. This so-called "framing effect" represents a striking violation of standard economic accounts of human rationality, although its underlying neurobiology is not understood. We found that the framing effect was specifically associated with amygdala activity, suggesting a key role for an emotional system in mediating decision biases. Moreover, across individuals, orbital and medial prefrontal cortex activity predicted a reduced susceptibility to the framing effect. This finding highlights the importance of incorporating emotional processes within models of human choice and suggests how the brain may modulate the effect of these biasing influences to approximate rationality.

Virus elimination in activated sludge systems: from batch tests to mathematical modeling.

PubMed

Haun, Emma; Ulbricht, Katharina; Nogueira, Regina; Rosenwinkel, Karl-Heinz

2014-01-01

A virus tool based on Activated Sludge Model No. 3 for modeling virus elimination in activated sludge systems was developed and calibrated with the results from laboratory-scale batch tests and from measurements in a municipal wastewater treatment plant (WWTP). The somatic coliphages were used as an indicator for human pathogenic enteric viruses. The extended model was used to simulate the virus concentration in batch tests and in a municipal full-scale WWTP under steady-state and dynamic conditions. The experimental and modeling results suggest that both adsorption and inactivation processes, modeled as reversible first-order reactions, contribute to virus elimination in activated sludge systems. The model should be a useful tool to estimate the number of viruses entering water bodies from the discharge of treated effluents.

Action perception as hypothesis testing.

PubMed

Donnarumma, Francesco; Costantini, Marcello; Ambrosini, Ettore; Friston, Karl; Pezzulo, Giovanni

2017-04-01

We present a novel computational model that describes action perception as an active inferential process that combines motor prediction (the reuse of our own motor system to predict perceived movements) and hypothesis testing (the use of eye movements to disambiguate amongst hypotheses). The system uses a generative model of how (arm and hand) actions are performed to generate hypothesis-specific visual predictions, and directs saccades to the most informative places of the visual scene to test these predictions - and underlying hypotheses. We test the model using eye movement data from a human action observation study. In both the human study and our model, saccades are proactive whenever context affords accurate action prediction; but uncertainty induces a more reactive gaze strategy, via tracking the observed movements. Our model offers a novel perspective on action observation that highlights its active nature based on prediction dynamics and hypothesis testing. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Contributions of climate change and human activities to runoff change in seven typical catchments across China.

PubMed

Zhai, Ran; Tao, Fulu

2017-12-15

Climate change and human activities are two major factors affecting water resource change. It is important to understand the roles of the major factors in affecting runoff change in different basins for watershed management. Here, we investigated the trends in climate and runoff in seven typical catchments in seven basins across China from 1961 to 2014. Then we attributed the runoff change to climate change and human activities in each catchment and in three time periods (1980s, 1990s and 2000s), using the VIC model and long-term runoff observation data. During 1961-2014, temperature increased significantly, while the trends in precipitation were insignificant in most of the catchments and inconsistent among the catchments. The runoff in most of the catchments showed a decreasing trend except the Yingluoxia catchment in the northwestern China. The contributions of climate change and human activities to runoff change varied in different catchments and time periods. In the 1980s, climate change contributed more to runoff change than human activities, which was 84%, 59%, -66%, -50%, 59%, 94%, and -59% in the Nianzishan, Yingluoxia, Xiahui, Yangjiaping, Sanjiangkou, Xixian, and Changle catchment, respectively. After that, human activities had played a more essential role in runoff change. In the 1990s and 2000s, human activities contributed more to runoff change than in the 1980s. The contribution by human activities accounted for 84%, -68%, and 67% in the Yingluoxia, Xiahui, and Sanjiangkou catchment, respectively, in the 1990s; and -96%, -67%, -94%, and -142% in the Nianzishan, Yangjiaping, Xixian, and Changle catchment, respectively, in the 2000s. It is also noted that after 2000 human activities caused decrease in runoff in all catchments except the Yingluoxia. Our findings highlight that the effects of human activities, such as increase in water withdrawal, land use/cover change, operation of dams and reservoirs, should be well managed. Copyright © 2017 Elsevier B.V. All rights reserved.

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.

Monitoring and decision making by people in man machine systems

NASA Technical Reports Server (NTRS)

Johannsen, G.

1979-01-01

The analysis of human monitoring and decision making behavior as well as its modeling are described. Classic and optimal control theoretical, monitoring models are surveyed. The relationship between attention allocation and eye movements is discussed. As an example of applications, the evaluation of predictor displays by means of the optimal control model is explained. Fault detection involving continuous signals and decision making behavior of a human operator engaged in fault diagnosis during different operation and maintenance situations are illustrated. Computer aided decision making is considered as a queueing problem. It is shown to what extent computer aids can be based on the state of human activity as measured by psychophysiological quantities. Finally, management information systems for different application areas are mentioned. The possibilities of mathematical modeling of human behavior in complex man machine systems are also critically assessed.

Cognitive engineering models in space systems

NASA Technical Reports Server (NTRS)

Mitchell, Christine M.

1992-01-01

NASA space systems, including mission operations on the ground and in space, are complex, dynamic, predominantly automated systems in which the human operator is a supervisory controller. The human operator monitors and fine-tunes computer-based control systems and is responsible for ensuring safe and efficient system operation. In such systems, the potential consequences of human mistakes and errors may be very large, and low probability of such events is likely. Thus, models of cognitive functions in complex systems are needed to describe human performance and form the theoretical basis of operator workstation design, including displays, controls, and decision support aids. The operator function model represents normative operator behavior-expected operator activities given current system state. The extension of the theoretical structure of the operator function model and its application to NASA Johnson mission operations and space station applications is discussed.

Using iTree Model in Clark County, Nevada

EPA Science Inventory

Ecosystem services are the services and benefits that human populations obtain from nature. Whether surrounded by a forested, coastal, or urban area, ecosystems provide recreation, food, shelter, cleaner air and water. As the climate and environment change due to human activity,...

What Drives Parents? A Case Sensitive Inquiry into Parents' Mode Preferences for the Journey to School

ERIC Educational Resources Information Center

Zuniga, Kelly Draper

2010-01-01

This dissertation uses a case-sensitive approach to examine an active travel intervention's diverse target population. It builds on a series of travel choice models, and draws key conceptual themes from Chapin's (1974) human activity model, which highlights opportunity-related and propensity-related factors associated with behaviors. The research…

Web-Based Tools for Modelling and Analysis of Multivariate Data: California Ozone Pollution Activity

ERIC Educational Resources Information Center

Dinov, Ivo D.; Christou, Nicolas

2011-01-01

This article presents a hands-on web-based activity motivated by the relation between human health and ozone pollution in California. This case study is based on multivariate data collected monthly at 20 locations in California between 1980 and 2006. Several strategies and tools for data interrogation and exploratory data analysis, model fitting…

Designing and Applying Web Assisted Activities to Be Used in Flipped Classroom Model

ERIC Educational Resources Information Center

Çetinkaya, Murat

2017-01-01

The purpose of this study is to develop personalized web assisted activities for the flipped classroom model applied in the "Human and Environment Interactions" unit of science lesson and to research its effect on students' achievement. The study was conducted with the 74 participation of 7th grade science lesson students within a period…

Operational forecasting of human-biometeorological conditions

NASA Astrophysics Data System (ADS)

Giannaros, T. M.; Lagouvardos, K.; Kotroni, V.; Matzarakis, A.

2018-03-01

This paper presents the development of an operational forecasting service focusing on human-biometeorological conditions. The service is based on the coupling of numerical weather prediction models with an advanced human-biometeorological model. Human thermal perception and stress forecasts are issued on a daily basis for Greece, in both point and gridded format. A user-friendly presentation approach is adopted for communicating the forecasts to the public via the worldwide web. The development of the presented service highlights the feasibility of replacing standard meteorological parameters and/or indices used in operational weather forecasting activities for assessing the thermal environment. This is of particular significance for providing effective, human-biometeorology-oriented, warnings for both heat waves and cold outbreaks.

Adjustable Autonomy and Human-Agent Teamwork in Practice: An Interim Report on Space Applications

NASA Technical Reports Server (NTRS)

Bradshaw, Jeffrey M.; Feltovich, Paul; Hoffman, Robert; Jeffers, Renia; Suri, Niranhan; Uszok, Andrzej; VanHoof, Ron; Acquisti, Alessandro; Prescott, Debbie

2003-01-01

We give a preliminary perspective on the basic principles and pitfalls of adjustable autonomy and human-centered teamwork. We then summarize the interim results of our study on the problem of work practice modeling and human-agent collaboration in space applications, the development of a broad model of human-agent teamwork grounded in practice, and the integration of the Brahms, KAoS, and NOMADS agent frameworks. We hope our work will benefit those who plan and participate in work activities in a wide variety of space applications, as well as those who are interested in design and execution tools for teams of robots that can function as effective assistants to humans.

In silico study of the human rhodopsin and meta rhodopsin II/S-arrestin complexes: impact of single point mutations related to retina degenerative diseases.

