Interactions between airway epithelial cells and dendritic cells during viral infections using an in vitro co-culture model

EPA Science Inventory

Rationale: Historically, single cell culture models have been limited in pathological and physiological relevance. A co-culture model of dendritic cells (DCs) and differentiated human airway epithelial cells was developed to examine potential interactions between these two cell t...

Capturing ecology in modeling approaches applied to environmental risk assessment of endocrine active chemicals in fish.

PubMed

Mintram, Kate S; Brown, A Ross; Maynard, Samuel K; Thorbek, Pernille; Tyler, Charles R

2018-02-01

Endocrine active chemicals (EACs) are widespread in freshwater environments and both laboratory and field based studies have shown reproductive effects in fish at environmentally relevant exposures. Environmental risk assessment (ERA) seeks to protect wildlife populations and prospective assessments rely on extrapolation from individual-level effects established for laboratory fish species to populations of wild fish using arbitrary safety factors. Population susceptibility to chemical effects, however, depends on exposure risk, physiological susceptibility, and population resilience, each of which can differ widely between fish species. Population models have significant potential to address these shortfalls and to include individual variability relating to life-history traits, demographic and density-dependent vital rates, and behaviors which arise from inter-organism and organism-environment interactions. Confidence in population models has recently resulted in the EU Commission stating that results derived from reliable models may be considered when assessing the relevance of adverse effects of EACs at the population level. This review critically assesses the potential risks posed by EACs for fish populations, considers the ecological factors influencing these risks and explores the benefits and challenges of applying population modeling (including individual-based modeling) in ERA for EACs in fish. We conclude that population modeling offers a way forward for incorporating greater environmental relevance in assessing the risks of EACs for fishes and for identifying key risk factors through sensitivity analysis. Individual-based models (IBMs) allow for the incorporation of physiological and behavioral endpoints relevant to EAC exposure effects, thus capturing both direct and indirect population-level effects.

A model for the solution structure of the rod arrestin tetramer.

PubMed

Hanson, Susan M; Dawson, Eric S; Francis, Derek J; Van Eps, Ned; Klug, Candice S; Hubbell, Wayne L; Meiler, Jens; Gurevich, Vsevolod V

2008-06-01

Visual rod arrestin has the ability to self-associate at physiological concentrations. We previously demonstrated that only monomeric arrestin can bind the receptor and that the arrestin tetramer in solution differs from that in the crystal. We employed the Rosetta docking software to generate molecular models of the physiologically relevant solution tetramer based on the monomeric arrestin crystal structure. The resulting models were filtered using the Rosetta energy function, experimental intersubunit distances measured with DEER spectroscopy, and intersubunit contact sites identified by mutagenesis and site-directed spin labeling. This resulted in a unique model for subsequent evaluation. The validity of the model is strongly supported by model-directed crosslinking and targeted mutagenesis that yields arrestin variants deficient in self-association. The structure of the solution tetramer explains its inability to bind rhodopsin and paves the way for experimental studies of the physiological role of rod arrestin self-association.

Developing a Physiologically-Based Pharmacokinetic Model Knowledgebase in Support of Provisional Model Construction.

PubMed

Lu, Jingtao; Goldsmith, Michael-Rock; Grulke, Christopher M; Chang, Daniel T; Brooks, Raina D; Leonard, Jeremy A; Phillips, Martin B; Hypes, Ethan D; Fair, Matthew J; Tornero-Velez, Rogelio; Johnson, Jeffre; Dary, Curtis C; Tan, Yu-Mei

2016-02-01

Developing physiologically-based pharmacokinetic (PBPK) models for chemicals can be resource-intensive, as neither chemical-specific parameters nor in vivo pharmacokinetic data are easily available for model construction. Previously developed, well-parameterized, and thoroughly-vetted models can be a great resource for the construction of models pertaining to new chemicals. A PBPK knowledgebase was compiled and developed from existing PBPK-related articles and used to develop new models. From 2,039 PBPK-related articles published between 1977 and 2013, 307 unique chemicals were identified for use as the basis of our knowledgebase. Keywords related to species, gender, developmental stages, and organs were analyzed from the articles within the PBPK knowledgebase. A correlation matrix of the 307 chemicals in the PBPK knowledgebase was calculated based on pharmacokinetic-relevant molecular descriptors. Chemicals in the PBPK knowledgebase were ranked based on their correlation toward ethylbenzene and gefitinib. Next, multiple chemicals were selected to represent exact matches, close analogues, or non-analogues of the target case study chemicals. Parameters, equations, or experimental data relevant to existing models for these chemicals and their analogues were used to construct new models, and model predictions were compared to observed values. This compiled knowledgebase provides a chemical structure-based approach for identifying PBPK models relevant to other chemical entities. Using suitable correlation metrics, we demonstrated that models of chemical analogues in the PBPK knowledgebase can guide the construction of PBPK models for other chemicals.

Developing a Physiologically-Based Pharmacokinetic Model Knowledgebase in Support of Provisional Model Construction

PubMed Central

Grulke, Christopher M.; Chang, Daniel T.; Brooks, Raina D.; Leonard, Jeremy A.; Phillips, Martin B.; Hypes, Ethan D.; Fair, Matthew J.; Tornero-Velez, Rogelio; Johnson, Jeffre; Dary, Curtis C.; Tan, Yu-Mei

2016-01-01

Developing physiologically-based pharmacokinetic (PBPK) models for chemicals can be resource-intensive, as neither chemical-specific parameters nor in vivo pharmacokinetic data are easily available for model construction. Previously developed, well-parameterized, and thoroughly-vetted models can be a great resource for the construction of models pertaining to new chemicals. A PBPK knowledgebase was compiled and developed from existing PBPK-related articles and used to develop new models. From 2,039 PBPK-related articles published between 1977 and 2013, 307 unique chemicals were identified for use as the basis of our knowledgebase. Keywords related to species, gender, developmental stages, and organs were analyzed from the articles within the PBPK knowledgebase. A correlation matrix of the 307 chemicals in the PBPK knowledgebase was calculated based on pharmacokinetic-relevant molecular descriptors. Chemicals in the PBPK knowledgebase were ranked based on their correlation toward ethylbenzene and gefitinib. Next, multiple chemicals were selected to represent exact matches, close analogues, or non-analogues of the target case study chemicals. Parameters, equations, or experimental data relevant to existing models for these chemicals and their analogues were used to construct new models, and model predictions were compared to observed values. This compiled knowledgebase provides a chemical structure-based approach for identifying PBPK models relevant to other chemical entities. Using suitable correlation metrics, we demonstrated that models of chemical analogues in the PBPK knowledgebase can guide the construction of PBPK models for other chemicals. PMID:26871706

Physiologically relevant organs on chips.

PubMed

Yum, Kyungsuk; Hong, Soon Gweon; Healy, Kevin E; Lee, Luke P

2014-01-01

Recent advances in integrating microengineering and tissue engineering have generated promising microengineered physiological models for experimental medicine and pharmaceutical research. Here we review the recent development of microengineered physiological systems, or also known as "ogans-on-chips", that reconstitute the physiologically critical features of specific human tissues and organs and their interactions. This technology uses microengineering approaches to construct organ-specific microenvironments, reconstituting tissue structures, tissue-tissue interactions and interfaces, and dynamic mechanical and biochemical stimuli found in specific organs, to direct cells to assemble into functional tissues. We first discuss microengineering approaches to reproduce the key elements of physiologically important, dynamic mechanical microenvironments, biochemical microenvironments, and microarchitectures of specific tissues and organs in microfluidic cell culture systems. This is followed by examples of microengineered individual organ models that incorporate the key elements of physiological microenvironments into single microfluidic cell culture systems to reproduce organ-level functions. Finally, microengineered multiple organ systems that simulate multiple organ interactions to better represent human physiology, including human responses to drugs, is covered in this review. This emerging organs-on-chips technology has the potential to become an alternative to 2D and 3D cell culture and animal models for experimental medicine, human disease modeling, drug development, and toxicology. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Infant digestion physiology and the relevance of in vitro biochemical models to test infant formula lipid digestion.

PubMed

Poquet, Laure; Wooster, Tim J

2016-08-01

Lipids play an important role in the diet of preterm and term infants providing a key energy source and essential lipid components for development. While a lot is known about adult lipid digestion, our understanding of infant digestion physiology is still incomplete, the greatest gap being on the biochemistry of the small intestine, particularly the activity and relative importance of the various lipases active in the intestine. The literature has been reviewed to identify the characteristics of lipid digestion of preterm and term infants, but also to better understand the physiology of the infant gastrointestinal tract compared to adults that impacts the absorption of lipids. The main differences are a higher gastric pH, submicellar bile salt concentration, a far more important role of gastric lipases as well as differences at the level of the intestinal barrier. Importantly, the consequences of improper in vitro replication of gastric digestions conditions (pH and lipase specificity) are demonstrated using examples from the most recent of studies. It is true that some animal models could be adapted to study infant lipid digestion physiology, however the ethical relevance of such models is questionable, hence the development of accurate in vitro models is a must. In vitro models that combine up to date knowledge of digestion biochemistry with intestinal cells in culture are the best choice to replicate digestion and absorption in infant population, this would allow the adaptation of infant formula for a better digestion and absorption of dietary lipids by preterm and term infants. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A Laparoscopic Swine Model of Noncompressible Torso Hemorrhage

DTIC Science & Technology

2014-01-01

Various porcine models of hemorrhage have been developed for civilian and military trauma research. However, the predominant contemporary models lack...significant predictors of mortality. CONCLUSION: This study describes a model of NCTH that reflects clinically relevant physiology in trauma and...uncontrolled hemorrhage. In addition, it quantitatively assesses the role of the swine contractile spleen in the described model. (J Trauma Acute Care Surg

Towards the virtual artery: a multiscale model for vascular physiology at the physics-chemistry-biology interface.

PubMed

Hoekstra, Alfons G; Alowayyed, Saad; Lorenz, Eric; Melnikova, Natalia; Mountrakis, Lampros; van Rooij, Britt; Svitenkov, Andrew; Závodszky, Gábor; Zun, Pavel

2016-11-13

This discussion paper introduces the concept of the Virtual Artery as a multiscale model for arterial physiology and pathologies at the physics-chemistry-biology (PCB) interface. The cellular level is identified as the mesoscopic level, and we argue that by coupling cell-based models with other relevant models on the macro- and microscale, a versatile model of arterial health and disease can be composed. We review the necessary ingredients, both models of arteries at many different scales, as well as generic methods to compose multiscale models. Next, we discuss how this can be combined into the virtual artery. Finally, we argue that the concept of models at the PCB interface could or perhaps should become a powerful paradigm, not only as in our case for studying physiology, but also for many other systems that have such PCB interfaces.This article is part of the themed issue 'Multiscale modelling at the physics-chemistry-biology interface'. © 2016 The Authors.

Modeling Diet-Induced Obesity with Obesity-Prone Rats: Implications for Studies in Females

PubMed Central

Giles, Erin D.; Jackman, Matthew R.; MacLean, Paul S.

2016-01-01

Obesity is a worldwide epidemic, and the comorbidities associated with obesity are numerous. Over the last two decades, we and others have employed an outbred rat model to study the development and persistence of obesity, as well as the metabolic complications that accompany excess weight. In this review, we summarize the strengths and limitations of this model and how it has been applied to further our understanding of human physiology in the context of weight loss and weight regain. We also discuss how the approach has been adapted over time for studies in females and female-specific physiological conditions, such as menopause and breast cancer. As excess weight and the accompanying metabolic complications have become common place in our society, we expect that this model will continue to provide a valuable translational tool to establish physiologically relevant connections to the basic science studies of obesity and body weight regulation. PMID:27933296

Controlled drug-release system based on pH-sensitive chloride-triggerable liposomes.

PubMed

Wehunt, Mark P; Winschel, Christine A; Khan, Ali K; Guo, Tai L; Abdrakhmanova, Galya R; Sidorov, Vladimir

2013-03-01

New pH-sensitive lipids were synthesized and utilized in formulations of liposomes suitable for controlled drug release. These liposomes contain various amounts of NaCl in the internal aqueous compartments. The release of the drug model is triggered by an application of HCl cotransporter and exogenous physiologically relevant NaCl solution. HCl cotransporter allows an uptake of HCl by liposomes to the extent of their being proportional to the transmembrane Cl(-) gradient. Therefore, each set of liposomes undergoes internal acidification, which, ultimately, leads to the hydrolysis of the pH-sensitive lipids and content release at the desired time. The developed system releases the drug model in a stepwise fashion, with the release stages separated by periods of low activity. These liposomes were found to be insensitive to physiological concentrations of human serum albumin and to be nontoxic to cells at concentrations exceeding pharmacological relevance. These results render this new drug-release model potentially suitable for in vivo applications.

Magnetic Resonance Imaging of Electrolysis.

PubMed Central

Meir, Arie; Hjouj, Mohammad; Rubinsky, Liel; Rubinsky, Boris

2015-01-01

This study explores the hypothesis that Magnetic Resonance Imaging (MRI) can image the process of electrolysis by detecting pH fronts. The study has relevance to real time control of cell ablation with electrolysis. To investigate the hypothesis we compare the following MR imaging sequences: T1 weighted, T2 weighted and Proton Density (PD), with optical images acquired using pH-sensitive dyes embedded in a physiological saline agar solution phantom treated with electrolysis and discrete measurements with a pH microprobe. We further demonstrate the biological relevance of our work using a bacterial E. Coli model, grown on the phantom. The results demonstrate the ability of MRI to image electrolysis produced pH changes in a physiological saline phantom and show that these changes correlate with cell death in the E. Coli model grown on the phantom. The results are promising and invite further experimental research. PMID:25659942

Biological role of bacterial inclusion bodies: a model for amyloid aggregation.

PubMed

García-Fruitós, Elena; Sabate, Raimon; de Groot, Natalia S; Villaverde, Antonio; Ventura, Salvador

2011-07-01

Inclusion bodies are insoluble protein aggregates usually found in recombinant bacteria when they are forced to produce heterologous protein species. These particles are formed by polypeptides that cross-interact through sterospecific contacts and that are steadily deposited in either the cell's cytoplasm or the periplasm. An important fraction of eukaryotic proteins form inclusion bodies in bacteria, which has posed major problems in the development of the biotechnology industry. Over the last decade, the fine dissection of the quality control system in bacteria and the recognition of the amyloid-like architecture of inclusion bodies have provided dramatic insights on the dynamic biology of these aggregates. We discuss here the relevant aspects, in the interface between cell physiology and structural biology, which make inclusion bodies unique models for the study of protein aggregation, amyloid formation and prion biology in a physiologically relevant background. © 2011 The Authors Journal compilation © 2011 FEBS.

The physiological equivalent temperature - a universal index for the biometeorological assessment of the thermal environment

NASA Astrophysics Data System (ADS)

Höppe, P.

With considerably increased coverage of weather information in the news media in recent years in many countries, there is also more demand for data that are applicable and useful for everyday life. Both the perception of the thermal component of weather as well as the appropriate clothing for thermal comfort result from the integral effects of all meteorological parameters relevant for heat exchange between the body and its environment. Regulatory physiological processes can affect the relative importance of meteorological parameters, e.g. wind velocity becomes more important when the body is sweating. In order to take into account all these factors, it is necessary to use a heat-balance model of the human body. The physiological equivalent temperature (PET) is based on the Munich Energy-balance Model for Individuals (MEMI), which models the thermal conditions of the human body in a physiologically relevant way. PET is defined as the air temperature at which, in a typical indoor setting (without wind and solar radiation), the heat budget of the human body is balanced with the same core and skin temperature as under the complex outdoor conditions to be assessed. This way PET enables a layperson to compare the integral effects of complex thermal conditions outside with his or her own experience indoors. On hot summer days, for example, with direct solar irradiation the PET value may be more than 20 K higher than the air temperature, on a windy day in winter up to 15 K lower.

Three-dimensional cell culture models for investigating human viruses.

PubMed

He, Bing; Chen, Guomin; Zeng, Yi

2016-10-01

Three-dimensional (3D) culture models are physiologically relevant, as they provide reproducible results, experimental flexibility and can be adapted for high-throughput experiments. Moreover, these models bridge the gap between traditional two-dimensional (2D) monolayer cultures and animal models. 3D culture systems have significantly advanced basic cell science and tissue engineering, especially in the fields of cell biology and physiology, stem cell research, regenerative medicine, cancer research, drug discovery, and gene and protein expression studies. In addition, 3D models can provide unique insight into bacteriology, virology, parasitology and host-pathogen interactions. This review summarizes and analyzes recent progress in human virological research with 3D cell culture models. We discuss viral growth, replication, proliferation, infection, virus-host interactions and antiviral drugs in 3D culture models.

Tunable Collagen I Hydrogels for Engineered Physiological Tissue Micro-Environments

PubMed Central

Antoine, Elizabeth E.; Vlachos, Pavlos P.; Rylander, Marissa N.

2015-01-01

Collagen I hydrogels are commonly used to mimic the extracellular matrix (ECM) for tissue engineering applications. However, the ability to design collagen I hydrogels similar to the properties of physiological tissues has been elusive. This is primarily due to the lack of quantitative correlations between multiple fabrication parameters and resulting material properties. This study aims to enable informed design and fabrication of collagen hydrogels in order to reliably and reproducibly mimic a variety of soft tissues. We developed empirical predictive models relating fabrication parameters with material and transport properties. These models were obtained through extensive experimental characterization of these properties, which include compression modulus, pore and fiber diameter, and diffusivity. Fabrication parameters were varied within biologically relevant ranges and included collagen concentration, polymerization pH, and polymerization temperature. The data obtained from this study elucidates previously unknown fabrication-property relationships, while the resulting equations facilitate informed a priori design of collagen hydrogels with prescribed properties. By enabling hydrogel fabrication by design, this study has the potential to greatly enhance the utility and relevance of collagen hydrogels in order to develop physiological tissue microenvironments for a wide range of tissue engineering applications. PMID:25822731

Low-shear modeled microgravity: a global environmental regulatory signal affecting bacterial gene expression, physiology, and pathogenesis

NASA Technical Reports Server (NTRS)

Nickerson, Cheryl A.; Ott, C. Mark; Wilson, James W.; Ramamurthy, Rajee; LeBlanc, Carly L.; Honer zu Bentrup, Kerstin; Hammond, Timothy; Pierson, Duane L.

2003-01-01

Bacteria inhabit an impressive variety of ecological niches and must adapt constantly to changing environmental conditions. While numerous environmental signals have been examined for their effect on bacteria, the effects of mechanical forces such as shear stress and gravity have only been investigated to a limited extent. However, several important studies have demonstrated a key role for the environmental signals of low shear and/or microgravity in the regulation of bacterial gene expression, physiology, and pathogenesis [Chem. Rec. 1 (2001) 333; Appl. Microbiol. Biotechnol. 54 (2000) 33; Appl. Environ. Microbiol. 63 (1997) 4090; J. Ind. Microbiol. 18 (1997) 22; Curr. Microbiol. 34(4) (1997) 199; Appl. Microbiol. Biotechnol. 56(3-4) (2001) 384; Infect Immun. 68(6) (2000) 3147; Cell 109(7) (2002) 913; Appl. Environ. Microbiol. 68(11) (2002) 5408; Proc. Natl. Acad. Sci. U. S. A. 99(21) (2002) 13807]. The response of bacteria to these environmental signals, which are similar to those encountered during prokaryotic life cycles, may provide insight into bacterial adaptations to physiologically relevant conditions. This review focuses on the current and potential future research trends aimed at understanding the effect of the mechanical forces of low shear and microgravity analogues on different bacterial parameters. In addition, this review also discusses the use of microgravity technology to generate physiologically relevant human tissue models for research in bacterial pathogenesis.

Integrating multi-scale data to create a virtual physiological mouse heart.

PubMed

Land, Sander; Niederer, Steven A; Louch, William E; Sejersted, Ole M; Smith, Nicolas P

2013-04-06

While the virtual physiological human (VPH) project has made great advances in human modelling, many of the tools and insights developed as part of this initiative are also applicable for facilitating mechanistic understanding of the physiology of a range of other species. This process, in turn, has the potential to provide human relevant insights via a different scientific path. Specifically, the increasing use of mice in experimental research, not yet fully complemented by a similar increase in computational modelling, is currently missing an important opportunity for using and interpreting this growing body of experimental data to improve our understanding of cardiac function. This overview describes our work to address this issue by creating a virtual physiological mouse model of the heart. We describe the similarities between human- and mouse-focused modelling, including the reuse of VPH tools, and the development of methods for investigating parameter sensitivity that are applicable across species. We show how previous results using this approach have already provided important biological insights, and how these can also be used to advance VPH heart models. Finally, we show an example application of this approach to test competing multi-scale hypotheses by investigating variations in length-dependent properties of cardiac muscle.

Integrating multi-scale data to create a virtual physiological mouse heart

PubMed Central

Land, Sander; Niederer, Steven A.; Louch, William E.; Sejersted, Ole M.; Smith, Nicolas P.

2013-01-01

While the virtual physiological human (VPH) project has made great advances in human modelling, many of the tools and insights developed as part of this initiative are also applicable for facilitating mechanistic understanding of the physiology of a range of other species. This process, in turn, has the potential to provide human relevant insights via a different scientific path. Specifically, the increasing use of mice in experimental research, not yet fully complemented by a similar increase in computational modelling, is currently missing an important opportunity for using and interpreting this growing body of experimental data to improve our understanding of cardiac function. This overview describes our work to address this issue by creating a virtual physiological mouse model of the heart. We describe the similarities between human- and mouse-focused modelling, including the reuse of VPH tools, and the development of methods for investigating parameter sensitivity that are applicable across species. We show how previous results using this approach have already provided important biological insights, and how these can also be used to advance VPH heart models. Finally, we show an example application of this approach to test competing multi-scale hypotheses by investigating variations in length-dependent properties of cardiac muscle. PMID:24427525

Mathematical modeling and spectrum analysis of the physiological patello-femoral pulse train produced by slow knee movement.

PubMed

Zhang, Y T; Frank, C B; Rangayyan, R M; Bell, G D

1992-09-01

Analysis of vibration signals emitted by the knee joint has the potential for the development of a noninvasive procedure for the diagnosis and monitoring of knee pathology. In order to obtain as much information as possible from the power density spectrum of the knee vibration signal, it is necessary to identify the physiological factors (or physiologically relevant parameters) that shape the spectrum. This paper presents a mathematical model for knee vibration signals, in particular the physiological patello-femoral pulse (PFP) train produced by slow knee movement. It demonstrates through the mathematical model that the repetition rate of the physiological PFP train introduces repeated peaks in the power spectrum, and that it affects the spectrum mainly at low frequencies. The theoretical results also show that the spectral peaks at multiples of the PFP repetition rate become more evident when the variance of the interpulse interval (IPI) is small, and that these spectral peaks shift toward higher frequencies with increasing PFP repetition rates. To evaluate the mathematical model, a simulation algorithm was developed, which generates PFP signals with adjustable repetition rate and IPI variance. Signals generated by simulation were seen to possess representative spectral characteristics typically observed in physiological PFP signals. This simulation procedure allows an interactive examination of several factors which affect the PFP train spectrum. Finally, in vivo measurements of physiological PFP signals of normal volunteers are presented. Results of simulations and analysis of signals recorded from human subjects support the mathematical model's prediction that the IPI statistics play a very significant role in determining the low-end power spectrum of the physiological PFP signal.(ABSTRACT TRUNCATED AT 250 WORDS)

Overview of exocrine pancreatic pathobiology.

PubMed

Pandiri, Arun R

2014-01-01

Exocrine pancreas is a source of several enzymes that are essential for the digestive process. The exocrine pancreatic secretion is tightly regulated by the neuroendocrine system. The endocrine pancreas is tightly integrated anatomically and physiologically with the exocrine pancreas and modulates its function. Compound-induced pancreatitis is not a common event in toxicology or drug development, but it becomes a significant liability when encountered. Understanding the species-specific differences in physiology is essential to understand the underlying pathobiology of pancreatic disease in animal models and its relevance to human disease. This review will mainly focus on understanding the morphology and physiology of the pancreas, unique islet-exocrine interactions, and pancreatitis.

Murine epithelial cells: isolation and culture.

PubMed

Davidson, Donald J; Gray, Michael A; Kilanowski, Fiona M; Tarran, Robert; Randell, Scott H; Sheppard, David N; Argent, Barry E; Dorin, Julia R

2004-08-01

We describe an air-liquid interface primary culture method for murine tracheal epithelial cells on semi-permeable membranes, forming polarized epithelia with a high transepithelial resistance, differentiation to ciliated and secretory cells, and physiologically appropriate expression of key genes and ion channels. We also describe the isolation of primary murine nasal epithelial cells for patch-clamp analysis, generating polarised cells with physiologically appropriate distribution and ion channel expression. These methods enable more physiologically relevant analysis of murine airway epithelial cells in vitro and ex vivo, better utilisation of transgenic mouse models of human pulmonary diseases, and have been approved by the European Working Group on CFTR expression.

Dealing with Diversity in Computational Cancer Modeling

PubMed Central

Johnson, David; McKeever, Steve; Stamatakos, Georgios; Dionysiou, Dimitra; Graf, Norbert; Sakkalis, Vangelis; Marias, Konstantinos; Wang, Zhihui; Deisboeck, Thomas S.

2013-01-01

This paper discusses the need for interconnecting computational cancer models from different sources and scales within clinically relevant scenarios to increase the accuracy of the models and speed up their clinical adaptation, validation, and eventual translation. We briefly review current interoperability efforts drawing upon our experiences with the development of in silico models for predictive oncology within a number of European Commission Virtual Physiological Human initiative projects on cancer. A clinically relevant scenario, addressing brain tumor modeling that illustrates the need for coupling models from different sources and levels of complexity, is described. General approaches to enabling interoperability using XML-based markup languages for biological modeling are reviewed, concluding with a discussion on efforts towards developing cancer-specific XML markup to couple multiple component models for predictive in silico oncology. PMID:23700360

A new standard model for milk yield in dairy cows based on udder physiology at the milking-session level.

PubMed

Gasqui, Patrick; Trommenschlager, Jean-Marie

2017-08-21

Milk production in dairy cow udders is a complex and dynamic physiological process that has resisted explanatory modelling thus far. The current standard model, Wood's model, is empirical in nature, represents yield in daily terms, and was published in 1967. Here, we have developed a dynamic and integrated explanatory model that describes milk yield at the scale of the milking session. Our approach allowed us to formally represent and mathematically relate biological features of known relevance while accounting for stochasticity and conditional elements in the form of explicit hypotheses, which could then be tested and validated using real-life data. Using an explanatory mathematical and biological model to explore a physiological process and pinpoint potential problems (i.e., "problem finding"), it is possible to filter out unimportant variables that can be ignored, retaining only those essential to generating the most realistic model possible. Such modelling efforts are multidisciplinary by necessity. It is also helpful downstream because model results can be compared with observed data, via parameter estimation using maximum likelihood and statistical testing using model residuals. The process in its entirety yields a coherent, robust, and thus repeatable, model.

Comparison of reduced models for blood flow using Runge–Kutta discontinuous Galerkin methods

PubMed Central

Puelz, Charles; Čanić, Sunčica; Rivière, Béatrice; Rusin, Craig G.

2017-01-01

One–dimensional blood flow models take the general form of nonlinear hyperbolic systems but differ in their formulation. One class of models considers the physically conserved quantities of mass and momentum, while another class describes mass and velocity. Further, the averaging process employed in the model derivation requires the specification of the axial velocity profile; this choice differentiates models within each class. Discrepancies among differing models have yet to be investigated. In this paper, we comment on some theoretical differences among models and systematically compare them for physiologically relevant vessel parameters, network topology, and boundary data. In particular, the effect of the velocity profile is investigated in the cases of both smooth and discontinuous solutions, and a recommendation for a physiological model is provided. The models are discretized by a class of Runge–Kutta discontinuous Galerkin methods. PMID:29081563

Effect of noisy stimulation on neurobiological sensitization systems and its role for normal and pathological physiology

NASA Astrophysics Data System (ADS)

Huber, Martin; Braun, Hans; Krieg, J.\\:Urgen-Christian

2004-03-01

Sensitization is discussed as an important phenomenon playing a role in normal physiology but also with respect to the initiation and progression of a variety of neuropsychiatric disorders such as epilepsia, substance-related disorders or recurrent affective disorders. The relevance to understand the dynamics of sensitization phenomena is emphasized by recent findings that even single stimulations can induce longlasting changes in biological systems. To address specific questions associated with the sensitization dynamics, we use a computational approach and develop simple but physiologically-plausible models. In the present study we examine the effect of noisy stimulation on sensitization development in the model. We consider sub- and suprathresold stimulations with varying noise intensities and determine as response measures the (i) absolute number of stimulus-induced sensitzations and (ii) the temporal relsation of stimulus-sensitization coupling. The findings indicate that stochastic effects including stochastic resonance might well contribute to the physiology of sensitization mechanisms under both nomal and pathological conditions.

ECVAM and new technologies for toxicity testing.

PubMed

Bouvier d'Yvoire, Michel; Bremer, Susanne; Casati, Silvia; Ceridono, Mara; Coecke, Sandra; Corvi, Raffaella; Eskes, Chantra; Gribaldo, Laura; Griesinger, Claudius; Knaut, Holger; Linge, Jens P; Roi, Annett; Zuang, Valérie

2012-01-01

The development of alternative empirical (testing) and non-empirical (non-testing) methods to traditional toxicological tests for complex human health effects is a tremendous task. Toxicants may potentially interfere with a vast number of physiological mechanisms thereby causing disturbances on various levels of complexity of human physiology. Only a limited number of mechanisms relevant for toxicity ('pathways' of toxicity) have been identified with certainty so far and, presumably, many more mechanisms by which toxicants cause adverse effects remain to be identified. Recapitulating in empirical model systems (i.e., in vitro test systems) all those relevant physiological mechanisms prone to be disturbed by toxicants and relevant for causing the toxicity effect in question poses an enormous challenge. First, the mechanism(s) of action of toxicants in relation to the most relevant adverse effects of a specific human health endpoint need to be identified. Subsequently, these mechanisms need to be modeled in reductionist test systems that allow assessing whether an unknown substance may operate via a specific (array of) mechanism(s). Ideally, such test systems should be relevant for the species of interest, i.e., based on human cells or modeling mechanisms present in humans. Since much of our understanding about toxicity mechanisms is based on studies using animal model systems (i.e., experimental animals or animal-derived cells), designing test systems that model mechanisms relevant for the human situation may be limited by the lack of relevant information from basic research. New technologies from molecular biology and cell biology, as well as progress in tissue engineering, imaging techniques and automated testing platforms hold the promise to alleviate some of the traditional difficulties associated with improving toxicity testing for complex endpoints. Such new technologies are expected (1) to accelerate the identification of toxicity pathways with human relevance that need to be modeled in test methods for toxicity testing (2) to enable the reconstruction of reductionist test systems modeling at a reduced level of complexity the target system/organ of interest (e.g., through tissue engineering, use of human-derived cell lines and stem cells etc.), (3) to allow the measurement of specific mechanisms relevant for a given health endpoint in such test methods (e.g., through gene and protein expression, changes in metabolites, receptor activation, changes in neural activity etc.), (4) to allow to measure toxicity mechanisms at higher throughput rates through the use of automated testing. In this chapter, we discuss the potential impact of new technologies on the development, optimization and use of empirical testing methods, grouped according to important toxicological endpoints. We highlight, from an ECVAM perspective, the areas of topical toxicity, skin absorption, reproductive and developmental toxicity, carcinogenicity/genotoxicity, sensitization, hematopoeisis and toxicokinetics and discuss strategic developments including ECVAM's database service on alternative methods. Neither the areas of toxicity discussed nor the highlighted new technologies represent comprehensive listings which would be an impossible endeavor in the context of a book chapter. However, we feel that these areas are of utmost importance and we predict that new technologies are likely to contribute significantly to test development in these fields. We summarize which new technologies are expected to contribute to the development of new alternative testing methods over the next few years and point out current and planned ECVAM projects for each of these areas.

Nutritional Systems Biology Modeling: From Molecular Mechanisms to Physiology

PubMed Central

de Graaf, Albert A.; Freidig, Andreas P.; De Roos, Baukje; Jamshidi, Neema; Heinemann, Matthias; Rullmann, Johan A.C.; Hall, Kevin D.; Adiels, Martin; van Ommen, Ben

2009-01-01

The use of computational modeling and simulation has increased in many biological fields, but despite their potential these techniques are only marginally applied in nutritional sciences. Nevertheless, recent applications of modeling have been instrumental in answering important nutritional questions from the cellular up to the physiological levels. Capturing the complexity of today's important nutritional research questions poses a challenge for modeling to become truly integrative in the consideration and interpretation of experimental data at widely differing scales of space and time. In this review, we discuss a selection of available modeling approaches and applications relevant for nutrition. We then put these models into perspective by categorizing them according to their space and time domain. Through this categorization process, we identified a dearth of models that consider processes occurring between the microscopic and macroscopic scale. We propose a “middle-out” strategy to develop the required full-scale, multilevel computational models. Exhaustive and accurate phenotyping, the use of the virtual patient concept, and the development of biomarkers from “-omics” signatures are identified as key elements of a successful systems biology modeling approach in nutrition research—one that integrates physiological mechanisms and data at multiple space and time scales. PMID:19956660

Alteration of pancreatic carcinoma and promyeloblastic cell adhesion in liver microvasculature by co-culture of hepatocytes, hepatic stellate cells and endothelial cells in a physiologically-relevant model.

PubMed

Danoy, Mathieu; Shinohara, Marie; Rizki-Safitri, Astia; Collard, Dominique; Senez, Vincent; Sakai, Yasuyuki

2017-04-18

In vitro models of the liver microvasculature, especially with respect to cancer cell extravasation, should include not only endothelial and cancer cells but also surrounding cells to mimic the physiological situation. To this end, in the present study, we established a physiologically-relevant hierarchical co-culture model by stacking layers of primary rat hepatocytes (Hep), hepatic stellate cells embedded in collagen gel (LX-2) and endothelial cells (HUVECs) on a specially designed oxygen-permeable polydimethylsiloxane PDMS bottom plate. The model was used to investigate the role and contribution of each of the three cell types in pancreatic cancer and promyeloblast cell adhesion. In particular, we showed an increase in albumin production by the primary hepatocytes and in the consumption of the produced vascular endothelial growth factors (VEGFs). Furthermore, in co-culture, the HUVECs exhibited a mature vascular endothelial and non-inflamed phenotype, as evidenced by Stabilin-1, lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), intercellular adhesion molecule (ICAM-1), and vascular adhesion protein-1 (VAP-1) expression. The HUVECs were also successfully activated with an inflammatory cytokine and their ICAM-1 response was found to be higher in monoculture compared to co-culture. Additionally, the adhesion of MiaPaCa-2 pancreatic cancer cells and HL60 promyeloblasts was tested in both cases (i.e.: activation or not by an inflammatory cytokine). It has been found that their adhesion was always reduced in the co-culture model. These results highlight the importance of integrating hepatic stellate cells in the design of biomimetic models of the hepatic endothelial barrier.

Comparing mechanistic and empirical approaches to modeling the thermal niche of almond

NASA Astrophysics Data System (ADS)

Parker, Lauren E.; Abatzoglou, John T.