PubMed

Mokarzel-Falcón, Leonardo; Padrón-García, Juan Alexander; Carrasco-Velar, Ramón; Berry, Colin; Montero-Cabrera, Luis A

2008-03-01

We propose two models of the human S-arrestin/rhodopsin complex in the inactive dark adapted rhodopsin and meta rhodopsin II form, obtained by homology modeling and knowledge based docking. First, a homology model for the human S-arrestin was built and validated by molecular dynamics, showing an average root mean square deviation difference from the pattern behavior of 0.76 A. Then, combining the human S-arrestin model and the modeled structure of the two human rhodopsin forms, we propose two models of interaction for the human S-arrestin/rhodopsin complex. The models involve two S-arrestin regions related to the N domain (residues 68-78; 170-182) and a third constituent of the C domain (248-253), with the rhodopsin C terminus (330-348). Of the 22 single point mutations related to retinitis pigmentosa and congenital night blindness located in the cytoplasmatic portion of rhodopsin or in S-arrestin, our models locate 16 in the interaction region and relate two others to possible dimer formation. Our calculations also predict that the light activated complex is more stable than the dark adapted rhodopsin and, therefore, of higher affinity to S-arrestin. 2008 Wiley-Liss, Inc.

Linking Theoretical Decision-making Mechanisms in the Simon Task with Electrophysiological Data: A Model-based Neuroscience Study in Humans.

PubMed

Servant, Mathieu; White, Corey; Montagnini, Anna; Burle, Borís

2016-10-01

A current challenge for decision-making research is in extending models of simple decisions to more complex and ecological choice situations. Conflict tasks (e.g., Simon, Stroop, Eriksen flanker) have been the focus of much interest, because they provide a decision-making context representative of everyday life experiences. Modeling efforts have led to an elaborated drift diffusion model for conflict tasks (DMC), which implements a superimposition of automatic and controlled decision activations. The DMC has proven to capture the diversity of behavioral conflict effects across various task contexts. This study combined DMC predictions with EEG and EMG measurements to test a set of linking propositions that specify the relationship between theoretical decision-making mechanisms involved in the Simon task and brain activity. Our results are consistent with a representation of the superimposed decision variable in the primary motor cortices. The decision variable was also observed in the EMG activity of response agonist muscles. These findings provide new insight into the neurophysiology of human decision-making. In return, they provide support for the DMC model framework.

Pathogenesis of Ebola Hemorrhagic Fever in Primate Models In Vivo and In Vitro

DTIC Science & Technology

2003-01-01

from the Philippine Islands (Jahrling et al., 1990). Hundreds of monkeys were infected (with high mortality) in this episode, but no human cases...reported that EBOV sGP binds to human neutrophils and inhibits early neutrophil activation . This study concluded that sGP diminished innate immunity...necrosis or apoptosis. However, viral infections can also exert changes in vascular endothelia indirectly, for example, by infecting and activating

Organisational Interoperability: Evaluation and Further Development of the OIM Model

DTIC Science & Technology

2003-06-01

an Organizational Interoperability Maturity Model (OIM) to evaluate interoperability at the organizational level. The OIM considers the human ... activity aspects of military operations, which are not covered in other models. This paper describes how the model has been used to identify problems and to

Protease activity, localization and inhibition in the human hair follicle.

PubMed

Bhogal, R K; Mouser, P E; Higgins, C A; Turner, G A

2014-02-01

In humans, the process of hair shedding, referred to as exogen, is believed to occur independently of the other hair cycle phases. Although the actual mechanisms involved in hair shedding are not fully known, it has been hypothesized that the processes leading to the final step of hair shedding may be driven by proteases and/or protease inhibitor activity. In this study, we investigated the presence of proteases and protease activity in naturally shed human hairs and assessed enzyme inhibition activity of test materials. We measured enzyme activity using a fluorescence-based assay and protein localization by indirect immunohistochemistry (IHC). We also developed an ex vivo skin model for measuring the force required to pull hair fibres from skin. Our data demonstrate the presence of protease activity in the tissue material surrounding club roots. We also demonstrated the localization of specific serine protease protein expression in human hair follicle by IHC. These data provide evidence demonstrating the presence of proteases around the hair club roots, which may play a role during exogen. We further tested the hypothesis that a novel protease inhibitor system (combination of Trichogen) and climbazole) could inhibit protease activity in hair fibre club root extracts collected from a range of ethnic groups (U.K., Brazil, China, first-generation Mexicans in the U.S.A., Thailand and Turkey) in both males and females. Furthermore, we demonstrated that this combination is capable of increasing the force required to remove hair in an ex vivo skin model system. These studies indicate the presence of proteolytic activity in the tissue surrounding the human hair club root and show that it is possible to inhibit this activity with a combination of Trichogen and climbazole. This technology may have potential to reduce excessive hair shedding. © 2013 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

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.

A Discrete Electromechanical Model for Human Cardiac Tissue: Effects of Stretch-Activated Currents and Stretch Conditions on Restitution Properties and Spiral Wave Dynamics

PubMed Central

Weise, Louis D.; Panfilov, Alexander V.

2013-01-01

We introduce an electromechanical model for human cardiac tissue which couples a biophysical model of cardiac excitation (Tusscher, Noble, Noble, Panfilov, 2006) and tension development (adjusted Niederer, Hunter, Smith, 2006 model) with a discrete elastic mass-lattice model. The equations for the excitation processes are solved with a finite difference approach, and the equations of the mass-lattice model are solved using Verlet integration. This allows the coupled problem to be solved with high numerical resolution. Passive mechanical properties of the mass-lattice model are described by a generalized Hooke's law for finite deformations (Seth material). Active mechanical contraction is initiated by changes of the intracellular calcium concentration, which is a variable of the electrical model. Mechanical deformation feeds back on the electrophysiology via stretch-activated ion channels whose conductivity is controlled by the local stretch of the medium. We apply the model to study how stretch-activated currents affect the action potential shape, restitution properties, and dynamics of spiral waves, under constant stretch, and dynamic stretch caused by active mechanical contraction. We find that stretch conditions substantially affect these properties via stretch-activated currents. In constantly stretched medium, we observe a substantial decrease in conduction velocity, and an increase of action potential duration; whereas, with dynamic stretch, action potential duration is increased only slightly, and the conduction velocity restitution curve becomes biphasic. Moreover, in constantly stretched medium, we find an increase of the core size and period of a spiral wave, but no change in rotation dynamics; in contrast, in the dynamically stretching medium, we observe spiral drift. Our results may be important to understand how altered stretch conditions affect the heart's functioning. PMID:23527160

A discrete electromechanical model for human cardiac tissue: effects of stretch-activated currents and stretch conditions on restitution properties and spiral wave dynamics.

PubMed

Weise, Louis D; Panfilov, Alexander V

2013-01-01

We introduce an electromechanical model for human cardiac tissue which couples a biophysical model of cardiac excitation (Tusscher, Noble, Noble, Panfilov, 2006) and tension development (adjusted Niederer, Hunter, Smith, 2006 model) with a discrete elastic mass-lattice model. The equations for the excitation processes are solved with a finite difference approach, and the equations of the mass-lattice model are solved using Verlet integration. This allows the coupled problem to be solved with high numerical resolution. Passive mechanical properties of the mass-lattice model are described by a generalized Hooke's law for finite deformations (Seth material). Active mechanical contraction is initiated by changes of the intracellular calcium concentration, which is a variable of the electrical model. Mechanical deformation feeds back on the electrophysiology via stretch-activated ion channels whose conductivity is controlled by the local stretch of the medium. We apply the model to study how stretch-activated currents affect the action potential shape, restitution properties, and dynamics of spiral waves, under constant stretch, and dynamic stretch caused by active mechanical contraction. We find that stretch conditions substantially affect these properties via stretch-activated currents. In constantly stretched medium, we observe a substantial decrease in conduction velocity, and an increase of action potential duration; whereas, with dynamic stretch, action potential duration is increased only slightly, and the conduction velocity restitution curve becomes biphasic. Moreover, in constantly stretched medium, we find an increase of the core size and period of a spiral wave, but no change in rotation dynamics; in contrast, in the dynamically stretching medium, we observe spiral drift. Our results may be important to understand how altered stretch conditions affect the heart's functioning.

Human cortical–hippocampal dialogue in wake and slow-wave sleep

PubMed Central

Mitra, Anish; Hacker, Carl D.; Pahwa, Mrinal; Tagliazucchi, Enzo; Laufs, Helmut; Leuthardt, Eric C.; Raichle, Marcus E.

2016-01-01

Declarative memory consolidation is hypothesized to require a two-stage, reciprocal cortical–hippocampal dialogue. According to this model, higher frequency signals convey information from the cortex to hippocampus during wakefulness, but in the reverse direction during slow-wave sleep (SWS). Conversely, lower-frequency activity propagates from the information “receiver” to the “sender” to coordinate the timing of information transfer. Reversal of sender/receiver roles across wake and SWS implies that higher- and lower-frequency signaling should reverse direction between the cortex and hippocampus. However, direct evidence of such a reversal has been lacking in humans. Here, we use human resting-state fMRI and electrocorticography to demonstrate that δ-band activity and infraslow activity propagate in opposite directions between the hippocampus and cerebral cortex. Moreover, both δ activity and infraslow activity reverse propagation directions between the hippocampus and cerebral cortex across wake and SWS. These findings provide direct evidence for state-dependent reversals in human cortical–hippocampal communication. PMID:27791089

Shear Forces during Blast, Not Abrupt Changes in Pressure Alone, Generate Calcium Activity in Human Brain Cells

DTIC Science & Technology

2012-06-29

the tissue-force interaction(s) and the cellular damage properties remain unresolved. Studies on a mechanical head model demonstrated high transient...that pressure transient. In vitro models of primary blast injury [5,18,19] are likewise limited by an absence of real-time, high spatial and temporal... models , as well as with human injuries in which expression of bTBI symptoms among different individuals that are exposed to the same blast is

An animal model for tinnitus.