2017-09-01

Delineating locations that are thermally viable for cultivating high-value crops can help to guide land use planning, agronomics, and water management. Three modeling approaches were used to identify the potential distribution and key thermal constraints on on almond cultivation across the southwestern United States (US), including two empirical species distribution models (SDMs)—one using commonly used bioclimatic variables (traditional SDM) and the other using more physiologically relevant climate variables (nontraditional SDM)—and a mechanistic model (MM) developed using published thermal limitations from field studies. While models showed comparable results over the majority of the domain, including over existing croplands with high almond density, the MM suggested the greatest potential for the geographic expansion of almond cultivation, with frost susceptibility and insufficient heat accumulation being the primary thermal constraints in the southwestern US. The traditional SDM over-predicted almond suitability in locations shown by the MM to be limited by frost, whereas the nontraditional SDM showed greater agreement with the MM in these locations, indicating that incorporating physiologically relevant variables in SDMs can improve predictions. Finally, opportunities for geographic expansion of almond cultivation under current climatic conditions in the region may be limited, suggesting that increasing production may rely on agronomical advances and densifying current almond plantations in existing locations.

Sex Differences in Androgen Regulation of Metabolism in Nonhuman Primates.

PubMed

True, Cadence; Abbott, David H; Roberts, Charles T; Varlamov, Oleg

2017-01-01

The in-depth characterization of sex differences relevant to human physiology requires the judicious use of a variety of animal models and human clinical data. Nonhuman primates (NHPs) represent an important experimental system that bridges rodent studies and clinical investigations. NHP studies have been especially useful in understanding the role of sex hormones in development and metabolism and also allow the elucidation of the effects of pertinent dietary influences on physiology pertinent to disease states such as obesity and diabetes. This chapter summarizes the current state of our understanding of androgen effects on male and female NHP metabolism relevant to hypogonadism in human males and polycystic ovary syndrome in human females. This review will also focus on the interaction between altered androgen levels and dietary restriction and excess, in particular the Western-style diet that underlies significant human pathophysiology.

SEX DIFFERENCES IN ANDROGEN REGULATION OF METABOLISM IN NONHUMAN PRIMATES

PubMed Central

True, Cadence; Abbott, David H.; Roberts, Charles T.; Varlamov, Oleg

2018-01-01

The in-depth characterization of sex differences relevant to human physiology requires the judicious use of a variety of animal models and human clinical data. Nonhuman primates (NHPs) represent an important experimental system that bridges rodent studies and clinical investigations. NHP studies have been especially useful in understanding the role of sex hormones in development and metabolism and also allow the elucidation of the effects of pertinent dietary influences on physiology pertinent to disease states such as obesity and diabetes. This chapter summarizes the current state of our understanding of androgen effects on male and female NHP metabolism relevant to hypogonadism in human males and polycystic ovary syndrome in human females, as well as the interaction between altered androgen levels and dietary restriction and excess, in particular the western-style diet that underlies significant human pathophysiology. PMID:29224110

THE IMPACT OF SCALING FACTOR VARIABILITY ON RISK-RELEVANT TOXICOKINETIC OUTCOMES IN CHILDREN: A CASE STUDY USING BROMODICHLOROMETHANE (BDCM)

EPA Science Inventory

Biotransformation rates (Vmax) extrapolated from in vitro data are used increasingly in human physiologically based pharmacokinetic (PBPK) models. Extrapolation of Vmax from in vitro data requires use of scaling factors, including mg of microsomal protein/g liver (MPPGL), nmol of...

Studying Biology to Understand Risk: Dosimetry Models and Quantitative Adverse Outcome Pathways

EPA Science Inventory

Confidence in the quantitative prediction of risk is increased when the prediction is based to as great an extent as possible on the relevant biological factors that constitute the pathway from exposure to adverse outcome. With the first examples now over 40 years old, physiologi...

Development of physiologically based toxicokinetic (PBTK) models for fish: Confessions of a former fish physiologist

EPA Science Inventory

Abstract: In toxicology, as in pharmacology, the fundamental paradigm used to describe chemical interactions with biological systems is the dose-response relationship. Depending on the chemical mode of action, however, the relevant expression of dose may any one of several metri...

The formation of quiescent glomerular endothelial cell monolayer in vitro is strongly dependent on the choice of extracellular matrix coating

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

Pajęcka, Kamilla, E-mail: kpaj@novonordisk.com; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus; Nielsen, Malik Nygaard

Background and aims: Nephropathy involves pathophysiological changes to the glomerulus. The primary glomerular endothelial cells (GEnCs) have emerged as an important tool for studying glomerulosclerotic mechanisms and in the screening process for drug-candidates. The success of the studies is dependent on the quality of the cell model. Therefore, we set out to establish an easy, reproducible model of the quiescent endothelial monolayer with the use of commercially available extracellular matrices (ECMs). Methods: Primary hGEnCs were seeded on various ECMs. Cell adhesion was monitored by an impedance sensing system. The localization of junctional proteins was assessed by immunofluorescence and the barriermore » function by passage of fluorescent dextrans and magnitude of VEGF response. Results: All ECM matrices except recombinant human laminin 111 (rhLN111) supported comparable cell proliferation. Culturing hGEnCs on rhLN521, rhLN511 or fibronectin resulted in a physiologically relevant barrier to 70 kDa dextrans which was 82% tighter than that formed on collagen type IV. Furthermore, only hGEnCs cultured on rhLN521 or rhLN511 showed plasma-membrane localized zonula occludens-1 and vascular endothelial cadherin indicative of proper tight and adherens junctions (AJ). Conclusion: We recommend culturing hGEnCs on the mature glomerular basement membrane laminin - rhLN521 – which, as the only commercially available ECM, promotes all of the characteristics of the quiescent hGEnC monolayer: cobblestone morphology, well-defined AJs and physiological perm-selectivity. - Highlights: • rhLN521, rhLN511 and hFN assure physiologically relevant permeability. • rhLN521 and rhLN511 ensure best cell morphology and adherens junction formation. • Collagen IV and I based coating results in disorganized hGEnC monolayer. • Physiologically relevant ECM may lead to down-regulation of self-produced matrices.« less

Using in vitro models for expression profiling studies on ethanol and drugs of abuse.

PubMed

Thibault, Christelle; Hassan, Sajida; Miles, Michael

2005-03-01

The use of expression profiling with microarrays offers great potential for studying the mechanisms of action of drugs of abuse. Studies with the intact nervous system seem likely to be most relevant to understanding the mechanisms of drug abuse-related behaviours. However, the use of expression profiling with in vitro culture models offers significant advantages for identifying details of cellular signalling actions and toxicity for drugs of abuse. This study discusses general issues of the use of microarrays and cell culture models for studies on drugs of abuse. Specific results from existing studies are also discussed, providing clear examples of relevance for in vitro studies on ethanol, nicotine, opiates, cannabinoids and hallucinogens such as LSD. In addition to providing details on signalling mechanisms relevant to the neurobiology of drugs of abuse, microarray studies on a variety of cell culture systems have also provided important information on mechanisms of cellular/organ toxicity with drugs of abuse. Efforts to integrate genomic studies on drugs of abuse with both in vivo and in vitro models offer the potential for novel mechanistic rigor and physiological relevance.

Thermal mechanisms of interaction of radiofrequency energy with biological systems with relevance to exposure guidelines.

PubMed

Foster, Kenneth R; Glaser, Roland

2007-06-01

This article reviews thermal mechanisms of interaction between radiofrequency (RF) fields and biological systems, focusing on theoretical frameworks that are of potential use in setting guidelines for human exposure to RF energy. Several classes of thermal mechanisms are reviewed that depend on the temperature increase or rate of temperature increase and the relevant dosimetric considerations associated with these mechanisms. In addition, attention is drawn to possible molecular and physiological reactions that could be induced by temperature elevations below 0.1 degrees, which are normal physiological responses to heat, and to the so-called microwave auditory effect, which is a physiologically trivial effect resulting from thermally-induced acoustic stimuli. It is suggested that some reported "nonthermal" effects of RF energy may be thermal in nature; also that subtle thermal effects from RF energy exist but have no consequence to health or safety. It is proposed that future revisions of exposure guidelines make more explicit use of thermal models and empirical data on thermal effects in quantifying potential hazards of RF fields.

Interpretation of physiological indicators of motivation: Caveats and recommendations.

PubMed

Richter, Michael; Slade, Kate

2017-09-01

Motivation scientists employing physiological measures to gather information about motivation-related states are at risk of committing two fundamental errors: overstating the inferences that can be drawn from their physiological measures and circular reasoning. We critically discuss two complementary approaches, Cacioppo and colleagues' model of psychophysiological relations and construct validation theory, to highlight the conditions under which these errors are committed and provide guidance on how to avoid them. In particular, we demonstrate that the direct inference from changes in a physiological measure to changes in a motivation-related state requires the demonstration that the measure is not related to other relevant psychological states. We also point out that circular reasoning can be avoided by separating the definition of the motivation-related state from the hypotheses that are empirically tested. Copyright © 2017 Elsevier B.V. All rights reserved.

Applying systems biology methods to the study of human physiology in extreme environments

PubMed Central

2013-01-01

Systems biology is defined in this review as ‘an iterative process of computational model building and experimental model revision with the aim of understanding or simulating complex biological systems’. We propose that, in practice, systems biology rests on three pillars: computation, the omics disciplines and repeated experimental perturbation of the system of interest. The number of ethical and physiologically relevant perturbations that can be used in experiments on healthy humans is extremely limited and principally comprises exercise, nutrition, infusions (e.g. Intralipid), some drugs and altered environment. Thus, we argue that systems biology and environmental physiology are natural symbionts for those interested in a system-level understanding of human biology. However, despite excellent progress in high-altitude genetics and several proteomics studies, systems biology research into human adaptation to extreme environments is in its infancy. A brief description and overview of systems biology in its current guise is given, followed by a mini review of computational methods used for modelling biological systems. Special attention is given to high-altitude research, metabolic network reconstruction and constraint-based modelling. PMID:23849719

A theoretical framework to model DSC-MRI data acquired in the presence of contrast agent extravasation

NASA Astrophysics Data System (ADS)

Quarles, C. C.; Gochberg, D. F.; Gore, J. C.; Yankeelov, T. E.

2009-10-01

Dynamic susceptibility contrast (DSC) MRI methods rely on compartmentalization of the contrast agent such that a susceptibility gradient can be induced between the contrast-containing compartment and adjacent spaces, such as between intravascular and extravascular spaces. When there is a disruption of the blood-brain barrier, as is frequently the case with brain tumors, a contrast agent leaks out of the vasculature, resulting in additional T1, T2 and T*2 relaxation effects in the extravascular space, thereby affecting the signal intensity time course and reducing the reliability of the computed hemodynamic parameters. In this study, a theoretical model describing these dynamic intra- and extravascular T1, T2 and T*2 relaxation interactions is proposed. The applicability of using the proposed model to investigate the influence of relevant MRI pulse sequences (e.g. echo time, flip angle), and physical (e.g. susceptibility calibration factors, pre-contrast relaxation rates) and physiological parameters (e.g. permeability, blood flow, compartmental volume fractions) on DSC-MRI signal time curves is demonstrated. Such a model could yield important insights into the biophysical basis of contrast-agent-extravasastion-induced effects on measured DSC-MRI signals and provide a means to investigate pulse sequence optimization and appropriate data analysis methods for the extraction of physiologically relevant imaging metrics.

A Microfabricated Platform for Generating Physiologically-Relevant Hepatocyte Zonation

NASA Astrophysics Data System (ADS)

McCarty, William J.; Usta, O. Berk; Yarmush, Martin L.

2016-05-01

In vitro liver models have been important tools for more than 40 years for academic research and preclinical toxicity screening by the pharmaceutical industry. Hepatocytes, the highly metabolic parenchymal cells of the liver, are efficient at different metabolic chemistries depending on their relative spatial location along the sinusoid from the portal triad to the central vein. Although replicating hepatocyte metabolic zonation is vitally important for physiologically-relevant in vitro liver tissue and organ models, it is most often completely overlooked. Here, we demonstrate the creation of spatially-controlled zonation across multiple hepatocyte metabolism levels through the application of precise concentration gradients of exogenous hormone (insulin and glucagon) and chemical (3-methylcholanthrene) induction agents in a microfluidic device. Observed gradients in glycogen storage via periodic acid-Schiff staining, urea production via carbamoyl phosphatase synthetase I staining, and cell viability after exposure to allyl alcohol and acetaminophen demonstrated the in vitro creation of hepatocyte carbohydrate, nitrogen, alcohol degradation, and drug conjugation metabolic zonation. This type of advanced control system will be crucial for studies evaluating drug metabolism and toxicology using in vitro constructs.

Correlation between vortices and wall shear stress in a curved artery model under pulsatile flow conditions

NASA Astrophysics Data System (ADS)

Cox, Christopher; Plesniak, Michael W.

2017-11-01

One of the most physiologically relevant factors within the cardiovascular system is the wall shear stress. The wall shear stress affects endothelial cells via mechanotransduction and atherosclerotic regions are strongly correlated with curvature and branching in the human vasculature, where the shear stress is both oscillatory and multidirectional. Also, the combined effect of curvature and pulsatility in cardiovascular flows produces unsteady vortices. In this work, our goal is to assess the correlation between multiple vortex pairs and wall shear stress. To accomplish this, we use an in-house high-order flux reconstruction Navier-Stokes solver to simulate pulsatile flow of a Newtonian blood-analog fluid through a rigid 180° curved artery model. We use a physiologically relevant flow rate and generate results using both fully developed and uniform entrance conditions, the latter motivated by the fact that flow upstream to a curved artery may not be fully developed. Under these two inflow conditions, we characterize the evolution of various vortex pairs and their subsequent effect on several wall shear stress metrics. Supported by GW Center for Biomimetics and Bioinspired Engineering.

Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block

PubMed Central

Hu, Yu-Feng; Dawkins, James Frederick; Cho, Hee Cheol; Marbán, Eduardo; Cingolani, Eugenio

2016-01-01

Somatic reprogramming by reexpression of the embryonic transcription factor T-box 18 (TBX18) converts cardiomyocytes into pacemaker cells. We hypothesized that this could be a viable therapeutic avenue for pacemaker-dependent patients afflicted with device-related complications, and therefore tested whether adenoviral TBX18 gene transfer could create biological pacemaker activity in vivo in a large-animal model of complete heart block. Biological pacemaker activity, originating from the intramyocardial injection site, was evident in TBX18-transduced animals starting at day 2 and persisted for the duration of the study (14 days) with minimal backup electronic pacemaker use. Relative to controls transduced with a reporter gene, TBX18-transduced animals exhibited enhanced autonomic responses and physiologically superior chronotropic support of physical activity. Induced sinoatrial node cells could be identified by their distinctive morphology at the site of injection in TBX18-transduced animals, but not in controls. No local or systemic safety concerns arose. Thus, minimally invasive TBX18 gene transfer creates physiologically relevant pacemaker activity in complete heart block, providing evidence for therapeutic somatic reprogramming in a clinically relevant disease model. PMID:25031269

The relationship between immediate relevant basic science knowledge and clinical knowledge: physiology knowledge and transthoracic echocardiography image interpretation.

PubMed

Nielsen, Dorte Guldbrand; Gotzsche, Ole; Sonne, Ole; Eika, Berit

2012-10-01

Two major views on the relationship between basic science knowledge and clinical knowledge stand out; the Two-world view seeing basic science and clinical science as two separate knowledge bases and the encapsulated knowledge view stating that basic science knowledge plays an overt role being encapsulated in the clinical knowledge. However, resent research has implied that a more complex relationship between the two knowledge bases exists. In this study, we explore the relationship between immediate relevant basic science (physiology) and clinical knowledge within a specific domain of medicine (echocardiography). Twenty eight medical students in their 3rd year and 45 physicians (15 interns, 15 cardiology residents and 15 cardiology consultants) took a multiple-choice test of physiology knowledge. The physicians also viewed images of a transthoracic echocardiography (TTE) examination and completed a checklist of possible pathologies found. A total score for each participant was calculated for the physiology test, and for all physicians also for the TTE checklist. Consultants scored significantly higher on the physiology test than did medical students and interns. A significant correlation between physiology test scores and TTE checklist scores was found for the cardiology residents only. Basic science knowledge of immediate relevance for daily clinical work expands with increased work experience within a specific domain. Consultants showed no relationship between physiology knowledge and TTE interpretation indicating that experts do not use basic science knowledge in routine daily practice, but knowledge of immediate relevance remains ready for use.

Alanyl-glutamine dipeptide restores the cytoprotective stress proteome of mesothelial cells exposed to peritoneal dialysis fluids.

PubMed

Kratochwill, Klaus; Boehm, Michael; Herzog, Rebecca; Lichtenauer, Anton Michael; Salzer, Elisabeth; Lechner, Michael; Kuster, Lilian; Bergmeister, Konstantin; Rizzi, Andreas; Mayer, Bernd; Aufricht, Christoph

2012-03-01

Exposure of mesothelial cells to peritoneal dialysis fluids (PDF) results in cytoprotective cellular stress responses (CSR) that counteract PDF-induced damage. In this study, we tested the hypothesis that the CSR may be inadequate in relevant models of peritoneal dialysis (PD) due to insufficient levels of glutamine, resulting in increased vulnerability against PDF cytotoxicity. We particularly investigated the role of alanyl-glutamine (Ala-Gln) dipeptide on the cytoprotective PDF stress proteome. Adequacy of CSR was investigated in two human in vitro models (immortalized cell line MeT-5A and mesothelial cells derived from peritoneal effluent of uraemic patients) following exposure to heat-sterilized glucose-based PDF (PD4-Dianeal, Baxter) diluted with medium and, in a comparative proteomics approach, at different levels of glutamine ranging from depletion (0 mM) via physiological (0.7 mM) to pharmacological levels (8 mM administered as Ala-Gln). Despite severe cellular injury, expression of cytoprotective proteins was dampened upon PDF exposure at physiological glutamine levels, indicating an inadequate CSR. Depletion of glutamine aggravated cell injury and further reduced the CSR, whereas addition of Ala-Gln at pharmacological level restored an adequate CSR, decreasing cellular damage in both PDF exposure systems. Ala-Gln specifically stimulated chaperoning activity, and cytoprotective processes were markedly enhanced in the PDF stress proteome. Taken together, this study demonstrates an inadequate CSR of mesothelial cells following PDF exposure associated with low and physiological levels of glutamine, indicating a new and potentially relevant pathomechanism. Supplementation of PDF with pharmacological doses of Ala-Gln restored the cytoprotective stress proteome, resulting in improved resistance of mesothelial cells to exposure to PDF. Future work will study the clinical relevance of CSR-mediated cytoprotection.

Combining the ‘bottom up’ and ‘top down’ approaches in pharmacokinetic modelling: fitting PBPK models to observed clinical data

PubMed Central

Tsamandouras, Nikolaos; Rostami-Hodjegan, Amin; Aarons, Leon

2015-01-01

Pharmacokinetic models range from being entirely exploratory and empirical, to semi-mechanistic and ultimately complex physiologically based pharmacokinetic (PBPK) models. This choice is conditional on the modelling purpose as well as the amount and quality of the available data. The main advantage of PBPK models is that they can be used to extrapolate outside the studied population and experimental conditions. The trade-off for this advantage is a complex system of differential equations with a considerable number of model parameters. When these parameters cannot be informed from in vitro or in silico experiments they are usually optimized with respect to observed clinical data. Parameter estimation in complex models is a challenging task associated with many methodological issues which are discussed here with specific recommendations. Concepts such as structural and practical identifiability are described with regards to PBPK modelling and the value of experimental design and sensitivity analyses is sketched out. Parameter estimation approaches are discussed, while we also highlight the importance of not neglecting the covariance structure between model parameters and the uncertainty and population variability that is associated with them. Finally the possibility of using model order reduction techniques and minimal semi-mechanistic models that retain the physiological-mechanistic nature only in the parts of the model which are relevant to the desired modelling purpose is emphasized. Careful attention to all the above issues allows us to integrate successfully information from in vitro or in silico experiments together with information deriving from observed clinical data and develop mechanistically sound models with clinical relevance. PMID:24033787

Emerging In Vitro Liver Technologies for Drug Metabolism and Inter-Organ Interactions

PubMed Central

Bale, Shyam Sundhar; Moore, Laura

2016-01-01

In vitro liver models provide essential information for evaluating drug metabolism, metabolite formation, and hepatotoxicity. Interfacing liver models with other organ models could provide insights into the desirable as well as unintended systemic side effects of therapeutic agents and their metabolites. Such information is invaluable for drug screening processes particularly in the context of secondary organ toxicity. While interfacing of liver models with other organ models has been achieved, platforms that effectively provide human-relevant precise information are needed. In this concise review, we discuss the current state-of-the-art of liver-based multiorgan cell culture platforms primarily from a drug and metabolite perspective, and highlight the importance of media-to-cell ratio in interfacing liver models with other organ models. In addition, we briefly discuss issues related to development of optimal liver models that include recent advances in hepatic cell lines, stem cells, and challenges associated with primary hepatocyte-based liver models. Liver-based multiorgan models that achieve physiologically relevant coupling of different organ models can have a broad impact in evaluating drug efficacy and toxicity, as well as mechanistic investigation of human-relevant disease conditions. PMID:27049038

PACAP receptor pharmacology and agonist bias: analysis in primary neurons and glia from the trigeminal ganglia and transfected cells

PubMed Central

Walker, C S; Sundrum, T; Hay, D L

2014-01-01

Background and Purpose A major challenge in the development of new medicines targeting GPCRs is the ability to quantify drug action in physiologically relevant models. Primary cell models that closely resemble the clinically relevant in vivo site of drug action are important translational tools in drug development. However, pharmacological studies in these models are generally very limited due to the methodology used. Experimental Approach We used a neuropeptide system to demonstrate the applicability of using highly sensitive signalling assays in primary cells. We quantified the action of pituitary adenylate cyclase-activating peptide (PACAP)-38, PACAP-27 and vasoactive intestinal polypeptide in primary cultures of neurons and glia derived from rat trigeminal ganglia (TG), comparing our observations to transfected cells. Key Results PACAP-responsive receptors in rat trigeminal neurons, glia and transfected PAC1n receptors were pharmacologically distinct. PACAP-38, but not PACAP-27, activated ERK in glia, while both forms stimulated cellular cAMP production. PACAP(6–38) also displayed cell-type-dependent, agonist-specific, antagonism. Conclusions and Implications The complexity of PACAP pharmacology in the TG may help to direct, more effectively, the development of disease treatments targeting the PACAP receptor. We suggest that these methodologies are broadly applicable to other primary cell types of human or animal origin, and that our approach may allow more thorough characterization of ligand properties in physiologically relevant cell types. PMID:24303997

Development of a Full-Thickness Human Gingiva Equivalent Constructed from Immortalized Keratinocytes and Fibroblasts.

PubMed

Buskermolen, Jeroen K; Reijnders, Christianne M A; Spiekstra, Sander W; Steinberg, Thorsten; Kleverlaan, Cornelis J; Feilzer, Albert J; Bakker, Astrid D; Gibbs, Susan

2016-08-01

Organotypic models make it possible to investigate the unique properties of oral mucosa in vitro. For gingiva, the use of human primary keratinocytes (KC) and fibroblasts (Fib) is limited due to the availability and size of donor biopsies. The use of physiologically relevant immortalized cell lines would solve these problems. The aim of this study was to develop fully differentiated human gingiva equivalents (GE) constructed entirely from cell lines, to compare them with the primary cell counterpart (Prim), and to test relevance in an in vitro wound healing assay. Reconstructed gingiva epithelium on a gingiva fibroblast-populated collagen hydrogel was constructed from cell lines (keratinocytes: TERT or HPV immortalized; fibroblasts: TERT immortalized) and compared to GE-Prim and native gingiva. GE were characterized by immunohistochemical staining for proliferation (Ki67), epithelial differentiation (K10, K13), and basement membrane (collagen type IV and laminin 5). To test functionality of GE-TERT, full-thickness wounds were introduced. Reepithelialization, fibroblast repopulation of hydrogel, metabolic activity (MTT assay), and (pro-)inflammatory cytokine release (enzyme-linked immunosorbent assay) were assessed during wound closure over 7 days. Significant differences in basal KC cytokine secretion (IL-1α, IL-18, and CXCL8) were only observed between KC-Prim and KC-HPV. When Fib-Prim and Fib-TERT were stimulated with TNF-α, no differences were observed regarding cytokine secretion (IL-6, CXCL8, and CCL2). GE-TERT histology, keratin, and basement membrane protein expression very closely represented native gingiva and GE-Prim. In contrast, the epithelium of GE made with HPV-immortalized KC was disorganized, showing suprabasal proliferating cells, limited keratinocyte differentiation, and the absence of basement membrane proteins. When a wound was introduced into the more physiologically relevant GE-TERT model, an immediate inflammatory response (IL-6, CCL2, and CXCL8) was observed followed by complete reepithelialization. Seven days after wounding, tissue integrity, metabolic activity, and cytokine levels had returned to the prewounded state. In conclusion, immortalized human gingiva KC and fibroblasts can be used to make physiologically relevant GE, which resemble either the healthy gingiva or a neoplastic disease model. These organotypic models will provide valuable tools to investigate oral mucosa biology and can also be used as an animal alternative for drug targeting, vaccination studies, microbial biofilm studies, and testing new therapeutics.

Development of a Full-Thickness Human Gingiva Equivalent Constructed from Immortalized Keratinocytes and Fibroblasts

PubMed Central

Buskermolen, Jeroen K.; Reijnders, Christianne M.A.; Spiekstra, Sander W.; Steinberg, Thorsten; Kleverlaan, Cornelis J.; Feilzer, Albert J.; Bakker, Astrid D.

2016-01-01

Organotypic models make it possible to investigate the unique properties of oral mucosa in vitro. For gingiva, the use of human primary keratinocytes (KC) and fibroblasts (Fib) is limited due to the availability and size of donor biopsies. The use of physiologically relevant immortalized cell lines would solve these problems. The aim of this study was to develop fully differentiated human gingiva equivalents (GE) constructed entirely from cell lines, to compare them with the primary cell counterpart (Prim), and to test relevance in an in vitro wound healing assay. Reconstructed gingiva epithelium on a gingiva fibroblast-populated collagen hydrogel was constructed from cell lines (keratinocytes: TERT or HPV immortalized; fibroblasts: TERT immortalized) and compared to GE-Prim and native gingiva. GE were characterized by immunohistochemical staining for proliferation (Ki67), epithelial differentiation (K10, K13), and basement membrane (collagen type IV and laminin 5). To test functionality of GE-TERT, full-thickness wounds were introduced. Reepithelialization, fibroblast repopulation of hydrogel, metabolic activity (MTT assay), and (pro-)inflammatory cytokine release (enzyme-linked immunosorbent assay) were assessed during wound closure over 7 days. Significant differences in basal KC cytokine secretion (IL-1α, IL-18, and CXCL8) were only observed between KC-Prim and KC-HPV. When Fib-Prim and Fib-TERT were stimulated with TNF-α, no differences were observed regarding cytokine secretion (IL-6, CXCL8, and CCL2). GE-TERT histology, keratin, and basement membrane protein expression very closely represented native gingiva and GE-Prim. In contrast, the epithelium of GE made with HPV-immortalized KC was disorganized, showing suprabasal proliferating cells, limited keratinocyte differentiation, and the absence of basement membrane proteins. When a wound was introduced into the more physiologically relevant GE-TERT model, an immediate inflammatory response (IL-6, CCL2, and CXCL8) was observed followed by complete reepithelialization. Seven days after wounding, tissue integrity, metabolic activity, and cytokine levels had returned to the prewounded state. In conclusion, immortalized human gingiva KC and fibroblasts can be used to make physiologically relevant GE, which resemble either the healthy gingiva or a neoplastic disease model. These organotypic models will provide valuable tools to investigate oral mucosa biology and can also be used as an animal alternative for drug targeting, vaccination studies, microbial biofilm studies, and testing new therapeutics. PMID:27406216

Physiologically Relevant Prosthetic Limb Movement Feedback for Upper and Lower Extremity Amputees

DTIC Science & Technology

2016-10-01

upper arm (elbow movement), Upper leg (knee movement) and lower leg ( ankle movement) to provide a physiologically relevant sense of limb movement...Additionally a BOA cable tensioning system is passed through these plates and anchored to the external surface of the socket. When tension is applied the

Knowledge Retention of Exercise Physiology Content between Athletes and Nonathletes

ERIC Educational Resources Information Center

Clark, Brian; Webster, Collin; Druger, Marvin

2006-01-01

Based on the idea that learning is linked to personal relevance, this study examined knowledge retention of exercise physiology content between college athletes and nonathletes. No differences were observed between the groups. These findings have implications on understanding the relationship between personal relevance and memory. (Contains 1…

In vitro microfluidic models of tumor microenvironment to screen transport of drugs and nanoparticles.

PubMed

Ozcelikkale, Altug; Moon, Hye-Ran; Linnes, Michael; Han, Bumsoo

2017-09-01

Advances in nanotechnology have enabled numerous types of nanoparticles (NPs) to improve drug delivery to tumors. While many NP systems have been proposed, their clinical translation has been less than anticipated primarily due to failure of current preclinical evaluation techniques to adequately model the complex interactions between the NP and physiological barriers of tumor microenvironment. This review focuses on microfluidic tumor models for characterization of delivery efficacy and toxicity of cancer nanomedicine. Microfluidics offer significant advantages over traditional macroscale cell cultures by enabling recapitulation of tumor microenvironment through precise control of physiological cues such as hydrostatic pressure, shear stress, oxygen, and nutrient gradients. Microfluidic systems have recently started to be adapted for screening of drugs and NPs under physiologically relevant settings. So far the two primary application areas of microfluidics in this area have been high-throughput screening using traditional culture settings such as single cells or multicellular tumor spheroids, and mimicry of tumor microenvironment for study of cancer-related cell-cell and cell-matrix interactions. These microfluidic technologies are also useful in modeling specific steps in NP delivery to tumor and characterize NP transport properties and outcomes by systematic variation of physiological conditions. Ultimately, it will be possible to design drug-screening platforms uniquely tailored for individual patient physiology using microfluidics. These in vitro models can contribute to development of precision medicine by enabling rapid and patient-specific evaluation of cancer nanomedicine. WIREs Nanomed Nanobiotechnol 2017, 9:e1460. doi: 10.1002/wnan.1460 For further resources related to this article, please visit the WIREs website. © 2017 Wiley Periodicals, Inc.

Porcine models of digestive disease: the future of large animal translational research

PubMed Central

Gonzalez, Liara M.; Moeser, Adam J.; Blikslager, Anthony T.

2015-01-01

There is increasing interest in non-rodent translational models for the study of human disease. The pig, in particular, serves as a useful animal model for the study of pathophysiological conditions relevant to the human intestine. This review assesses currently used porcine models of gastrointestinal physiology and disease and provides a rationale for the use of these models for future translational studies. The pig has proven its utility for the study of fundamental disease conditions such as ischemia/ reperfusion injury, stress-induced intestinal dysfunction, and short bowel syndrome. Pigs have also shown great promise for the study of intestinal barrier function, surgical tissue manipulation and intervention, as well as biomaterial implantation and tissue transplantation. Advantages of pig models highlighted by these studies include the physiological similarity to human intestine as well as to mechanisms of human disease. Emerging future directions for porcine models of human disease include the fields of transgenics and stem cell biology, with exciting implications for regenerative medicine. PMID:25655839

Efficient solvers for coupled models in respiratory mechanics.

PubMed

Verdugo, Francesc; Roth, Christian J; Yoshihara, Lena; Wall, Wolfgang A

2017-02-01

We present efficient preconditioners for one of the most physiologically relevant pulmonary models currently available. Our underlying motivation is to enable the efficient simulation of such a lung model on high-performance computing platforms in order to assess mechanical ventilation strategies and contributing to design more protective patient-specific ventilation treatments. The system of linear equations to be solved using the proposed preconditioners is essentially the monolithic system arising in fluid-structure interaction (FSI) extended by additional algebraic constraints. The introduction of these constraints leads to a saddle point problem that cannot be solved with usual FSI preconditioners available in the literature. The key ingredient in this work is to use the idea of the semi-implicit method for pressure-linked equations (SIMPLE) for getting rid of the saddle point structure, resulting in a standard FSI problem that can be treated with available techniques. The numerical examples show that the resulting preconditioners approach the optimal performance of multigrid methods, even though the lung model is a complex multiphysics problem. Moreover, the preconditioners are robust enough to deal with physiologically relevant simulations involving complex real-world patient-specific lung geometries. The same approach is applicable to other challenging biomedical applications where coupling between flow and tissue deformations is modeled with additional algebraic constraints. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Applications of minimal physiologically-based pharmacokinetic models

PubMed Central

Cao, Yanguang

2012-01-01

Conventional mammillary models are frequently used for pharmacokinetic (PK) analysis when only blood or plasma data are available. Such models depend on the quality of the drug disposition data and have vague biological features. An alternative minimal-physiologically-based PK (minimal-PBPK) modeling approach is proposed which inherits and lumps major physiologic attributes from whole-body PBPK models. The body and model are represented as actual blood and tissue usually total body weight) volumes, fractions (fd) of cardiac output with Fick’s Law of Perfusion, tissue/blood partitioning (Kp), and systemic or intrinsic clearance. Analyzing only blood or plasma concentrations versus time, the minimal-PBPK models parsimoniously generate physiologically-relevant PK parameters which are more easily interpreted than those from mam-millary models. The minimal-PBPK models were applied to four types of therapeutic agents and conditions. The models well captured the human PK profiles of 22 selected beta-lactam antibiotics allowing comparison of fitted and calculated Kp values. Adding a classical hepatic compartment with hepatic blood flow allowed joint fitting of oral and intravenous (IV) data for four hepatic elimination drugs (dihydrocodeine, verapamil, repaglinide, midazolam) providing separate estimates of hepatic intrinsic clearance, non-hepatic clearance, and pre-hepatic bioavailability. The basic model was integrated with allometric scaling principles to simultaneously describe moxifloxacin PK in five species with common Kp and fd values. A basic model assigning clearance to the tissue compartment well characterized plasma concentrations of six monoclonal antibodies in human subjects, providing good concordance of predictions with expected tissue kinetics. The proposed minimal-PBPK modeling approach offers an alternative and more rational basis for assessing PK than compartmental models. PMID:23179857

Behavioral abnormalities in prion protein knockout mice and the potential relevance of PrPc for the cytoskeleton

USDA-ARS?s Scientific Manuscript database

The cellular prion protein (PrPC) is a highly conserved protein, which is anchored to the outer surface of the plasma membrane. Even though its physiological function has already been investigated in different cell or mouse models where PrPC expression is either up-regulated or depleted, its exact p...

Mode of Action and Human Relevance Analysis for Nuclear Receptor-Mediated Liver Toxicity: A Case Study with Phenobarbital as a Model Constitutive Androstane Receptor (CAR) Activator

EPA Science Inventory

The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are key nuclear receptors involved in the regulation of cellular responses. to exposure to many xenobiotics and various physiological processes. Phenobarbital (PB) is a non­ genotoxic i...

A first step towards a consensus static in vitro model for simulating full-term infant digestion.

PubMed

Ménard, O; Bourlieu, C; De Oliveira, S C; Dellarosa, N; Laghi, L; Carrière, F; Capozzi, F; Dupont, D; Deglaire, A

2018-02-01

In vitro alternatives to clinical trials are used for studying human food digestion. For simulating infant digestion, only a few models, lacking physiological relevance, are available. Thanks to an extensive literature review of the in vivo infant digestive conditions, a gastrointestinal static in vitro model was developed for infants born at term and aged 28days. The model was applied to the digestion of a commercial infant formula. Kinetics of digestion, as well as the structural evolution, were compared with those obtained while submitting the same formula to the adult international consensus protocol of in vitro static digestion. The kinetics of proteolysis and lipolysis differed according to the physiological stage resulting mainly from the reduced level of enzymes and bile salts, as well as the higher gastric pH in the infant model. This in vitro static model of infant digestion is of interest for scientists, food or pharmaceutical manufacturers. Copyright © 2017 Elsevier Ltd. All rights reserved.

Influence of physiological phenology on the seasonal pattern of ecosystem respiration in deciduous forests.

PubMed

Migliavacca, Mirco; Reichstein, Markus; Richardson, Andrew D; Mahecha, Miguel D; Cremonese, Edoardo; Delpierre, Nicolas; Galvagno, Marta; Law, Beverly E; Wohlfahrt, Georg; Black, T Andrew; Carvalhais, Nuno; Ceccherini, Guido; Chen, Jiquan; Gobron, Nadine; Koffi, Ernest; Munger, J William; Perez-Priego, Oscar; Robustelli, Monica; Tomelleri, Enrico; Cescatti, Alessandro

2015-01-01

Understanding the environmental and biotic drivers of respiration at the ecosystem level is a prerequisite to further improve scenarios of the global carbon cycle. In this study we investigated the relevance of physiological phenology, defined as seasonal changes in plant physiological properties, for explaining the temporal dynamics of ecosystem respiration (RECO) in deciduous forests. Previous studies showed that empirical RECO models can be substantially improved by considering the biotic dependency of RECO on the short-term productivity (e.g., daily gross primary production, GPP) in addition to the well-known environmental controls of temperature and water availability. Here, we use a model-data integration approach to investigate the added value of physiological phenology, represented by the first temporal derivative of GPP, or alternatively of the fraction of absorbed photosynthetically active radiation, for modeling RECO at 19 deciduous broadleaved forests in the FLUXNET La Thuile database. The new data-oriented semiempirical model leads to an 8% decrease in root mean square error (RMSE) and a 6% increase in the modeling efficiency (EF) of modeled RECO when compared to a version of the model that does not consider the physiological phenology. The reduction of the model-observation bias occurred mainly at the monthly time scale, and in spring and summer, while a smaller reduction was observed at the annual time scale. The proposed approach did not improve the model performance at several sites, and we identified as potential causes the plant canopy heterogeneity and the use of air temperature as a driver of ecosystem respiration instead of soil temperature. However, in the majority of sites the model-error remained unchanged regardless of the driving temperature. Overall, our results point toward the potential for improving current approaches for modeling RECO in deciduous forests by including the phenological cycle of the canopy. © 2014 John Wiley & Sons Ltd.

An action potential-driven model of soleus muscle activation dynamics for locomotor-like movements

NASA Astrophysics Data System (ADS)

Kim, Hojeong; Sandercock, Thomas G.; Heckman, C. J.

2015-08-01

Objective. The goal of this study was to develop a physiologically plausible, computationally robust model for muscle activation dynamics (A(t)) under physiologically relevant excitation and movement. Approach. The interaction of excitation and movement on A(t) was investigated comparing the force production between a cat soleus muscle and its Hill-type model. For capturing A(t) under excitation and movement variation, a modular modeling framework was proposed comprising of three compartments: (1) spikes-to-[Ca2+]; (2) [Ca2+]-to-A; and (3) A-to-force transformation. The individual signal transformations were modeled based on physiological factors so that the parameter values could be separately determined for individual modules directly based on experimental data. Main results. The strong dependency of A(t) on excitation frequency and muscle length was found during both isometric and dynamically-moving contractions. The identified dependencies of A(t) under the static and dynamic conditions could be incorporated in the modular modeling framework by modulating the model parameters as a function of movement input. The new modeling approach was also applicable to cat soleus muscles producing waveforms independent of those used to set the model parameters. Significance. This study provides a modeling framework for spike-driven muscle responses during movement, that is suitable not only for insights into molecular mechanisms underlying muscle behaviors but also for large scale simulations.

Guiding the osteogenic fate of mouse and human mesenchymal stem cells through feedback system control.

PubMed

Honda, Yoshitomo; Ding, Xianting; Mussano, Federico; Wiberg, Akira; Ho, Chih-Ming; Nishimura, Ichiro

2013-12-05

Stem cell-based disease modeling presents unique opportunities for mechanistic elucidation and therapeutic targeting. The stable induction of fate-specific differentiation is an essential prerequisite for stem cell-based strategy. Bone morphogenetic protein 2 (BMP-2) initiates receptor-regulated Smad phosphorylation, leading to the osteogenic differentiation of mesenchymal stromal/stem cells (MSC) in vitro; however, it requires supra-physiological concentrations, presenting a bottleneck problem for large-scale drug screening. Here, we report the use of a double-objective feedback system control (FSC) with a differential evolution (DE) algorithm to identify osteogenic cocktails of extrinsic factors. Cocktails containing significantly reduced doses of BMP-2 in combination with physiologically relevant doses of dexamethasone, ascorbic acid, beta-glycerophosphate, heparin, retinoic acid and vitamin D achieved accelerated in vitro mineralization of mouse and human MSC. These results provide insight into constructive approaches of FSC to determine the applicable functional and physiological environment for MSC in disease modeling, drug screening and tissue engineering.

Predicting physiological capacity of human load carriage - a review.

PubMed

Drain, Jace; Billing, Daniel; Neesham-Smith, Daniel; Aisbett, Brad

2016-01-01

This review article aims to evaluate a proposed maximum acceptable work duration model for load carriage tasks. It is contended that this concept has particular relevance to physically demanding occupations such as military and firefighting. Personnel in these occupations are often required to perform very physically demanding tasks, over varying time periods, often involving load carriage. Previous research has investigated concepts related to physiological workload limits in occupational settings (e.g. industrial). Evidence suggests however, that existing (unloaded) workload guidelines are not appropriate for load carriage tasks. The utility of this model warrants further work to enable prediction of load carriage durations across a range of functional workloads for physically demanding occupations. If the maximum duration for which personnel can physiologically sustain a load carriage task could be accurately predicted, commanders and supervisors could better plan for and manage tasks to ensure operational imperatives were met whilst minimising health risks for their workers. Copyright © 2015 Elsevier Ltd and The Ergonomics Society. All rights reserved.

Guiding the osteogenic fate of mouse and human mesenchymal stem cells through feedback system control

PubMed Central

Honda, Yoshitomo; Ding, Xianting; Mussano, Federico; Wiberg, Akira; Ho, Chih-ming; Nishimura, Ichiro

2013-01-01

Stem cell-based disease modeling presents unique opportunities for mechanistic elucidation and therapeutic targeting. The stable induction of fate-specific differentiation is an essential prerequisite for stem cell-based strategy. Bone morphogenetic protein 2 (BMP-2) initiates receptor-regulated Smad phosphorylation, leading to the osteogenic differentiation of mesenchymal stromal/stem cells (MSC) in vitro; however, it requires supra-physiological concentrations, presenting a bottleneck problem for large-scale drug screening. Here, we report the use of a double-objective feedback system control (FSC) with a differential evolution (DE) algorithm to identify osteogenic cocktails of extrinsic factors. Cocktails containing significantly reduced doses of BMP-2 in combination with physiologically relevant doses of dexamethasone, ascorbic acid, beta-glycerophosphate, heparin, retinoic acid and vitamin D achieved accelerated in vitro mineralization of mouse and human MSC. These results provide insight into constructive approaches of FSC to determine the applicable functional and physiological environment for MSC in disease modeling, drug screening and tissue engineering. PMID:24305548

The promise of the state space approach to time series analysis for nursing research.

PubMed

Levy, Janet A; Elser, Heather E; Knobel, Robin B

2012-01-01

Nursing research, particularly related to physiological development, often depends on the collection of time series data. The state space approach to time series analysis has great potential to answer exploratory questions relevant to physiological development but has not been used extensively in nursing. The aim of the study was to introduce the state space approach to time series analysis and demonstrate potential applicability to neonatal monitoring and physiology. We present a set of univariate state space models; each one describing a process that generates a variable of interest over time. Each model is presented algebraically and a realization of the process is presented graphically from simulated data. This is followed by a discussion of how the model has been or may be used in two nursing projects on neonatal physiological development. The defining feature of the state space approach is the decomposition of the series into components that are functions of time; specifically, slowly varying level, faster varying periodic, and irregular components. State space models potentially simulate developmental processes where a phenomenon emerges and disappears before stabilizing, where the periodic component may become more regular with time, or where the developmental trajectory of a phenomenon is irregular. The ultimate contribution of this approach to nursing science will require close collaboration and cross-disciplinary education between nurses and statisticians.

Microphysiological modeling of the reproductive tract: a fertile endeavor.

PubMed

Eddie, Sharon L; Kim, J Julie; Woodruff, Teresa K; Burdette, Joanna E

2014-09-01

Preclinical toxicity testing in animal models is a cornerstone of the drug development process, yet it is often unable to predict adverse effects and tolerability issues in human subjects. Species-specific responses to investigational drugs have led researchers to utilize human tissues and cells to better estimate human toxicity. Unfortunately, human cell-derived models are imperfect because toxicity is assessed in isolation, removed from the normal physiologic microenvironment. Microphysiological modeling often referred to as 'organ-on-a-chip' or 'human-on-a-chip' places human tissue into a microfluidic system that mimics the complexity of human in vivo physiology, thereby allowing for toxicity testing on several cell types, tissues, and organs within a more biologically relevant environment. Here we describe important concepts when developing a repro-on-a-chip model. The development of female and male reproductive microfluidic systems is critical to sex-based in vitro toxicity and drug testing. This review addresses the biological and physiological aspects of the male and female reproductive systems in vivo and what should be considered when designing a microphysiological human-on-a-chip model. Additionally, interactions between the reproductive tract and other systems are explored, focusing on the impact of factors and hormones produced by the reproductive tract and disease pathophysiology. © 2014 by the Society for Experimental Biology and Medicine.

Use of chemostat cultures mimicking different phases of wine fermentations as a tool for quantitative physiological analysis

PubMed Central

2014-01-01

Background Saccharomyces cerevisiae is the most relevant yeast species conducting the alcoholic fermentation that takes place during winemaking. Although the physiology of this model organism has been extensively studied, systematic quantitative physiology studies of this yeast under winemaking conditions are still scarce, thus limiting the understanding of fermentative metabolism of wine yeast strains and the systematic description, modelling and prediction of fermentation processes. In this study, we implemented and validated the use of chemostat cultures as a tool to simulate different stages of a standard wine fermentation, thereby allowing to implement metabolic flux analyses describing the sequence of metabolic states of S. cerevisae along the wine fermentation. Results Chemostat cultures mimicking the different stages of standard wine fermentations of S. cerevisiae EC1118 were performed using a synthetic must and strict anaerobic conditions. The simulated stages corresponded to the onset of the exponential growth phase, late exponential growth phase and cells just entering stationary phase, at dilution rates of 0.27, 0.04, 0.007 h−1, respectively. Notably, measured substrate uptake and product formation rates at each steady state condition were generally within the range of corresponding conversion rates estimated during the different batch fermentation stages. Moreover, chemostat data were further used for metabolic flux analysis, where biomass composition data for each condition was considered in the stoichiometric model. Metabolic flux distributions were coherent with previous analyses based on batch cultivations data and the pseudo-steady state assumption. Conclusions Steady state conditions obtained in chemostat cultures reflect the environmental conditions and physiological states of S. cerevisiae corresponding to the different growth stages of a typical batch wine fermentation, thereby showing the potential of this experimental approach to systematically study the effect of environmental relevant factors such as temperature, sugar concentration, C/N ratio or (micro) oxygenation on the fermentative metabolism of wine yeast strains. PMID:24928139

Conservation physiology across scales: insights from the marine realm

PubMed Central

Cooke, Steven J.; Killen, Shaun S.; Metcalfe, Julian D.; McKenzie, David J.; Mouillot, David; Jørgensen, Christian; Peck, Myron A.

2014-01-01

As the field of conservation physiology develops and becomes increasingly integrated with ecology and conservation science, the fundamental concept of scale is being recognized as important, particularly for ensuring that physiological knowledge is contextualized in a manner most relevant to policy makers, conservation practitioners and stakeholders. Failure to consider the importance of scale in conservation physiology—both the challenges and the opportunities that it creates—will impede the ability of this discipline to generate the scientific understanding needed to contribute to meaningful conservation outcomes. Here, we have focused on five aspects of scale: biological, spatial, temporal, allometric and phylogenetic. We also considered the scale of policy and policy application relevant to those five types of scale as well as the merits of upscaling and downscaling to explore and address conservation problems. Although relevant to all systems (e.g. freshwater, terrestrial) we have used examples from the marine realm, with a particular emphasis on fishes, given the fact that there is existing discourse regarding scale and its relevance for marine conservation and management. Our synthesis revealed that all five aspects of scale are relevant to conservation physiology, with many aspects inherently linked. It is apparent that there are both opportunities and challenges afforded by working across scales but, to understand mechanisms underlying conservation problems, it is essential to consider scale of all sorts and to work across scales to the greatest extent possible. Moreover, given that the scales in biological processes will often not match policy and management scales, conservation physiology needs to show how it is relevant to aspects at different policy/management scales, change the scales at which policy/management intervention is applied or be prepared to be ignored. PMID:27293645

Growth of the coccolithophore Emiliania huxleyi in light- and nutrient-limited batch reactors: relevance for the BIOSOPE deep ecological niche of coccolithophores

NASA Astrophysics Data System (ADS)

Perrin, Laura; Probert, Ian; Langer, Gerald; Aloisi, Giovanni

2016-11-01

Coccolithophores are unicellular calcifying marine algae that play an important role in the oceanic carbon cycle via their cellular processes of photosynthesis (a CO2 sink) and calcification (a CO2 source). In contrast to the well-studied, surface-water coccolithophore blooms visible from satellites, the lower photic zone is a poorly known but potentially important ecological niche for coccolithophores in terms of primary production and carbon export to the deep ocean. In this study, the physiological responses of an Emiliania huxleyi strain to conditions simulating the deep niche in the oligotrophic gyres along the BIOSOPE transect in the South Pacific Gyre were investigated. We carried out batch culture experiments with an E. huxleyi strain isolated from the BIOSOPE transect, reproducing the in situ conditions of light and nutrient (nitrate and phosphate) limitation. By simulating coccolithophore growth using an internal stores (Droop) model, we were able to constrain fundamental physiological parameters for this E. huxleyi strain. We show that simple batch experiments, in conjunction with physiological modelling, can provide reliable estimates of fundamental physiological parameters for E. huxleyi that are usually obtained experimentally in more time-consuming and costly chemostat experiments. The combination of culture experiments, physiological modelling and in situ data from the BIOSOPE cruise show that E. huxleyi growth in the deep BIOSOPE niche is limited by availability of light and nitrate. This study contributes more widely to the understanding of E. huxleyi physiology and behaviour in a low-light and oligotrophic environment of the ocean.

Causes of Low and High Citation Potentials in Science: Citation Analysis of Biochemistry and Plant Physiology Journals.

ERIC Educational Resources Information Center

Marton, Janos

1983-01-01

Citation data of 16 biochemistry and plant physiology journals show that reasons for lower citation potentials of plant physiology articles are: (1) readership is narrower for plant physiology journals; (2) plant physiologists can cite fewer thematically relevant new articles; and (3) plant physiology research fields are more isolated. References…

An Organotypic Liver System for Tumor Progression

DTIC Science & Technology

2006-04-01

a physiologically relevant microreactor that has proved suitable for organotypic liver culture to investigate metastatic seeding. The sub-millimeter...metastasis. Our objective is to utilize a physiologically relevant microreactor that has proved suitable for organotypic liver culture (3) to...C Yates, D B Stolz, L Griffith, A Wells (2004) Direct Visualization of Prostate Cancer Progression Utilizing a Bioreactor. American Association

[Digital signal processing of a novel neuron discharge model stimulation strategy for cochlear implants].

PubMed

Yang, Yiwei; Xu, Yuejin; Miu, Jichang; Zhou, Linghong; Xiao, Zhongju

2012-10-01

To apply the classic leakage integrate-and-fire models, based on the mechanism of the generation of physiological auditory stimulation, in the information processing coding of cochlear implants to improve the auditory result. The results of algorithm simulation in digital signal processor (DSP) were imported into Matlab for a comparative analysis. Compared with CIS coding, the algorithm of membrane potential integrate-and-fire (MPIF) allowed more natural pulse discharge in a pseudo-random manner to better fit the physiological structures. The MPIF algorithm can effectively solve the problem of the dynamic structure of the delivered auditory information sequence issued in the auditory center and allowed integration of the stimulating pulses and time coding to ensure the coherence and relevance of the stimulating pulse time.

Drosophila melanogaster as a High-Throughput Model for Host-Microbiota Interactions.

PubMed

Trinder, Mark; Daisley, Brendan A; Dube, Josh S; Reid, Gregor

2017-01-01

Microbiota research often assumes that differences in abundance and identity of microorganisms have unique influences on host physiology. To test this concept mechanistically, germ-free mice are colonized with microbial communities to assess causation. Due to the cost, infrastructure challenges, and time-consuming nature of germ-free mouse models, an alternative approach is needed to investigate host-microbial interactions. Drosophila melanogaster (fruit flies) can be used as a high throughput in vivo screening model of host-microbiome interactions as they are affordable, convenient, and replicable. D. melanogaster were essential in discovering components of the innate immune response to pathogens. However, axenic D. melanogaster can easily be generated for microbiome studies without the need for ethical considerations. The simplified microbiota structure enables researchers to evaluate permutations of how each microbial species within the microbiota contribute to host phenotypes of interest. This enables the possibility of thorough strain-level analysis of host and microbial properties relevant to physiological outcomes. Moreover, a wide range of mutant D. melanogaster strains can be affordably obtained from public stock centers. Given this, D. melanogaster can be used to identify candidate mechanisms of host-microbe symbioses relevant to pathogen exclusion, innate immunity modulation, diet, xenobiotics, and probiotic/prebiotic properties in a high throughput manner. This perspective comments on the most promising areas of microbiota research that could immediately benefit from using the D. melanogaster model.

Low-dose ionizing radiation limitations to seed germination: Results from a model linking physiological characteristics and developmental-dynamics simulation strategy.

PubMed

Liu, Hui; Hu, Dawei; Dong, Chen; Fu, Yuming; Liu, Guanghui; Qin, Youcai; Sun, Yi; Liu, Dianlei; Li, Lei; Liu, Hong

2017-08-01

There is much uncertainty about the risks of seed germination after repeated or protracted environmental low-dose ionizing radiation exposure. The purpose of this study is to explore the influence mechanism of low-dose ionizing radiation on wheat seed germination using a model linking physiological characteristics and developmental-dynamics simulation. A low-dose ionizing radiation environment simulator was built to investigate wheat (Triticum aestivum L.) seeds germination process and then a kinetic model expressing the relationship between wheat seed germination dynamics and low-dose ionizing radiation intensity variations was developed by experimental data, plant physiology, relevant hypotheses and system dynamics, and sufficiently validated and accredited by computer simulation. Germination percentages were showing no differences in response to different dose rates. However, root and shoot lengths were reduced significantly. Plasma governing equations were set up and the finite element analysis demonstrated H 2 O, CO 2 , O 2 as well as the seed physiological responses to the low-dose ionizing radiation. The kinetic model was highly valid, and simultaneously the related influence mechanism of low-dose ionizing radiation on wheat seed germination proposed in the modeling process was also adequately verified. Collectively these data demonstrate that low-dose ionizing radiation has an important effect on absorbing water, consuming O 2 and releasing CO 2 , which means the risk for embryo and endosperm development was higher. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Model Incorporating Some of the Mechanical and Biochemical Factors Underlying Clot Formation and Dissolution in Flowing Blood

DOE PAGES

Anand, M.; Rajagopal, K.; Rajagopal, K. R.

2003-01-01

Multiple interacting mechanisms control the formation and dissolution of clots to maintain blood in a state of delicate balance. In addition to a myriad of biochemical reactions, rheological factors also play a crucial role in modulating the response of blood to external stimuli. To date, a comprehensive model for clot formation and dissolution, that takes into account the biochemical, medical and rheological factors, has not been put into place, the existing models emphasizing either one or the other of the factors. In this paper, after discussing the various biochemical, physiologic and rheological factors at some length, we develop a modelmore » for clot formation and dissolution that incorporates many of the relevant crucial factors that have a bearing on the problem. The model, though just a first step towards understanding a complex phenomenon, goes further than previous models in integrating the biochemical, physiologic and rheological factors that come into play.« less

Role of Coronary Myogenic Response in Pressure-Flow Autoregulation in Swine: A Meta-Analysis With Coronary Flow Modeling

PubMed Central

Dick, Gregory M.; Namani, Ravi; Patel, Bhavesh; Kassab, Ghassan S.

2018-01-01

Myogenic responses (pressure-dependent contractions) of coronary arterioles play a role in autoregulation (relatively constant flow vs. pressure). Publications on myogenic reactivity in swine coronaries vary in caliber, analysis, and degree of responsiveness. Further, data on myogenic responses and autoregulation in swine have not been completely compiled, compared, and modeled. Thus, it has been difficult to understand these physiological phenomena. Our purpose was to: (a) analyze myogenic data with standard criteria; (b) assign results to diameter categories defined by morphometry; and (c) use our novel multiscale flow model to determine the extent to which ex vivo myogenic reactivity can explain autoregulation in vivo. When myogenic responses from the literature are an input for our model, the predicted coronary autoregulation approaches in vivo observations. More complete and appropriate data are now available to investigate the regulation of coronary blood flow in swine, a highly relevant model for human physiology and disease. PMID:29875686

Free-floating epithelial micro-tissue arrays: a low cost and versatile technique.

PubMed

Flood, P; Alvarez, L; Reynaud, E G

2016-10-11

Three-dimensional (3D) tissue models are invaluable tools that can closely reflect the in vivo physiological environment. However, they are usually difficult to develop, have a low throughput and are often costly; limiting their utility to most laboratories. The recent availability of inexpensive additive manufacturing printers and open source 3D design software offers us the possibility to easily create affordable 3D cell culture platforms. To demonstrate this, we established a simple, inexpensive and robust method for producing arrays of free-floating epithelial micro-tissues. Using a combination of 3D computer aided design and 3D printing, hydrogel micro-moulding and collagen cell encapsulation we engineered microenvironments that consistently direct the growth of micro-tissue arrays. We described the adaptability of this technique by testing several immortalised epithelial cell lines (MDCK, A549, Caco-2) and by generating branching morphology and micron to millimetre scaled micro-tissues. We established by fluorescence and electron microscopy that micro-tissues are polarised, have cell type specific differentiated phenotypes and regain native in vivo tissue qualities. Finally, using Salmonella typhimurium we show micro-tissues display a more physiologically relevant infection response compared to epithelial monolayers grown on permeable filter supports. In summary, we have developed a robust and adaptable technique for producing arrays of epithelial micro-tissues. This in vitro model has the potential to be a valuable tool for studying epithelial cell and tissue function/architecture in a physiologically relevant context.

The Constraints, Construction, and Verification of a Strain-Specific Physiologically Based Pharmacokinetic Rat Model.

PubMed

Musther, Helen; Harwood, Matthew D; Yang, Jiansong; Turner, David B; Rostami-Hodjegan, Amin; Jamei, Masoud

2017-09-01

The use of in vitro-in vivo extrapolation (IVIVE) techniques, mechanistically incorporated within physiologically based pharmacokinetic (PBPK) models, can harness in vitro drug data and enhance understanding of in vivo pharmacokinetics. This study's objective was to develop a user-friendly rat (250 g, male Sprague-Dawley) IVIVE-linked PBPK model. A 13-compartment PBPK model including mechanistic absorption models was developed, with required system data (anatomical, physiological, and relevant IVIVE scaling factors) collated from literature and analyzed. Overall, 178 system parameter values for the model are provided. This study also highlights gaps in available system data required for strain-specific rat PBPK model development. The model's functionality and performance were assessed using previous literature-sourced in vitro properties for diazepam, metoprolol, and midazolam. The results of simulations were compared against observed pharmacokinetic rat data. Predicted and observed concentration profiles in 10 tissues for diazepam after a single intravenous (i.v.) dose making use of either observed i.v. clearance (CL iv ) or in vitro hepatocyte intrinsic clearance (CL int ) for simulations generally led to good predictions in various tissue compartments. Overall, all i.v. plasma concentration profiles were successfully predicted. However, there were challenges in predicting oral plasma concentration profiles for metoprolol and midazolam, and the potential reasons and according solutions are discussed. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Isolated heart models: cardiovascular system studies and technological advances.

PubMed

Olejnickova, Veronika; Novakova, Marie; Provaznik, Ivo

2015-07-01

Isolated heart model is a relevant tool for cardiovascular system studies. It represents a highly reproducible model for studying broad spectrum of biochemical, physiological, morphological, and pharmaceutical parameters, including analysis of intrinsic heart mechanics, metabolism, and coronary vascular response. Results obtained in this model are under no influence of other organ systems, plasma concentration of hormones or ions and influence of autonomic nervous system. The review describes various isolated heart models, the modes of heart perfusion, and advantages and limitations of various experimental setups. It reports the improvements of perfusion setup according to Langendorff introduced by the authors.

Integrating physiological threshold experiments with climate modeling to project mangrove range limits

NASA Astrophysics Data System (ADS)

Cavanaugh, K. C.; Kellner, J.; Cook-Patton, S.; Williams, P.; Feller, I. C.; Parker, J.

2014-12-01

Due to limitations of purely correlative species distribution models, there is a need for more integration of experimental approaches when studying impacts of climate change on species distributions. Here we used controlled experiments to identify physiological thresholds that control poleward range limits of three species of mangroves found in North America. We found that all three species exhibited a threshold response to extreme cold, but freeze tolerance thresholds varied among species. From these experiments we developed a climate metric, freeze degree days (FDD), which incorporates both the intensity and frequency of freezes. When included in distribution models, FDD was a better predictor of mangrove presence/absence than other temperature-based metrics. Using 27 years of satellite imagery, we linked FDD to past changes in mangrove abundance in Florida, further supporting the relevance of FDD. We then used downscaled climate projections of FDD to project poleward migration of these range limits over the next 50 years.

Application of machine learning techniques to analyse the effects of physical exercise in ventricular fibrillation.

PubMed

Caravaca, Juan; Soria-Olivas, Emilio; Bataller, Manuel; Serrano, Antonio J; Such-Miquel, Luis; Vila-Francés, Joan; Guerrero, Juan F

2014-02-01

This work presents the application of machine learning techniques to analyse the influence of physical exercise in the physiological properties of the heart, during ventricular fibrillation. To this end, different kinds of classifiers (linear and neural models) are used to classify between trained and sedentary rabbit hearts. The use of those classifiers in combination with a wrapper feature selection algorithm allows to extract knowledge about the most relevant features in the problem. The obtained results show that neural models outperform linear classifiers (better performance indices and a better dimensionality reduction). The most relevant features to describe the benefits of physical exercise are those related to myocardial heterogeneity, mean activation rate and activation complexity. © 2013 Published by Elsevier Ltd.

A physiome interoperability roadmap for personalized drug development

PubMed Central

2016-01-01

The goal of developing therapies and dosage regimes for characterized subgroups of the general population can be facilitated by the use of simulation models able to incorporate information about inter-individual variability in drug disposition (pharmacokinetics), toxicity and response effect (pharmacodynamics). Such observed variability can have multiple causes at various scales, ranging from gross anatomical differences to differences in genome sequence. Relevant data for many of these aspects, particularly related to molecular assays (known as ‘-omics’), are available in online resources, but identification and assignment to appropriate model variables and parameters is a significant bottleneck in the model development process. Through its efforts to standardize annotation with consequent increase in data usability, the human physiome project has a vital role in improving productivity in model development and, thus, the development of personalized therapy regimes. Here, we review the current status of personalized medicine in clinical practice, outline some of the challenges that must be overcome in order to expand its applicability, and discuss the relevance of personalized medicine to the more widespread challenges being faced in drug discovery and development. We then review some of (i) the key data resources available for use in model development and (ii) the potential areas where advances made within the physiome modelling community could contribute to physiologically based pharmacokinetic and physiologically based pharmacokinetic/pharmacodynamic modelling in support of personalized drug development. We conclude by proposing a roadmap to further guide the physiome community in its on-going efforts to improve data usability, and integration with modelling efforts in the support of personalized medicine development. PMID:27051513

Translational Modeling in Schizophrenia: Predicting Human Dopamine D2 Receptor Occupancy.

PubMed

Johnson, Martin; Kozielska, Magdalena; Pilla Reddy, Venkatesh; Vermeulen, An; Barton, Hugh A; Grimwood, Sarah; de Greef, Rik; Groothuis, Geny M M; Danhof, Meindert; Proost, Johannes H

2016-04-01

To assess the ability of a previously developed hybrid physiology-based pharmacokinetic-pharmacodynamic (PBPKPD) model in rats to predict the dopamine D2 receptor occupancy (D2RO) in human striatum following administration of antipsychotic drugs. A hybrid PBPKPD model, previously developed using information on plasma concentrations, brain exposure and D2RO in rats, was used as the basis for the prediction of D2RO in human. The rat pharmacokinetic and brain physiology parameters were substituted with human population pharmacokinetic parameters and human physiological information. To predict the passive transport across the human blood-brain barrier, apparent permeability values were scaled based on rat and human brain endothelial surface area. Active efflux clearance in brain was scaled from rat to human using both human brain endothelial surface area and MDR1 expression. Binding constants at the D2 receptor were scaled based on the differences between in vitro and in vivo systems of the same species. The predictive power of this physiology-based approach was determined by comparing the D2RO predictions with the observed human D2RO of six antipsychotics at clinically relevant doses. Predicted human D2RO was in good agreement with clinically observed D2RO for five antipsychotics. Models using in vitro information predicted human D2RO well for most of the compounds evaluated in this analysis. However, human D2RO was under-predicted for haloperidol. The rat hybrid PBPKPD model structure, integrated with in vitro information and human pharmacokinetic and physiological information, constitutes a scientific basis to predict the time course of D2RO in man.

Multifunctional enzymes from reduced genomes - model proteins for simple primordial metabolism?

PubMed

Seelig, Burckhard

2017-08-01

Billions of years of evolution have yielded today's complex metabolic networks driven by efficient and highly specialized enzymes. In contrast, the metabolism of the earliest cellular life forms was likely much simpler with only a few enzymes of comparatively low activity. It has been speculated that these early enzymes had low specificities and in turn were able to perform multiple functions. In this issue of Molecular Microbiology, Ferla et al. describe examples of enzymes that catalyze chemically distinct reactions while using the same active site. Most importantly, the authors demonstrated that the comparatively weak activities of these multifunctional enzymes are each physiologically relevant. These findings contrast with simply promiscuous enzyme activities, which have been described numerous times but are not physiologically relevant. Ferla et al. elegantly combined initial bioinformatics searches for enzyme candidates with sound kinetic measurements, evolutionary considerations and even structural discussions. The phenomenon of multifunctionality appears to be a mechanism for bacteria with reduced genomes to compensate for their lack of certain enzymes. In the broader context of evolution, these organisms could be considered living model systems to study features of long-extinct early cellular life. © 2017 John Wiley & Sons Ltd.

THE PASSIVE PROPERTIES OF MUSCLE FIBERS ARE VELOCITY DEPENDENT

PubMed Central

Rehorn, Michael R.; Schroer, Alison K.; Blemker, Silvia S.

2014-01-01

The passive properties of skeletal muscle play an important role in muscle function. While the passive quasi-static elastic properties of muscle fibers have been well characterized, the dynamic visco-elastic passive behavior of fibers has garnered less attention. In particular, it is unclear how the visco-elastic properties are influenced by lengthening velocity, in particular for the range of physiologically relevant velocities. The goals of this work were to: (i) measure the effects of lengthening velocity on the peak stresses within single muscle fibers to determine how passive behavior changes over a range of physiologically relevant lengthening rates (0.1–10 Lo/s), and (ii) develop a mathematical model of fiber viscoelasticity based on these measurements. We found that passive properties depend on strain rate, in particular at the low loading rates (0.1–3 Lo/s), and that the measured behavior can be predicted across a range of loading rates and time histories with a quasi-linear viscoelastic model. In the future, these results can be used to determine the impact of viscoelastic behavior on intramuscular stresses and forces during a variety of dynamic movements. PMID:24360198

The recovery time course of the endothelial-cell glycocalyx in vivo and its implications in vitro

PubMed Central

Potter, Daniel R.; Jiang, John; Damiano, Edward R.

2009-01-01

Compelling evidence continues to emerge suggesting that the glycocalyx surface layer on vascular endothelial cells plays a determining role in numerous physiological processes including inflammation, microvascular permeability, and endothelial mechanotransduction. Previous research has shown that enzymes degrade the glycocalyx, while inflammation causes shedding of the layer. To track the endogenous recovery of the glycocalyx in vivo, we used fluorescent micro-particle image velocimetry (µ-PIV) in mouse cremaster-muscle venules to estimate the hydrodynamically relevant glycocalyx thickness 1, 3, 5, and 7 days after enzymatic or cytokine-mediated degradation of the layer. Results indicate that after acute degradation of the glycocalyx, 5–7 days are required for the layer to endogenously restore itself to its native hydrodynamically relevant thickness in vivo. In light of these findings, and since demonstrable evidence has emerged that standard cell-culture conditions are not conducive to providing the environment and/or cellular conditions necessary to produce and maintain a physiologically relevant cell-surface glycocalyx in vitro, we sought to determine if merely the passage of time would be sufficient to promote the production of a hydrodynamically relevant glycocalyx on a confluent monolayer of human umbilical vein endothelial cells (HUVECs). Using µ-PIV, we found that the hydrodynamically relevant glycocalyx was substantially absent 7 days post-confluence on HUVEC-lined cylindrical collagen microchannels maintained under standard culture conditions. Thus it remains to be determined how a hydrodynamically relevant glycocalyx surface layer can be synthesized and maintained in culture before the endothelial-cell culture model can be used to elucidate glycocalyx-mediated mechanisms of endothelial-cell function. PMID:19443840

Three-Dimensional Rotating Wall Vessel-Derived Cell Culture Models for Studying Virus-Host Interactions

PubMed Central

Gardner, Jameson K.; Herbst-Kralovetz, Melissa M.

2016-01-01

The key to better understanding complex virus-host interactions is the utilization of robust three-dimensional (3D) human cell cultures that effectively recapitulate native tissue architecture and model the microenvironment. A lack of physiologically-relevant animal models for many viruses has limited the elucidation of factors that influence viral pathogenesis and of complex host immune mechanisms. Conventional monolayer cell cultures may support viral infection, but are unable to form the tissue structures and complex microenvironments that mimic host physiology and, therefore, limiting their translational utility. The rotating wall vessel (RWV) bioreactor was designed by the National Aeronautics and Space Administration (NASA) to model microgravity and was later found to more accurately reproduce features of human tissue in vivo. Cells grown in RWV bioreactors develop in a low fluid-shear environment, which enables cells to form complex 3D tissue-like aggregates. A wide variety of human tissues (from neuronal to vaginal tissue) have been grown in RWV bioreactors and have been shown to support productive viral infection and physiological meaningful host responses. The in vivo-like characteristics and cellular features of the human 3D RWV-derived aggregates make them ideal model systems to effectively recapitulate pathophysiology and host responses necessary to conduct rigorous basic science, preclinical and translational studies. PMID:27834891

Simulations of motor unit number estimation techniques

NASA Astrophysics Data System (ADS)

Major, Lora A.; Jones, Kelvin E.

2005-06-01

Motor unit number estimation (MUNE) is an electrodiagnostic procedure used to evaluate the number of motor axons connected to a muscle. All MUNE techniques rely on assumptions that must be fulfilled to produce a valid estimate. As there is no gold standard to compare the MUNE techniques against, we have developed a model of the relevant neuromuscular physiology and have used this model to simulate various MUNE techniques. The model allows for a quantitative analysis of candidate MUNE techniques that will hopefully contribute to consensus regarding a standard procedure for performing MUNE.

Proteomic analysis of synaptoneurosomes highlights the relevant role of local translation in the hippocampus.