PubMed

Jastreboff, P J; Brennan, J F; Sasaki, C T

1988-03-01

Subjective tinnitus remains obscure, widespread, and without apparent cure. In the absence of a suitable animal model, past investigations took place in humans, resulting in studies that were understandably restricted by the nature of human investigation. Within this context, the development of a valid animal model would be considered a major breakthrough in this field of investigation. Our results showed changes in the spontaneous activity of single neurons in the inferior colliculus, consistent with abnormally increased neuronal activity within the auditory pathways after manipulations known to produce tinnitus in man. A procedure based on a Pavlovian conditioned suppression paradigm was recently developed that allows us to measure tinnitus behaviorally in conscious animals. Accordingly, an animal model of tinnitus is proposed that permits tests of hypotheses relating to tinnitus generation, allowing the accommodation of interventional strategies for the treatment of this widespread auditory disorder.

QSAR and docking based semi-synthesis and in vitro evaluation of 18 β-glycyrrhetinic acid derivatives against human lung cancer cell line A-549.

PubMed

Yadav, Dharmendra Kumar; Kalani, Komal; Khan, Feroz; Srivastava, Santosh Kumar

2013-12-01

For the prediction of anticancer activity of glycyrrhetinic acid (GA-1) analogs against the human lung cancer cell line (A-549), a QSAR model was developed by forward stepwise multiple linear regression methodology. The regression coefficient (r(2)) and prediction accuracy (rCV(2)) of the QSAR model were taken 0.94 and 0.82, respectively in terms of correlation. The QSAR study indicates that the dipole moments, size of smallest ring, amine counts, hydroxyl and nitro functional groups are correlated well with cytotoxic activity. The docking studies showed high binding affinity of the predicted active compounds against the lung cancer target EGFR. These active glycyrrhetinic acid derivatives were then semi-synthesized, characterized and in-vitro tested for anticancer activity. The experimental results were in agreement with the predicted values and the ethyl oxalyl derivative of GA-1 (GA-3) showed equal cytotoxic activity to that of standard anticancer drug paclitaxel.

An integrated land change model for projecting future climate and land change scenarios

USGS Publications Warehouse

Wimberly, Michael; Sohl, Terry L.; Lamsal, Aashis; Liu, Zhihua; Hawbaker, Todd J.

2013-01-01

Climate change will have myriad effects on ecosystems worldwide, and natural and anthropogenic disturbances will be key drivers of these dynamics. In addition to climatic effects, continual expansion of human settlement into fire-prone forests will alter fire regimes, increase human vulnerability, and constrain future forest management options. There is a need for modeling tools to support the simulation and assessment of new management strategies over large regions in the context of changing climate, shifting development patterns, and an expanding wildland-urban interface. To address this need, we developed a prototype land change simulator that combines human-driven land use change (derived from the FORE-SCE model) with natural disturbances and vegetation dynamics (derived from the LADS model) and incorporates novel feedbacks between human land use and disturbance regimes. The prototype model was implemented in a test region encompassing the Denver metropolitan area along with its surrounding forested and agricultural landscapes. Initial results document the feasibility of integrated land change modeling at a regional scale but also highlighted conceptual and technical challenges for this type of model integration. Ongoing development will focus on improving climate sensitivities and modeling constraints imposed by climate change and human population growth on forest management activities.

Functional assessment of human enhancer activities using whole-genome STARR-sequencing.

PubMed

Liu, Yuwen; Yu, Shan; Dhiman, Vineet K; Brunetti, Tonya; Eckart, Heather; White, Kevin P

2017-11-20

Genome-wide quantification of enhancer activity in the human genome has proven to be a challenging problem. Recent efforts have led to the development of powerful tools for enhancer quantification. However, because of genome size and complexity, these tools have yet to be applied to the whole human genome.  In the current study, we use a human prostate cancer cell line, LNCaP as a model to perform whole human genome STARR-seq (WHG-STARR-seq) to reliably obtain an assessment of enhancer activity. This approach builds upon previously developed STARR-seq in the fly genome and CapSTARR-seq techniques in targeted human genomic regions. With an improved library preparation strategy, our approach greatly increases the library complexity per unit of starting material, which makes it feasible and cost-effective to explore the landscape of regulatory activity in the much larger human genome. In addition to our ability to identify active, accessible enhancers located in open chromatin regions, we can also detect sequences with the potential for enhancer activity that are located in inaccessible, closed chromatin regions. When treated with the histone deacetylase inhibitor, Trichostatin A, genes nearby this latter class of enhancers are up-regulated, demonstrating the potential for endogenous functionality of these regulatory elements. WHG-STARR-seq provides an improved approach to current pipelines for analysis of high complexity genomes to gain a better understanding of the intricacies of transcriptional regulation.

Quantifying the magnitude of the impact of climate change and human activity on runoff decline in Mian River Basin, China.

PubMed

Fan, Jing; Tian, Fei; Yang, Yonghui; Han, Shumin; Qiu, Guoyu

2010-01-01

Runoff in North China has been dramatically declining in recent decades. Although climate change and human activity have been recognized as the primary driving factors, the magnitude of impact of each of the above factors on runoff decline is still not entirely clear. In this study, Mian River Basin (a watershed that is heavily influenced by human activity) was used as a proxy to quantify the contributions of human and climate to runoff decline in North China. SWAT (Soil and Water Assessment Tool) model was used to isolate the possible impacts of man and climate. SWAT simulations suggest that while climate change accounts for only 23.89% of total decline in mean annual runoff, human activity accounts for the larger 76.11% in the basin. The gap between the simulated and measured runoff has been widening since 1978, which can only be explained in terms of increasing human activity in the region. Furthermore, comparisons of similar annual precipitation in 3 dry-years and 3 wet-years representing hydrological processes in the 1970s, 1980s, and 1990s were used to isolate the magnitude of runoff decline under similar annual precipitations. The results clearly show that human activity, rather than climate, is the main driving factor of runoff decline in the basin.

Environmental contaminants activate human and polar bear (Ursus maritimus) pregnane X receptors (PXR, NR1I2) differently

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

Lille-Langøy, Roger, E-mail: Roger.lille-langoy@bio.uib.no; Goldstone, Jared V.; Rusten, Marte

Background: Many persistent organic pollutants (POPs) accumulate readily in polar bears because of their position as apex predators in Arctic food webs. The pregnane X receptor (PXR, formally NR1I2, here proposed to be named promiscuous xenobiotic receptor) is a xenobiotic sensor that is directly involved in metabolizing pathways of a wide range of environmental contaminants. Objectives: In the present study, we comparably assess the ability of 51 selected pharmaceuticals, pesticides and emerging contaminants to activate PXRs from polar bears and humans using an in vitro luciferase reporter gene assay. Results: We found that polar bear PXR is activated by amore » wide range of our test compounds (68%) but has a slightly more narrow ligand specificity than human PXR that was activated by 86% of the 51 test compounds. The majority of the agonists identified (70%) produces a stronger induction of the reporter gene via human PXR than via polar bear PXR, however with some notable and environmentally relevant exceptions. Conclusions: Due to the observed differences in activation of polar bear and human PXRs, exposure of each species to environmental agents is likely to induce biotransformation differently in the two species. Bioinformatics analyses and structural modeling studies suggest that amino acids that are not part of the ligand-binding domain and do not interact with the ligand can modulate receptor activation. - Highlights: • Comparative study of ligand activation of human and polar bear PXRs. • Polar bear PXR is a promiscuous ligand-activated nuclear receptor but less so than human PXR. • Environmental contaminants activate human and polar bear PXRs differently. • Expression and ligand promiscuity indicate that PXR is a xenosensor in polar bears.« less

ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling

PubMed Central

Goossens, Steven; Radaelli, Enrico; Blanchet, Odile; Durinck, Kaat; Van der Meulen, Joni; Peirs, Sofie; Taghon, Tom; Tremblay, Cedric S.; Costa, Magdaline; Ghahremani, Morvarid Farhang; De Medts, Jelle; Bartunkova, Sonia; Haigh, Katharina; Schwab, Claire; Farla, Natalie; Pieters, Tim; Matthijssens, Filip; Van Roy, Nadine; Best, J. Adam; Deswarte, Kim; Bogaert, Pieter; Carmichael, Catherine; Rickard, Adam; Suryani, Santi; Bracken, Lauryn S.; Alserihi, Raed; Canté-Barrett, Kirsten; Haenebalcke, Lieven; Clappier, Emmanuelle; Rondou, Pieter; Slowicka, Karolina; Huylebroeck, Danny; Goldrath, Ananda W.; Janzen, Viktor; McCormack, Matthew P.; Lock, Richard B.; Curtis, David J.; Harrison, Christine; Berx, Geert; Speleman, Frank; Meijerink, Jules P. P.; Soulier, Jean; Van Vlierberghe, Pieter; Haigh, Jody J.