PubMed

Benito, Itziar; Casañas, Juan José; Montesinos, María Luz

2018-06-19

Several proteomic analyses have been performed on synaptic fractions isolated from cortex or even total brain, resulting in preparations with a high synaptic heterogeneity and complexity. Synaptoneurosomes (SNs) are subcellular membranous elements that contain sealed pre- and post-synaptic components. They are obtained by subcellular fractionation of brain homogenates and serve as a suitable model to study many aspects of the synapse physiology. Here we report the proteomic content of SNs isolated from hippocampus of adult mice, a brain region involved in memory that presents lower synaptic heterogeneity than cortex. Interestingly, in addition to pre- and post-synaptic proteins, we found that proteins involved in RNA binding and translation were overrepresented in our preparation. These results validate the protocol we previously reported for SNs isolation, and, as reported by other authors, highlight the relevance of local synaptic translation for hippocampal physiology. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Clarifying the Roles of Homeostasis and Allostasis in Physiological Regulation

PubMed Central

Ramsay, Douglas S.; Woods, Stephen C.

2014-01-01

Homeostasis, the dominant explanatory framework for physiological regulation, has undergone significant revision in recent years, with contemporary models differing significantly from the original formulation. Allostasis, an alternative view of physiological regulation, goes beyond its homeostatic roots, offering novel insights relevant to our understanding and treatment of several chronic health conditions. Despite growing enthusiasm for allostasis, the concept remains diffuse, due in part to ambiguity as to how the term is understood and used, impeding meaningful translational and clinical research on allostasis. Here we provide a more focused understanding of homeostasis and allostasis by explaining how both play a role in physiological regulation, and a critical analysis of regulation suggests how homeostasis and allostasis can be distinguished. Rather than focusing on changes in the value of a regulated variable (e.g., body temperature, body adiposity, or reward), research investigating the activity and relationship among the multiple regulatory loops that influence the value of these regulated variables may be the key to distinguishing homeostasis and allostasis. The mechanisms underlying physiological regulation and dysregulation are likely to have important implications for health and disease. PMID:24730599

In-cell thermodynamics and a new role for protein surfaces.

PubMed

Smith, Austin E; Zhou, Larry Z; Gorensek, Annelise H; Senske, Michael; Pielak, Gary J

2016-02-16

There is abundant, physiologically relevant knowledge about protein cores; they are hydrophobic, exquisitely well packed, and nearly all hydrogen bonds are satisfied. An equivalent understanding of protein surfaces has remained elusive because proteins are almost exclusively studied in vitro in simple aqueous solutions. Here, we establish the essential physiological roles played by protein surfaces by measuring the equilibrium thermodynamics and kinetics of protein folding in the complex environment of living Escherichia coli cells, and under physiologically relevant in vitro conditions. Fluorine NMR data on the 7-kDa globular N-terminal SH3 domain of Drosophila signal transduction protein drk (SH3) show that charge-charge interactions are fundamental to protein stability and folding kinetics in cells. Our results contradict predictions from accepted theories of macromolecular crowding and show that cosolutes commonly used to mimic the cellular interior do not yield physiologically relevant information. As such, we provide the foundation for a complete picture of protein chemistry in cells.

Comparative and integrative metabolomics reveal that S-nitrosation inhibits physiologically relevant metabolic enzymes.

PubMed

Bruegger, Joel J; Smith, Brian C; Wynia-Smith, Sarah L; Marletta, Michael A

2018-04-27

Cysteine S -nitrosation is a reversible post-translational modification mediated by nitric oxide ( • NO)-derived agents. S -Nitrosation participates in cellular signaling and is associated with several diseases such as cancer, cardiovascular diseases, and neuronal disorders. Despite the physiological importance of this nonclassical • NO-signaling pathway, little is understood about how much S -nitrosation affects protein function. Moreover, identifying physiologically relevant targets of S -nitrosation is difficult because of the dynamics of transnitrosation and a limited understanding of the physiological mechanisms leading to selective protein S -nitrosation. To identify proteins whose activities are modulated by S -nitrosation, we performed a metabolomics study comparing WT and endothelial nitric-oxide synthase knockout mice. We integrated our results with those of a previous proteomics study that identified physiologically relevant S -nitrosated cysteines, and we found that the activity of at least 21 metabolic enzymes might be regulated by S -nitrosation. We cloned, expressed, and purified four of these enzymes and observed that S -nitrosation inhibits the metabolic enzymes 6-phosphogluconate dehydrogenase, Δ1-pyrroline-5-carboxylate dehydrogenase, catechol- O -methyltransferase, and d-3-phosphoglycerate dehydrogenase. Furthermore, using site-directed mutagenesis, we identified the predominant cysteine residue influencing the observed activity changes in each enzyme. In summary, using an integrated metabolomics approach, we have identified several physiologically relevant S -nitrosation targets, including metabolic enzymes, which are inhibited by this modification, and we have found the cysteines modified by S -nitrosation in each enzyme. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

A G Protein-biased Designer G Protein-coupled Receptor Useful for Studying the Physiological Relevance of Gq/11-dependent Signaling Pathways.

PubMed

Hu, Jianxin; Stern, Matthew; Gimenez, Luis E; Wanka, Lizzy; Zhu, Lu; Rossi, Mario; Meister, Jaroslawna; Inoue, Asuka; Beck-Sickinger, Annette G; Gurevich, Vsevolod V; Wess, Jürgen

2016-04-08

Designerreceptorsexclusivelyactivated by adesignerdrug (DREADDs) are clozapine-N-oxide-sensitive designer G protein-coupled receptors (GPCRs) that have emerged as powerful novel chemogenetic tools to study the physiological relevance of GPCR signaling pathways in specific cell types or tissues. Like endogenous GPCRs, clozapine-N-oxide-activated DREADDs do not only activate heterotrimeric G proteins but can also trigger β-arrestin-dependent (G protein-independent) signaling. To dissect the relative physiological relevance of G protein-mediatedversusβ-arrestin-mediated signaling in different cell types or physiological processes, the availability of G protein- and β-arrestin-biased DREADDs would be highly desirable. In this study, we report the development of a mutationally modified version of a non-biased DREADD derived from the M3muscarinic receptor that can activate Gq/11with high efficacy but lacks the ability to interact with β-arrestins. We also demonstrate that this novel DREADD is activein vivoand that cell type-selective expression of this new designer receptor can provide novel insights into the physiological roles of G protein (Gq/11)-dependentversusβ-arrestin-dependent signaling in hepatocytes. Thus, this novel Gq/11-biased DREADD represents a powerful new tool to study the physiological relevance of Gq/11-dependent signaling in distinct tissues and cell types, in the absence of β-arrestin-mediated cellular effects. Such studies should guide the development of novel classes of functionally biased ligands that show high efficacy in various pathophysiological conditions but display a reduced incidence of side effects. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Conservation physiology in practice: how physiological knowledge has improved our ability to sustainably manage Pacific salmon during up-river migration.

PubMed

Cooke, Steven J; Hinch, Scott G; Donaldson, Michael R; Clark, Timothy D; Eliason, Erika J; Crossin, Glenn T; Raby, Graham D; Jeffries, Ken M; Lapointe, Mike; Miller, Kristi; Patterson, David A; Farrell, Anthony P

2012-06-19

Despite growing interest in conservation physiology, practical examples of how physiology has helped to understand or to solve conservation problems remain scarce. Over the past decade, an interdisciplinary research team has used a conservation physiology approach to address topical conservation concerns for Pacific salmon. Here, we review how novel applications of tools such as physiological telemetry, functional genomics and laboratory experiments on cardiorespiratory physiology have shed light on the effect of fisheries capture and release, disease and individual condition, and stock-specific consequences of warming river temperatures, respectively, and discuss how these findings have or have not benefited Pacific salmon management. Overall, physiological tools have provided remarkable insights into the effects of fisheries capture and have helped to enhance techniques for facilitating recovery from fisheries capture. Stock-specific cardiorespiratory thresholds for thermal tolerances have been identified for sockeye salmon and can be used by managers to better predict migration success, representing a rare example that links a physiological scope to fitness in the wild population. Functional genomics approaches have identified physiological signatures predictive of individual migration mortality. Although fisheries managers are primarily concerned with population-level processes, understanding the causes of en route mortality provides a mechanistic explanation and can be used to refine management models. We discuss the challenges that we have overcome, as well as those that we continue to face, in making conservation physiology relevant to managers of Pacific salmon.

Conservation physiology in practice: how physiological knowledge has improved our ability to sustainably manage Pacific salmon during up-river migration

PubMed Central

Cooke, Steven J.; Hinch, Scott G.; Donaldson, Michael R.; Clark, Timothy D.; Eliason, Erika J.; Crossin, Glenn T.; Raby, Graham D.; Jeffries, Ken M.; Lapointe, Mike; Miller, Kristi; Patterson, David A.; Farrell, Anthony P.

2012-01-01

Despite growing interest in conservation physiology, practical examples of how physiology has helped to understand or to solve conservation problems remain scarce. Over the past decade, an interdisciplinary research team has used a conservation physiology approach to address topical conservation concerns for Pacific salmon. Here, we review how novel applications of tools such as physiological telemetry, functional genomics and laboratory experiments on cardiorespiratory physiology have shed light on the effect of fisheries capture and release, disease and individual condition, and stock-specific consequences of warming river temperatures, respectively, and discuss how these findings have or have not benefited Pacific salmon management. Overall, physiological tools have provided remarkable insights into the effects of fisheries capture and have helped to enhance techniques for facilitating recovery from fisheries capture. Stock-specific cardiorespiratory thresholds for thermal tolerances have been identified for sockeye salmon and can be used by managers to better predict migration success, representing a rare example that links a physiological scope to fitness in the wild population. Functional genomics approaches have identified physiological signatures predictive of individual migration mortality. Although fisheries managers are primarily concerned with population-level processes, understanding the causes of en route mortality provides a mechanistic explanation and can be used to refine management models. We discuss the challenges that we have overcome, as well as those that we continue to face, in making conservation physiology relevant to managers of Pacific salmon. PMID:22566681

Mining functionally relevant gene sets for analyzing physiologically novel clinical expression data.

PubMed

Turcan, Sevin; Vetter, Douglas E; Maron, Jill L; Wei, Xintao; Slonim, Donna K

2011-01-01

Gene set analyses have become a standard approach for increasing the sensitivity of transcriptomic studies. However, analytical methods incorporating gene sets require the availability of pre-defined gene sets relevant to the underlying physiology being studied. For novel physiological problems, relevant gene sets may be unavailable or existing gene set databases may bias the results towards only the best-studied of the relevant biological processes. We describe a successful attempt to mine novel functional gene sets for translational projects where the underlying physiology is not necessarily well characterized in existing annotation databases. We choose targeted training data from public expression data repositories and define new criteria for selecting biclusters to serve as candidate gene sets. Many of the discovered gene sets show little or no enrichment for informative Gene Ontology terms or other functional annotation. However, we observe that such gene sets show coherent differential expression in new clinical test data sets, even if derived from different species, tissues, and disease states. We demonstrate the efficacy of this method on a human metabolic data set, where we discover novel, uncharacterized gene sets that are diagnostic of diabetes, and on additional data sets related to neuronal processes and human development. Our results suggest that our approach may be an efficient way to generate a collection of gene sets relevant to the analysis of data for novel clinical applications where existing functional annotation is relatively incomplete.

A Database as a Service for the Healthcare System to Store Physiological Signal Data.

PubMed

Chang, Hsien-Tsung; Lin, Tsai-Huei

2016-01-01

Wearable devices that measure physiological signals to help develop self-health management habits have become increasingly popular in recent years. These records are conducive for follow-up health and medical care. In this study, based on the characteristics of the observed physiological signal records- 1) a large number of users, 2) a large amount of data, 3) low information variability, 4) data privacy authorization, and 5) data access by designated users-we wish to resolve physiological signal record-relevant issues utilizing the advantages of the Database as a Service (DaaS) model. Storing a large amount of data using file patterns can reduce database load, allowing users to access data efficiently; the privacy control settings allow users to store data securely. The results of the experiment show that the proposed system has better database access performance than a traditional relational database, with a small difference in database volume, thus proving that the proposed system can improve data storage performance.

A Database as a Service for the Healthcare System to Store Physiological Signal Data

PubMed Central

Lin, Tsai-Huei

2016-01-01

Wearable devices that measure physiological signals to help develop self-health management habits have become increasingly popular in recent years. These records are conducive for follow-up health and medical care. In this study, based on the characteristics of the observed physiological signal records– 1) a large number of users, 2) a large amount of data, 3) low information variability, 4) data privacy authorization, and 5) data access by designated users—we wish to resolve physiological signal record-relevant issues utilizing the advantages of the Database as a Service (DaaS) model. Storing a large amount of data using file patterns can reduce database load, allowing users to access data efficiently; the privacy control settings allow users to store data securely. The results of the experiment show that the proposed system has better database access performance than a traditional relational database, with a small difference in database volume, thus proving that the proposed system can improve data storage performance. PMID:28033415

Three-Dimensional Organotypic Co-Culture Model of Intestinal Epithelial Cells and Macrophages to Study "Salmonella Enterica" Colonization Patterns

NASA Technical Reports Server (NTRS)

Ott, Mark; Yang, J; Barilla, J.; Crabbe, A.; Sarker, S. F.; Liu, Y.

2017-01-01

Three-dimensional/3-D organotypic models of human intestinal epithelium mimic the differentiated form and function of parental tissues often not exhibited by 2-D monolayers and respond to Salmonella in ways that reflect in vivo infections. To further enhance the physiological relevance of 3-D models to more closely approximate in vivo intestinal microenvironments during infection, we developed and validated a novel 3-D intestinal co-culture model containing multiple epithelial cell types and phagocytic macrophages, and applied to study enteric infection by different Salmonella pathovars.

Sinusoidal voltage protocols for rapid characterisation of ion channel kinetics.

PubMed

Beattie, Kylie A; Hill, Adam P; Bardenet, Rémi; Cui, Yi; Vandenberg, Jamie I; Gavaghan, David J; de Boer, Teun P; Mirams, Gary R

2018-03-24

Ion current kinetics are commonly represented by current-voltage relationships, time constant-voltage relationships and subsequently mathematical models fitted to these. These experiments take substantial time, which means they are rarely performed in the same cell. Rather than traditional square-wave voltage clamps, we fitted a model to the current evoked by a novel sum-of-sinusoids voltage clamp that was only 8 s long. Short protocols that can be performed multiple times within a single cell will offer many new opportunities to measure how ion current kinetics are affected by changing conditions. The new model predicts the current under traditional square-wave protocols well, with better predictions of underlying currents than literature models. The current under a novel physiologically relevant series of action potential clamps is predicted extremely well. The short sinusoidal protocols allow a model to be fully fitted to individual cells, allowing us to examine cell-cell variability in current kinetics for the first time. Understanding the roles of ion currents is crucial to predict the action of pharmaceuticals and mutations in different scenarios, and thereby to guide clinical interventions in the heart, brain and other electrophysiological systems. Our ability to predict how ion currents contribute to cellular electrophysiology is in turn critically dependent on our characterisation of ion channel kinetics - the voltage-dependent rates of transition between open, closed and inactivated channel states. We present a new method for rapidly exploring and characterising ion channel kinetics, applying it to the hERG potassium channel as an example, with the aim of generating a quantitatively predictive representation of the ion current. We fitted a mathematical model to currents evoked by a novel 8 second sinusoidal voltage clamp in CHO cells overexpressing hERG1a. The model was then used to predict over 5 minutes of recordings in the same cell in response to further protocols: a series of traditional square step voltage clamps, and also a novel voltage clamp comprising a collection of physiologically relevant action potentials. We demonstrate that we can make predictive cell-specific models that outperform the use of averaged data from a number of different cells, and thereby examine which changes in gating are responsible for cell-cell variability in current kinetics. Our technique allows rapid collection of consistent and high quality data, from single cells, and produces more predictive mathematical ion channel models than traditional approaches. © 2018 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

Attention modifies sound level detection in young children.

PubMed

Sussman, Elyse S; Steinschneider, Mitchell

2011-07-01

Have you ever shouted your child's name from the kitchen while they were watching television in the living room to no avail, so you shout their name again, only louder? Yet, still no response. The current study provides evidence that young children process loudness changes differently than pitch changes when they are engaged in another task such as watching a video. Intensity level changes were physiologically detected only when they were behaviorally relevant, but frequency level changes were physiologically detected without task relevance in younger children. This suggests that changes in pitch rather than changes in volume may be more effective in evoking a response when sounds are unexpected. Further, even though behavioral ability may appear to be similar in younger and older children, attention-based physiologic responses differ from automatic physiologic processes in children. Results indicate that 1) the automatic auditory processes leading to more efficient higher-level skills continue to become refined through childhood; and 2) there are different time courses for the maturation of physiological processes encoding the distinct acoustic attributes of sound pitch and sound intensity. The relevance of these findings to sound perception in real-world environments is discussed.

Building an experimental model of the human body with non-physiological parameters.

PubMed

Labuz, Joseph M; Moraes, Christopher; Mertz, David R; Leung, Brendan M; Takayama, Shuichi

2017-03-01

New advances in engineering and biomedical technology have enabled recent efforts to capture essential aspects of human physiology in microscale, in-vitro systems. The application of these advances to experimentally model complex processes in an integrated platform - commonly called a 'human-on-a-chip (HOC)' - requires that relevant compartments and parameters be sized correctly relative to each other and to the system as a whole. Empirical observation, theoretical treatments of resource distribution systems and natural experiments can all be used to inform rational design of such a system, but technical and fundamental challenges (e.g. small system blood volumes and context-dependent cell metabolism, respectively) pose substantial, unaddressed obstacles. Here, we put forth two fundamental principles for HOC design: inducing in-vivo -like cellular metabolic rates is necessary and may be accomplished in-vitro by limiting O 2 availability and that the effects of increased blood volumes on drug concentration can be mitigated through pharmacokinetics-based treatments of solute distribution. Combining these principles with natural observation and engineering workarounds, we derive a complete set of design criteria for a practically realizable, physiologically faithful, five-organ millionth-scale (× 10 -6 ) microfluidic model of the human body.

Building an experimental model of the human body with non-physiological parameters

PubMed Central

Labuz, Joseph M.; Moraes, Christopher; Mertz, David R.; Leung, Brendan M.; Takayama, Shuichi

2017-01-01

New advances in engineering and biomedical technology have enabled recent efforts to capture essential aspects of human physiology in microscale, in-vitro systems. The application of these advances to experimentally model complex processes in an integrated platform — commonly called a ‘human-on-a-chip (HOC)’ — requires that relevant compartments and parameters be sized correctly relative to each other and to the system as a whole. Empirical observation, theoretical treatments of resource distribution systems and natural experiments can all be used to inform rational design of such a system, but technical and fundamental challenges (e.g. small system blood volumes and context-dependent cell metabolism, respectively) pose substantial, unaddressed obstacles. Here, we put forth two fundamental principles for HOC design: inducing in-vivo-like cellular metabolic rates is necessary and may be accomplished in-vitro by limiting O2 availability and that the effects of increased blood volumes on drug concentration can be mitigated through pharmacokinetics-based treatments of solute distribution. Combining these principles with natural observation and engineering workarounds, we derive a complete set of design criteria for a practically realizable, physiologically faithful, five-organ millionth-scale (× 10−6) microfluidic model of the human body. PMID:28713851

Personalized physiological medicine.

PubMed

Ince, Can

2017-12-28

This paper introduces the concept of personalized physiological medicine that is specifically directed at the needs of the critically ill patient. This differs from the conventional view of personalized medicine, characterized by biomarkers and gene profiling, instead focusing on time-variant changes in the pathophysiology and regulation of various organ systems and their cellular and subcellular constituents. I propose that personalized physiological medicine is composed of four pillars relevant to the critically ill patient. Pillar 1 is defined by the frailty and fitness of the patient and their physiological reserve to cope with the stress of critical illness and therapy. Pillar 2 involves monitoring of the key physiological variables of the different organ systems and their response to disease and therapy. Pillar 3 concerns the evaluation of the success of resuscitation by assessment of the hemodynamic coherence between the systemic and microcirculation and parenchyma of the organ systems. Finally, pillar 4 is defined by the integration of the physiological and clinical data into a time-learning adaptive model of the patient to provide feedback about the function of organ systems and to guide and assess the response to disease and therapy. I discuss each pillar and describe the challenges to research and development that will allow the realization of personalized physiological medicine to be practiced at the bedside for critically ill patients.

Models and signal processing for an implanted ethanol bio-sensor.

PubMed

Han, Jae-Joon; Doerschuk, Peter C; Gelfand, Saul B; O'Connor, Sean J

2008-02-01

The understanding of drinking patterns leading to alcoholism has been hindered by an inability to unobtrusively measure ethanol consumption over periods of weeks to months in the community environment. An implantable ethanol sensor is under development using microelectromechanical systems technology. For safety and user acceptability issues, the sensor will be implanted subcutaneously and, therefore, measure peripheral-tissue ethanol concentration. Determining ethanol consumption and kinetics in other compartments from the time course of peripheral-tissue ethanol concentration requires sophisticated signal processing based on detailed descriptions of the relevant physiology. A statistical signal processing system based on detailed models of the physiology and using extended Kalman filtering and dynamic programming tools is described which can estimate the time series of ethanol concentration in blood, liver, and peripheral tissue and the time series of ethanol consumption based on peripheral-tissue ethanol concentration measurements.

Modeling Physiological Events in 2D vs. 3D Cell Culture

PubMed Central

Duval, Kayla; Grover, Hannah; Han, Li-Hsin; Mou, Yongchao; Pegoraro, Adrian F.; Fredberg, Jeffery

2017-01-01

Cell culture has become an indispensable tool to help uncover fundamental biophysical and biomolecular mechanisms by which cells assemble into tissues and organs, how these tissues function, and how that function becomes disrupted in disease. Cell culture is now widely used in biomedical research, tissue engineering, regenerative medicine, and industrial practices. Although flat, two-dimensional (2D) cell culture has predominated, recent research has shifted toward culture using three-dimensional (3D) structures, and more realistic biochemical and biomechanical microenvironments. Nevertheless, in 3D cell culture, many challenges remain, including the tissue-tissue interface, the mechanical microenvironment, and the spatiotemporal distributions of oxygen, nutrients, and metabolic wastes. Here, we review 2D and 3D cell culture methods, discuss advantages and limitations of these techniques in modeling physiologically and pathologically relevant processes, and suggest directions for future research. PMID:28615311

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

PubMed

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

2014-08-01

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

Teaching Cardiac Electrophysiology Modeling to Undergraduate Students: Laboratory Exercises and GPU Programming for the Study of Arrhythmias and Spiral Wave Dynamics

ERIC Educational Resources Information Center

Bartocci, Ezio; Singh, Rupinder; von Stein, Frederick B.; Amedome, Avessie; Caceres, Alan Joseph J.; Castillo, Juan; Closser, Evan; Deards, Gabriel; Goltsev, Andriy; Ines, Roumwelle Sta.; Isbilir, Cem; Marc, Joan K.; Moore, Diquan; Pardi, Dana; Sadhu, Sandeep; Sanchez, Samuel; Sharma, Pooja; Singh, Anoopa; Rogers, Joshua; Wolinetz, Aron; Grosso-Applewhite, Terri; Zhao, Kai; Filipski, Andrew B.; Gilmour, Robert F., Jr.; Grosu, Radu; Glimm, James; Smolka, Scott A.; Cherry, Elizabeth M.; Clarke, Edmund M.; Griffeth, Nancy; Fenton, Flavio H.

2011-01-01

As part of a 3-wk intersession workshop funded by a National Science Foundation Expeditions in Computing award, 15 undergraduate students from the City University of New York collaborated on a study aimed at characterizing the voltage dynamics and arrhythmogenic behavior of cardiac cells for a broad range of physiologically relevant conditions…

A network-based approach for semi-quantitative knowledge mining and its application to yield variability

NASA Astrophysics Data System (ADS)

Schauberger, Bernhard; Rolinski, Susanne; Müller, Christoph

2016-12-01

Variability of crop yields is detrimental for food security. Under climate change its amplitude is likely to increase, thus it is essential to understand the underlying causes and mechanisms. Crop models are the primary tool to project future changes in crop yields under climate change. A systematic overview of drivers and mechanisms of crop yield variability (YV) can thus inform crop model development and facilitate improved understanding of climate change impacts on crop yields. Yet there is a vast body of literature on crop physiology and YV, which makes a prioritization of mechanisms for implementation in models challenging. Therefore this paper takes on a novel approach to systematically mine and organize existing knowledge from the literature. The aim is to identify important mechanisms lacking in models, which can help to set priorities in model improvement. We structure knowledge from the literature in a semi-quantitative network. This network consists of complex interactions between growing conditions, plant physiology and crop yield. We utilize the resulting network structure to assign relative importance to causes of YV and related plant physiological processes. As expected, our findings confirm existing knowledge, in particular on the dominant role of temperature and precipitation, but also highlight other important drivers of YV. More importantly, our method allows for identifying the relevant physiological processes that transmit variability in growing conditions to variability in yield. We can identify explicit targets for the improvement of crop models. The network can additionally guide model development by outlining complex interactions between processes and by easily retrieving quantitative information for each of the 350 interactions. We show the validity of our network method as a structured, consistent and scalable dictionary of literature. The method can easily be applied to many other research fields.

A comprehensive Guyton model analysis of physiologic responses to preadapting the blood volume as a countermeasure to fluid shifts

NASA Technical Reports Server (NTRS)

Simanonok, K. E.; Srinivasan, R. S.; Myrick, E. E.; Blomkalns, A. L.; Charles, J. B.

1994-01-01

The Guyton model of fluid, electrolyte, and circulatory regulation is an extensive mathematical model capable of simulating a variety of experimental conditions. It has been modified for use at NASA to simulate head-down tilt, a frequently used analog of weightlessness. Weightlessness causes a headward shift of body fluids that is believed to expand central blood volume, triggering a series of physiologic responses resulting in large losses of body fluids. We used the modified Guyton model to test the hypothesis that preadaptation of the blood volume before weightless exposure could counteract the central volume expansion caused by fluid shifts, and thereby attenuate the circulatory and renal responses that result in body fluid losses. Simulation results show that circulatory preadaptation, by a procedure resembling blood donation immediately before head-down bedrest, is effective in damping the physiologic responses to fluid shifts and reducing body fluid losses. After 10 hours of head-down tilt, preadaptation also produces higher blood volume, extracellular volume, and total body water for 20 to 30 days of bedrest, compared with non-preadapted control. These results indicate that circulatory preadaptation before current Space Shuttle missions may be beneficial for the maintenance of reentry and postflight orthostatic tolerance in astronauts. This paper presents a comprehensive examination of the simulation results pertaining to changes in relevant physiologic variables produced by blood volume reduction before a prolonged head-down tilt. The objectives were to study and develop the countermeasure theoretically, to aid in planning experimental studies of the countermeasure, and to identify potentially disadvantageous physiologic responses that may be caused by the countermeasure.

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

NASA Astrophysics Data System (ADS)

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

2014-05-01

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

Kinetic modeling in PET imaging of hypoxia

PubMed Central

Li, Fan; Joergensen, Jesper T; Hansen, Anders E; Kjaer, Andreas

2014-01-01

Tumor hypoxia is associated with increased therapeutic resistance leading to poor treatment outcome. Therefore the ability to detect and quantify intratumoral oxygenation could play an important role in future individual personalized treatment strategies. Positron Emission Tomography (PET) can be used for non-invasive mapping of tissue oxygenation in vivo and several hypoxia specific PET tracers have been developed. Evaluation of PET data in the clinic is commonly based on visual assessment together with semiquantitative measurements e.g. standard uptake value (SUV). However, dynamic PET contains additional valuable information on the temporal changes in tracer distribution. Kinetic modeling can be used to extract relevant pharmacokinetic parameters of tracer behavior in vivo that reflects relevant physiological processes. In this paper, we review the potential contribution of kinetic analysis for PET imaging of hypoxia. PMID:25250200

Vestibular animal models: contributions to understanding physiology and disease.

PubMed

Straka, Hans; Zwergal, Andreas; Cullen, Kathleen E

2016-04-01

Our knowledge of the vestibular sensory system, its functional significance for gaze and posture stabilization, and its capability to ensure accurate spatial orientation perception and spatial navigation has greatly benefitted from experimental approaches using a variety of vertebrate species. This review summarizes the attempts to establish the roles of semicircular canal and otolith endorgans in these functions followed by an overview of the most relevant fields of vestibular research including major findings that have advanced our understanding of how this system exerts its influence on reflexive and cognitive challenges encountered during daily life. In particular, we highlight the contributions of different animal models and the advantage of using a comparative research approach. Cross-species comparisons have established that the morpho-physiological properties underlying vestibular signal processing are evolutionarily inherent, thereby disclosing general principles. Based on the documented success of this approach, we suggest that future research employing a balanced spectrum of standard animal models such as fish/frog, mouse and primate will optimize our progress in understanding vestibular processing in health and disease. Moreover, we propose that this should be further supplemented by research employing more "exotic" species that offer unique experimental access and/or have specific vestibular adaptations due to unusual locomotor capabilities or lifestyles. Taken together this strategy will expedite our understanding of the basic principles underlying vestibular computations to reveal relevant translational aspects. Accordingly, studies employing animal models are indispensible and even mandatory for the development of new treatments, medication and technical aids (implants) for patients with vestibular pathologies.

Visual presentation of a medical physiology seminar modifies dental students' perception of its clinical significance.

PubMed

Vuletic, L; Spalj, S; Peros, K

2016-02-01

The primary objective of this study was to assess whether exposing dental students to visual stimuli related to dental profession during the medical physiology seminar could affect their perception of the clinical relevance of the topic. A self-administered questionnaire on attitudes towards medical physiology was conducted amongst 105 students of the School of Dental Medicine in Zagreb, Croatia, aged 19-24 years (80% females) following a seminar on respiratory system physiology. Power-point presentation accompanying the seminar for a total of 52 students (study group) was enriched with pictures related to dental practice in order to assess whether these pictures could make the topic appear more clinically relevant for a future dentist. The results of the survey indicated that dental students in the study group perceived the topic of the seminar as more important for them as future dentists when compared to the perception of the control group (P = 0.025). The results of this survey encourage physiology lecturers to present medical physiology as clinically relevant for dental students whenever possible as this could increase students' interest in the subject and their motivation for learning. Such an approach could be particularly beneficial if there is a significant time gap between basic courses and involvement of students into clinical training for it could promote meaningful learning. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Pair Comparison Study of the Relevance of Nine Basic Science Courses

ERIC Educational Resources Information Center

Spilman, Edra L.; Spilman, Helen W.

1975-01-01

Reports a survey study in which basic science courses were rated according to relevance. Notes approaches for making the anatomy disciplines more relevant because results showed them of lowest relevancy compared with physiology, pathology, and pharmacology which were rated of highest relevance and with biochemistry and microbiology which fell…

Bioengineered silk scaffolds in 3D tissue modeling with focus on mammary tissues.

PubMed

Maghdouri-White, Yas; Bowlin, Gary L; Lemmon, Christopher A; Dréau, Didier

2016-02-01

In vitro generation of three-dimensional (3D) biological tissues and organ-like structures is a promising strategy to study and closely model complex aspects of the molecular, cellular, and physiological interactions of tissue. In particular, in vitro 3D tissue modeling holds promises to further our understanding of breast development. Indeed, biologically relevant 3D structures that combine mammary cells and engineered matrices have improved our knowledge of mammary tissue growth, organization, and differentiation. Several polymeric biomaterials have been used as scaffolds to engineer 3D mammary tissues. Among those, silk fibroin-based biomaterials have many biologically relevant properties and have been successfully used in multiple medical applications. Here, we review the recent advances in engineered scaffolds with an emphasis on breast-like tissue generation and the benefits of modified silk-based scaffolds. Copyright © 2015 Elsevier B.V. All rights reserved.

Temporal controls of the asymmetric cell division cycle in Caulobacter crescentus.

PubMed

Li, Shenghua; Brazhnik, Paul; Sobral, Bruno; Tyson, John J

2009-08-01

The asymmetric cell division cycle of Caulobacter crescentus is orchestrated by an elaborate gene-protein regulatory network, centered on three major control proteins, DnaA, GcrA and CtrA. The regulatory network is cast into a quantitative computational model to investigate in a systematic fashion how these three proteins control the relevant genetic, biochemical and physiological properties of proliferating bacteria. Different controls for both swarmer and stalked cell cycles are represented in the mathematical scheme. The model is validated against observed phenotypes of wild-type cells and relevant mutants, and it predicts the phenotypes of novel mutants and of known mutants under novel experimental conditions. Because the cell cycle control proteins of Caulobacter are conserved across many species of alpha-proteobacteria, the model we are proposing here may be applicable to other genera of importance to agriculture and medicine (e.g., Rhizobium, Brucella).

Integrating modelling and phenotyping approaches to identify and screen complex traits - Illustration for transpiration efficiency in cereals.

PubMed

Chenu, K; van Oosterom, E J; McLean, G; Deifel, K S; Fletcher, A; Geetika, G; Tirfessa, A; Mace, E S; Jordan, D R; Sulman, R; Hammer, G L

2018-02-21

Following advances in genetics, genomics, and phenotyping, trait selection in breeding is limited by our ability to understand interactions within the plants and with their environments, and to target traits of most relevance for the target population of environments. We propose an integrated approach that combines insights from crop modelling, physiology, genetics, and breeding to identify traits valuable for yield gain in the target population of environments, develop relevant high-throughput phenotyping platforms, and identify genetic controls and their values in production environments. This paper uses transpiration efficiency (biomass produced per unit of water used) as an example of a complex trait of interest to illustrate how the approach can guide modelling, phenotyping, and selection in a breeding program. We believe that this approach, by integrating insights from diverse disciplines, can increase the resource use efficiency of breeding programs for improving yield gains in target populations of environments.

New physiologically-relevant liver tissue model based on hierarchically cocultured primary rat hepatocytes with liver endothelial cells.

PubMed

Xiao, Wenjin; Perry, Guillaume; Komori, Kikuo; Sakai, Yasuyuki

2015-11-01

To develop an in vitro liver tissue equivalent, hepatocytes should be cocultured with liver non-parenchymal cells to mimic the in vivo physiological microenvironments. In this work, we describe a physiologically-relevant liver tissue model by hierarchically organizing layers of primary rat hepatocytes and human liver sinusoidal endothelial cells (TMNK-1) on an oxygen-permeable polydimethylsiloxane (PDMS) membrane, which facilitates direct oxygenation by diffusion through the membrane. This in vivo-mimicking hierarchical coculture was obtained by simply proceeding the overlay of TMNK-1 cells on the hepatocyte layer re-formed on the collagen immobilized PDMS membranes. The comparison of hepatic functionalities was achieved between coculture and sandwich culture with Matrigel, in the presence and absence of direct oxygenation. A complete double-layered structure of functional liver cells with vertical contact between hepatocytes and TMNK-1 was successfully constructed in the coculture with direct oxygen supply and was well-maintained for 14 days. The hepatocytes in this hierarchical culture exhibited improved survival, functional bile canaliculi formation, cellular level polarization and maintenance of metabolic activities including Cyp1A1/2 activity and albumin production. By contrast, the two cell populations formed discontinuous monolayers on the same surfaces in the non-oxygen-permeable cultures. These results demonstrate that (i) the direct oxygenation through the PDMS membranes enables very simple formation of a hierarchical structure consisting of a hepatocyte layer and a layer of TMNK-1 and (ii) we may include other non-parenchymal cells in this format easily, which can be widely applicable to other epithelial organs.

WAT-on-a-chip: A physiologically relevant microfluidic system incorporating white adipose tissue

PubMed Central

Loskill, Peter; Sezhian, Thiagarajan; Tharp, Kevin; Lee-Montiel, Felipe T.; Jeeawoody, Shaheen; Reese, Willie Mae; Zushin, Pete-James H.; Stahl, Andreas; Healy, Kevin E.

2017-01-01

Organ-on-a-chip systems possess a promising future as drug screening assays and as testbeds for disease modeling in the context of both single-organ systems and multi-organ-chips. Although it comprises approximately one fourth of the body weight of a healthy human, an organ frequently overlooked in this context is white adipose tissue (WAT). WAT-on-a-chip systems are required to create safety profiles of a large number of drugs due to their interactions with adipose tissue and other organs via paracrine signals, fatty acid release, and drug levels through sequestration. We report a WAT-on-a-chip system with a footprint of less than 1 mm2 consisting of a separate media channel and WAT chamber connected via small micropores. Analogous to the in vivo blood circulation, convective transport is thereby confined to the vasculature-like structures and the tissues protected from shear stresses. Numerical and analytical modeling revealed that the flow rates in the WAT chambers are less than 1/100 of the input flow rate. Using optimized injection parameters, we were able to inject pre-adipocytes, which subsequently formed adipose tissue featuring fully functional lipid metabolism. The physiologically relevant microfluidic environment of the WAT-chip supported long term culture of the functional adipose tissue for more than two weeks. Due to its physiological, highly controlled, and computationally predictable character, the system has the potential to be a powerful tool for the study of adipose tissue associated diseases such as obesity and type 2 diabetes. PMID:28418430

Teaching Stress Physiology Using Zebrafish ("Danio Rerio")

ERIC Educational Resources Information Center

Cooper, Michael; Dhawale, Shree; Mustafa, Ahmed

2009-01-01

A straightforward and inexpensive laboratory experiment is presented that investigates the physiological stress response of zebrafish after a 5 degree C increase in water temperature. This experiment is designed for an undergraduate physiology lab and allows students to learn the scientific method and relevant laboratory techniques without causing…

Phun Week: Understanding Physiology

ERIC Educational Resources Information Center

Limson, Mel; Matyas, Marsha Lakes

2009-01-01

Topics such as sports, exercise, health, and nutrition can make the science of physiology relevant and engaging for students. In addition, many lessons on these topics, such as those on the cardiovascular, respiratory, and digestive systems, align with national and state life science education standards. Physiology Understanding Week (PhUn…

Computational analysis of the regulation of Ca2+ dynamics in rat ventricular myocytes

NASA Astrophysics Data System (ADS)

Bugenhagen, Scott M.; Beard, Daniel A.

2015-10-01

Force-frequency relationships of isolated cardiac myocytes show complex behaviors that are thought to be specific to both the species and the conditions associated with the experimental preparation. Ca2+ signaling plays an important role in shaping the force-frequency relationship, and understanding the properties of the force-frequency relationship in vivo requires an understanding of Ca2+ dynamics under physiologically relevant conditions. Ca2+ signaling is itself a complicated process that is best understood on a quantitative level via biophysically based computational simulation. Although a large number of models are available in the literature, the models are often a conglomeration of components parameterized to data of incompatible species and/or experimental conditions. In addition, few models account for modulation of Ca2+ dynamics via β-adrenergic and calmodulin-dependent protein kinase II (CaMKII) signaling pathways even though they are hypothesized to play an important regulatory role in vivo. Both protein-kinase-A and CaMKII are known to phosphorylate a variety of targets known to be involved in Ca2+ signaling, but the effects of these pathways on the frequency- and inotrope-dependence of Ca2+ dynamics are not currently well understood. In order to better understand Ca2+ dynamics under physiological conditions relevant to rat, a previous computational model is adapted and re-parameterized to a self-consistent dataset obtained under physiological temperature and pacing frequency and updated to include β-adrenergic and CaMKII regulatory pathways. The necessity of specific effector mechanisms of these pathways in capturing inotrope- and frequency-dependence of the data is tested by attempting to fit the data while including and/or excluding those effector components. We find that: (1) β-adrenergic-mediated phosphorylation of the L-type calcium channel (LCC) (and not of phospholamban (PLB)) is sufficient to explain the inotrope-dependence; and (2) that CaMKII-mediated regulation of neither the LCC nor of PLB is required to explain the frequency-dependence of the data.

A Multi-Scale Sampling Strategy for Detecting Physiologically Significant Signals in AVIRIS Imagery

NASA Technical Reports Server (NTRS)

Gamon, John A.; Lee, Lai-Fun; Qiu, Hong-Lie; Davis, Stephen; Roberts, Dar A.; Ustin, Susan L.

1998-01-01

Models of photosynthetic production at ecosystem and global scales require multiple input parameters specifying physical and physiological surface features. While certain physical parameters (e.g., absorbed photosynthetically active radiation) can be derived from current satellite sensors, other physiologically relevant measures (e.g., vegetation type, water status, carboxylation capacity, or photosynthetic light-use efficiency), are not generally directly available from current satellite sensors at the appropriate geographic scale. Consequently, many model parameters must be assumed or derived from independent sources, often at an inappropriate scale. An abundance of ecophysiological studies at the leaf and canopy scales suggests strong physiological control of vegetation-atmosphere CO2 and water vapor fluxes, particularly in evergreen vegetation subjected to diurnal or seasonal stresses. For example hot, dry conditions can lead to stomatal closure, and associated "downregulation" of photosynthetic biochemical processes, a phenomenon often manifested as a "midday photosynthetic depression". A recent study with the revised simple biosphere (SiB2) model demonstrated that photosynthetic downregulation can significantly impact global climate. However, at the global scale, the exact significance of downregulation remains unclear, largely because appropriate physiological measures are generally unavailable at this scale. Clearly, there is a need to develop reliable ways of extracting physiologically relevant information from remote sensing. Narrow-band spectrometers offer many opportunities for deriving physiological parameters needed for ecosystem and global scale photosynthetic models. Experimental studies on the ground at the leaf- to stand-scale have indicated that several narrow-band features can be used to detect plant physiological status. One physiological signal is caused by xanthophyll cycle pigment activity, and is often expressed as the Photochemical Reflectance Index (PRI). Because the xanthophyll cycle pigments are photoregulatory pigments closely linked to photosynthetic function, this index can be used to derive relative photosynthetic rates. An additional signal with physiological significance is the 970 nm water absorption band, which provides a measure of liquid water content. This feature has been quantified both using a simple 2-band ratio (900/970 nm, here referred to as the "Water Band Index" or WBI;), and using the "continuum removal" method. Current atmospheric correction methods for AVIRIS imagery also obtain quantitative expressions of surface liquid water absorption based on the 970 nm water band and may be comparable to ground-based estimates of water content using this feature. However, physiological interpretations of both the PRI and the WBI are best understood at the leaf and canopy scales, where complications of atmospheric interference and complex stand and landscape features can be minimized, and where experimental manipulations can be readily applied. Currently it is not known whether these physiological indices can be used to derive meaningful physiological information from AVIRIS imagery. In addition to the problem of atmospheric interference, another challenge is that any simple physiological index can be confounded by multiple factors unrelated to physiology, and this problem can become more severe at progressively larger spatial scales. For example, previous work has suggested that both the PRI and the WBI, are strongly correlated with other optical measures of canopy structure (e.g., the Normalized Difference Vegetation Index or green vegetation fraction), indicating a confounding effect of structure on physiological signals at the larger, landscape scale. Furthermore, the normal operating mode of most imaging spectrometers does not allow simultaneous, ground truthing at a level of detail needed for physiological sampling. Additionally, manipulative experiments of physiology are difficult to apply at a geographic scale suitable for comparison with remote imagery, which often works at spatial scales that are several orders of magnitude larger than those typically used for physiological studies. These limitations require the consideration of alternative approaches to validating physiological information derived from AVIRIS data. In this report, we present a multi-scale sampling approach to detecting physiologically significant signals in narrow-band spectra. This approach explores the multi-dimensional data space provided by narrow-band spectrometry, and combines AVIRIS imagery at a large scale, with ground spectral sampling at an intermediate scale, and detailed ecophysiological measurements at a fine scale, to examine seasonally and spatially changing relationships between multiple structural and physiological variables. Examples of this approach are provided by simultaneous sampling of the Normalized Difference Vegetation Index (NDVI), an index of fractional PAR interception and green vegetation cover, the Water Band Index (WBI, an index of liquid water absorption, and the Photochemical Reflectance Index (PRI, an index of xanthophyll cycle pigment activity and photosynthetic light-use efficiency. By directly linking changing optical properties sampled on the ground with measurable physiological states, we hope to develop a basis for interpreting similar signals in AVIRIS imagery.

On the analysis of complex biological supply chains: From Process Systems Engineering to Quantitative Systems Pharmacology.

PubMed

Rao, Rohit T; Scherholz, Megerle L; Hartmanshenn, Clara; Bae, Seul-A; Androulakis, Ioannis P

2017-12-05

The use of models in biology has become particularly relevant as it enables investigators to develop a mechanistic framework for understanding the operating principles of living systems as well as in quantitatively predicting their response to both pathological perturbations and pharmacological interventions. This application has resulted in a synergistic convergence of systems biology and pharmacokinetic-pharmacodynamic modeling techniques that has led to the emergence of quantitative systems pharmacology (QSP). In this review, we discuss how the foundational principles of chemical process systems engineering inform the progressive development of more physiologically-based systems biology models.

PICUS v1.6 - enhancing the water cycle within a hybrid ecosystem model to assess the provision of drinking water in a changing climate

NASA Astrophysics Data System (ADS)

Schimmel, A.; Rammer, W.; Lexer, M. J.

2012-04-01

The PICUS model is a hybrid ecosystem model which is based on a 3D patch model and a physiological stand level production model. The model includes, among others, a submodel of bark beetle disturbances in Norway spruce and a management module allowing any silvicultural treatment to be mimicked realistically. It has been tested intensively for its ability to realistically reproduce tree growth and stand dynamics in complex structured mixed and mono-species temperate forest ecosystems. In several applications the models capacity to generate relevant forest related attributes which were subsequently fed into indicator systems to assess sustainable forest management under current and future climatic conditions has been proven. However, the relatively coarse monthly temporal resolution of the driving climate data as well as the process resolution of the major water relations within the simulated ecosystem hampered the inclusion of more detailed physiologically based assessments of drought conditions and water provisioning ecosystem services. In this contribution we present the improved model version PICUS v1.6 focusing on the newly implemented logic for the water cycle calculations. Transpiration, evaporation from leave surfaces and the forest floor, snow cover and snow melt as well as soil water dynamics in several soil horizons are covered. In enhancing the model overarching goal was to retain the large-scale applicability by keeping the input requirements to a minimum while improving the physiological foundation of water related ecosystem processes. The new model version is tested against empirical time series data. Future model applications are outlined.

Physiologically Based Pharmacokinetic Modeling Suggests Limited Drug–Drug Interaction Between Clopidogrel and Dasabuvir

PubMed Central

Fu, W; Badri, P; Bow, DAJ; Fischer, V

2017-01-01

Dasabuvir, a nonnucleoside NS5B polymerase inhibitor, is a sensitive substrate of cytochrome P450 (CYP) 2C8 with a potential for drug–drug interaction (DDI) with clopidogrel. A physiologically based pharmacokinetic (PBPK) model was developed for dasabuvir to evaluate the DDI potential with clopidogrel, the acyl‐β‐D glucuronide metabolite of which has been reported as a strong mechanism‐based inhibitor of CYP2C8 based on an interaction with repaglinide. In addition, the PBPK model for clopidogrel and its metabolite were updated with additional in vitro data. Sensitivity analyses using these PBPK models suggested that CYP2C8 inhibition by clopidogrel acyl‐β‐D glucuronide may not be as potent as previously suggested. The dasabuvir and updated clopidogrel PBPK models predict a moderate increase of 1.5–1.9‐fold for Cmax and 1.9–2.8‐fold for AUC of dasabuvir when coadministered with clopidogrel. While the PBPK results suggest there is a potential for DDI between dasabuvir and clopidogrel, the magnitude is not expected to be clinically relevant. PMID:28411400

A mathematical model of coronary blood flow control: simulation of patient-specific three-dimensional hemodynamics during exercise.

PubMed

Arthurs, Christopher J; Lau, Kevin D; Asrress, Kaleab N; Redwood, Simon R; Figueroa, C Alberto

2016-05-01

This work presents a mathematical model of the metabolic feedback and adrenergic feedforward control of coronary blood flow that occur during variations in the cardiac workload. It is based on the physiological observations that coronary blood flow closely follows myocardial oxygen demand, that myocardial oxygen debts are repaid, and that control oscillations occur when the system is perturbed and so are phenomenological in nature. Using clinical data, we demonstrate that the model can provide patient-specific estimates of coronary blood flow changes between rest and exercise, requiring only the patient's heart rate and peak aortic pressure as input. The model can be used in zero-dimensional lumped parameter network studies or as a boundary condition for three-dimensional multidomain Navier-Stokes blood flow simulations. For the first time, this model provides feedback control of the coronary vascular resistance, which can be used to enhance the physiological accuracy of any hemodynamic simulation, which includes both a heart model and coronary arteries. This has particular relevance to patient-specific simulation for which heart rate and aortic pressure recordings are available. In addition to providing a simulation tool, under our assumptions, the derivation of our model shows that β-feedforward control of the coronary microvascular resistance is a mathematical necessity and that the metabolic feedback control must be dependent on two error signals: the historical myocardial oxygen debt, and the instantaneous myocardial oxygen deficit. Copyright © 2016 the American Physiological Society.

UTCI—Why another thermal index?

NASA Astrophysics Data System (ADS)

Jendritzky, Gerd; de Dear, Richard; Havenith, George

2012-05-01

Existing procedures for the assessment of the thermal environment in the fields of public weather services, public health systems, precautionary planning, urban design, tourism and recreation and climate impact research exhibit significant shortcomings. This is most evident for simple (mostly two-parameter) indices, when comparing them to complete heat budget models developed since the 1960s. ISB Commission 6 took up the idea of developing a Universal Thermal Climate Index (UTCI) based on the most advanced multi-node model of thermoregulation representing progress in science within the last three to four decades, both in thermo-physiological and heat exchange theory. Creating the essential research synergies for the development of UTCI required pooling the resources of multidisciplinary experts in the fields of thermal physiology, mathematical modelling, occupational medicine, meteorological data handling (in particular radiation modelling) and application development in a network. It was possible to extend the expertise of ISB Commission 6 substantially by COST (a European programme promoting Cooperation in Science and Technology) Action 730 so that finally over 45 scientists from 23 countries (Australia, Canada, Israel, several Europe countries, New Zealand, and the United States) worked together. The work was performed under the umbrella of the WMO Commission on Climatology (CCl). After extensive evaluations, Fiala's multi-node human physiology and thermal comfort model (FPC) was adopted for this study. The model was validated extensively, applying as yet unused data from other research groups, and extended for the purposes of the project. This model was coupled with a state-of-the-art clothing model taking into consideration behavioural adaptation of clothing insulation by the general urban population in response to actual environmental temperature. UTCI was then derived conceptually as an equivalent temperature (ET). Thus, for any combination of air temperature, wind, radiation, and humidity (stress), UTCI is defined as the isothermal air temperature of the reference condition that would elicit the same dynamic response (strain) of the physiological model. As UTCI is based on contemporary science its use will standardise applications in the major fields of human biometeorology, thus making research results comparable and physiologically relevant.

Factors circulating in the blood of type 2 diabetes mellitus patients affect osteoblast maturation – Description of a novel in vitro model

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

Ehnert, Sabrina, E-mail: sabrina.ehnert@gmail.com; Freude, Thomas, E-mail: tfreude@bgu-tuebingen.de; Ihle, Christoph, E-mail: cihle@bgu-tuebingen.de

Type 2 diabetes mellitus (T2DM) is one of the most frequent metabolic disorders in industrialized countries. Among other complications, T2DM patients have an increased fracture risk and delayed fracture healing. We have demonstrated that supraphysiological glucose and insulin levels inhibit primary human osteoblasts' maturation. We aimed at developing a more physiologically relevant in vitro model to analyze T2DM-mediated osteoblast changes. Therefore, SCP-1-immortalized pre-osteoblasts were differentiated with T2DM or control (non-obese and obese) sera. Between both control groups, no significant changes were observed. Proliferation was significantly increased (1.69-fold), while AP activity and matrix mineralization was significantly reduced in the T2DM group.more » Expression levels of osteogenic marker genes and transcription factors were altered, e.g. down-regulation of RUNX2 and SP-7 or up-regulation of STAT1, in the T2DM group. Active TGF-β levels were significantly increased (1.46-fold) in T2DM patients' sera. SCP-1 cells treated with these sera showed significantly increased TGF-β signaling (2.47-fold). Signaling inhibition effectively restored osteoblast maturation in the T2DM group. Summarizing our data, SCP-1 cells differentiated in the presence of T2DM patients' serum exhibit reduced osteoblast function. Thus, this model has a high physiological impact, as it can identify circulating factors in T2DM patients' blood that may affect bone function, e.g. TGF-β. - Highlights: • We present here a physiologically relevant in vitro model for diabetic osteopathy. • Blood of T2DM patients contains factors that affect osteoblasts' function. • The model developed here can be used to identify these factors, e.g. TGF-β. • Blocking TGF-β signaling partly rescues the osteoblasts' function in the T2DM group. • The model is useful to demonstrate the role of single factors in diabetic osteopathy.« less

Personalized, relevance-based Multimodal Robotic Imaging and augmented reality for Computer Assisted Interventions.

PubMed

Navab, Nassir; Fellow, Miccai; Hennersperger, Christoph; Frisch, Benjamin; Fürst, Bernhard

2016-10-01

In the last decade, many researchers in medical image computing and computer assisted interventions across the world focused on the development of the Virtual Physiological Human (VPH), aiming at changing the practice of medicine from classification and treatment of diseases to that of modeling and treating patients. These projects resulted in major advancements in segmentation, registration, morphological, physiological and biomechanical modeling based on state of art medical imaging as well as other sensory data. However, a major issue which has not yet come into the focus is personalizing intra-operative imaging, allowing for optimal treatment. In this paper, we discuss the personalization of imaging and visualization process with particular focus on satisfying the challenging requirements of computer assisted interventions. We discuss such requirements and review a series of scientific contributions made by our research team to tackle some of these major challenges. Copyright © 2016. Published by Elsevier B.V.

Niche-based screening identifies small-molecule inhibitors of leukemia stem cells.

PubMed

Hartwell, Kimberly A; Miller, Peter G; Mukherjee, Siddhartha; Kahn, Alissa R; Stewart, Alison L; Logan, David J; Negri, Joseph M; Duvet, Mildred; Järås, Marcus; Puram, Rishi; Dancik, Vlado; Al-Shahrour, Fatima; Kindler, Thomas; Tothova, Zuzana; Chattopadhyay, Shrikanta; Hasaka, Thomas; Narayan, Rajiv; Dai, Mingji; Huang, Christina; Shterental, Sebastian; Chu, Lisa P; Haydu, J Erika; Shieh, Jae Hung; Steensma, David P; Munoz, Benito; Bittker, Joshua A; Shamji, Alykhan F; Clemons, Paul A; Tolliday, Nicola J; Carpenter, Anne E; Gilliland, D Gary; Stern, Andrew M; Moore, Malcolm A S; Scadden, David T; Schreiber, Stuart L; Ebert, Benjamin L; Golub, Todd R

2013-12-01

Efforts to develop more effective therapies for acute leukemia may benefit from high-throughput screening systems that reflect the complex physiology of the disease, including leukemia stem cells (LSCs) and supportive interactions with the bone marrow microenvironment. The therapeutic targeting of LSCs is challenging because LSCs are highly similar to normal hematopoietic stem and progenitor cells (HSPCs) and are protected by stromal cells in vivo. We screened 14,718 compounds in a leukemia-stroma co-culture system for inhibition of cobblestone formation, a cellular behavior associated with stem-cell function. Among those compounds that inhibited malignant cells but spared HSPCs was the cholesterol-lowering drug lovastatin. Lovastatin showed anti-LSC activity in vitro and in an in vivo bone marrow transplantation model. Mechanistic studies demonstrated that the effect was on target, via inhibition of HMG-CoA reductase. These results illustrate the power of merging physiologically relevant models with high-throughput screening.

Niche-based screening identifies small-molecule inhibitors of leukemia stem cells

PubMed Central

Mukherjee, Siddhartha; Kahn, Alissa R; Stewart, Alison L; Logan, David J; Negri, Joseph M; Duvet, Mildred; Järås, Marcus; Puram, Rishi; Dancik, Vlado; Al-Shahrour, Fatima; Kindler, Thomas; Tothova, Zuzana; Chattopadhyay, Shrikanta; Hasaka, Thomas; Narayan, Rajiv; Dai, Mingji; Huang, Christina; Shterental, Sebastian; Chu, Lisa P; Haydu, J Erika; Shieh, Jae Hung; Steensma, David P; Munoz, Benito; Bittker, Joshua A; Shamji, Alykhan F; Clemons, Paul A; Tolliday, Nicola J; Carpenter, Anne E; Gilliland, D Gary; Stern, Andrew M; Moore, Malcolm A S; Scadden, David T; Schreiber, Stuart L; Ebert, Benjamin L; Golub, Todd R

2014-01-01

Efforts to develop more effective therapies for acute leukemia may benefit from high-throughput screening systems that reflect the complex physiology of the disease, including leukemia stem cells (LSCs) and supportive interactions with the bone-marrow microenvironment. The therapeutic targeting of LSCs is challenging because LSCs are highly similar to normal hematopoietic stem and progenitor cells (HSPCs) and are protected by stromal cells in vivo. We screened 14,718 compounds in a leukemia-stroma co-culture system for inhibition of cobblestone formation, a cellular behavior associated with stem-cell function. Among those that inhibited malignant cells but spared HSPCs was the cholesterol-lowering drug lovastatin. Lovastatin showed anti-LSC activity in vitro and in an in vivo bone marrow transplantation model. Mechanistic studies demonstrated that the effect was on-target, via inhibition of HMGCoA reductase. These results illustrate the power of merging physiologically-relevant models with high-throughput screening. PMID:24161946

Biophysical characterization of α-synuclein and its controversial structure

PubMed Central

Alderson, T Reid; Markley, John L

2013-01-01

α-synuclein, a presynaptic protein of poorly defined function, constitutes the main component of Parkinson disease-associated Lewy bodies. Extensive biophysical investigations have provided evidence that isolated α-synuclein is an intrinsically disordered protein (IDP) in vitro. Subsequently serving as a model IDP in numerous studies, α-synuclein has aided in the development of many technologies used to characterize IDPs and arguably represents the most thoroughly analyzed IDP to date. Recent reports, however, have challenged the disordered nature of α-synuclein inside cells and have instead proposed a physiologically relevant helical tetramer. Despite α-synuclein’s rich biophysical history, a single coherent picture has not yet emerged concerning its in vivo structure, dynamics, and physiological role(s). We present herein a review of the biophysical discoveries, developments, and models pertinent to the characterization of α-synuclein’s structure and analysis of the native tetramer controversy. PMID:24634806

A data-driven modeling approach to stochastic computation for low-energy biomedical devices.

PubMed

Lee, Kyong Ho; Jang, Kuk Jin; Shoeb, Ali; Verma, Naveen

2011-01-01

Low-power devices that can detect clinically relevant correlations in physiologically-complex patient signals can enable systems capable of closed-loop response (e.g., controlled actuation of therapeutic stimulators, continuous recording of disease states, etc.). In ultra-low-power platforms, however, hardware error sources are becoming increasingly limiting. In this paper, we present how data-driven methods, which allow us to accurately model physiological signals, also allow us to effectively model and overcome prominent hardware error sources with nearly no additional overhead. Two applications, EEG-based seizure detection and ECG-based arrhythmia-beat classification, are synthesized to a logic-gate implementation, and two prominent error sources are introduced: (1) SRAM bit-cell errors and (2) logic-gate switching errors ('stuck-at' faults). Using patient data from the CHB-MIT and MIT-BIH databases, performance similar to error-free hardware is achieved even for very high fault rates (up to 0.5 for SRAMs and 7 × 10(-2) for logic) that cause computational bit error rates as high as 50%.

Eccentric Contraction-Induced Muscle Injury: Reproducible, Quantitative, Physiological Models to Impair Skeletal Muscle’s Capacity to Generate Force

PubMed Central

Call, Jarrod A.; Lowe, Dawn A.

2018-01-01

In order to investigate the molecular and cellular mechanisms of muscle regeneration an experimental injury model is required. Advantages of eccentric contraction-induced injury are that it is a controllable, reproducible, and physiologically relevant model to cause muscle injury, with injury being defined as a loss of force generating capacity. While eccentric contractions can be incorporated into conscious animal study designs such as downhill treadmill running, electrophysiological approaches to elicit eccentric contractions and examine muscle contractility, for example before and after the injurious eccentric contractions, allows researchers to circumvent common issues in determining muscle function in a conscious animal (e.g., unwillingness to participate). Herein, we describe in vitro and in vivo methods that are reliable, repeatable, and truly maximal because the muscle contractions are evoked in a controlled, quantifiable manner independent of subject motivation. Both methods can be used to initiate eccentric contraction-induced injury and are suitable for monitoring functional muscle regeneration hours to days to weeks post-injury. PMID:27492161

A COMPREHENSIVE INSIGHT ON OCULAR PHARMACOKINETICS

PubMed Central

Agrahari, Vibhuti; Mandal, Abhirup; Agrahari, Vivek; Trinh, Hoang My; Joseph, Mary; Ray, Animikh; Hadji, Hicheme; Mitra, Ranjana; Pal, Dhananjay; Mitra, Ashim K.

2017-01-01

Eye is a distinctive organ with protective anatomy and physiology. Several pharmacokinetics compartment model of ocular drug delivery has been developed for describing the absorption, distribution and elimination of ocular drugs in the eye. Determining pharmacokinetics parameters in ocular tissues is a major challenge because of the complex anatomy and dynamic physiological barrier of the eye. In this review, pharmacokinetics of these compartments exploring different drugs, delivery systems and routes of administration are discussed including factors affecting intraocular bioavailability. Factors such as pre-corneal fluid drainage, drug binding to tear proteins, systemic drug absorption, corneal factors, melanin binding, drug metabolism renders ocular delivery challenging and elaborated in this manuscript. Several compartment models are discussed those are developed in ocular drug delivery to study the pharmacokinetics parameters. There are several transporters present in both anterior and posterior segments of the eye which play a significant role in ocular pharmacokinetics and summarized briefly. Moreover, several ocular pharmacokinetics animal models and relevant studies are reviewed and discussed in addition to the pharmacokinetics of various ocular formulations. PMID:27798766

Nonstandard working schedules and health: the systematic search for a comprehensive model.

PubMed

Merkus, Suzanne L; Holte, Kari Anne; Huysmans, Maaike A; van Mechelen, Willem; van der Beek, Allard J

2015-10-23

Theoretical models on shift work fall short of describing relevant health-related pathways associated with the broader concept of nonstandard working schedules. Shift work models neither combine relevant working time characteristics applicable to nonstandard schedules nor include the role of rest periods and recovery in the development of health complaints. Therefore, this paper aimed to develop a comprehensive model on nonstandard working schedules to address these shortcomings. A literature review was conducted using a systematic search and selection process. Two searches were performed: one associating the working time characteristics time-of-day and working time duration with health and one associating recovery after work with health. Data extracted from the models were used to develop a comprehensive model on nonstandard working schedules and health. For models on the working time characteristics, the search strategy yielded 3044 references, of which 26 met the inclusion criteria that contained 22 distinctive models. For models on recovery after work, the search strategy yielded 896 references, of which seven met the inclusion criteria containing seven distinctive models. Of the models on the working time characteristics, three combined time-of-day with working time duration, 18 were on time-of-day (i.e. shift work), and one was on working time duration. The model developed in the paper has a comprehensive approach to working hours and other work-related risk factors and proposes that they should be balanced by positive non-work factors to maintain health. Physiological processes leading to health complaints are circadian disruption, sleep deprivation, and activation that should be counterbalanced by (re-)entrainment, restorative sleep, and recovery, respectively, to maintain health. A comprehensive model on nonstandard working schedules and health was developed. The model proposes that work and non-work as well as their associated physiological processes need to be balanced to maintain good health. The model gives researchers a useful overview over the various risk factors and pathways associated with health that should be considered when studying any form of nonstandard working schedule.

Mechanosensation and the Primary Cilium

NASA Astrophysics Data System (ADS)

Glaser, Joseph; Resnick, Andrew

2010-10-01

The primary cilium has come under increased scrutiny as a site for mechano- and chemosensation by cells. We have undertaken a program of study using mouse renal cell lines from the cortical collecting duct to quantify how mechanical forces arising from fluid shear are transduced into cellular responses. Fluid flow through a model nephron has been analyzed to determine the in vivo forces. A novel tissue culture flow chamber permitting accurate reproduction of physiologically relevant conditions has been calibrated. We have determined that in vivo conditions can be accurately modeled in our flow chamber.

The brain as a system of nested but partially overlapping networks. Heuristic relevance of the model for brain physiology and pathology.

PubMed

Agnati, L F; Guidolin, D; Fuxe, K

2007-01-01

A new model of the brain organization is proposed. The model is based on the assumption that a global molecular network enmeshes the entire central nervous system. Thus, brain extra-cellular and intra-cellular molecular networks are proposed to communicate at the level of special plasma membrane regions (e.g., the lipid rafts) where horizontal molecular networks can represent input/output regions allowing the cell to have informational exchanges with the extracellular environment. Furthermore, some "pervasive signals" such as field potentials, pressure waves and thermal gradients that affect large parts of the brain cellular and molecular networks are discussed. Finally, at least two learning paradigms are analyzed taking into account the possible role of Volume Transmission: the so-called model of "temporal difference learning" and the "Turing B-unorganised machine". The relevance of this new view of brain organization for a deeper understanding of some neurophysiological and neuropathological aspects of its function is briefly discussed.

Organismal climatology: analyzing environmental variability at scales relevant to physiological stress.

PubMed

Helmuth, Brian; Broitman, Bernardo R; Yamane, Lauren; Gilman, Sarah E; Mach, Katharine; Mislan, K A S; Denny, Mark W

2010-03-15

Predicting when, where and with what magnitude climate change is likely to affect the fitness, abundance and distribution of organisms and the functioning of ecosystems has emerged as a high priority for scientists and resource managers. However, even in cases where we have detailed knowledge of current species' range boundaries, we often do not understand what, if any, aspects of weather and climate act to set these limits. This shortcoming significantly curtails our capacity to predict potential future range shifts in response to climate change, especially since the factors that set range boundaries under those novel conditions may be different from those that set limits today. We quantitatively examine a nine-year time series of temperature records relevant to the body temperatures of intertidal mussels as measured using biomimetic sensors. Specifically, we explore how a 'climatology' of body temperatures, as opposed to long-term records of habitat-level parameters such as air and water temperatures, can be used to extrapolate meaningful spatial and temporal patterns of physiological stress. Using different metrics that correspond to various aspects of physiological stress (seasonal means, cumulative temperature and the return time of extremes) we show that these potential environmental stressors do not always occur in synchrony with one another. Our analysis also shows that patterns of animal temperature are not well correlated with simple, commonly used metrics such as air temperature. Detailed physiological studies can provide guidance to predicting the effects of global climate change on natural ecosystems but only if we concomitantly record, archive and model environmental signals at appropriate scales.

Frontiers in the Teaching of Physiology. Computer Literacy and Simulation.

ERIC Educational Resources Information Center

Tidball, Charles S., Ed.; Shelesnyak, M. C., Ed.

Provided is a collection of papers on computer literacy and simulation originally published in The Physiology Teacher, supplemented by additional papers and a glossary of terms relevant to the field. The 12 papers are presented in five sections. An affirmation of conventional physiology laboratory exercises, coping with computer terminology, and…

Computational physiology and the Physiome Project.

PubMed

Crampin, Edmund J; Halstead, Matthew; Hunter, Peter; Nielsen, Poul; Noble, Denis; Smith, Nicolas; Tawhai, Merryn

2004-01-01

Bioengineering analyses of physiological systems use the computational solution of physical conservation laws on anatomically detailed geometric models to understand the physiological function of intact organs in terms of the properties and behaviour of the cells and tissues within the organ. By linking behaviour in a quantitative, mathematically defined sense across multiple scales of biological organization--from proteins to cells, tissues, organs and organ systems--these methods have the potential to link patient-specific knowledge at the two ends of these spatial scales. A genetic profile linked to cardiac ion channel mutations, for example, can be interpreted in relation to body surface ECG measurements via a mathematical model of the heart and torso, which includes the spatial distribution of cardiac ion channels throughout the myocardium and the individual kinetics for each of the approximately 50 types of ion channel, exchanger or pump known to be present in the heart. Similarly, linking molecular defects such as mutations of chloride ion channels in lung epithelial cells to the integrated function of the intact lung requires models that include the detailed anatomy of the lungs, the physics of air flow, blood flow and gas exchange, together with the large deformation mechanics of breathing. Organizing this large body of knowledge into a coherent framework for modelling requires the development of ontologies, markup languages for encoding models, and web-accessible distributed databases. In this article we review the state of the field at all the relevant levels, and the tools that are being developed to tackle such complexity. Integrative physiology is central to the interpretation of genomic and proteomic data, and is becoming a highly quantitative, computer-intensive discipline.

Physiologically-based pharmacokinetic model of vaginally administered dapivirine ring and film formulations.

PubMed

Kay, Katherine; Shah, Dhaval K; Rohan, Lisa; Bies, Robert

2018-05-01

A physiologically-based pharmacokinetic (PBPK) model of the vaginal space was developed with the aim of predicting concentrations in the vaginal and cervical space. These predictions can be used to optimize the probability of success of vaginally administered dapivirine (DPV) for HIV prevention. We focus on vaginal delivery using either a ring or film. A PBPK model describing the physiological structure of the vaginal tissue and fluid was defined mathematically and implemented in MATLAB. Literature reviews provided estimates for relevant physiological and physiochemical parameters. Drug concentration-time profiles were simulated in luminal fluids, vaginal tissue and plasma after administration of ring or film. Patient data were extracted from published clinical trials and used to test model predictions. The DPV ring simulations tested the two dosing regimens and predicted PK profiles and area under the curve of luminal fluids (29 079 and 33 067 mg h l -1 in groups A and B, respectively) and plasma (0.177 and 0.211 mg h l -1 ) closely matched those reported (within one standard deviation). While the DPV film study reported drug concentration at only one time point per patient, our simulated profiles pass through reported concentration range. HIV is a major public health issue and vaginal microbicides have the potential to provide a crucial, female-controlled option for protection. The PBPK model successfully simulated realistic representations of drug PK. It provides a reliable, inexpensive and accessible platform where potential effectiveness of new compounds and the robustness of treatment modalities for pre-exposure prophylaxis can be evaluated. © 2018 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

The mystery of membrane organization: composition, regulation and physiological relevance of lipid rafts

PubMed Central

Sezgin, Erdinc; Levental, Ilya; Mayor, Satyajit; Eggeling, Christian

2017-01-01

Cellular plasma membranes are laterally heterogeneous, featuring a variety of distinct subcompartments that differ in their biophysical properties and composition. A large body of research has focused on understanding the basis for this heterogeneity and its physiological relevance. The membrane raft hypothesis formalized a physicochemical principle for a subtype of such lateral membrane heterogeneity, wherein the preferential associations of cholesterol and saturated lipids drives the formation of relatively packed (ordered) membrane domains that selectively recruit certain lipids and proteins. Recent years have yielded new insights into this concept and its in vivo relevance, primarily owing to the development of biochemical and biophysical technologies. PMID:28356571

Development and characterization of a 3D multicell microtissue culture model of airway smooth muscle.