2015-01-01

Early T-cell precursor leukaemia (ETP-ALL) is a high-risk subtype of human leukaemia that is poorly understood at the molecular level. Here we report translocations targeting the zinc finger E-box-binding transcription factor ZEB2 as a recurrent genetic lesion in immature/ETP-ALL. Using a conditional gain-of-function mouse model, we demonstrate that sustained Zeb2 expression initiates T-cell leukaemia. Moreover, Zeb2-driven mouse leukaemia exhibit some features of the human immature/ETP-ALL gene expression signature, as well as an enhanced leukaemia-initiation potential and activated Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signalling through transcriptional activation of IL7R. This study reveals ZEB2 as an oncogene in the biology of immature/ETP-ALL and paves the way towards pre-clinical studies of novel compounds for the treatment of this aggressive subtype of human T-ALL using our Zeb2-driven mouse model. PMID:25565005

Ontology-driven education: Teaching anatomy with intelligent 3D games on the web

NASA Astrophysics Data System (ADS)

Nilsen, Trond

Human anatomy is a challenging and intimidating subject whose understanding is essential to good medical practice, taught primarily using a combination of lectures and the dissection of human cadavers. Lectures are cheap and scalable, but do a poor job of teaching spatial understanding, whereas dissection lets students experience the body's interior first-hand, but is expensive, cannot be repeated, and is often imperfect. Educational games and online learning activities have the potential to supplement these teaching methods in a cheap and relatively effective way, but they are difficult for educators to customize for particular curricula and lack the tutoring support that human instructors provide. I present an approach to the creation of learning activities for anatomy called ontology-driven education, in which the Foundational Model of Anatomy, an ontological representation of knowledge about anatomy, is leveraged to generate educational content, model student knowledge, and support learning activities and games in a configurable web-based educational framework for anatomy.

Cross-species assessments of motor and exploratory behavior related to bipolar disorder.

PubMed

Henry, Brook L; Minassian, Arpi; Young, Jared W; Paulus, Martin P; Geyer, Mark A; Perry, William

2010-07-01

Alterations in exploratory behavior are a fundamental feature of bipolar mania, typically characterized as motor hyperactivity and increased goal-directed behavior in response to environmental cues. In contrast, abnormal exploration associated with schizophrenia and depression can manifest as prominent withdrawal, limited motor activity, and inattention to the environment. While motor abnormalities are cited frequently as clinical manifestations of these disorders, relatively few empirical studies have quantified human exploratory behavior. This article reviews the literature characterizing motor and exploratory behavior associated with bipolar disorder and genetic and pharmacological animal models of the illness. Despite sophisticated assessment of exploratory behavior in rodents, objective quantification of human motor activity has been limited primarily to actigraphy studies with poor cross-species translational value. Furthermore, symptoms that reflect the cardinal features of bipolar disorder have proven difficult to establish in putative animal models of this illness. Recently, however, novel tools such as the human behavioral pattern monitor provide multivariate translational measures of motor and exploratory activity, enabling improved understanding of the neurobiology underlying psychiatric disorders.

An Energy Model for Viewing Embodied Human Capital Theory

ERIC Educational Resources Information Center

Kaufman, Neil A.; Geroy, Gary D.

2007-01-01

Human capital development is one of the emerging areas of study with regard to social science theory, practice, and research. A relatively new concept, human capital is described in terms of individual knowledge skills and experience. It is currently expressed as a function of education as well as a measure of economic activity. Little theory…

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.

Prostate Cancer Xenograft Inhibitory Activity and Pharmacokinetics of Decursinol, a Metabolite of Angelica gigas Pyranocoumarins, in Mouse Models.

PubMed

Wu, Wei; Tang, Su-Ni; Zhang, Yong; Puppala, Manohar; Cooper, Timothy K; Xing, Chengguo; Jiang, Cheng; Lü, Junxuan

2017-01-01

We have previously shown that the ethanol extract of dried Angelica gigas Nakai (AGN) root exerts anticancer activity against androgen receptor (AR)-negative human DU145 and PC-3 prostate cancer xenografts and primary carcinogenesis in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. The major pyranocoumarin isomers decursin (D) and decursinol angelate (DA), when provided at equi-molar intake to that provided by AGN extract, accounted for the inhibitory efficacy against precancerous epithelial lesions in TRAMP mice. Since we and others have shown in rodents and humans that D and DA rapidly and extensively convert to decursinol, here we tested whether decursinol might be an in vivo active compound for suppressing xenograft growth of human prostate cancer cells expressing AR. In SCID-NSG mice carrying subcutaneously inoculated human LNCaP/AR-Luc cells overexpressing the wild type AR, we compared the efficacy of 4.5[Formula: see text]mg decursinol per mouse with equi-molar dose of 6[Formula: see text]mg D/DA per mouse. The result showed that decursinol decreased xenograft tumor growth by 75% and the lung metastasis, whereas D/DA exerted a much less effect. Measurement of plasma decursinol concentration, at 3[Formula: see text]h after the last dose of respective dosing regimen, showed higher circulating level in the decursinol-treated NSG mice than in the D/DA-treated mice. In a subsequent single-dose pharmacokinetic experiment, decursinol dosing led to 3.7-fold area under curve (AUC) of plasma decursinol over that achieved by equi-molar D/DA dosing. PK advantage notwithstanding, decursinol represents an active compound to exert in vivo prostate cancer growth and metastasis inhibitory activity in the preclinical model.

Activity of the hypoxia-activated prodrug, TH-302, in preclinical human acute myeloid leukemia models.

PubMed

Portwood, Scott; Lal, Deepika; Hsu, Yung-Chun; Vargas, Rodrigo; Johnson, Megan K; Wetzler, Meir; Hart, Charles P; Wang, Eunice S

2013-12-01

Acute myeloid leukemia (AML) is an aggressive hematologic neoplasm. Recent evidence has shown the bone marrow microenvironment in patients with AML to be intrinsically hypoxic. Adaptive cellular responses by leukemia cells to survive under low oxygenation also confer chemoresistance. We therefore asked whether therapeutic exploitation of marrow hypoxia via the hypoxia-activated nitrogen mustard prodrug, TH-302, could effectively inhibit AML growth. We assessed the effects of hypoxia and TH-302 on human AML cells, primary samples, and systemic xenograft models. We observed that human AML cells and primary AML colonies cultured under chronic hypoxia (1% O2, 72 hours) exhibited reduced sensitivity to cytarabine-induced apoptosis as compared with normoxic controls. TH-302 treatment resulted in dose- and hypoxia-dependent apoptosis and cell death in diverse AML cells. TH-302 preferentially decreased proliferation, reduced HIF-1α expression, induced cell-cycle arrest, and enhanced double-stranded DNA breaks in hypoxic AML cells. Hypoxia-induced reactive oxygen species by AML cells were also diminished. In systemic human AML xenografts (HEL, HL60), TH-302 [50 mg/kg intraperitoneally (i.p.) 5 times per week] inhibited disease progression and prolonged overall survival. TH-302 treatment reduced the number of hypoxic cells within leukemic bone marrows and was not associated with hematologic toxicities in nonleukemic or leukemic mice. Later initiation of TH-302 treatment in advanced AML disease was as effective as earlier TH-302 treatment in xenograft models. Our results establish the preclinical activity of TH-302 in AML and provide the rationale for further clinical studies of this and other hypoxia-activated agents for leukemia therapy. ©2013 AACR.

A composite model of the human postcapillary venule for investigation of microvascular leukocyte recruitment

PubMed Central

Lauridsen, Holly M.; Pober, Jordan S.; Gonzalez, Anjelica L.

2014-01-01

Neutrophil extravasation occurs across postcapillary venules, structures composed of endothelial cells (ECs), pericytes (PCs), and basement membrane (BM). We constructed composite models of the human postcapillary venule, combining ECs with PCs or PC-deposited BM, to better study this process. Quiescent and tumor necrosis factor α (TNF-α)-activated composites demonstrated in situ-like expression of cadherins, E-selectin, intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), platelet-endothelial cell adhesion molecule 1 (PECAM-1), CD99, and interleukin 8 (IL-8). After TNF-α activation, the ECs supported greater neutrophil adhesion (66.1 vs. 23.7% of input cells) and transmigration (35.1 vs. 7.20% of input cells) than did the PCs, but the composites behaved comparably (no significant difference) to ECs in both assays. TNF-α-activated EC-conditioned medium (CM) increased transmigration across the PCs, whereas TNF-α-activated PC-CM decreased transmigration across the ECs, and culturing on PC-derived BM decreased both adhesion to and transmigration across the ECs. Anti-very late antigen 4 (VLA-4; on neutrophils) inhibited adhesion to TNF-α-activated composites, but not to ECs alone. Anti-CD99 (expressed on all 3 cell types) inhibited transmigration across the composites (14.5% of control) more than across the ECs (39.0% of control), and venular shear stress reduced transmigration across the ECs (17.3% of static) more than across the composites (36.7% of static). These results provide proof of concept that our composite human EC/PC/BM venular construct can reveal new interactions in the inflammatory cascade.—Lauridsen, H. M., Pober, J. S., Gonzalez, A. L. A composite model of the human postcapillary venule for investigation of microvascular leukocyte recruitment. PMID:24297702

(−) Arctigenin and (+) Pinoresinol Are Antagonists of the Human Thyroid Hormone Receptor β

PubMed Central

2015-01-01

Lignans are important biologically active dietary polyphenolic compounds. Consumption of foods that are rich in lignans is associated with positive health effects. Using modeling tools to probe the ligand-binding pockets of molecular receptors, we found that lignans have high docking affinity for the human thyroid hormone receptor β. Follow-up experimental results show that lignans (−) arctigenin and (+) pinoresinol are antagonists of the human thyroid hormone receptor β. The modeled complexes show key plausible interactions between the two ligands and important amino acid residues of the receptor. PMID:25383984

The function of dog models in developing gene therapy strategies for human health.