PubMed

West, Adrian R; Zaman, Nishat; Cole, Darren J; Walker, Matthew J; Legant, Wesley R; Boudou, Thomas; Chen, Christopher S; Favreau, John T; Gaudette, Glenn R; Cowley, Elizabeth A; Maksym, Geoffrey N

2013-01-01

Airway smooth muscle (ASM) cellular and molecular biology is typically studied with single-cell cultures grown on flat 2D substrates. However, cells in vivo exist as part of complex 3D structures, and it is well established in other cell types that altering substrate geometry exerts potent effects on phenotype and function. These factors may be especially relevant to asthma, a disease characterized by structural remodeling of the airway wall, and highlights a need for more physiologically relevant models of ASM function. We utilized a tissue engineering platform known as microfabricated tissue gauges to develop a 3D culture model of ASM featuring arrays of ∼0.4 mm long, ∼350 cell "microtissues" capable of simultaneous contractile force measurement and cell-level microscopy. ASM-only microtissues generated baseline tension, exhibited strong cellular organization, and developed actin stress fibers, but lost structural integrity and dissociated from the cantilevers within 3 days. Addition of 3T3-fibroblasts dramatically improved survival times without affecting tension development or morphology. ASM-3T3 microtissues contracted similarly to ex vivo ASM, exhibiting reproducible responses to a range of contractile and relaxant agents. Compared with 2D cultures, microtissues demonstrated identical responses to acetylcholine and KCl, but not histamine, forskolin, or cytochalasin D, suggesting that contractility is regulated by substrate geometry. Microtissues represent a novel model for studying ASM, incorporating a physiological 3D structure, realistic mechanical environment, coculture of multiple cells types, and comparable contractile properties to existing models. This new model allows for rapid screening of biochemical and mechanical factors to provide insight into ASM dysfunction in asthma.

PPDB - A tool for investigation of plants physiology based on gene ontology.

PubMed

Sharma, Ajay Shiv; Gupta, Hari Om; Prasad, Rajendra

2014-09-02

Representing the way forward, from functional genomics and its ontology to functional understanding and physiological model, in a computationally tractable fashion is one of the ongoing challenges faced by computational biology. To tackle the standpoint, we herein feature the applications of contemporary database management to the development of PPDB, a searching and browsing tool for the Plants Physiology Database that is based upon the mining of a large amount of gene ontology data currently available. The working principles and search options associated with the PPDB are publicly available and freely accessible on-line ( http://www.iitr.ernet.in/ajayshiv/ ) through a user friendly environment generated by means of Drupal-6.24. By knowing that genes are expressed in temporally and spatially characteristic patterns and that their functionally distinct products often reside in specific cellular compartments and may be part of one or more multi-component complexes, this sort of work is intended to be relevant for investigating the functional relationships of gene products at a system level and, thus, helps us approach to the full physiology.

PPDB: A Tool for Investigation of Plants Physiology Based on Gene Ontology.

PubMed

Sharma, Ajay Shiv; Gupta, Hari Om; Prasad, Rajendra

2015-09-01

Representing the way forward, from functional genomics and its ontology to functional understanding and physiological model, in a computationally tractable fashion is one of the ongoing challenges faced by computational biology. To tackle the standpoint, we herein feature the applications of contemporary database management to the development of PPDB, a searching and browsing tool for the Plants Physiology Database that is based upon the mining of a large amount of gene ontology data currently available. The working principles and search options associated with the PPDB are publicly available and freely accessible online ( http://www.iitr.ac.in/ajayshiv/ ) through a user-friendly environment generated by means of Drupal-6.24. By knowing that genes are expressed in temporally and spatially characteristic patterns and that their functionally distinct products often reside in specific cellular compartments and may be part of one or more multicomponent complexes, this sort of work is intended to be relevant for investigating the functional relationships of gene products at a system level and, thus, helps us approach to the full physiology.

Compromising σ-1 Receptors at the Endoplasmic Reticulum Render Cytotoxicity to Physiologically Relevant Concentrations of Dopamine in a Nuclear Factor-κB/Bcl-2-Dependent Mechanism: Potential Relevance to Parkinson's Disease

PubMed Central

Mori, Tomohisa; Hayashi, Teruo

2012-01-01

The endoplasmic reticulum (ER) chaperone σ-1 receptor (Sig-1R) is cytoprotective against ER stress-induced apoptosis. The level of Sig-1Rs in the brain was reported to be lower in early parkinsonian patients. Because dopamine (DA) toxicity is well known to be involved in the etiology of Parkinson's disease, we tested in this study whether a relationship might exist between Sig-1Rs and DA-induced cytotoxicity in a cellular model by using Chinese hamster ovary (CHO) cells. DA in physiological concentrations (e.g., lower than 10 μM) does not cause apoptosis. However, the same concentrations of DA cause apoptosis in Sig-1R knockdown CHO cells. In search of a mechanistic explanation, we found that unfolded protein response is not involved. Rather, the level of protective protein Bcl-2 is critically involved in this DA/Sig-1R knockdown-induced apoptosis. Specifically, the DA/Sig-1R knockdown causes a synergistic proteasomal conversion of nuclear factor κB (NF-κB) p105 to the active form of p50, which is known to down-regulate the transcription of Bcl-2. It is noteworthy that the DA/Sig-1R knockdown-induced apoptosis is blocked by the overexpression of Bcl-2. Our results therefore indicate that DA is involved in the activation of NF-κB and suggest that endogenous Sig-1Rs are tonically inhibiting the proteasomal conversion/activation of NF-κB caused by physiologically relevant concentrations of DA that would otherwise cause apoptosis. Thus, Sig-1Rs and associated ligands may represent new therapeutic targets for the treatment of parkinsonism. PMID:22399814

Supra-physiological folic acid concentrations induce aberrant DNA methylation in normal human cells in vitro.

PubMed

Charles, Michelle A; Johnson, Ian T; Belshaw, Nigel J

2012-07-01

The micronutrients folate and selenium may modulate DNA methylation patterns by affecting intracellular levels of the methyl donor S-adenosylmethionine (SAM) and/or the product of methylation reactions S-adenosylhomocysteine (SAH). WI-38 fibroblasts and FHC colon epithelial cells were cultured in the presence of two forms of folate or four forms of selenium at physiologically-relevant doses, and their effects on LINE-1 methylation, gene-specific CpG island (CGI) methylation and intracellular SAM:SAH were determined. At physiologically-relevant doses the forms of folate or selenium had no effect on LINE-1 or CGI methylation, nor on intracellular SAM:SAH. However the commercial cell culture media used for the selenium studies, containing supra-physiological concentrations of folic acid, induced LINE-1 hypomethylation, CGI hypermethylation and decreased intracellular SAM:SAH in both cell lines. We conclude that the exposure of normal human cells to supra-physiological folic acid concentrations present in commercial cell culture media perturbs the intracellular SAM:SAH ratio and induces aberrant DNA methylation.

Oxygen demand of perfused heart preparations: how electromechanical function and inadequate oxygenation affect physiology and optical measurements.

PubMed

Kuzmiak-Glancy, Sarah; Jaimes, Rafael; Wengrowski, Anastasia M; Kay, Matthew W

2015-06-01

What is the topic of this review? This review discusses how the function and electrophysiology of isolated perfused hearts are affected by oxygenation and energy utilization. The impact of oxygenation on fluorescence measurements in perfused hearts is also discussed. What advances does it highlight? Recent studies have illuminated the inherent differences in electromechanical function, energy utilization rate and oxygen requirements between the primary types of excised heart preparations. A summary and analysis of how these variables affect experimental results are necessary to elevate the physiological relevance of these approaches in order to advance the field of whole-heart research. The ex vivo perfused heart recreates important aspects of in vivo conditions to provide insight into whole-organ function. In this review we discuss multiple types of ex vivo heart preparations, explain how closely each mimic in vivo function, and discuss how changes in electromechanical function and inadequate oxygenation of ex vivo perfused hearts may affect measurements of physiology. Hearts that perform physiological work have high oxygen demand and are likely to experience hypoxia when perfused with a crystalloid perfusate. Adequate myocardial oxygenation is critically important for obtaining physiologically relevant measurements, so when designing experiments the type of ex vivo preparation and the capacity of perfusate to deliver oxygen must be carefully considered. When workload is low, such as during interventions that inhibit contraction, oxygen demand is also low, which could dramatically alter a physiological response to experimental variables. Changes in oxygenation also alter the optical properties of cardiac tissue, an effect that may influence optical signals measured from both endogenous and exogenous fluorophores. Careful consideration of oxygen supply, working condition, and wavelengths used to acquire optical signals is critical for obtaining physiologically relevant measurements during ex vivo perfused heart studies. © 2015 The Authors. Experimental Physiology © 2015 The Physiological Society.

Design optimization for accurate flow simulations in 3D printed vascular phantoms derived from computed tomography angiography

NASA Astrophysics Data System (ADS)

Sommer, Kelsey; Izzo, Rick L.; Shepard, Lauren; Podgorsak, Alexander R.; Rudin, Stephen; Siddiqui, Adnan H.; Wilson, Michael F.; Angel, Erin; Said, Zaid; Springer, Michael; Ionita, Ciprian N.

2017-03-01

3D printing has been used to create complex arterial phantoms to advance device testing and physiological condition evaluation. Stereolithographic (STL) files of patient-specific cardiovascular anatomy are acquired to build cardiac vasculature through advanced mesh-manipulation techniques. Management of distal branches in the arterial tree is important to make such phantoms practicable. We investigated methods to manage the distal arterial flow resistance and pressure thus creating physiologically and geometrically accurate phantoms that can be used for simulations of image-guided interventional procedures with new devices. Patient specific CT data were imported into a Vital Imaging workstation, segmented, and exported as STL files. Using a mesh-manipulation program (Meshmixer) we created flow models of the coronary tree. Distal arteries were connected to a compliance chamber. The phantom was then printed using a Stratasys Connex3 multimaterial printer: the vessel in TangoPlus and the fluid flow simulation chamber in Vero. The model was connected to a programmable pump and pressure sensors measured flow characteristics through the phantoms. Physiological flow simulations for patient-specific vasculature were done for six cardiac models (three different vasculatures comparing two new designs). For the coronary phantom we obtained physiologically relevant waves which oscillated between 80 and 120 mmHg and a flow rate of 125 ml/min, within the literature reported values. The pressure wave was similar with those acquired in human patients. Thus we demonstrated that 3D printed phantoms can be used not only to reproduce the correct patient anatomy for device testing in image-guided interventions, but also for physiological simulations. This has great potential to advance treatment assessment and diagnosis.

The acclimative biogeochemical model of the southern North Sea

NASA Astrophysics Data System (ADS)

Kerimoglu, Onur; Hofmeister, Richard; Maerz, Joeran; Riethmüller, Rolf; Wirtz, Kai W.

2017-10-01

Ecosystem models often rely on heuristic descriptions of autotrophic growth that fail to reproduce various stationary and dynamic states of phytoplankton cellular composition observed in laboratory experiments. Here, we present the integration of an advanced phytoplankton growth model within a coupled three-dimensional physical-biogeochemical model and the application of the model system to the southern North Sea (SNS) defined on a relatively high resolution (˜ 1.5-4.5 km) curvilinear grid. The autotrophic growth model, recently introduced by Wirtz and Kerimoglu (2016), is based on a set of novel concepts for the allocation of internal resources and operation of cellular metabolism. The coupled model system consists of the General Estuarine Transport Model (GETM) as the hydrodynamical driver, a lower-trophic-level model and a simple sediment diagenesis model. We force the model system with realistic atmospheric and riverine fluxes, background turbidity caused by suspended particulate matter (SPM) and open ocean boundary conditions. For a simulation for the period 2000-2010, we show that the model system satisfactorily reproduces the physical and biogeochemical states of the system within the German Bight characterized by steep salinity; nutrient and chlorophyll (Chl) gradients, as inferred from comparisons against observation data from long-term monitoring stations; sparse in situ measurements; continuous transects; and satellites. The model also displays skill in capturing the formation of thin chlorophyll layers at the pycnocline, which is frequently observed within the stratified regions during summer. A sensitivity analysis reveals that the vertical distributions of phytoplankton concentrations estimated by the model can be qualitatively sensitive to the description of the light climate and dependence of sinking rates on the internal nutrient reserves. A non-acclimative (fixed-physiology) version of the model predicted entirely different vertical profiles, suggesting that accounting for physiological flexibility might be relevant for a consistent representation of the vertical distribution of phytoplankton biomass. Our results point to significant variability in the cellular chlorophyll-to-carbon ratio (Chl : C) across seasons and the coastal to offshore transition. Up to 3-fold-higher Chl : C at the coastal areas in comparison to those at the offshore areas contribute to the steepness of the chlorophyll gradient. The model also predicts much higher phytoplankton concentrations at the coastal areas in comparison to its non-acclimative equivalent. Hence, findings of this study provide evidence for the relevance of physiological flexibility, here reflected by spatial and seasonal variations in Chl : C, for a realistic description of biogeochemical fluxes, particularly in the environments displaying strong resource gradients.

Revisiting concepts of thermal physiology: Predicting responses of mammals to climate change.

PubMed

Mitchell, Duncan; Snelling, Edward P; Hetem, Robyn S; Maloney, Shane K; Strauss, Willem Maartin; Fuller, Andrea

2018-02-26

The accuracy of predictive models (also known as mechanistic or causal models) of animal responses to climate change depends on properly incorporating the principles of heat transfer and thermoregulation into those models. Regrettably, proper incorporation of these principles is not always evident. We have revisited the relevant principles of thermal physiology and analysed how they have been applied in predictive models of large mammals, which are particularly vulnerable, to climate change. We considered dry heat exchange, evaporative heat transfer, the thermoneutral zone and homeothermy, and we examined the roles of size and shape in the thermal physiology of large mammals. We report on the following misconceptions in influential predictive models: underestimation of the role of radiant heat transfer, misassignment of the role and misunderstanding of the sustainability of evaporative cooling, misinterpretation of the thermoneutral zone as a zone of thermal tolerance or as a zone of sustainable energetics, confusion of upper critical temperature and critical thermal maximum, overestimation of the metabolic energy cost of evaporative cooling, failure to appreciate that the current advantages of size and shape will become disadvantageous as climate change advances, misassumptions about skin temperature and, lastly, misconceptions about the relationship between body core temperature and its variability with body mass in large mammals. Not all misconceptions invalidate the models, but we believe that preventing inappropriate assumptions from propagating will improve model accuracy, especially as models progress beyond their current typically static format to include genetic and epigenetic adaptation that can result in phenotypic plasticity. © 2018 The Authors. Journal of Animal Ecology © 2018 British Ecological Society.

Dynamic analysis of CO₂ labeling and cell respiration using membrane-inlet mass spectrometry.

PubMed

Yang, Tae Hoon

2014-01-01

Here, we introduce a mass spectrometry-based analytical method and relevant technical details for dynamic cell respiration and CO2 labeling analysis. Such measurements can be utilized as additional information and constraints for model-based (13)C metabolic flux analysis. Dissolved dynamics of oxygen consumption and CO2 mass isotopomer evolution from (13)C-labeled tracer substrates through different cellular processes can be precisely measured on-line using a miniaturized reactor system equipped with a membrane-inlet mass spectrometer. The corresponding specific rates of physiologically relevant gases and CO2 mass isotopomers can be quantified within a short-term range based on the liquid-phase dynamics of dissolved fermentation gases.

Evidence and Function Relevance of Native DOR-MOR Heteromers.

PubMed

Cahill, Catherine M; Ong, Edmund

2018-04-10

Opioid receptors are the sites of action for morphine and most other clinically used opioid drugs. Abundant evidence now demonstrates that different opioid receptor types can physically associate to form heteromers. Owing to their constituent monomers' involvement in analgesia, mu/delta opioid receptor (M/DOR) heteromers have been a particular focus of attention. Understandings of the physiological relevance and indisputable proof of M/DOR formation in vivo are still evolving. This aspect of the field has been slow to progress in large part by the limitations of most available experimental models; recently however, promising progress is being made. As a result, the long-repeated promise of opioid receptor heteromers as selective therapeutic targets is now being realized.

Women and Women's Issues in Industrial and Physiological Psychology.

ERIC Educational Resources Information Center

Knight, Patrick A.; And Others

In the area of industrial/organizational (I/O) psychology and physiological psychology, issues of gender have only begun to be addressed. An examination of the recent literatures in I/O and physiological psychology was undertaken to document the extent to which women are used as research subjects, to determine whether or not research relevant to…

Multidrug Efflux Systems in Microaerobic and Anaerobic Bacteria

PubMed Central

Xu, Zeling; Yan, Aixin

2015-01-01

Active drug efflux constitutes an important mechanism of antibiotic and multidrug resistance in bacteria. Understanding the distribution, expression, and physiological functions of multidrug efflux pumps, especially under physiologically and clinically relevant conditions of the pathogens, is the key to combat drug resistance. In animal hosts, most wounded, infected and inflamed tissues display low oxygen tensions. In this article, we summarize research development on multidrug efflux pumps in the medicinally relevant microaerobic and anaerobic pathogens and their implications in the effort to combat drug-resistant infections. PMID:27025630

Medical student attitudes toward kidney physiology and nephrology: a qualitative study.

PubMed

Roberts, John K; Sparks, Matthew A; Lehrich, Ruediger W

2016-11-01

Interest in nephrology among trainees is waning in the USA. Early perceptions and attitudes to subject matter can be linked to the quality of pre-clinical curricula. We wanted to explore these attitudes in the setting of modern curriculum redesign. We utilized Q methodology to understand first-year medical student attitudes after an innovative kidney physiology curriculum redesign that focuses on blending multiple learning methods. First-year medical students were invited to take a Q sort survey at the conclusion of a kidney physiology course. Students prioritized statements related to their understanding of kidney physiology, learning preferences, preferred course characteristics, perceived clinical relevance of kidney physiology, and interest in nephrology as a career. Factor analysis was performed to identify different student viewpoints. At the conclusion of our modified course, all students (n = 108) were invited to take the survey and 44 (41%) Q sorts were returned. Two dominant viewpoints were defined according to interest in nephrology. The Potentials are students who understand kidney physiology, perceive kidney physiology as clinically relevant, attend class sessions, utilize videos, and are willing to shadow a nephrologist. The Uninterested are students who are less satisfied with their kidney physiology knowledge, prefer to study alone with a textbook, avoid lectures, and are not interested in learning about nephrology. In an updated renal physiology course, students that use multiple learning methods also have favorable attitudes toward learning kidney physiology. Thus, modern curriculum changes that accommodate a variety of learning styles may promote positive attitudes toward nephrology.

Obesity and drug pharmacology: a review of the influence of obesity on pharmacokinetic and pharmacodynamic parameters.

PubMed

Smit, Cornelis; De Hoogd, Sjoerd; Brüggemann, Roger J M; Knibbe, Catherijne A J

2018-03-01

The rising prevalence of obesity confronts clinicians with dosing problems in the (extreme) overweight population. Obesity has a great impact on key organs that play a role in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs, however the ultimate impact of these changes on how to adapt the dose may not always be known. Areas covered: In this review, physiological changes associated with obesity are discussed. An overview is provided on the alterations in absorption, distribution, drug metabolism and clearance in (morbid) obesity focusing on general principles that can be extracted from pharmacokinetic studies. Also, relevant pharmacodynamic considerations in obesity are discussed. Expert opinion: Over the last two decades, increased knowledge is generated on PK and PD in obesity. Future research should focus on filling in the knowledge gaps that remain, especially in connecting obesity-related physiological changes with changes in PK and/or PD and vice versa. Ultimately, this knowledge can be used to develop physiologically based PK and PD models on the basis of quantitative systems pharmacology principles. Moreover, efforts should focus on thorough prospective evaluation of developed model-based doses with subsequent implementation of these dosing recommendations in clinical practice.

The development of multi-model rehabilitation training system for lower limb sitting function

NASA Astrophysics Data System (ADS)

Wu, Jianfeng; Sun, Yue; Wu, Qun

2017-04-01

The multi-model rehabilitation training system was manufactured according to the demands of patients' practical training. Through the use of the patient's exercise physiology information, the ability of muscle force and movement efficiency of the patient were identified. Following with medical rehabilitation therapy, the training model, a combination of active and passive training, was proposed to enhance the training efficiency and rehabilitation effect. Furthermore, taking the sitting movement training as an example, the research theory was applied in knee rehabilitation training. The results of the research provid technical support and practical reference to the relevant training equipment designs and clinical applications.

21st Century Cell Culture for 21st Century Toxicology.

PubMed

Pamies, David; Hartung, Thomas

2017-01-17

There is no good science in bad models. Cell culture is especially prone to artifacts. A number of novel cell culture technologies have become more broadly available in the 21st century, which allow overcoming limitations of traditional culture and are more physiologically relevant. These include the use of stem-cell derived human cells, cocultures of different cell types, scaffolds and extracellular matrices, perfusion platforms (such as microfluidics), 3D culture, organ-on-chip technologies, tissue architecture, and organ functionality. The physiological relevance of such models is further enhanced by the measurement of biomarkers (e.g., key events of pathways), organ specific functionality, and more comprehensive assessment cell responses by high-content methods. These approaches are still rarely combined to create microphysiological systems. The complexity of the combination of these technologies can generate results closer to the in vivo situation but increases the number of parameters to control, bringing some new challenges. In fact, we do not argue that all cell culture needs to be that sophisticated. The efforts taken are determined by the purpose of our experiments and tests. If only a very specific molecular target to cell response is of interest, a very simple model, which reflects this, might be much more suited to allow standardization and high-throughput. However, the less defined the end point of interest and cellular response are, the better we should approximate organ- or tissue-like culture conditions to make physiological responses more probable. Besides these technologic advances, important progress in the quality assurance and reporting on cell cultures as well as the validation of cellular test systems brings the utility of cell cultures to a new level. The advancement and broader implementation of Good Cell Culture Practice (GCCP) is key here. In toxicology, this is a major prerequisite for meaningful and reliable results, ultimately supporting risk assessment and product development decisions.

Establishment and Characterization of an Air-Liquid Canine Corneal Organ Culture Model To Study Acute Herpes Keratitis

PubMed Central

Harman, Rebecca M.; Bussche, Leen; Ledbetter, Eric C.

2014-01-01

ABSTRACT Despite the clinical importance of herpes simplex virus (HSV)-induced ocular disease, the underlying pathophysiology of the disease remains poorly understood, in part due to the lack of adequate virus–natural-host models in which to study the cellular and viral factors involved in acute corneal infection. We developed an air-liquid canine corneal organ culture model and evaluated its susceptibility to canine herpesvirus type 1 (CHV-1) in order to study ocular herpes in a physiologically relevant natural host model. Canine corneas were maintained in culture at an air-liquid interface for up to 25 days, and no degenerative changes were observed in the corneal epithelium during cultivation using histology for morphometric analyses, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assays, and transmission electron microscopy (TEM). Next, canine corneas were inoculated with CHV-1 for 48 h, and at that time point postinfection, viral plaques could be visualized in the corneal epithelium and viral DNA copies were detected in both the infected corneas and culture supernatants. In addition, we found that canine corneas produced proinflammatory cytokines in response to CHV-1 infection similarly to what has been described for HSV-1. This emphasizes the value of our model as a virus–natural-host model to study ocular herpesvirus infections. IMPORTANCE This study is the first to describe the establishment of an air-liquid canine corneal organ culture model as a useful model to study ocular herpesvirus infections. The advantages of this physiologically relevant model include the fact that (i) it provides a system in which ocular herpes can be studied in a virus–natural-host setting and (ii) it reduces the number of experimental animals needed. In addition, this long-term explant culture model may also facilitate research in other fields where noninfectious and infectious ocular diseases of dogs and humans are being studied. PMID:25231295

Forebrain networks and the control of feeding by environmental learned cues

PubMed Central

Petrovich, Gorica D.

2013-01-01

The motivation to eat is driven by a complex sum of physiological and non-physiological influences computed by the brain. Physiological signals that inform the brain about energy and nutrient needs are the primary drivers, but environmental signals unrelated to energy balance also control appetite and eating. The two components could act in concert to support the homeostatic regulation of food intake. Often, however, environmental influences rival physiological control and stimulate eating irrespective of satiety, or inhibit eating irrespective of hunger. If persistent, such maladaptive challenges to the physiological system could lead to dysregulated eating and ultimately to eating disorders. Nevertheless, the brain mechanisms underlying environmental contribution in the control of food intake are poorly understood. This paper provides an overview in recent advances in deciphering the critical brain systems using rodent models for environmental control by learned cues. These models use associative learning to compete with the physiological control, and in one preparation food cues stimulate a meal despite satiety, while in another preparation fear cues stop a meal despite hunger. Thus far, four forebrain regions have been identified as part of the essential cue induced feeding circuitry. These are telencephalic areas critical for associative learning, memory encoding, and decision making, the amygdala, hippocampus and prefrontal cortex and the lateral hypothalamus, which functions to integrate feeding, reward, and motivation. This circuitry also engages two orexigenic peptides, ghrelin and orexin. A parallel amygdalar circuitry supports fear cue cessation of feeding. These findings illuminate the brain mechanisms underlying environmental control of food intake and might be also relevant to aspects of human appetite and maladaptive overeating and undereating. PMID:23562305

In Vivo Predictive Dissolution (IPD) and Biopharmaceutical Modeling and Simulation: Future Use of Modern Approaches and Methodologies in a Regulatory Context.

PubMed

Lennernäs, H; Lindahl, A; Van Peer, A; Ollier, C; Flanagan, T; Lionberger, R; Nordmark, A; Yamashita, S; Yu, L; Amidon, G L; Fischer, V; Sjögren, E; Zane, P; McAllister, M; Abrahamsson, B

2017-04-03

The overall objective of OrBiTo, a project within Innovative Medicines Initiative (IMI), is to streamline and optimize the development of orally administered drug products through the creation and efficient application of biopharmaceutics tools. This toolkit will include both experimental and computational models developed on improved understanding of the highly dynamic gastrointestinal (GI) physiology relevant to the GI absorption of drug products in both fasted and fed states. A part of the annual OrBiTo meeting in 2015 was dedicated to the presentation of the most recent progress in the development of the regulatory use of PBPK in silico modeling, in vivo predictive dissolution (IPD) tests, and their application to biowaivers. There are still several areas for improvement of in vitro dissolution testing by means of generating results relevant for the intraluminal conditions in the GI tract. The major opportunity is probably in combining IPD testing and physiologically based in silico models where the in vitro data provide input to the absorption predictions. The OrBiTo project and other current research projects include definition of test media representative for the more distal parts of the GI tract, models capturing supersaturation and precipitation phenomena, and influence of motility waves on shear and other forces of hydrodynamic origin, addressing the interindividual variability in composition and characteristics of GI fluids, food effects, definition of biorelevant buffer systems, and intestinal water volumes. In conclusion, there is currently a mismatch between the extensive industrial usage of modern in vivo predictive tools and very limited inclusion of such data in regulatory files. However, there is a great interest among all stakeholders to introduce recent progresses in prediction of in vivo GI drug absorption into regulatory context.

An experimental model of allergic asthma in cats sensitized to house dust mite or bermuda grass allergen.

PubMed

Norris Reinero, Carol R; Decile, Kendra C; Berghaus, Roy D; Williams, Kurt J; Leutenegger, Christian M; Walby, William F; Schelegle, Edward S; Hyde, Dallas M; Gershwin, Laurel J

2004-10-01

Animal models are used to mimic human asthma, however, not all models replicate the major characteristics of the human disease. Spontaneous development of asthma with hallmark features similar to humans has been documented to occur with relative frequency in only one animal species, the cat. We hypothesized that we could develop an experimental model of feline asthma using clinically relevant aeroallergens identified from cases of naturally developing feline asthma, and characterize immunologic, physiologic, and pathologic changes over 1 year. House dust mite (HDMA) and Bermuda grass (BGA) allergen were selected by screening 10 privately owned pet cats with spontaneous asthma using a serum allergen-specific IgE ELISA. Parenteral sensitization and aerosol challenges were used to replicate the naturally developing disease in research cats. The asthmatic phenotype was characterized using intradermal skin testing, serum allergen-specific IgE ELISA, serum and bronchoalveolar lavage fluid (BALF) IgG and IgA ELISAs, airway hyperresponsiveness testing, BALF cytology, cytokine profiles using TaqMan PCR, and histopathologic evaluation. Sensitization with HDMA or BGA in cats led to allergen-specific IgE production, allergen-specific serum and BALF IgG and IgA production, airway hyperreactivity, airway eosinophilia, an acute T helper 2 cytokine profile in peripheral blood mononuclear cells and BALF cells, and histologic evidence of airway remodeling. Using clinically relevant aeroallergens to sensitize and challenge the cat provides an additional animal model to study the immunopathophysiologic mechanisms of allergic asthma. Chronic exposure to allergen in the cat leads to a variety of immunologic, physiologic, and pathologic changes that mimic the features seen in human asthma.

Do infants find snakes aversive? Infants' physiological responses to "fear-relevant" stimuli.

PubMed

Thrasher, Cat; LoBue, Vanessa

2016-02-01

In the current research, we sought to measure infants' physiological responses to snakes-one of the world's most widely feared stimuli-to examine whether they find snakes aversive or merely attention grabbing. Using a similar method to DeLoache and LoBue (Developmental Science, 2009, Vol. 12, pp. 201-207), 6- to 9-month-olds watched a series of multimodal (both auditory and visual) stimuli: a video of a snake (fear-relevant) or an elephant (non-fear-relevant) paired with either a fearful or happy auditory track. We measured physiological responses to the pairs of stimuli, including startle magnitude, latency to startle, and heart rate. Results suggest that snakes capture infants' attention; infants showed the fastest startle responses and lowest average heart rate to the snakes, especially when paired with a fearful voice. Unexpectedly, they also showed significantly reduced startle magnitude during this same snake video plus fearful voice combination. The results are discussed with respect to theoretical perspectives on fear acquisition. Copyright © 2015 Elsevier Inc. All rights reserved.

Binding of trivalent chromium to serum transferrin is sufficiently rapid to be physiologically relevant.

PubMed

Deng, Ge; Wu, Kristi; Cruce, Alex A; Bowman, Michael K; Vincent, John B

2015-02-01

Transferrin, the major iron transport protein in the blood, also transports trivalent chromium in vivo. Recent in vitro studies have, however, suggested that the binding of chromic ions to apotransferrin is too slow to be biologically relevant. Nevertheless, the in vitro studies have generally failed to adequately take physiological bicarbonate concentrations into account. In aqueous buffer (with ambient (bi)carbonate concentrations), the binding of chromium to transferrin is too slow to be physiologically relevant, taking days to reach equilibrium with the protein's associated conformational changes. However, in the presence of 25mM (bi)carbonate, the concentration in human blood, chromic ions bind rapidly and tightly to transferrin. Details of the kinetics of chromium binding to human serum transferrin and conalbumin (egg white transferrin) in the presence of bicarbonate and other major potential chromium ligands are described and are consistent with transferrin being the major chromic ion transporter from the blood to tissues. Copyright © 2014 Elsevier Inc. All rights reserved.

From Inverse Problems in Mathematical Physiology to Quantitative Differential Diagnoses

PubMed Central

Zenker, Sven; Rubin, Jonathan; Clermont, Gilles

2007-01-01

The improved capacity to acquire quantitative data in a clinical setting has generally failed to improve outcomes in acutely ill patients, suggesting a need for advances in computer-supported data interpretation and decision making. In particular, the application of mathematical models of experimentally elucidated physiological mechanisms could augment the interpretation of quantitative, patient-specific information and help to better target therapy. Yet, such models are typically complex and nonlinear, a reality that often precludes the identification of unique parameters and states of the model that best represent available data. Hypothesizing that this non-uniqueness can convey useful information, we implemented a simplified simulation of a common differential diagnostic process (hypotension in an acute care setting), using a combination of a mathematical model of the cardiovascular system, a stochastic measurement model, and Bayesian inference techniques to quantify parameter and state uncertainty. The output of this procedure is a probability density function on the space of model parameters and initial conditions for a particular patient, based on prior population information together with patient-specific clinical observations. We show that multimodal posterior probability density functions arise naturally, even when unimodal and uninformative priors are used. The peaks of these densities correspond to clinically relevant differential diagnoses and can, in the simplified simulation setting, be constrained to a single diagnosis by assimilating additional observations from dynamical interventions (e.g., fluid challenge). We conclude that the ill-posedness of the inverse problem in quantitative physiology is not merely a technical obstacle, but rather reflects clinical reality and, when addressed adequately in the solution process, provides a novel link between mathematically described physiological knowledge and the clinical concept of differential diagnoses. We outline possible steps toward translating this computational approach to the bedside, to supplement today's evidence-based medicine with a quantitatively founded model-based medicine that integrates mechanistic knowledge with patient-specific information. PMID:17997590

Oral Exposure and Absorption of Toxicants

EPA Science Inventory

This chapter provides an overview of the toxicokinetics of orally absorbed xenobiotics. This includes a description of the basic anatomy and physiology of the digestive tract most relevant to the absorption process. In addition, differences in anatomy and physiology between human...

Dynamical complexity in a mean-field model of human EEG

NASA Astrophysics Data System (ADS)

Frascoli, Federico; Dafilis, Mathew P.; van Veen, Lennaert; Bojak, Ingo; Liley, David T. J.

2008-12-01

A recently proposed mean-field theory of mammalian cortex rhythmogenesis describes the salient features of electrical activity in the cerebral macrocolumn, with the use of inhibitory and excitatory neuronal populations (Liley et al 2002). This model is capable of producing a range of important human EEG (electroencephalogram) features such as the alpha rhythm, the 40 Hz activity thought to be associated with conscious awareness (Bojak & Liley 2007) and the changes in EEG spectral power associated with general anesthetic effect (Bojak & Liley 2005). From the point of view of nonlinear dynamics, the model entails a vast parameter space within which multistability, pseudoperiodic regimes, various routes to chaos, fat fractals and rich bifurcation scenarios occur for physiologically relevant parameter values (van Veen & Liley 2006). The origin and the character of this complex behaviour, and its relevance for EEG activity will be illustrated. The existence of short-lived unstable brain states will also be discussed in terms of the available theoretical and experimental results. A perspective on future analysis will conclude the presentation.

The metabolism of the human brain studied with positron emission tomography

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

Greitz, T.; Ingvar, D.H.; Widen, L.

1985-01-01

This volume presents coverage of the use of positron emission tomography (PET) to study the human brain. The contributors assess new developments in high-resolution positron emission tomography, cyclotrons, radiochemistry, and tracer kinetic models, and explore the use of PET in brain energy metabolism, blood flow, and protein synthesis measurements, receptor analysis, and pH determinations, In addition, they discuss the relevance and applications of positron emission tomography from the perspectives of physiology, neurology, and psychiatry.

The Virtual Physiological Human ToolKit.

PubMed

Cooper, Jonathan; Cervenansky, Frederic; De Fabritiis, Gianni; Fenner, John; Friboulet, Denis; Giorgino, Toni; Manos, Steven; Martelli, Yves; Villà-Freixa, Jordi; Zasada, Stefan; Lloyd, Sharon; McCormack, Keith; Coveney, Peter V

2010-08-28

The Virtual Physiological Human (VPH) is a major European e-Science initiative intended to support the development of patient-specific computer models and their application in personalized and predictive healthcare. The VPH Network of Excellence (VPH-NoE) project is tasked with facilitating interaction between the various VPH projects and addressing issues of common concern. A key deliverable is the 'VPH ToolKit'--a collection of tools, methodologies and services to support and enable VPH research, integrating and extending existing work across Europe towards greater interoperability and sustainability. Owing to the diverse nature of the field, a single monolithic 'toolkit' is incapable of addressing the needs of the VPH. Rather, the VPH ToolKit should be considered more as a 'toolbox' of relevant technologies, interacting around a common set of standards. The latter apply to the information used by tools, including any data and the VPH models themselves, and also to the naming and categorizing of entities and concepts involved. Furthermore, the technologies and methodologies available need to be widely disseminated, and relevant tools and services easily found by researchers. The VPH-NoE has thus created an online resource for the VPH community to meet this need. It consists of a database of tools, methods and services for VPH research, with a Web front-end. This has facilities for searching the database, for adding or updating entries, and for providing user feedback on entries. Anyone is welcome to contribute.

Physiologically-relevant measurements of flow through coils and stents: towards improved modeling of endovascular treatment of intracranial aneurysms

NASA Astrophysics Data System (ADS)

Barbour, Michael; Levitt, Michael; Geindreau, Christian; Rolland Du Roscoat, Sabine; Johnson, Luke; Chivukula, Keshav; Aliseda, Alberto

2016-11-01

The hemodynamic environment in cerebral aneurysms undergoing flow-diverting stent (FDS) or coil embolization treatment plays a critical role in long-term outcomes. Standard modeling approaches to endovascular coils and FDS simplify the complex geometry into a homogenous porous volume or surface through the addition of a Darcy-Brinkman pressure loss term in the momentum equation. The inertial and viscous loss coefficients are typically derived from published in vitro studies of pressure loss across FDS and coils placed in a straight tube, where the only fluid path is across the treatment - an unrealistic representation of treatment apposition in vivo. The pressure drop across FDS and coils in side branch aneurysms located on curved parent vessels is measured. Using PIV, the velocity at the aneurysm neck plane is reconstructed and used to determine loss coefficients for better models of endovascular coils or FDS that account for physiological placement and vessel curvature. These improved models are incorporated into CFD simulations and validated against in vitro model PIV velocity, as well as compared to microCT-based coil/stent-resolving CFD simulations of patient-specific treated aneurysm flow.

Comparative aspects of rodent and nonrodent animal models for mechanistic and translational diabetes research.

PubMed

Renner, Simone; Dobenecker, Britta; Blutke, Andreas; Zöls, Susanne; Wanke, Rüdiger; Ritzmann, Mathias; Wolf, Eckhard

2016-07-01

The prevalence of diabetes mellitus, which currently affects 387 million people worldwide, is permanently rising in both adults and adolescents. Despite numerous treatment options, diabetes mellitus is a progressive disease with severe comorbidities, such as nephropathy, neuropathy, and retinopathy, as well as cardiovascular disease. Therefore, animal models predictive of the efficacy and safety of novel compounds in humans are of great value to address the unmet need for improved therapeutics. Although rodent models provide important mechanistic insights, their predictive value for therapeutic outcomes in humans is limited. In recent years, the pig has gained importance for biomedical research because of its close similarity to human anatomy, physiology, size, and, in contrast to non-human primates, better ethical acceptance. In this review, anatomic, biochemical, physiological, and morphologic aspects relevant to diabetes research will be compared between different animal species, that is, mouse, rat, rabbit, pig, and non-human primates. The value of the pig as a model organism for diabetes research will be highlighted, and (dis)advantages of the currently available approaches for the generation of pig models exhibiting characteristics of metabolic syndrome or type 2 diabetes mellitus will be discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

Zebrafish Models of Prader-Willi Syndrome: Fast Track to Pharmacotherapeutics

PubMed Central

Spikol, Emma D.; Laverriere, Caroline E.; Robnett, Maya; Carter, Gabriela; Wolfe, Erin; Glasgow, Eric

2016-01-01

Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder characterized by an insatiable appetite, leading to chronic overeating and obesity. Additional features include short stature, intellectual disability, behavioral problems and incomplete sexual development. Although significant progress has been made in understanding the genetic basis of PWS, the mechanisms underlying the pathogenesis of the disorder remain poorly understood. Treatment for PWS consists mainly of palliative therapies; curative therapies are sorely needed. Zebrafish, Danio rerio, represent a promising way forward for elucidating physiological problems such as obesity and identifying new pharmacotherapeutic options for PWS. Over the last decade, an increased appreciation for the highly conserved biology among vertebrates and the ability to perform high-throughput drug screening has seen an explosion in the use of zebrafish for disease modeling and drug discovery. Here, we review recent advances in developing zebrafish models of human disease. Aspects of zebrafish genetics and physiology that are relevant to PWS will be discussed, and the advantages and disadvantages of zebrafish models will be contrasted with current animal models for this syndrome. Finally, we will present a paradigm for drug screening in zebrafish that is potentially the fastest route for identifying and delivering curative pharmacotherapies to PWS patients. PMID:27857842

RNAi in the mouse: rapid and affordable gene function studies in a vertebrate system.

PubMed

Rytlewski, Julie A; Beronja, Slobodan

2015-01-01

The addition of RNA interference (RNAi) to the mammalian genomic toolbox has significantly expanded our ability to use higher-order models in studies of development and disease. The mouse, in particular, has benefited most from RNAi technology. Unique combinations of RNAi vectors and delivery methods now offer a broad platform for gene silencing in transgenic mice, enabling the design of new physiologically relevant models. The era of RNAi mice has accelerated the pace of genetic study and made high-throughput screens not only feasible but also affordable. © 2014 Wiley Periodicals, Inc.

Alternative functional in vitro models of human intestinal epithelia

PubMed Central

Kauffman, Amanda L.; Gyurdieva, Alexandra V.; Mabus, John R.; Ferguson, Chrissa; Yan, Zhengyin; Hornby, Pamela J.

2013-01-01

Physiologically relevant sources of absorptive intestinal epithelial cells are crucial for human drug transport studies. Human adenocarcinoma-derived intestinal cell lines, such as Caco-2, offer conveniences of easy culture maintenance and scalability, but do not fully recapitulate in vivo intestinal phenotypes. Additional sources of renewable physiologically relevant human intestinal cells would provide a much needed tool for drug discovery and intestinal physiology. We compared two alternative sources of human intestinal cells, commercially available primary human intestinal epithelial cells (hInEpCs) and induced pluripotent stem cell (iPSC)-derived intestinal cells to Caco-2, for use in in vitro transwell monolayer intestinal transport assays. To achieve this for iPSC-derived cells, intestinal organogenesis was adapted to transwell differentiation. Intestinal cells were assessed by marker expression through immunocytochemical and mRNA expression analyses, monolayer integrity through Transepithelial Electrical Resistance (TEER) measurements and molecule permeability, and functionality by taking advantage the well-characterized intestinal transport mechanisms. In most cases, marker expression for primary hInEpCs and iPSC-derived cells appeared to be as good as or better than Caco-2. Furthermore, transwell monolayers exhibited high TEER with low permeability. Primary hInEpCs showed molecule efflux indicative of P-glycoprotein (Pgp) transport. Primary hInEpCs and iPSC-derived cells also showed neonatal Fc receptor-dependent binding of immunoglobulin G variants. Primary hInEpCs and iPSC-derived intestinal cells exhibit expected marker expression and demonstrate basic functional monolayer formation, similar to or better than Caco-2. These cells could offer an alternative source of human intestinal cells for understanding normal intestinal epithelial physiology and drug transport. PMID:23847534

Alternative functional in vitro models of human intestinal epithelia.

PubMed

Kauffman, Amanda L; Gyurdieva, Alexandra V; Mabus, John R; Ferguson, Chrissa; Yan, Zhengyin; Hornby, Pamela J

2013-01-01

Physiologically relevant sources of absorptive intestinal epithelial cells are crucial for human drug transport studies. Human adenocarcinoma-derived intestinal cell lines, such as Caco-2, offer conveniences of easy culture maintenance and scalability, but do not fully recapitulate in vivo intestinal phenotypes. Additional sources of renewable physiologically relevant human intestinal cells would provide a much needed tool for drug discovery and intestinal physiology. We compared two alternative sources of human intestinal cells, commercially available primary human intestinal epithelial cells (hInEpCs) and induced pluripotent stem cell (iPSC)-derived intestinal cells to Caco-2, for use in in vitro transwell monolayer intestinal transport assays. To achieve this for iPSC-derived cells, intestinal organogenesis was adapted to transwell differentiation. Intestinal cells were assessed by marker expression through immunocytochemical and mRNA expression analyses, monolayer integrity through Transepithelial Electrical Resistance (TEER) measurements and molecule permeability, and functionality by taking advantage the well-characterized intestinal transport mechanisms. In most cases, marker expression for primary hInEpCs and iPSC-derived cells appeared to be as good as or better than Caco-2. Furthermore, transwell monolayers exhibited high TEER with low permeability. Primary hInEpCs showed molecule efflux indicative of P-glycoprotein (Pgp) transport. Primary hInEpCs and iPSC-derived cells also showed neonatal Fc receptor-dependent binding of immunoglobulin G variants. Primary hInEpCs and iPSC-derived intestinal cells exhibit expected marker expression and demonstrate basic functional monolayer formation, similar to or better than Caco-2. These cells could offer an alternative source of human intestinal cells for understanding normal intestinal epithelial physiology and drug transport.

"Thinking ethics": a novel, pilot, proof-of-concept program of integrating ethics into the Physiology curriculum in South India.

PubMed

D, Savitha; Vaz, Manjulika; Vaz, Mario

2017-06-01

Integrating medical ethics into the physiology teaching-learning program has been largely unexplored in India. The objective of this exercise was to introduce an interactive and integrated ethics program into the Physiology course of first-year medical students and to evaluate their perceptions. Sixty medical students (30 men, 30 women) underwent 11 sessions over a 7-mo period. Two of the Physiology faculty conducted these sessions (20-30 min each) during the routine physiology (theory/practicals) classes that were of shorter duration and could, therefore, accommodate the discussion of related ethical issues. This exercise was in addition to the separate ethics classes conducted by the Medical Ethics department. The sessions were open ended, student centered, and designed to stimulate critical thinking. The students' perceptions were obtained through a semistructured questionnaire and focused group discussions. The students found the program unique, thought provoking, fully integrated, and relevant. It seldom interfered with the physiology teaching. They felt that the program sensitized them about ethical issues and prepared them for their clinical years, to be "ethical doctors." Neutral observers who evaluated each session felt that the integrated program was relevant to the preclinical year and that the program was appropriate in its content, delivery, and student involvement. An ethics course taught in integration with Physiology curriculum was found to be beneficial, feasible, and compatible with Physiology by students as well as neutral observers. Copyright © 2017 the American Physiological Society.

Thermosensory perception regulates speed of movement in response to temperature changes in Drosophila melanogaster.

PubMed

Soto-Padilla, Andrea; Ruijsink, Rick; Sibon, Ody C M; van Rijn, Hedderik; Billeter, Jean-Christophe

2018-04-12

Temperature influences physiology and behavior of all organisms. For ectotherms, which lack central temperature regulation, temperature adaptation requires sheltering from or moving to a heat source. As temperature constrains the rate of metabolic reactions, it can directly affect ectotherm physiology and thus behavioral performance. This direct effect is particularly relevant for insects whose small body readily equilibrates with ambient temperature. In fact, models of enzyme kinetics applied to insect behavior predict performance at different temperatures, suggesting that thermal physiology governs behavior. However, insects also possess thermosensory neurons critical for locating preferred temperatures, showing cognitive control. This suggests that temperature-related behavior can emerge directly from a physiological effect, indirectly as consequence of thermosensory processing, or through both. To separate the roles of thermal physiology and cognitive control, we developed an arena that allows fast temperature changes in time and space, and in which animals' movements are automatically quantified. We exposed wild-type and thermosensory receptor mutants Drosophila melanogaster to a dynamic temperature environment and tracked their movements. The locomotor speed of wild-type flies closely matched models of enzyme kinetics, but the behavior of thermosensory mutants did not. Mutations in thermosensory receptor dTrpA1 ( Transient receptor potential ) expressed in the brain resulted in a complete lack of response to temperature changes, while mutation in peripheral thermosensory receptor Gr28b(D) resulted in diminished response. We conclude that flies react to temperature through cognitive control, informed by interactions between various thermosensory neurons, whose behavioral output resembles that of enzyme kinetics. © 2018. Published by The Company of Biologists Ltd.

Brief Report: A Pilot Study of Parent-Child Biobehavioral Synchrony in Autism Spectrum Disorder.

PubMed

Baker, Jason K; Fenning, Rachel M; Howland, Mariann A; Baucom, Brian R; Moffitt, Jacquelyn; Erath, Stephen A

2015-12-01

The theory of biobehavioral synchrony proposes that the predictive power of parent-child attunement likely lies in the manner with which behaviors are aligned with relevant biological processes. Symptoms of autism spectrum disorder (ASD) may challenge the formation of behavioral and physiological synchrony, but maintenance of such parent-child attunement could prove beneficial. The present study is the first to examine parent-child physiological synchrony in ASD. Parent and child electrodermal activity (EDA) was measured continuously during naturalistic free play. Parent-child EDA synchrony (positive covariation) was positively correlated with observed parent-child emotional attunement. Hierarchical linear modeling revealed that child ASD symptoms moderated the association between parent EDA and child EDA, such that EDA synchrony was stronger for children with lower ASD symptom levels.

Relevance of human anatomy in daily clinical practice.

PubMed

Arráez-Aybar, Luis-Alfonso; Sánchez-Montesinos, Indalecio; Mirapeix, Rosa-M; Mompeo-Corredera, Blanca; Sañudo-Tejero, Jose-Ramón

2010-12-20

the aim of this study has been to evaluate the relevance of gross human anatomy in daily clinical practice and to compare it to that of other basic sciences (biochemistry, bioethics, cytohistology, microbiology, pharmacology, physiology, psychology). a total of 1250 questionnaires were distributed among 38 different medical speciality professionals. Answers were analyzed taking into account speciality (medical, surgery and others), professional status (training physician or staff member) and professional experience. the response rate was 42.9% (n=536). Gross human anatomy was considered the most relevant basic discipline for surgical specialists, while pharmacology and physiology were most relevant for medical specialists. Knowledge of anatomy was also considered fundamental for understanding neurological or musculoskeletal disorders. In undergraduate programmes, the most important focuses in teaching anatomy were radiological, topographical and functional anatomy followed by systematic anatomy. In daily medical practice anatomy was considered basic for physical examination, symptom interpretation and interpretation of radiological images. When professional status or professional experience was considered, small variations were shown and there were no significant differences related to gender or community. our results underline the relevance of basic sciences (gross anatomy, physiology, and pharmacology) in daily professional activity. Evidence-based studies such as ours, lend greater credibility and objectivity to the role of gross anatomy in the undergraduate training of health professionals and should help to establish a more appropriate curriculum for future professionals. 2010 Elsevier GmbH. All rights reserved.

Theoretical analysis of insulin-dependent glucose uptake heterogeneity in 3D bioreactor cell culture.

PubMed

Magrofuoco, Enrico; Elvassore, Nicola; Doyle, Francis J

2012-01-01

Three-dimensional (3D) cell cultures in bioreactors are becoming relevant as models for biological and physiological in vitro studies. In such systems, mathematical models can assist the experiment design that links the macroscopic properties to single-cell responses. We investigated the relationship between biochemical stimuli and cell response within a 3D cell culture in scaffold with heterogeneous porosity. Specifically, we studied the effect of insulin on the local glucose metabolism as a function of 3D pore size distribution. The multiscale mathematical model combines the mass transport within a 3D scaffold and a signaling pathways model. It considers the scaffold heterogeneity, and it describes spatiotemporal concentration of metabolites, biochemical stimuli, and cell density. The signaling model was integrated into this model, linking the local insulin concentration at cell membrane to the glucose uptake rate through glucose transporter type 4 (GLUT4) translocation from the cytosol to the cell membrane. The integrated model determines the cell response heterogeneities in a single channel, hence the biological response distribution in a 3D system. It also provides macroscopic outcomes to evaluate the feasibility of an experimental measurement of the system response. From our analysis, it became apparent that the flow rate is the most important operative variable, and that an optimum value ensures a fast and detectable cell response. This model on insulin-dependent glucose consumption rate offers insight into the cell metabolism physiology, which is a fundamental requirement for the study metabolic disorder such as Type 2 diabetes mellitus, in which the physiological insulin-dependent glucose metabolism is impaired. Copyright © 2012 American Institute of Chemical Engineers (AIChE).

Allometric scaling in-vitro

NASA Astrophysics Data System (ADS)

Ahluwalia, Arti

2017-02-01

About two decades ago, West and coworkers established a model which predicts that metabolic rate follows a three quarter power relationship with the mass of an organism, based on the premise that tissues are supplied nutrients through a fractal distribution network. Quarter power scaling is widely considered a universal law of biology and it is generally accepted that were in-vitro cultures to obey allometric metabolic scaling, they would have more predictive potential and could, for instance, provide a viable substitute for animals in research. This paper outlines a theoretical and computational framework for establishing quarter power scaling in three-dimensional spherical constructs in-vitro, starting where fractal distribution ends. Allometric scaling in non-vascular spherical tissue constructs was assessed using models of Michaelis Menten oxygen consumption and diffusion. The models demonstrate that physiological scaling is maintained when about 5 to 60% of the construct is exposed to oxygen concentrations less than the Michaelis Menten constant, with a significant concentration gradient in the sphere. The results have important implications for the design of downscaled in-vitro systems with physiological relevance.

Human Intestinal Enteroids: a New Model To Study Human Rotavirus Infection, Host Restriction, and Pathophysiology

PubMed Central

Saxena, Kapil; Blutt, Sarah E.; Ettayebi, Khalil; Zeng, Xi-Lei; Broughman, James R.; Crawford, Sue E.; Karandikar, Umesh C.; Sastri, Narayan P.; Conner, Margaret E.; Opekun, Antone R.; Graham, David Y.; Qureshi, Waqar; Sherman, Vadim; Foulke-Abel, Jennifer; In, Julie; Kovbasnjuk, Olga; Zachos, Nicholas C.; Donowitz, Mark

2015-01-01

ABSTRACT Human gastrointestinal tract research is limited by the paucity of in vitro intestinal cell models that recapitulate the cellular diversity and complex functions of human physiology and disease pathology. Human intestinal enteroid (HIE) cultures contain multiple intestinal epithelial cell types that comprise the intestinal epithelium (enterocytes and goblet, enteroendocrine, and Paneth cells) and are physiologically active based on responses to agonists. We evaluated these nontransformed, three-dimensional HIE cultures as models for pathogenic infections in the small intestine by examining whether HIEs from different regions of the small intestine from different patients are susceptible to human rotavirus (HRV) infection. Little is known about HRVs, as they generally replicate poorly in transformed cell lines, and host range restriction prevents their replication in many animal models, whereas many animal rotaviruses (ARVs) exhibit a broader host range and replicate in mice. Using HRVs, including the Rotarix RV1 vaccine strain, and ARVs, we evaluated host susceptibility, virus production, and cellular responses of HIEs. HRVs infect at higher rates and grow to higher titers than do ARVs. HRVs infect differentiated enterocytes and enteroendocrine cells, and viroplasms and lipid droplets are induced. Heterogeneity in replication was seen in HIEs from different patients. HRV infection and RV enterotoxin treatment of HIEs caused physiological lumenal expansion detected by time-lapse microscopy, recapitulating one of the hallmarks of rotavirus-induced diarrhea. These results demonstrate that HIEs are a novel pathophysiological model that will allow the study of HRV biology, including host restriction, cell type restriction, and virus-induced fluid secretion. IMPORTANCE Our research establishes HIEs as nontransformed cell culture models to understand human intestinal physiology and pathophysiology and the epithelial response, including host restriction of gastrointestinal infections such as HRV infection. HRVs remain a major worldwide cause of diarrhea-associated morbidity and mortality in children ≤5 years of age. Current in vitro models of rotavirus infection rely primarily on the use of animal rotaviruses because HRV growth is limited in most transformed cell lines and animal models. We demonstrate that HIEs are novel, cellularly diverse, and physiologically relevant epithelial cell cultures that recapitulate in vivo properties of HRV infection. HIEs will allow the study of HRV biology, including human host-pathogen and live, attenuated vaccine interactions; host and cell type restriction; virus-induced fluid secretion; cell-cell communication within the epithelium; and the epithelial response to infection in cultures from genetically diverse individuals. Finally, drug therapies to prevent/treat diarrheal disease can be tested in these physiologically active cultures. PMID:26446608

Dose-dependent DNA adduct formation by cinnamaldehyde and other food-borne α,β-unsaturated aldehydes predicted by physiologically based in silico modelling.

PubMed

Kiwamoto, R; Ploeg, D; Rietjens, I M C M; Punt, A

2016-03-01

Genotoxicity of α,β-unsaturated aldehydes shown in vitro raises a concern for the use of the aldehydes as food flavourings, while at low dose exposures the formation of DNA adducts may be prevented by detoxification. Unlike many α,β-unsaturated aldehydes for which in vivo data are absent, cinnamaldehyde was shown to be not genotoxic or carcinogenic in vivo. The present study aimed at comparing dose-dependent DNA adduct formation by cinnamaldehyde and 18 acyclic food-borne α,β-unsaturated aldehydes using physiologically based kinetic/dynamic (PBK/D) modelling. In rats, cinnamaldehyde was predicted to induce higher DNA adducts levels than 6 out of the 18 α,β-unsaturated aldehydes, indicating that these 6 aldehydes may also test negative in vivo. At the highest cinnamaldehyde dose that tested negative in vivo, cinnamaldehyde was predicted to form at least three orders of magnitude higher levels of DNA adducts than the 18 aldehydes at their respective estimated daily intake. These results suggest that for all the 18 α,β-unsaturated aldehydes DNA adduct formation at doses relevant for human dietary exposure may not raise a concern. The present study illustrates a possible use of physiologically based in silico modelling to facilitate a science-based comparison and read-across on the possible risks posed by DNA reactive agents. Copyright © 2015 Elsevier B.V. All rights reserved.

Neuromodulators: available agents, physiology, and anatomy.

PubMed

Nettar, Kartik; Maas, Corey

2011-12-01

Neuromodulators have risen to the forefront of aesthetic medicine. By reversibly relaxing target muscles, neuromodulators exhibit their effect by softening hyperfunctional lines. An understanding of their physiology, relevant facial anatomy, and current agents is imperative for a successful aesthetic practice. © Thieme Medical Publishers.

Ecosystems Biology Approaches To Determine Key Fitness Traits of Soil Microorganisms

NASA Astrophysics Data System (ADS)

Brodie, E.; Zhalnina, K.; Karaoz, U.; Cho, H.; Nuccio, E. E.; Shi, S.; Lipton, M. S.; Zhou, J.; Pett-Ridge, J.; Northen, T.; Firestone, M.

2014-12-01

The application of theoretical approaches such as trait-based modeling represent powerful tools to explain and perhaps predict complex patterns in microbial distribution and function across environmental gradients in space and time. These models are mostly deterministic and where available are built upon a detailed understanding of microbial physiology and response to environmental factors. However as most soil microorganisms have not been cultivated, for the majority our understanding is limited to insights from environmental 'omic information. Information gleaned from 'omic studies of complex systems should be regarded as providing hypotheses, and these hypotheses should be tested under controlled laboratory conditions if they are to be propagated into deterministic models. In a semi-arid Mediterranean grassland system we are attempting to dissect microbial communities into functional guilds with defined physiological traits and are using a range of 'omics approaches to characterize their metabolic potential and niche preference. Initially, two physiologically relevant time points (peak plant activity and prior to wet-up) were sampled and metagenomes sequenced deeply (600-900 Gbp). Following assembly, differential coverage and nucleotide frequency binning were carried out to yield draft genomes. In addition, using a range of cultivation media we have isolated a broad range of bacteria representing abundant bacterial genotypes and with genome sequences of almost 40 isolates are testing genomic predictions regarding growth rate, temperature and substrate utilization in vitro. This presentation will discuss the opportunities and challenges in parameterizing microbial functional guilds from environmental 'omic information for use in trait-based models.

Two ribosome recruitment sites direct multiple translation events within HIV1 Gag open reading frame.

PubMed

Deforges, Jules; de Breyne, Sylvain; Ameur, Melissa; Ulryck, Nathalie; Chamond, Nathalie; Saaidi, Afaf; Ponty, Yann; Ohlmann, Theophile; Sargueil, Bruno

2017-07-07

In the late phase of the HIV virus cycle, the unspliced genomic RNA is exported to the cytoplasm for the necessary translation of the Gag and Gag-pol polyproteins. Three distinct translation initiation mechanisms ensuring Gag production have been described with little rationale for their multiplicity. The Gag-IRES has the singularity to be located within Gag ORF and to directly interact with ribosomal 40S. Aiming at elucidating the specificity and the relevance of this interaction, we probed HIV-1 Gag-IRES structure and developed an innovative integrative modelling strategy to take into account all the gathered information. We propose a novel Gag-IRES secondary structure strongly supported by all experimental data. We further demonstrate the presence of two regions within Gag-IRES that independently and directly interact with the ribosome. Importantly, these binding sites are functionally relevant to Gag translation both in vitro and ex vivo. This work provides insight into the Gag-IRES molecular mechanism and gives compelling evidence for its physiological importance. It allows us to propose original hypotheses about the IRES physiological role and conservation among primate lentiviruses. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

The crystal structure of the regulatory domain of the human sodium-driven chloride/bicarbonate exchanger.

PubMed

Alvadia, Carolina M; Sommer, Theis; Bjerregaard-Andersen, Kaare; Damkier, Helle Hasager; Montrasio, Michele; Aalkjaer, Christian; Morth, J Preben

2017-09-21

The sodium-driven chloride/bicarbonate exchanger (NDCBE) is essential for maintaining homeostatic pH in neurons. The crystal structure at 2.8 Å resolution of the regulatory N-terminal domain of human NDCBE represents the first crystal structure of an electroneutral sodium-bicarbonate cotransporter. The crystal structure forms an equivalent dimeric interface as observed for the cytoplasmic domain of Band 3, and thus establishes that the consensus motif VTVLP is the key minimal dimerization motif. The VTVLP motif is highly conserved and likely to be the physiologically relevant interface for all other members of the SLC4 family. A novel conserved Zn 2+ -binding motif present in the N-terminal domain of NDCBE is identified and characterized in vitro. Cellular studies confirm the Zn 2+ dependent transport of two electroneutral bicarbonate transporters, NCBE and NBCn1. The Zn 2+ site is mapped to a cluster of histidines close to the conserved ETARWLKFEE motif and likely plays a role in the regulation of this important motif. The combined structural and bioinformatics analysis provides a model that predicts with additional confidence the physiologically relevant interface between the cytoplasmic domain and the transmembrane domain.

Engineering self-contained DNA circuit for proximity recognition and localized signal amplification of target biomolecules

PubMed Central

Ang, Yan Shan; Yung, Lin-Yue Lanry

2014-01-01

Biomolecular interactions have important cellular implications, however, a simple method for the sensing of such proximal events is lacking in the current molecular toolbox. We designed a dynamic DNA circuit capable of recognizing targets in close proximity to initiate a pre-programmed signal transduction process resulting in localized signal amplification. The entire circuit was engineered to be self-contained, i.e. it can self-assemble onto individual target molecules autonomously and form localized signal with minimal cross-talk. α-thrombin was used as a model protein to evaluate the performance of the individual modules and the overall circuit for proximity interaction under physiologically relevant buffer condition. The circuit achieved good selectivity in presence of non-specific protein and interfering serum matrix and successfully detected for physiologically relevant α-thrombin concentration (50 nM–5 μM) in a single mixing step without any further washing. The formation of localized signal at the interaction site can be enhanced kinetically through the control of temperature and probe concentration. This work provides a basic general framework from which other circuit modules can be adapted for the sensing of other biomolecular or cellular interaction of interest. PMID:25056307

Animal thermoregulation: a review of insulation, physiology and behaviour relevant to temperature control in buildings.

PubMed

McCafferty, D J; Pandraud, G; Gilles, J; Fabra-Puchol, M; Henry, P-Y

2017-12-28

Birds and mammals have evolved many thermal adaptations that are relevant to the bioinspired design of temperature control systems and energy management in buildings. Similar to many buildings, endothermic animals generate internal metabolic heat, are well insulated, regulate their temperature within set limits, modify microclimate and adjust thermal exchange with their environment. We review the major components of animal thermoregulation in endothermic birds and mammals that are pertinent to building engineering, in a world where climate is changing and reduction in energy use is needed. In animals, adjustment of insulation together with physiological and behavioural responses to changing environmental conditions fine-tune spatial and temporal regulation of body temperature, while also minimizing energy expenditure. These biological adaptations are characteristically flexible, allowing animals to alter their body temperatures to hourly, daily, or annual demands for energy. They exemplify how buildings could become more thermally reactive to meteorological fluctuations, capitalising on dynamic thermal materials and system properties. Based on this synthesis, we suggest that heat transfer modelling could be used to simulate these flexible biomimetic features and assess their success in reducing energy costs while maintaining thermal comfort for given building types.

The Use of Silk as a Scaffold for Mature, Sustainable Unilocular Adipose 3D Tissue Engineered Systems.

PubMed

Abbott, Rosalyn D; Wang, Rebecca Y; Reagan, Michaela R; Chen, Ying; Borowsky, Francis E; Zieba, Adam; Marra, Kacey G; Rubin, J Peter; Ghobrial, Irene M; Kaplan, David L

2016-07-01

There is a critical need for monitoring physiologically relevant, sustainable, human adipose tissues in vitro to gain new insights into metabolic diseases. To support long-term culture, a 3D silk scaffold assisted culture system is developed that maintains mature unilocular adipocytes ex vivo in coculture with preadipocytes, endothelial cells, and smooth muscle cells obtained from small volumes of liquefied adipose samples. Without the silk scaffold, adipose tissue explants cannot be sustained in long-term culture (3 months) due to their fragility. Adjustments to media components are used to tune lipid metabolism and proliferation, in addition to responsiveness to an inflammatory stimulus. Interestingly, patient specific responses to TNFα stimulation are observed, providing a proof-of-concept translational technique for patient specific disease modeling in the future. In summary, this novel 3D scaffold assisted approach is required for establishing physiologically relevant, sustainable, human adipose tissue systems from small volumes of lipoaspirate, making this methodology of great value to studies of metabolism, adipokine-driven diseases, and other diseases where the roles of adipocytes are only now becoming uncovered. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Circulatory shear flow alters the viability and proliferation of circulating colon cancer cells

NASA Astrophysics Data System (ADS)

Fan, Rong; Emery, Travis; Zhang, Yongguo; Xia, Yuxuan; Sun, Jun; Wan, Jiandi

2016-06-01

During cancer metastasis, circulating tumor cells constantly experience hemodynamic shear stress in the circulation. Cellular responses to shear stress including cell viability and proliferation thus play critical roles in cancer metastasis. Here, we developed a microfluidic approach to establish a circulatory microenvironment and studied circulating human colon cancer HCT116 cells in response to a variety of magnitude of shear stress and circulating time. Our results showed that cell viability decreased with the increase of circulating time, but increased with the magnitude of wall shear stress. Proliferation of cells survived from circulation could be maintained when physiologically relevant wall shear stresses were applied. High wall shear stress (60.5 dyne/cm2), however, led to decreased cell proliferation at long circulating time (1 h). We further showed that the expression levels of β-catenin and c-myc, proliferation regulators, were significantly enhanced by increasing wall shear stress. The presented study provides a new insight to the roles of circulatory shear stress in cellular responses of circulating tumor cells in a physiologically relevant model, and thus will be of interest for the study of cancer cell mechanosensing and cancer metastasis.

Non-climatic thermal adaptation: implications for species' responses to climate warming.

PubMed

Marshall, David J; McQuaid, Christopher D; Williams, Gray A

2010-10-23

There is considerable interest in understanding how ectothermic animals may physiologically and behaviourally buffer the effects of climate warming. Much less consideration is being given to how organisms might adapt to non-climatic heat sources in ways that could confound predictions for responses of species and communities to climate warming. Although adaptation to non-climatic heat sources (solar and geothermal) seems likely in some marine species, climate warming predictions for marine ectotherms are largely based on adaptation to climatically relevant heat sources (air or surface sea water temperature). Here, we show that non-climatic solar heating underlies thermal resistance adaptation in a rocky-eulittoral-fringe snail. Comparisons of the maximum temperatures of the air, the snail's body and the rock substratum with solar irradiance and physiological performance show that the highest body temperature is primarily controlled by solar heating and re-radiation, and that the snail's upper lethal temperature exceeds the highest climatically relevant regional air temperature by approximately 22°C. Non-climatic thermal adaptation probably features widely among marine and terrestrial ectotherms and because it could enable species to tolerate climatic rises in air temperature, it deserves more consideration in general and for inclusion into climate warming models.

Generation of functional cardiomyocytes from rat embryonic and induced pluripotent stem cells using feeder-free expansion and differentiation in suspension culture.

PubMed

Dahlmann, Julia; Awad, George; Dolny, Carsten; Weinert, Sönke; Richter, Karin; Fischer, Klaus-Dieter; Munsch, Thomas; Leßmann, Volkmar; Volleth, Marianne; Zenker, Martin; Chen, Yaoyao; Merkl, Claudia; Schnieke, Angelika; Baraki, Hassina; Kutschka, Ingo; Kensah, George

2018-01-01

The possibility to generate cardiomyocytes from pluripotent stem cells in vitro has enormous significance for basic research, disease modeling, drug development and heart repair. The concept of heart muscle reconstruction has been studied and optimized in the rat model using rat primary cardiovascular cells or xenogeneic pluripotent stem cell derived-cardiomyocytes for years. However, the lack of rat pluripotent stem cells (rPSCs) and their cardiovascular derivatives prevented the establishment of an authentic clinically relevant syngeneic or allogeneic rat heart regeneration model. In this study, we comparatively explored the potential of recently available rat embryonic stem cells (rESCs) and induced pluripotent stem cells (riPSCs) as a source for cardiomyocytes (CMs). We developed feeder cell-free culture conditions facilitating the expansion of undifferentiated rPSCs and initiated cardiac differentiation by embryoid body (EB)-formation in agarose microwell arrays, which substituted the robust but labor-intensive hanging drop (HD) method. Ascorbic acid was identified as an efficient enhancer of cardiac differentiation in both rPSC types by significantly increasing the number of beating EBs (3.6 ± 1.6-fold for rESCs and 17.6 ± 3.2-fold for riPSCs). These optimizations resulted in a differentiation efficiency of up to 20% cTnTpos rPSC-derived CMs. CMs showed spontaneous contractions, expressed cardiac markers and had typical morphological features. Electrophysiology of riPSC-CMs revealed different cardiac subtypes and physiological responses to cardio-active drugs. In conclusion, we describe rPSCs as a robust source of CMs, which is a prerequisite for detailed preclinical studies of myocardial reconstruction in a physiologically and immunologically relevant small animal model.

Titanium Dioxide Nanoparticle Ingestion Alters Nutrient Absorption in an In Vitro Model of the Small Intestine

PubMed Central

Guo, Zhongyuan; Martucci, Nicole J.; Moreno-Olivas, Fabiola; Tako, Elad; Mahler, Gretchen J.