PubMed

Nowend, Keri L; Starr-Moss, Alison N; Murphy, Keith E

2011-08-01

The domestic dog is of great benefit to humankind, not only through companionship and working activities cultivated through domestication and selective breeding, but also as a model for biomedical research. Many single-gene traits have been well-characterized at the genomic level, and recent advances in whole-genome association studies will allow for better understanding of complex, multigenic hereditary diseases. Additionally, the dog serves as an invaluable large animal model for assessment of novel therapeutic agents. Thus, the dog has filled a crucial step in the translation of basic research to new treatment regimens for various human diseases. Four well-characterized diseases in canine models are discussed as they relate to other animal model availability, novel therapeutic approach, and extrapolation to human gene therapy trials.

Potent Antitumor Effects of Combination Therapy With IFNs and Monocytes in Mouse Models of Established Human Ovarian and Melanoma Tumors

PubMed Central

Nakashima, Hideyuki; Miyake, Kotaro; Clark, Christopher R; Bekisz, Joseph; Finbloom, Joel; Husain, Syed R.; Baron, Samuel; Puri, Raj K.; Zoon, Kathryn C.

2012-01-01

Interferon-activated monocytes are known to exert cytocidal activity against tumor cells in vitro. Here, we have examined whether a combination of IFN-α2a and IFN-γ and human monocytes mediate significant antitumor effects against human ovarian and melanoma tumor xenografts in mouse models. OVCAR-3 tumors were treated i.t. with monocytes alone, IFN-α2a and IFN-γ alone or combination of all three on day 0, 15 or 30 post-tumor implantation. Mice receiving combination therapy beginning day 15 showed significantly reduced tumor growth and prolonged survival including complete regression in 40% mice., Tumor volumes measured on day 80 in mice receiving combination therapy (206 mm3) were significantly smaller than those of mice receiving the IFNs alone (1041 mm3), monocytes alone (1111 mm3) or untreated controls (1728 mm3). Similarly, combination therapy with monocytes and IFNs of much larger tumor also inhibited OVCAR-3 tumor growth. Immunohistochemistry studies showed a large number of activated macrophages (CD31+/CD68+) infiltrating into OVCAR-3 tumors and higher densities of IL-12, IP10 and NOS2, markers of M1 (classical) macrophages in tumors treated with combination therapy compared to the controls. Interestingly, IFNs activated macrophages induced apoptosis of OVCAR-3 tumor cells as monocytes alone or IFNs alone did not mediate significant apoptosis. Similar antitumor activity was observed in the LOX melanoma mouse model, but not as profound as seen with the OVCAR-3 tumors. Administration of either mixture of monocytes and IFN-α2a or monocytes and IFN-γ did not inhibit Lox melanoma growth; however a significant inhibition was observed when tumors were treated with a mixture of monocytes, IFN-α2a and IFN-γ. These results indicate that monocytes and both IFN-α2a and IFN-γ may be required to mediate profound antitumor effect against human ovarian and melanoma tumors in mouse models. PMID:22159517

Current challenges in distinguishing climatic and anthropogenic contributions to alpine grassland variation on the Tibetan Plateau.

PubMed

Li, Lanhui; Zhang, Yili; Liu, Linshan; Wu, Jianshuang; Li, Shicheng; Zhang, Haiyan; Zhang, Binghua; Ding, Mingjun; Wang, Zhaofeng; Paudel, Basanta

2018-06-01

Quantifying the impact of climate change and human activities on grassland dynamics is an essential step for developing sustainable grassland ecosystem management strategies. However, the direction and magnitude of climate change and human activities in driving alpine grassland dynamic over the Tibetan Plateau remain under debates. Here, we systematically reviewed the relevant studies on the methods, main conclusions, and causes for the inconsistency in distinguishing the respective contribution of climatic and anthropogenic forces to alpine grassland dynamic. Both manipulative experiments and traditional statistical analysis show that climate warming increase biomass in alpine meadows and decrease in alpine steppes, while both alpine steppes and meadows benefit from an increase in precipitation or soil moisture. Overgrazing is a major factor for the degradation of alpine grassland in local areas with high level of human activity intensity. However, across the entire Tibetan Plateau and its subregions, four views characterize the remaining controversies: alpine grassland changes are primarily due to (1) climatic force, (2) nonclimatic force, (3) combination of anthropogenic and climatic force, or (4) alternation of anthropogenic and climatic force. Furthermore, these views also show spatial inconsistencies. Differences on the source and quality of remote sensing products, the structure and parameter of models, and overlooking the spatiotemporal heterogeneity of human activity intensity contribute to current disagreements. In this review, we highlight the necessity for taking the spatiotemporal heterogeneity of human activity intensity into account in the models of attribution assessment, and the importance for accurate validation of climatic and anthropogenic contribution to alpine grassland variation at multiple scales for future studies.

Quantifying the influences of various ecological factors on land surface temperature of urban forests.

PubMed

Ren, Yin; Deng, Lu-Ying; Zuo, Shu-Di; Song, Xiao-Dong; Liao, Yi-Lan; Xu, Cheng-Dong; Chen, Qi; Hua, Li-Zhong; Li, Zheng-Wei

2016-09-01

Identifying factors that influence the land surface temperature (LST) of urban forests can help improve simulations and predictions of spatial patterns of urban cool islands. This requires a quantitative analytical method that combines spatial statistical analysis with multi-source observational data. The purpose of this study was to reveal how human activities and ecological factors jointly influence LST in clustering regions (hot or cool spots) of urban forests. Using Xiamen City, China from 1996 to 2006 as a case study, we explored the interactions between human activities and ecological factors, as well as their influences on urban forest LST. Population density was selected as a proxy for human activity. We integrated multi-source data (forest inventory, digital elevation models (DEM), population, and remote sensing imagery) to develop a database on a unified urban scale. The driving mechanism of urban forest LST was revealed through a combination of multi-source spatial data and spatial statistical analysis of clustering regions. The results showed that the main factors contributing to urban forest LST were dominant tree species and elevation. The interactions between human activity and specific ecological factors linearly or nonlinearly increased LST in urban forests. Strong interactions between elevation and dominant species were generally observed and were prevalent in either hot or cold spots areas in different years. In conclusion, quantitative studies based on spatial statistics and GeogDetector models should be conducted in urban areas to reveal interactions between human activities, ecological factors, and LST. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mutations in PIK3CA are infrequent in neuroblastoma

PubMed Central

Dam, Vincent; Morgan, Brian T; Mazanek, Pavel; Hogarty, Michael D

2006-01-01

Background Neuroblastoma is a frequently lethal pediatric cancer in which MYCN genomic amplification is highly correlated with aggressive disease. Deregulated MYC genes require co-operative lesions to foster tumourigenesis and both direct and indirect evidence support activated Ras signaling for this purpose in many cancers. Yet Ras genes and Braf, while often activated in cancer cells, are infrequent targets for activation in neuroblastoma. Recently, the Ras effector PIK3CA was shown to be activated in diverse human cancers. We therefore assessed PIK3CA for mutation in human neuroblastomas, as well as in neuroblastomas arising in transgenic mice with MYCN overexpressed in neural-crest tissues. In this murine model we additionally surveyed for Ras family and Braf mutations as these have not been previously reported. Methods Sixty-nine human neuroblastomas (42 primary tumors and 27 cell lines) were sequenced for PIK3CA activating mutations within the C2, helical and kinase domain "hot spots" where 80% of mutations cluster. Constitutional DNA was sequenced in cases with confirmed alterations to assess for germline or somatic acquisition. Additionally, Ras family members (Hras1, Kras2 and Nras) and the downstream effectors Pik3ca and Braf, were sequenced from twenty-five neuroblastomas arising in neuroblastoma-prone transgenic mice. Results We identified mutations in the PIK3CA gene in 2 of 69 human neuroblastomas (2.9%). Neither mutation (R524M and E982D) has been studied to date for effects on lipid kinase activity. Though both occurred in tumors with MYCN amplification the overall rate of PIK3CA mutations in MYCN amplified and single-copy tumors did not differ appreciably (2 of 31 versus 0 of 38, respectively). Further, no activating mutations were identified in a survey of Ras signal transduction genes (including Hras1, Kras2, Nras, Pik3ca, or Braf genes) in twenty-five neuroblastic tumors arising in the MYCN-initiated transgenic mouse model. Conclusion These data suggest that activating mutations in the Ras/Raf-MAPK/PI3K signaling cascades occur infrequently in neuroblastoma. Further, despite compelling evidence for MYC and RAS cooperation in vitro and in vivo to promote tumourigenesis, activation of RAS signal transduction does not constitute a preferred secondary pathway in neuroblastomas with MYCN deregulation in either human tumors or murine models. PMID:16822308

Myostatin promotes the wasting of human myoblast cultures through promoting ubiquitin-proteasome pathway-mediated loss of sarcomeric proteins.

PubMed

Lokireddy, Sudarsanareddy; Mouly, Vincent; Butler-Browne, Gillian; Gluckman, Peter D; Sharma, Mridula; Kambadur, Ravi; McFarlane, Craig

2011-12-01

Myostatin is a negative regulator of skeletal muscle growth and in fact acts as a potent inducer of "cachectic-like" muscle wasting in mice. The mechanism of action of myostatin in promoting muscle wasting has been predominantly studied in murine models. Despite numerous reports linking elevated levels of myostatin to human skeletal muscle wasting conditions, little is currently known about the signaling mechanism(s) through which myostatin promotes human skeletal muscle wasting. Therefore, in this present study we describe in further detail the mechanisms behind myostatin regulation of human skeletal muscle wasting using an in vitro human primary myotube atrophy model. Treatment of human myotube populations with myostatin promoted dramatic myotubular atrophy. Mechanistically, myostatin-induced myotube atrophy resulted in reduced p-AKT concomitant with the accumulation of active dephosphorylated Forkhead Box-O (FOXO1) and FOXO3. We further show that addition of myostatin results in enhanced activation of atrogin-1 and muscle-specific RING finger protein 1 (MURF1) and reduced expression of both myosin light chain (MYL) and myosin heavy chain (MYH). In addition, we found that myostatin-induced loss of MYL and MYH proteins is dependent on the activity of the proteasome and mediated via SMAD3-dependent regulation of FOXO1 and atrogin-1. Therefore, these data suggest that the mechanism through which myostatin promotes muscle wasting is very well conserved between species, and that myostatin-induced human myotube atrophy is mediated through inhibition of insulin-like growth factor (IGF)/phosphoinositide 3-kinase (PI3-K)/AKT signaling and enhanced activation of the ubiquitin-proteasome pathway and elevated protein degradation.

Modelling the role of Tax expression in HTLV-I persistence in vivo.

PubMed

Li, Michael Y; Lim, Aaron G

2011-12-01

Human T-lymphotropic virus type I (HTLV-I) is a persistent human retrovirus characterized by life-long infection and risk of developing HAM/TSP, a progressive neurological and inflammatory disease, and adult T-cell leukemia (ATL). Chronically infected individuals often harbor high proviral loads despite maintaining a persistently activated immune response. Based on a new hypothesis for the persistence of HTLV-I infection, a three-dimensional compartmental model is constructed that describes the dynamic interactions among latently infected target cells, target-cell activation, and immune responses to HTLV-I, with an emphasis on understanding the role of Tax expression in the persistence of HTLV-I.

Acute Neuroimmune Modulation Attenuates the Development of Anxiety-Like Freezing Behavior in an Animal Model of Traumatic Brain Injury

PubMed Central

Rodgers, Krista M.; Bercum, Florencia M.; McCallum, Danielle L.; Rudy, Jerry W.; Frey, Lauren C.; Johnson, Kirk W.; Watkins, Linda R.

2012-01-01

Abstract Chronic anxiety is a common and debilitating result of traumatic brain injury (TBI) in humans. While little is known about the neural mechanisms of this disorder, inflammation resulting from activation of the brain's immune response to insult has been implicated in both human post-traumatic anxiety and in recently developed animal models. In this study, we used a lateral fluid percussion injury (LFPI) model of TBI in the rat and examined freezing behavior as a measure of post-traumatic anxiety. We found that LFPI produced anxiety-like freezing behavior accompanied by increased reactive gliosis (reflecting neuroimmune inflammatory responses) in key brain structures associated with anxiety: the amygdala, insula, and hippocampus. Acute peri-injury administration of ibudilast (MN166), a glial cell activation inhibitor, suppressed both reactive gliosis and freezing behavior, and continued neuroprotective effects were apparent several months post-injury. These results support the conclusion that inflammation produced by neuroimmune responses to TBI play a role in post-traumatic anxiety, and that acute suppression of injury-induced glial cell activation may have promise for the prevention of post-traumatic anxiety in humans. PMID:22435644

AVAILABLE MICRO-ACTIVITY DATA AND THEIR APPLICABILITY TO AGGREGATE EXPOSURE MODELING

EPA Science Inventory

Several human exposure models have been developed in recent years to address children's aggregate and cumulative exposures to pesticides under the Food Quality Protection Act of 1996. These models estimate children's exposures via all significant routes and pathways including ...

Blocking immunosuppression by human Tregs in vivo with antibodies targeting integrin αVβ8.

PubMed

Stockis, Julie; Liénart, Stéphanie; Colau, Didier; Collignon, Amandine; Nishimura, Stephen L; Sheppard, Dean; Coulie, Pierre G; Lucas, Sophie

2017-11-21

Human regulatory T cells (Tregs) suppress other T cells by converting the latent, inactive form of TGF-β1 into active TGF-β1. In Tregs, TGF-β1 activation requires GARP, a transmembrane protein that binds and presents latent TGF-β1 on the surface of Tregs stimulated through their T cell receptor. However, GARP is not sufficient because transduction of GARP in non-Treg T cells does not induce active TGF-β1 production. RGD-binding integrins were shown to activate TGF-β1 in several non-T cell types. Here we show that αVβ8 dimers are present on stimulated human Tregs but not in other T cells, and that antibodies against αV or β8 subunits block TGF-β1 activation in vitro. We also show that αV and β8 interact with GARP/latent TGF-β1 complexes in human Tregs. Finally, a blocking antibody against β8 inhibited immunosuppression by human Tregs in a model of xenogeneic graft-vs.-host disease induced by the transfer of human T cells in immunodeficient mice. These results show that TGF-β1 activation on the surface of human Tregs implies an interaction between the integrin αVβ8 and GARP/latent TGF-β1 complexes. Immunosuppression by human Tregs can be inhibited by antibodies against GARP or against the integrin β8 subunit. Such antibodies may prove beneficial against cancer or chronic infections.

Forebrain Mechanisms of Nociception and Pain: Analysis through Imaging

NASA Astrophysics Data System (ADS)

Casey, Kenneth L.

1999-07-01

Pain is a unified experience composed of interacting discriminative, affective-motivational, and cognitive components, each of which is mediated and modulated through forebrain mechanisms acting at spinal, brainstem, and cerebral levels. The size of the human forebrain in relation to the spinal cord gives anatomical emphasis to forebrain control over nociceptive processing. Human forebrain pathology can cause pain without the activation of nociceptors. Functional imaging of the normal human brain with positron emission tomography (PET) shows synaptically induced increases in regional cerebral blood flow (rCBF) in several regions specifically during pain. We have examined the variables of gender, type of noxious stimulus, and the origin of nociceptive input as potential determinants of the pattern and intensity of rCBF responses. The structures most consistently activated across genders and during contact heat pain, cold pain, cutaneous laser pain or intramuscular pain were the contralateral insula and anterior cingulate cortex, the bilateral thalamus and premotor cortex, and the cerebellar vermis. These regions are commonly activated in PET studies of pain conducted by other investigators, and the intensity of the brain rCBF response correlates parametrically with perceived pain intensity. To complement the human studies, we developed an animal model for investigating stimulus-induced rCBF responses in the rat. In accord with behavioral measures and the results of human PET, there is a progressive and selective activation of somatosensory and limbic system structures in the brain and brainstem following the subcutaneous injection of formalin. The animal model and human PET studies should be mutually reinforcing and thus facilitate progress in understanding forebrain mechanisms of normal and pathological pain.

Rethinking food anticipatory activity in the activity-based anorexia rat model.

PubMed

Wu, Hemmings; van Kuyck, Kris; Tambuyzer, Tim; Luyten, Laura; Aerts, Jean-Marie; Nuttin, Bart

2014-01-29

When a rat is on a limited fixed-time food schedule with full access to a running wheel (activity-based anorexia model, ABA), its activity level will increase hours prior to the feeding period. This activity, called food-anticipatory activity (FAA), is a hypothesized parallel to the hyperactivity symptom in human anorexia nervosa. To investigate in depth the characteristics of FAA, we retrospectively analyzed the level of FAA and activities during other periods in ABA rats. To our surprise, rats with the most body weight loss have the lowest level of FAA, which contradicts the previously established link between FAA and the severity of ABA symptoms. On the contrary, our study shows that postprandial activities are more directly related to weight loss. We conclude that FAA alone may not be sufficient to reflect model severity, and activities during other periods may be of potential value in studies using ABA model.

USING POPULATION MODELS TO EVALUATE RISK IN POPULATION OF BIRDS

EPA Science Inventory

Wildlife populations are exposed to varying habitat structure and quality, as well as an array of human-induced environmental stressors. Predicting the consequences to a real population of one perturbation (e.g. a pesticide application) without considering other human activities ...

Computational Molecular Modeling Methods Applied to Screening for Toxicity

EPA Science Inventory

The risk to human health and the environment of chemicals that result from human activity often must be evaluated when relevant elements of the preferred data set are unavailable. Therefore, strategies are needed that estimate this information and prioritize the outstanding data...

An Overview of the NASA Aviation Safety Program (AVSP) Systemwide Accident Prevention (SWAP) Human Performance Modeling (HPM) Element

NASA Technical Reports Server (NTRS)

Foyle, David C.; Goodman, Allen; Hooley, Becky L.

2003-01-01

An overview is provided of the Human Performance Modeling (HPM) element within the NASA Aviation Safety Program (AvSP). Two separate model development tracks for performance modeling of real-world aviation environments are described: the first focuses on the advancement of cognitive modeling tools for system design, while the second centers on a prescriptive engineering model of activity tracking for error detection and analysis. A progressive implementation strategy for both tracks is discussed in which increasingly more complex, safety-relevant applications are undertaken to extend the state-of-the-art, as well as to reveal potential human-system vulnerabilities in the aviation domain. Of particular interest is the ability to predict the precursors to error and to assess potential mitigation strategies associated with the operational use of future flight deck technologies.

Development of Open Brain Simulator for Human Biomechatronics

NASA Astrophysics Data System (ADS)

Otake, Mihoko; Takagi, Toshihisa; Asama, Hajime

Modeling and simulation based on mechanisms is important in order to design and control mechatronic systems. In particular, in-depth understanding and realistic modeling of biological systems is indispensable for biomechatronics. This paper presents open brain simulator, which estimates the neural state of human through external measurement for the purpose of improving motor and social skills. Macroscopic anatomical nervous systems model was built which can be connected to the musculoskeletal model. Microscopic anatomical and physiological neural models were interfaced to the macroscopic model. Neural activities of somatosensory area and Purkinje cell were calculated from motion capture data. The simulator provides technical infrastructure for human biomechatronics, which is promising for the novel diagnosis of neurological disorders and their treatments through medication and movement therapy, and for motor learning support system supporting acquisition of motor skill considering neural mechanism.

Studying the Accuracy of Software Process Elicitation: The User Articulated Model

ERIC Educational Resources Information Center

Crabtree, Carlton A.

2010-01-01

Process models are often the basis for demonstrating improvement and compliance in software engineering organizations. A descriptive model is a type of process model describing the human activities in software development that actually occur. The purpose of a descriptive model is to provide a documented baseline for further process improvement…

Design, synthesis and in vitro evaluation of 18β-glycyrrhetinic acid derivatives for anticancer activity against human breast cancer cell line MCF-7.

PubMed

Yadav, Dharmendra Kumar; Kalani, Komal; Singh, Abhishek K; Khan, Feroz; Srivastava, Santosh K; Pant, Aditya B

2014-01-01

In the present work, QSAR model was derived by multiple linear regression method for the prediction of anticancer activity of 18β-glycyrrhetinic acid derivatives against the human breast cancer cell line MCF-7. The QSAR model for anti-proliferative activity against MCF-7 showed high correlation (r(2)=0.90 and rCV(2)=0.83) and indicated that chemical descriptors namely, dipole moment (debye), steric energy (kcal/mole), heat of formation (kcal/mole), ionization potential (eV), LogP, LUMO energy (eV) and shape index (basic kappa, order 3) correlate well with activity. The QSAR virtually predicted that active derivatives were first semi-synthesized and characterized on the basis of their (1)H and (13)C NMR spectroscopic data and then were in-vitro tested against MCF-7 cancer cell line. In particular, octylamide derivative of glycyrrhetinic acid GA-12 has marked cytotoxic activity against MCF-7 similar to that of standard anticancer drug paclitaxel. The biological assays of active derivative selected by virtual screening showed significant experimental activity.

Probabilistic image modeling with an extended chain graph for human activity recognition and image segmentation.

PubMed

Zhang, Lei; Zeng, Zhi; Ji, Qiang

2011-09-01

Chain graph (CG) is a hybrid probabilistic graphical model (PGM) capable of modeling heterogeneous relationships among random variables. So far, however, its application in image and video analysis is very limited due to lack of principled learning and inference methods for a CG of general topology. To overcome this limitation, we introduce methods to extend the conventional chain-like CG model to CG model with more general topology and the associated methods for learning and inference in such a general CG model. Specifically, we propose techniques to systematically construct a generally structured CG, to parameterize this model, to derive its joint probability distribution, to perform joint parameter learning, and to perform probabilistic inference in this model. To demonstrate the utility of such an extended CG, we apply it to two challenging image and video analysis problems: human activity recognition and image segmentation. The experimental results show improved performance of the extended CG model over the conventional directed or undirected PGMs. This study demonstrates the promise of the extended CG for effective modeling and inference of complex real-world problems.

Genetic control of the alternative pathway of complement in humans and age-related macular degeneration

PubMed Central

Hecker, Laura A.; Edwards, Albert O.; Ryu, Euijung; Tosakulwong, Nirubol; Baratz, Keith H.; Brown, William L.; Issa, Peter Charbel; Scholl, Hendrik P.; Pollok-Kopp, Beatrix; Schmid-Kubista, Katharina E.; Bailey, Kent R.; Oppermann, Martin

2010-01-01

Activation of the alternative pathway of complement is implicated in common neurodegenerative diseases including age-related macular degeneration (AMD). We explored the impact of common variation in genes encoding proteins of the alternative pathway on complement activation in human blood and in AMD. Genetic variation across the genes encoding complement factor H (CFH), factor B (CFB) and component 3 (C3) was determined. The influence of common haplotypes defining transcriptional and translational units on complement activation in blood was determined in a quantitative genomic association study. Individual haplotypes in CFH and CFB were associated with distinct and novel effects on plasma levels of precursors, regulators and activation products of the alternative pathway of complement in human blood. Further, genetic variation in CFH thought to influence cell surface regulation of complement did not alter plasma complement levels in human blood. Plasma markers of chronic activation (split-products Ba and C3d) and an activating enzyme (factor D) were elevated in AMD subjects. Most of the elevation in AMD was accounted for by the genetic variation controlling complement activation in human blood. Activation of the alternative pathway of complement in blood is under genetic control and increases with age. The genetic variation associated with increased activation of complement in human blood also increased the risk of AMD. Our data are consistent with a disease model in which genetic variation in the complement system increases the risk of AMD by a combination of systemic complement activation and abnormal regulation of complement activation in local tissues. PMID:19825847

Biomechanical Evaluation of an Electric Power-Assisted Bicycle by a Musculoskeletal Model

NASA Astrophysics Data System (ADS)

Takehara, Shoichiro; Murakami, Musashi; Hase, Kazunori

In this study, we construct an evaluation system for the muscular activity of the lower limbs when a human pedals an electric power-assisted bicycle. The evaluation system is composed of an electric power-assisted bicycle, a numerical simulator and a motion capture system. The electric power-assisted bicycle in this study has a pedal with an attached force sensor. The numerical simulator for pedaling motion is a musculoskeletal model of a human. The motion capture system measures the joint angles of the lower limb. We examine the influence of the electric power-assisted force on each muscle of the human trunk and legs. First, an experiment of pedaling motion is performed. Then, the musculoskeletal model is calculated by using the experimental data. We discuss the influence on each muscle by electric power-assist. It is found that the muscular activity is decreased by the electric power-assist bicycle, and the reduction of the muscular force required for pedaling motion was quantitatively shown for every muscle.

Modeling the target acquisition performance of active imaging systems

NASA Astrophysics Data System (ADS)

Espinola, Richard L.; Jacobs, Eddie L.; Halford, Carl E.; Vollmerhausen, Richard; Tofsted, David H.

2007-04-01

Recent development of active imaging system technology in the defense and security community have driven the need for a theoretical understanding of its operation and performance in military applications such as target acquisition. In this paper, the modeling of active imaging systems, developed at the U.S. Army RDECOM CERDEC Night Vision & Electronic Sensors Directorate, is presented with particular emphasis on the impact of coherent effects such as speckle and atmospheric scintillation. Experimental results from human perception tests are in good agreement with the model results, validating the modeling of coherent effects as additional noise sources. Example trade studies on the design of a conceptual active imaging system to mitigate deleterious coherent effects are shown.

Modeling the target acquisition performance of active imaging systems.

PubMed

Espinola, Richard L; Jacobs, Eddie L; Halford, Carl E; Vollmerhausen, Richard; Tofsted, David H

2007-04-02

Recent development of active imaging system technology in the defense and security community have driven the need for a theoretical understanding of its operation and performance in military applications such as target acquisition. In this paper, the modeling of active imaging systems, developed at the U.S. Army RDECOM CERDEC Night Vision & Electronic Sensors Directorate, is presented with particular emphasis on the impact of coherent effects such as speckle and atmospheric scintillation. Experimental results from human perception tests are in good agreement with the model results, validating the modeling of coherent effects as additional noise sources. Example trade studies on the design of a conceptual active imaging system to mitigate deleterious coherent effects are shown.

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.

Characterization of In Vitro Engineered Human Adipose Tissues: Relevant Adipokine Secretion and Impact of TNF-α

PubMed Central

Aubin, Kim; Safoine, Meryem; Proulx, Maryse; Audet-Casgrain, Marie-Alice; Côté, Jean-François; Têtu, Félix-André; Roy, Alphonse; Fradette, Julie

2015-01-01

Representative modelling of human adipose tissue functions is central to metabolic research. Tridimensional models able to recreate human adipogenesis in a physiological tissue-like context in vitro are still scarce. We describe the engineering of white adipose tissues reconstructed from their cultured adipose-derived stromal precursor cells. We hypothesize that these reconstructed tissues can recapitulate key functions of AT under basal and pro-inflammatory conditions. These tissues, featuring human adipocytes surrounded by stroma, were stable and metabolically active in long-term cultures (at least 11 weeks). Secretion of major adipokines and growth factors by the reconstructed tissues was determined and compared to media conditioned by human native fat explants. Interestingly, the secretory profiles of the reconstructed adipose tissues indicated an abundant production of leptin, PAI-1 and angiopoietin-1 proteins, while higher HGF levels were detected for the human fat explants. We next demonstrated the responsiveness of the tissues to the pro-inflammatory stimulus TNF-α, as reflected by modulation of MCP-1, NGF and HGF secretion, while VEGF and leptin protein expression did not vary. TNF-α exposure induced changes in gene expression for adipocyte metabolism-associated mRNAs such as SLC2A4, FASN and LIPE, as well as for genes implicated in NF-κB activation. Finally, this model was customized to feature adipocytes representative of progressive stages of differentiation, thereby allowing investigations using newly differentiated or more mature adipocytes. In conclusion, we produced tridimensional tissues engineered in vitro that are able to recapitulate key characteristics of subcutaneous white adipose tissue. These tissues are produced from human cells and their neo-synthesized matrix elements without exogenous or synthetic biomaterials. Therefore, they represent unique tools to investigate the effects of pharmacologically active products on human stromal cells, extracellular matrix and differentiated adipocytes, in addition to compounds modulating adipogenesis from precursor cells. PMID:26367137

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

Modelling large scale human activity in San Francisco

NASA Astrophysics Data System (ADS)

Gonzalez, Marta

2010-03-01

Diverse group of people with a wide variety of schedules, activities and travel needs compose our cities nowadays. This represents a big challenge for modeling travel behaviors in urban environments; those models are of crucial interest for a wide variety of applications such as traffic forecasting, spreading of viruses, or measuring human exposure to air pollutants. The traditional means to obtain knowledge about travel behavior is limited to surveys on travel journeys. The obtained information is based in questionnaires that are usually costly to implement and with intrinsic limitations to cover large number of individuals and some problems of reliability. Using mobile phone data, we explore the basic characteristics of a model of human travel: The distribution of agents is proportional to the population density of a given region, and each agent has a characteristic trajectory size contain information on frequency of visits to different locations. Additionally we use a complementary data set given by smart subway fare cards offering us information about the exact time of each passenger getting in or getting out of the subway station and the coordinates of it. This allows us to uncover the temporal aspects of the mobility. Since we have the actual time and place of individual's origin and destination we can understand the temporal patterns in each visited location with further details. Integrating two described data set we provide a dynamical model of human travels that incorporates different aspects observed empirically.

Progress on Reconstructed Human Skin Models for Allergy Research and Identifying Contact Sensitizers.

PubMed

Rodrigues Neves, Charlotte; Gibbs, Susan

2018-06-23

Contact with the skin is inevitable or desirable for daily life products such as cosmetics, hair dyes, perfumes, drugs, household products, and industrial and agricultural products. Whereas the majority of these products are harmless, a number can become metabolized and/or activate the immunological defense via innate and adaptive mechanisms resulting in sensitization and allergic contact dermatitis upon following exposures to the same substance. Therefore, strict safety (hazard) assessment of actives and ingredients in products and drugs applied to the skin is essential to determine I) whether the chemical is a potential sensitizer and if so II) what is the safe concentration for human exposure to prevent sensitization from occurring. Ex vivo skin is a valuable model for skin penetration studies but due to logistical and viability limitations the development of in vitro alternatives is required. The aim of this review is to give a clear overview of the organotypic in vitro skin models (reconstructed human epidermis, reconstructed human skin, immune competent skin models incorporating Langerhans Cells and T-cells, skin-on-chip) that are currently commercially available or which are being used in a laboratory research setting for hazard assessment of potential sensitizers and for investigating the mechanisms (sensitization key events 1-4) related to allergic contact dermatitis. The limitations of the models, their current applications, and their future potential in replacing animals in allergy-related science are discussed.

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.

Trajectory data analyses for pedestrian space-time activity study.

PubMed

Qi, Feng; Du, Fei

2013-02-25

It is well recognized that human movement in the spatial and temporal dimensions has direct influence on disease transmission(1-3). An infectious disease typically spreads via contact between infected and susceptible individuals in their overlapped activity spaces. Therefore, daily mobility-activity information can be used as an indicator to measure exposures to risk factors of infection. However, a major difficulty and thus the reason for paucity of studies of infectious disease transmission at the micro scale arise from the lack of detailed individual mobility data. Previously in transportation and tourism research detailed space-time activity data often relied on the time-space diary technique, which requires subjects to actively record their activities in time and space. This is highly demanding for the participants and collaboration from the participants greatly affects the quality of data(4). Modern technologies such as GPS and mobile communications have made possible the automatic collection of trajectory data. The data collected, however, is not ideal for modeling human space-time activities, limited by the accuracies of existing devices. There is also no readily available tool for efficient processing of the data for human behavior study. We present here a suite of methods and an integrated ArcGIS desktop-based visual interface for the pre-processing and spatiotemporal analyses of trajectory data. We provide examples of how such processing may be used to model human space-time activities, especially with error-rich pedestrian trajectory data, that could be useful in public health studies such as infectious disease transmission modeling. The procedure presented includes pre-processing, trajectory segmentation, activity space characterization, density estimation and visualization, and a few other exploratory analysis methods. Pre-processing is the cleaning of noisy raw trajectory data. We introduce an interactive visual pre-processing interface as well as an automatic module. Trajectory segmentation(5) involves the identification of indoor and outdoor parts from pre-processed space-time tracks. Again, both interactive visual segmentation and automatic segmentation are supported. Segmented space-time tracks are then analyzed to derive characteristics of one's activity space such as activity radius etc. Density estimation and visualization are used to examine large amount of trajectory data to model hot spots and interactions. We demonstrate both density surface mapping(6) and density volume rendering(7). We also include a couple of other exploratory data analyses (EDA) and visualizations tools, such as Google Earth animation support and connection analysis. The suite of analytical as well as visual methods presented in this paper may be applied to any trajectory data for space-time activity studies.

Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics.

PubMed

Migale, Roberta; MacIntyre, David A; Cacciatore, Stefano; Lee, Yun S; Hagberg, Henrik; Herbert, Bronwen R; Johnson, Mark R; Peebles, Donald; Waddington, Simon N; Bennett, Phillip R

2016-06-13

Preterm birth is now recognized as the primary cause of infant mortality worldwide. Interplay between hormonal and inflammatory signaling in the uterus modulates the onset of contractions; however, the relative contribution of each remains unclear. In this study we aimed to characterize temporal transcriptome changes in the uterus preceding term labor and preterm labor (PTL) induced by progesterone withdrawal or inflammation in the mouse and compare these findings with human data. Myometrium was collected at multiple time points during gestation and labor from three murine models of parturition: (1) term gestation; (2) PTL induced by RU486; and (3) PTL induced by lipopolysaccharide (LPS). RNA was extracted and cDNA libraries were prepared and sequenced using the Illumina HiSeq 2000 system. Resulting RNA-Seq data were analyzed using multivariate modeling approaches as well as pathway and causal network analyses and compared against human myometrial transcriptome data. We identified a core set of temporal myometrial gene changes associated with term labor and PTL in the mouse induced by either inflammation or progesterone withdrawal. Progesterone withdrawal initiated labor without inflammatory gene activation, yet LPS activation of uterine inflammation was sufficient to override the repressive effects of progesterone and induce a laboring phenotype. Comparison of human and mouse uterine transcriptomic datasets revealed that human labor more closely resembles inflammation-induced PTL in the mouse. Labor in the mouse can be achieved through inflammatory gene activation yet these changes are not a requisite for labor itself. Human labor more closely resembles LPS-induced PTL in the mouse, supporting an essential role for inflammatory mediators in human "functional progesterone withdrawal." This improved understanding of inflammatory and progesterone influence on the uterine transcriptome has important implications for the development of PTL prevention strategies.

Immunotherapy of Alzheimer's disease (AD): from murine models to anti-amyloid beta (Abeta) human monoclonal antibodies.

PubMed

Geylis, Valeria; Steinitz, Michael

2006-01-01

The deposition of amyloid beta (Abeta) protein is a key pathological feature in Alzheimer's disease (AD). In murine models of AD, both active and passive immunization against Abeta induce a marked reduction in amyloid brain burden and an improvement in cognitive functions. Preliminary results of a prematurely terminated clinical trial where AD patients were actively vaccinated with aggregated Abeta bear resemblance to those documented in murine models. Passive immunization of AD patients with anti-Abeta antibodies, in particular human antibodies, is a strategy that provides a more cautious management and control of any undesired side effects. Sera of all healthy adults contain anti-Abeta IgG autoimmune antibodies. Hence antigen-committed human B-cells are easily immortalized by Epstein-Barr virus (EBV) into anti-Abeta secreting cell lines. Two anti-Abeta human monoclonal antibodies which we recently prepared bind to the N-terminus of Abeta peptide and were shown to stain amyloid plaques in non-fixed brain sections from an AD patient. It is anticipated that specifically selected anti-Abeta human monoclonal antibodies could reduce and inhibit deposits of amyloid in brain while avoiding the cognitive decline that characterizes AD. In the future, this type of antibody may prove to be a promising immune therapy for the disease.

What should I do next? Using shared representations to solve interaction problems.

PubMed

Pezzulo, Giovanni; Dindo, Haris

2011-06-01

Studies on how "the social mind" works reveal that cognitive agents engaged in joint actions actively estimate and influence another's cognitive variables and form shared representations with them. (How) do shared representations enhance coordination? In this paper, we provide a probabilistic model of joint action that emphasizes how shared representations help solving interaction problems. We focus on two aspects of the model. First, we discuss how shared representations permit to coordinate at the level of cognitive variables (beliefs, intentions, and actions) and determine a coherent unfolding of action execution and predictive processes in the brains of two agents. Second, we discuss the importance of signaling actions as part of a strategy for sharing representations and the active guidance of another's actions toward the achievement of a joint goal. Furthermore, we present data from a human-computer experiment (the Tower Game) in which two agents (human and computer) have to build together a tower made of colored blocks, but only the human knows the constellation of the tower to be built (e.g., red-blue-red-blue-…). We report evidence that humans use signaling strategies that take another's uncertainty into consideration, and that in turn our model is able to use humans' actions as cues to "align" its representations and to select complementary actions.