2017-01-01

Ingestion of titanium dioxide (TiO2) nanoparticles from products such as agricultural chemicals, processed food, and nutritional supplements is nearly unavoidable. The gastrointestinal tract serves as a critical interface between the body and the external environment, and is the site of essential nutrient absorption. The goal of this study was to examine the effects of ingesting the 30 nm TiO2 nanoparticles with an in vitro cell culture model of the small intestinal epithelium, and to determine how acute or chronic exposure to nano-TiO2 influences intestinal barrier function, reactive oxygen species generation, proinflammatory signaling, nutrient absorption (iron, zinc, fatty acids), and brush border membrane enzyme function (intestinal alkaline phosphatase). A Caco-2/HT29-MTX cell culture model was exposed to physiologically relevant doses of TiO2 nanoparticles for acute (four hours) or chronic (five days) time periods. Exposure to TiO2 nanoparticles significantly decreased intestinal barrier function following chronic exposure. Reactive oxygen species (ROS) generation, proinflammatory signaling, and intestinal alkaline phosphatase activity all showed increases in response to nano-TiO2. Iron, zinc, and fatty acid transport were significantly decreased following exposure to TiO2 nanoparticles. This is because nanoparticle exposure induced a decrease in absorptive microvilli in the intestinal epithelial cells. Nutrient transporter protein gene expression was also altered, suggesting that cells are working to regulate the transport mechanisms disturbed by nanoparticle ingestion. Overall, these results show that intestinal epithelial cells are affected at a functional level by physiologically relevant exposure to nanoparticles commonly ingested from food. PMID:28944308

The porcine lung as a potential model for cystic fibrosis

PubMed Central

Rogers, Christopher S.; Abraham, William M.; Brogden, Kim A.; Engelhardt, John F.; Fisher, John T.; McCray, Paul B.; McLennan, Geoffrey; Meyerholz, David K.; Namati, Eman; Ostedgaard, Lynda S.; Prather, Randall S.; Sabater, Juan R.; Stoltz, David Anthony; Zabner, Joseph; Welsh, Michael J.

2008-01-01

Airway disease currently causes most of the morbidity and mortality in patients with cystic fibrosis (CF). However, understanding the pathogenesis of CF lung disease and developing novel therapeutic strategies have been hampered by the limitations of current models. Although the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) has been targeted in mice, CF mice fail to develop lung or pancreatic disease like that in humans. In many respects, the anatomy, biochemistry, physiology, size, and genetics of pigs resemble those of humans. Thus pigs with a targeted CFTR gene might provide a good model for CF. Here, we review aspects of porcine airways and lung that are relevant to CF. PMID:18487356

An integrated QSAR-PBK/D modelling approach for predicting detoxification and DNA adduct formation of 18 acyclic food-borne α,β-unsaturated aldehydes

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

Kiwamoto, R., E-mail: reiko.kiwamoto@wur.nl; Spenkelink, A.; Rietjens, I.M.C.M.

Acyclic α,β-unsaturated aldehydes present in food raise a concern because the α,β-unsaturated aldehyde moiety is considered a structural alert for genotoxicity. However, controversy remains on whether in vivo at realistic dietary exposure DNA adduct formation is significant. The aim of the present study was to develop physiologically based kinetic/dynamic (PBK/D) models to examine dose-dependent detoxification and DNA adduct formation of a group of 18 food-borne acyclic α,β-unsaturated aldehydes without 2- or 3-alkylation, and with no more than one conjugated double bond. Parameters for the PBK/D models were obtained using quantitative structure–activity relationships (QSARs) defined with a training set of sixmore » selected aldehydes. Using the QSARs, PBK/D models for the other 12 aldehydes were defined. Results revealed that DNA adduct formation in the liver increases with decreasing bulkiness of the molecule especially due to less efficient detoxification. 2-Propenal (acrolein) was identified to induce the highest DNA adduct levels. At realistic dietary intake, the predicted DNA adduct levels for all aldehydes were two orders of magnitude lower than endogenous background levels observed in disease free human liver, suggesting that for all 18 aldehydes DNA adduct formation is negligible at the relevant levels of dietary intake. The present study provides a proof of principle for the use of QSAR-based PBK/D modelling to facilitate group evaluations and read-across in risk assessment. - Highlights: • Physiologically based in silico models were made for 18 α,β-unsaturated aldehydes. • Kinetic parameters were determined by in vitro incubations and a QSAR approach. • DNA adduct formation was negligible at levels relevant for dietary intake. • The use of QSAR-based PBK/D modelling facilitates group evaluations and read-across.« less

HuPSON: the human physiology simulation ontology.

PubMed

Gündel, Michaela; Younesi, Erfan; Malhotra, Ashutosh; Wang, Jiali; Li, Hui; Zhang, Bijun; de Bono, Bernard; Mevissen, Heinz-Theodor; Hofmann-Apitius, Martin

2013-11-22

Large biomedical simulation initiatives, such as the Virtual Physiological Human (VPH), are substantially dependent on controlled vocabularies to facilitate the exchange of information, of data and of models. Hindering these initiatives is a lack of a comprehensive ontology that covers the essential concepts of the simulation domain. We propose a first version of a newly constructed ontology, HuPSON, as a basis for shared semantics and interoperability of simulations, of models, of algorithms and of other resources in this domain. The ontology is based on the Basic Formal Ontology, and adheres to the MIREOT principles; the constructed ontology has been evaluated via structural features, competency questions and use case scenarios.The ontology is freely available at: http://www.scai.fraunhofer.de/en/business-research-areas/bioinformatics/downloads.html (owl files) and http://bishop.scai.fraunhofer.de/scaiview/ (browser). HuPSON provides a framework for a) annotating simulation experiments, b) retrieving relevant information that are required for modelling, c) enabling interoperability of algorithmic approaches used in biomedical simulation, d) comparing simulation results and e) linking knowledge-based approaches to simulation-based approaches. It is meant to foster a more rapid uptake of semantic technologies in the modelling and simulation domain, with particular focus on the VPH domain.

Addressing Early Life Sensitivity Using Physiologically Based Pharmacokinetic Modeling and In Vitro to In Vivo Extrapolation

PubMed Central

Yoon, Miyoung; Clewell, Harvey J.

2016-01-01

Physiologically based pharmacokinetic (PBPK) modeling can provide an effective way to utilize in vitro and in silico based information in modern risk assessment for children and other potentially sensitive populations. In this review, we describe the process of in vitro to in vivo extrapolation (IVIVE) to develop PBPK models for a chemical in different ages in order to predict the target tissue exposure at the age of concern in humans. We present our on-going studies on pyrethroids as a proof of concept to guide the readers through the IVIVE steps using the metabolism data collected either from age-specific liver donors or expressed enzymes in conjunction with enzyme ontogeny information to provide age-appropriate metabolism parameters in the PBPK model in the rat and human, respectively. The approach we present here is readily applicable to not just to other pyrethroids, but also to other environmental chemicals and drugs. Establishment of an in vitro and in silico-based evaluation strategy in conjunction with relevant exposure information in humans is of great importance in risk assessment for potentially vulnerable populations like early ages where the necessary information for decision making is limited. PMID:26977255

Addressing Early Life Sensitivity Using Physiologically Based Pharmacokinetic Modeling and In Vitro to In Vivo Extrapolation.

PubMed

Yoon, Miyoung; Clewell, Harvey J

2016-01-01

Physiologically based pharmacokinetic (PBPK) modeling can provide an effective way to utilize in vitro and in silico based information in modern risk assessment for children and other potentially sensitive populations. In this review, we describe the process of in vitro to in vivo extrapolation (IVIVE) to develop PBPK models for a chemical in different ages in order to predict the target tissue exposure at the age of concern in humans. We present our on-going studies on pyrethroids as a proof of concept to guide the readers through the IVIVE steps using the metabolism data collected either from age-specific liver donors or expressed enzymes in conjunction with enzyme ontogeny information to provide age-appropriate metabolism parameters in the PBPK model in the rat and human, respectively. The approach we present here is readily applicable to not just to other pyrethroids, but also to other environmental chemicals and drugs. Establishment of an in vitro and in silico-based evaluation strategy in conjunction with relevant exposure information in humans is of great importance in risk assessment for potentially vulnerable populations like early ages where the necessary information for decision making is limited.

Use of ferrets for electrophysiologic monitoring of ion transport

PubMed Central

Kaza, Niroop; Raju, S. Vamsee; Cadillac, Joan M.; Trombley, John A.; Rasmussen, Lawrence; Tang, Liping; Dohm, Erik; Harrod, Kevin S.

2017-01-01

Limited success achieved in translating basic science discoveries into clinical applications for chronic airway diseases is attributed to differences in respiratory anatomy and physiology, poor approximation of pathologic processes, and lack of correlative clinical endpoints between humans and laboratory animal models. Here, we discuss advantages of using ferrets (Mustela putorus furo) as a model for improved understanding of human airway physiology and demonstrate assays for quantifying airway epithelial ion transport in vivo and ex vivo, and establish air-liquid interface cultures of ferret airway epithelial cells as a complementary in vitro model for mechanistic studies. We present data here that establishes the feasibility of measuring these human disease endpoints in ferrets. Briefly, potential difference across the nasal and the lower airway epithelium in ferrets could be consistently assessed, were highly reproducible, and responsive to experimental interventions. Additionally, ferret airway epithelial cells were amenable to primary cell culture methods for in vitro experiments as was the use of ferret tracheal explants as an ex vivo system for assessing ion transport. The feasibility of conducting multiple assessments of disease outcomes supports the adoption of ferrets as a highly relevant model for research in obstructive airway diseases. PMID:29077751

Use of ferrets for electrophysiologic monitoring of ion transport.

PubMed

Kaza, Niroop; Raju, S Vamsee; Cadillac, Joan M; Trombley, John A; Rasmussen, Lawrence; Tang, Liping; Dohm, Erik; Harrod, Kevin S; Rowe, Steven M

2017-01-01

Limited success achieved in translating basic science discoveries into clinical applications for chronic airway diseases is attributed to differences in respiratory anatomy and physiology, poor approximation of pathologic processes, and lack of correlative clinical endpoints between humans and laboratory animal models. Here, we discuss advantages of using ferrets (Mustela putorus furo) as a model for improved understanding of human airway physiology and demonstrate assays for quantifying airway epithelial ion transport in vivo and ex vivo, and establish air-liquid interface cultures of ferret airway epithelial cells as a complementary in vitro model for mechanistic studies. We present data here that establishes the feasibility of measuring these human disease endpoints in ferrets. Briefly, potential difference across the nasal and the lower airway epithelium in ferrets could be consistently assessed, were highly reproducible, and responsive to experimental interventions. Additionally, ferret airway epithelial cells were amenable to primary cell culture methods for in vitro experiments as was the use of ferret tracheal explants as an ex vivo system for assessing ion transport. The feasibility of conducting multiple assessments of disease outcomes supports the adoption of ferrets as a highly relevant model for research in obstructive airway diseases.

Development of PBPK Models for Gasoline in Adult and ...

EPA Pesticide Factsheets

Concern for potential developmental effects of exposure to gasoline-ethanol blends has grown along with their increased use in the US fuel supply. Physiologically-based pharmacokinetic (PBPK) models for these complex mixtures were developed to address dosimetric issues related to selection of exposure concentrations for in vivo toxicity studies. Sub-models for individual hydrocarbon (HC) constituents were first developed and calibrated with published literature or QSAR-derived data where available. Successfully calibrated sub-models for individual HCs were combined, assuming competitive metabolic inhibition in the liver, and a priori simulations of mixture interactions were performed. Blood HC concentration data were collected from exposed adult non-pregnant (NP) rats (9K ppm total HC vapor, 6h/day) to evaluate performance of the NP mixture model. This model was then converted to a pregnant (PG) rat mixture model using gestational growth equations that enabled a priori estimation of life-stage specific kinetic differences. To address the impact of changing relevant physiological parameters from NP to PG, the PG mixture model was first calibrated against the NP data. The PG mixture model was then evaluated against data from PG rats that were subsequently exposed (9K ppm/6.33h gestation days (GD) 9-20). Overall, the mixture models adequately simulated concentrations of HCs in blood from single (NP) or repeated (PG) exposures (within ~2-3 fold of measured values of

Modeling the interaction between the intra-aortic balloon pump and the cardiovascular system: the effect of timing.

PubMed

Schampaert, Stéphanie; Rutten, Marcel C M; van T Veer, Marcel; van Nunen, Lokien X; Tonino, Pim A L; Pijls, Nico H J; van de Vosse, Frans N

2013-01-01

Because of the large number of interaction factors involved, the effects of the intra-aortic balloon pump (IABP) have not been investigated deeply. To enhance its clinical efficiency and to better define indications for use, advanced models are required to test the interaction between the IABP and the cardiovascular system. A patient with mild blood pressure depression and a lowered cardiac output is modeled in a lumped parameter computational model, developed with physiologically representative elements for relevant components of circulation and device. IABP support is applied, and the moments of balloon inflation and deflation are varied around their conventional timing modes. For validation purposes, timing is adapted within acceptable ranges in ten patients undergoing IABP therapy for typical clinical indications. In both model and patients, the IABP induces a diastolic blood pressure augmentation as well as a systolic reduction in afterload. The support capabilities of the IABP benefit the most when the balloon is deflated simultaneously with ventricular contraction, whereas inflation before onset of diastole unconditionally interferes with ejection. The physiologic response makes the model an excellent tool for testing the interaction between the IABP and the cardiovascular system, and how alterations of specific IABP parameters (i.e., timing) affect this coupling.

Application of physiologically based pharmacokinetic modeling in setting acute exposure guideline levels for methylene chloride.

PubMed

Bos, Peter Martinus Jozef; Zeilmaker, Marco Jacob; van Eijkeren, Jan Cornelis Henri

2006-06-01

Acute exposure guideline levels (AEGLs) are derived to protect the human population from adverse health effects in case of single exposure due to an accidental release of chemicals into the atmosphere. AEGLs are set at three different levels of increasing toxicity for exposure durations ranging from 10 min to 8 h. In the AEGL setting for methylene chloride, specific additional topics had to be addressed. This included a change of relevant toxicity endpoint within the 10-min to 8-h exposure time range from central nervous system depression caused by the parent compound to formation of carboxyhemoglobin (COHb) via biotransformation to carbon monoxide. Additionally, the biotransformation of methylene chloride includes both a saturable step as well as genetic polymorphism of the glutathione transferase involved. Physiologically based pharmacokinetic modeling was considered to be the appropriate tool to address all these topics in an adequate way. Two available PBPK models were combined and extended with additional algorithms for the estimation of the maximum COHb levels. The model was validated and verified with data obtained from volunteer studies. It was concluded that all the mentioned topics could be adequately accounted for by the PBPK model. The AEGL values as calculated with the model were substantiated by experimental data with volunteers and are concluded to be practically applicable.

MSX2 in ameloblast cell fate and activity

PubMed Central

Babajko, Sylvie; de La Dure-Molla, Muriel; Jedeon, Katia; Berdal, Ariane

2015-01-01

While many effectors have been identified in enamel matrix and cells via genetic studies, physiological networks underlying their expression levels and thus the natural spectrum of enamel thickness and degree of mineralization are now just emerging. Several transcription factors are candidates for enamel gene expression regulation and thus the control of enamel quality. Some of these factors, such as MSX2, are mainly confined to the dental epithelium. MSX2 homeoprotein controls several stages of the ameloblast life cycle. This chapter introduces MSX2 and its target genes in the ameloblast and provides an overview of knowledge regarding its effects in vivo in transgenic mouse models. Currently available in vitro data on the role of MSX2 as a transcription factor and its links to other players in ameloblast gene regulation are considered. MSX2 modulations are relevant to the interplay between developmental, hormonal and environmental pathways and in vivo investigations, notably in the rodent incisor, have provided insight into dental physiology. Indeed, in vivo models are particularly promising for investigating enamel formation and MSX2 function in ameloblast cell fate. MSX2 may be central to the temporal-spatial restriction of enamel protein production by the dental epithelium and thus regulation of enamel quality (thickness and mineralization level) under physiological and pathological conditions. Studies on MSX2 show that amelogenesis is not an isolated process but is part of the more general physiology of coordinated dental-bone complex growth. PMID:25601840

A neurally plausible parallel distributed processing model of event-related potential word reading data.

PubMed

Laszlo, Sarah; Plaut, David C

2012-03-01

The Parallel Distributed Processing (PDP) framework has significant potential for producing models of cognitive tasks that approximate how the brain performs the same tasks. To date, however, there has been relatively little contact between PDP modeling and data from cognitive neuroscience. In an attempt to advance the relationship between explicit, computational models and physiological data collected during the performance of cognitive tasks, we developed a PDP model of visual word recognition which simulates key results from the ERP reading literature, while simultaneously being able to successfully perform lexical decision-a benchmark task for reading models. Simulations reveal that the model's success depends on the implementation of several neurally plausible features in its architecture which are sufficiently domain-general to be relevant to cognitive modeling more generally. Copyright © 2011 Elsevier Inc. All rights reserved.

Physiological profile of fighters influences training organisation in combat sports: response to Del Vecchio, Hirata, and Franchini (2011).

PubMed

Paillard, Thierry

2011-12-01

The article by Del Vecchio, et al. (2011) provides relevant information to trainers about the effort-pause ratio during mixed martial arts matches. Taking into account the physiological profiles of fighters would increase interest in these findings.

Parallel particle filters for online identification of mechanistic mathematical models of physiology from monitoring data: performance and real-time scalability in simulation scenarios.

PubMed

Zenker, Sven

2010-08-01

Combining mechanistic mathematical models of physiology with quantitative observations using probabilistic inference may offer advantages over established approaches to computerized decision support in acute care medicine. Particle filters (PF) can perform such inference successively as data becomes available. The potential of PF for real-time state estimation (SE) for a model of cardiovascular physiology is explored using parallel computers and the ability to achieve joint state and parameter estimation (JSPE) given minimal prior knowledge tested. A parallelized sequential importance sampling/resampling algorithm was implemented and its scalability for the pure SE problem for a non-linear five-dimensional ODE model of the cardiovascular system evaluated on a Cray XT3 using up to 1,024 cores. JSPE was implemented using a state augmentation approach with artificial stochastic evolution of the parameters. Its performance when simultaneously estimating the 5 states and 18 unknown parameters when given observations only of arterial pressure, central venous pressure, heart rate, and, optionally, cardiac output, was evaluated in a simulated bleeding/resuscitation scenario. SE was successful and scaled up to 1,024 cores with appropriate algorithm parametrization, with real-time equivalent performance for up to 10 million particles. JSPE in the described underdetermined scenario achieved excellent reproduction of observables and qualitative tracking of enddiastolic ventricular volumes and sympathetic nervous activity. However, only a subset of the posterior distributions of parameters concentrated around the true values for parts of the estimated trajectories. Parallelized PF's performance makes their application to complex mathematical models of physiology for the purpose of clinical data interpretation, prediction, and therapy optimization appear promising. JSPE in the described extremely underdetermined scenario nevertheless extracted information of potential clinical relevance from the data in this simulation setting. However, fully satisfactory resolution of this problem when minimal prior knowledge about parameter values is available will require further methodological improvements, which are discussed.

Deliberate acquisition of competence in physiological breech birth: A grounded theory study.

PubMed

Walker, Shawn; Scamell, Mandie; Parker, Pam

2018-06-01

Research suggests that the skill and experience of the attendant significantly affect the outcomes of vaginal breech births, yet practitioner experience levels are minimal within many contemporary maternity care systems. Due to minimal experience and cultural resistance, few practitioners offer vaginal breech birth, and many practice guidelines and training programmes recommend delivery techniques requiring supine maternal position. Fewer practitioners have skills to support physiological breech birth, involving active maternal movement and choice of birthing position, including upright postures such as kneeling, standing, squatting, or on a birth stool. How professionals learn complex skills contrary to those taught in their local practice settings is unclear. How do professionals develop competence and expertise in physiological breech birth? Nine midwives and five obstetricians with experience facilitating upright physiological breech births participated in semi-structured interviews. Data were analysed iteratively using constructivist grounded theory methods to develop an empirical theory of physiological breech skill acquisition. Among the participants in this research, the deliberate acquisition of competence in physiological breech birth included stages of affinity with physiological birth, critical awareness, intention, identity and responsibility. Expert practitioners operating across local and national boundaries guided less experienced practitioners. The results depict a specialist learning model which could be formalised in sympathetic training programmes, and evaluated. It may also be relevant to developing competence in other specialist/expert roles and innovative practices. Deliberate development of local communities of practice may support professionals to acquire elusive breech skills in a sustainable way. Copyright © 2017 Australian College of Midwives. Published by Elsevier Ltd. All rights reserved.

In vitro method for assessing the biomechanics of the patellofemoral joint following total knee arthroplasty.

PubMed

Coles, L G; Gheduzzi, S; Miles, A W

2014-12-01

The patellofemoral joint is a common site of pain and failure following total knee arthroplasty. A contributory factor may be adverse patellofemoral biomechanics. Cadaveric investigations are commonly used to assess the biomechanics of the joint, but are associated with high inter-specimen variability and often cannot be carried out at physiological levels of loading. This study aimed to evaluate the suitability of a novel knee simulator for investigating patellofemoral joint biomechanics. This simulator specifically facilitated the extended assessment of patellofemoral joint biomechanics under physiological levels of loading. The simulator allowed the knee to move in 6 degrees of freedom under quadriceps actuation and included a simulation of the action of the hamstrings. Prostheses were implanted on synthetic bones and key soft tissues were modelled with a synthetic analogue. In order to evaluate the physiological relevance and repeatability of the simulator, measurements were made of the quadriceps force and the force, contact area and pressure within the patellofemoral joint using load cells, pressure-sensitive film, and a flexible pressure sensor. The results were in agreement with those previously reported in the literature, confirming that the simulator is able to provide a realistic physiological loading situation. Under physiological loading, average standard deviations of force and area measurements were substantially lower and comparable to those reported in previous cadaveric studies, respectively. The simulator replicates the physiological environment and has been demonstrated to allow the initial investigation of factors affecting patellofemoral biomechanics following total knee arthroplasty. © IMechE 2014.

Emotion recognition based on physiological changes in music listening.

PubMed

Kim, Jonghwa; André, Elisabeth

2008-12-01

Little attention has been paid so far to physiological signals for emotion recognition compared to audiovisual emotion channels such as facial expression or speech. This paper investigates the potential of physiological signals as reliable channels for emotion recognition. All essential stages of an automatic recognition system are discussed, from the recording of a physiological dataset to a feature-based multiclass classification. In order to collect a physiological dataset from multiple subjects over many weeks, we used a musical induction method which spontaneously leads subjects to real emotional states, without any deliberate lab setting. Four-channel biosensors were used to measure electromyogram, electrocardiogram, skin conductivity and respiration changes. A wide range of physiological features from various analysis domains, including time/frequency, entropy, geometric analysis, subband spectra, multiscale entropy, etc., is proposed in order to find the best emotion-relevant features and to correlate them with emotional states. The best features extracted are specified in detail and their effectiveness is proven by classification results. Classification of four musical emotions (positive/high arousal, negative/high arousal, negative/low arousal, positive/low arousal) is performed by using an extended linear discriminant analysis (pLDA). Furthermore, by exploiting a dichotomic property of the 2D emotion model, we develop a novel scheme of emotion-specific multilevel dichotomous classification (EMDC) and compare its performance with direct multiclass classification using the pLDA. Improved recognition accuracy of 95\\% and 70\\% for subject-dependent and subject-independent classification, respectively, is achieved by using the EMDC scheme.

Bioprinting for cancer research.

PubMed

Knowlton, Stephanie; Onal, Sevgi; Yu, Chu Hsiang; Zhao, Jean J; Tasoglu, Savas

2015-09-01

Bioprinting offers the ability to create highly complex 3D architectures with living cells. This cutting-edge technique has significantly gained popularity and applicability in several fields. Bioprinting methods have been developed to effectively and rapidly pattern living cells, biological macromolecules, and biomaterials. These technologies hold great potential for applications in cancer research. Bioprinted cancer models represent a significant improvement over previous 2D models by mimicking 3D complexity and facilitating physiologically relevant cell-cell and cell-matrix interactions. Here we review bioprinting methods based on inkjet, microextrusion, and laser technologies and compare 3D cancer models with 2D cancer models. We discuss bioprinted models that mimic the tumor microenvironment, providing a platform for deeper understanding of cancer pathology, anticancer drug screening, and cancer treatment development. Copyright © 2015 Elsevier Ltd. All rights reserved.

Modeling the Normal and Neoplastic Cell Cycle with 'Realistic Boolean Genetic Networks': Their Application for Understanding Carcinogenesis and Assessing Therapeutic Strategies

NASA Technical Reports Server (NTRS)

Szallasi, Zoltan; Liang, Shoudan

2000-01-01

In this paper we show how Boolean genetic networks could be used to address complex problems in cancer biology. First, we describe a general strategy to generate Boolean genetic networks that incorporate all relevant biochemical and physiological parameters and cover all of their regulatory interactions in a deterministic manner. Second, we introduce 'realistic Boolean genetic networks' that produce time series measurements very similar to those detected in actual biological systems. Third, we outline a series of essential questions related to cancer biology and cancer therapy that could be addressed by the use of 'realistic Boolean genetic network' modeling.

Exploring Genetic, Genomic, and Phenotypic Data at the Rat Genome Database

PubMed Central

Laulederkind, Stanley J. F.; Hayman, G. Thomas; Wang, Shur-Jen; Lowry, Timothy F.; Nigam, Rajni; Petri, Victoria; Smith, Jennifer R.; Dwinell, Melinda R.; Jacob, Howard J.; Shimoyama, Mary

2013-01-01

The laboratory rat, Rattus norvegicus, is an important model of human health and disease, and experimental findings in the rat have relevance to human physiology and disease. The Rat Genome Database (RGD, http://rgd.mcw.edu) is a model organism database that provides access to a wide variety of curated rat data including disease associations, phenotypes, pathways, molecular functions, biological processes and cellular components for genes, quantitative trait loci, and strains. We present an overview of the database followed by specific examples that can be used to gain experience in employing RGD to explore the wealth of functional data available for the rat. PMID:23255149

Communication: Modeling electrolyte mixtures with concentration dependent dielectric permittivity

NASA Astrophysics Data System (ADS)

Chen, Hsieh; Panagiotopoulos, Athanassios Z.

2018-01-01

We report a new implicit-solvent simulation model for electrolyte mixtures based on the concept of concentration dependent dielectric permittivity. A combining rule is found to predict the dielectric permittivity of electrolyte mixtures based on the experimentally measured dielectric permittivity for pure electrolytes as well as the mole fractions of the electrolytes in mixtures. Using grand canonical Monte Carlo simulations, we demonstrate that this approach allows us to accurately reproduce the mean ionic activity coefficients of NaCl in NaCl-CaCl2 mixtures at ionic strengths up to I = 3M. These results are important for thermodynamic studies of geologically relevant brines and physiological fluids.

Infection of the endothelium by members of the order Rickettsiales

PubMed Central

Valbuena, Gustavo; Walker, David H.

2010-01-01

Summary The vascular endothelium is the main target of a limited number of infectious agents; Rickettsia, Ehrlichia ruminantium, and Orientia tsutsugamushi are among them. These arthropod-transmitted obligately-intracellular bacteria cause serious systemic diseases that are not infrequently lethal. In this review, we discuss the bacterial biology, vector biology, and clinical aspects of these conditions with particular emphasis on the interactions of these bacteria with the vascular endothelium and how it responds to intracellular infection. The study of these bacteria in relevant in vivo models is likely to offer new insights into the physiology of the endothelium that have not been revealed by other models. PMID:19967137

Translational neurocardiology: preclinical models and cardioneural integrative aspects.

PubMed

Ardell, J L; Andresen, M C; Armour, J A; Billman, G E; Chen, P-S; Foreman, R D; Herring, N; O'Leary, D S; Sabbah, H N; Schultz, H D; Sunagawa, K; Zucker, I H

2016-07-15

Neuronal elements distributed throughout the cardiac nervous system, from the level of the insular cortex to the intrinsic cardiac nervous system, are in constant communication with one another to ensure that cardiac output matches the dynamic process of regional blood flow demand. Neural elements in their various 'levels' become differentially recruited in the transduction of sensory inputs arising from the heart, major vessels, other visceral organs and somatic structures to optimize neuronal coordination of regional cardiac function. This White Paper will review the relevant aspects of the structural and functional organization for autonomic control of the heart in normal conditions, how these systems remodel/adapt during cardiac disease, and finally how such knowledge can be leveraged in the evolving realm of autonomic regulation therapy for cardiac therapeutics. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

[G spot--myths and reality].

PubMed

Pastor, Zlatko

2010-05-01

The purpose of this review is to give an overview of anatomical and physiological assumptions of female sexual response. To notify on new models of female sexual behavior. To clarify and discuss some of the hypothesis concerning the theory of forms, nature and possibilities of female sexual response in particular relating to the area known as the G spot. Systematic review. GONA, Private Sexological Centre, Prague. Current literature review. Female sexual responses are very variable in their display. The female sexual response is modified by anatomical and physiological capabilities of each individual. Emotional and psychogenic factors have an important role. Interpretation of by science unsubstantiated hypothesis or marginal facts in sexual life as standard facts may lead to female sexual dysfunctions and relationship issues. Existence of a specific anatomical structure known as the G spot has not been proven by any relevant scientific studies.

A simple sensing mechanism for wireless, passive pressure sensors.

PubMed

Drazan, John F; Wassick, Michael T; Dahle, Reena; Beardslee, Luke A; Cady, Nathaniel C; Ledet, Eric H

2016-08-01

We have developed a simple wireless pressure sensor that consists of only three electrically isolated components. Two conductive spirals are separated by a closed cell foam that deforms when exposed to changing pressures. This deformation changes the capacitance and thus the resonant frequency of the sensors. Prototype sensors were submerged and wirelessly interrogated while being exposed to physiologically relevant pressures from 10 to 130 mmHg. Sensors consistently exhibited a sensitivity of 4.35 kHz/mmHg which is sufficient for resolving physiologically relevant pressure changes in vivo. These simple sensors have the potential for in vivo pressure sensing.

Physiological and Transcriptional Responses of Different Industrial Microbes at Near-Zero Specific Growth Rates.

PubMed

Ercan, Onur; Bisschops, Markus M M; Overkamp, Wout; Jørgensen, Thomas R; Ram, Arthur F; Smid, Eddy J; Pronk, Jack T; Kuipers, Oscar P; Daran-Lapujade, Pascale; Kleerebezem, Michiel

2015-09-01

The current knowledge of the physiology and gene expression of industrially relevant microorganisms is largely based on laboratory studies under conditions of rapid growth and high metabolic activity. However, in natural ecosystems and industrial processes, microbes frequently encounter severe calorie restriction. As a consequence, microbial growth rates in such settings can be extremely slow and even approach zero. Furthermore, uncoupling microbial growth from product formation, while cellular integrity and activity are maintained, offers perspectives that are economically highly interesting. Retentostat cultures have been employed to investigate microbial physiology at (near-)zero growth rates. This minireview compares information from recent physiological and gene expression studies on retentostat cultures of the industrially relevant microorganisms Lactobacillus plantarum, Lactococcus lactis, Bacillus subtilis, Saccharomyces cerevisiae, and Aspergillus niger. Shared responses of these organisms to (near-)zero growth rates include increased stress tolerance and a downregulation of genes involved in protein synthesis. Other adaptations, such as changes in morphology and (secondary) metabolite production, were species specific. This comparison underlines the industrial and scientific significance of further research on microbial (near-)zero growth physiology. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Controversial constitutive TSHR activity: patients, physiology, and in vitro characterization.

PubMed

Huth, S; Jaeschke, H; Schaarschmidt, J; Paschke, R

2014-06-01

G protein-coupled receptors constitute a large family of transmembrane receptors, which activate cellular responses by signal transmission and regulation of second messenger metabolism after ligand binding. For several of these receptors it is known that they also signal ligand-independently. The G protein-coupled thyroid stimulating hormone receptor (TSHR) is characterized by a high level of constitutive activity in the wild type state. However, little is known yet concerning the physiological relevance of the constitutive wild type TSHR activity. Certainly, knowledge of the physiological relevance of constitutive wild type receptor activity is necessary to better understand thyroid physiology and it is a prerequisite for the development of better therapies for nonautoimmune hyperthyroidism and thyroid cancer. Based on a literature search regarding all published TSHR mutations, this review covers several mutations which are clearly associated with a hyperthyroidism-phenotype, but interestingly show a lack of constitutive activity determined by in vitro characterization. Possible reasons for the observed discrepancies between clinical phenotypes and in vitro characterization results for constitutive TSHR activity are reviewed. All current in vitro characterization methods for constitutive TSHR mutations are "preliminary attempts" and may well be revised by more comprehensive and even better approaches. However, a standardized approach for the determination of constitutive activity can help to identify TSHR mutations for which the investigation of additional signaling mechanisms would be most interesting to find explanations for the current clinical phenotype/in vitro discrepancies and thereby also define suitable methods to explore the physiological relevance of constitutive wild type TSHR activity. © Georg Thieme Verlag KG Stuttgart · New York.

A dynamic and mechanistic model of PCB bioaccumulation in the European hake ( Merluccius merluccius)

NASA Astrophysics Data System (ADS)

Bodiguel, Xavier; Maury, Olivier; Mellon-Duval, Capucine; Roupsard, François; Le Guellec, Anne-Marie; Loizeau, Véronique

2009-08-01

Bioaccumulation is difficult to document because responses differ among chemical compounds, with environmental conditions, and physiological processes characteristic of each species. We use a mechanistic model, based on the Dynamic Energy Budget (DEB) theory, to take into account this complexity and study factors impacting accumulation of organic pollutants in fish through ontogeny. The bioaccumulation model proposed is a comprehensive approach that relates evolution of hake PCB contamination to physiological information about the fish, such as diet, metabolism, reserve and reproduction status. The species studied is the European hake ( Merluccius merluccius, L. 1758). The model is applied to study the total concentration and the lipid normalised concentration of 4 PCB congeners in male and female hakes from the Gulf of Lions (NW Mediterranean sea) and the Bay of Biscay (NE Atlantic ocean). Outputs of the model compare consistently to measurements over the life span of fish. Simulation results clearly demonstrate the relative effects of food contamination, growth and reproduction on the PCB bioaccumulation in hake. The same species living in different habitats and exposed to different PCB prey concentrations exhibit marked difference in the body accumulation of PCBs. At the adult stage, female hakes have a lower PCB concentration compared to males for a given length. We successfully simulated these sex-specific PCB concentrations by considering two mechanisms: a higher energy allocation to growth for females and a transfer of PCBs from the female to its eggs when allocating lipids from reserve to eggs. Finally, by its mechanistic description of physiological processes, the model is relevant for other species and sets the stage for a mechanistic understanding of toxicity and ecological effects of organic contaminants in marine organisms.

Characterization of Human Hippocampal Neural Stem/Progenitor Cells and Their Application to Physiologically Relevant Assays for Multiple Ionotropic Glutamate Receptors.

PubMed

Fukushima, Kazuyuki; Tabata, Yoshikuni; Imaizumi, Yoichi; Kohmura, Naohiro; Sugawara, Michiko; Sawada, Kohei; Yamazaki, Kazuto; Ito, Masashi

2014-09-01

The hippocampus is an important brain region that is involved in neurological disorders such as Alzheimer disease, schizophrenia, and epilepsy. Ionotropic glutamate receptors-namely,N-methyl-D-aspartate (NMDA) receptors (NMDARs), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors (AMPARs), and kainic acid (KA) receptors (KARs)-are well known to be involved in these diseases by mediating long-term potentiation, excitotoxicity, or both. To predict the therapeutic efficacy and neuronal toxicity of drug candidates acting on these receptors, physiologically relevant systems for assaying brain region-specific human neural cells are necessary. Here, we characterized the functional differentiation of human fetal hippocampus-derived neural stem/progenitor cells-namely, HIP-009 cells. Calcium rise assay demonstrated that, after a 4-week differentiation, the cells responded to NMDA (EC50= 7.5 ± 0.4 µM; n= 4), AMPA (EC50= 2.5 ± 0.1 µM; n= 3), or KA (EC50= 33.5 ± 1.1 µM; n= 3) in a concentration-dependent manner. An AMPA-evoked calcium rise was observed in the absence of the desensitization inhibitor cyclothiazide. In addition, the calcium rise induced by these agonists was inhibited by antagonists for each receptor-namely, MK-801 for NMDA stimulation (IC50= 0.6 ± 0.1 µM; n= 4) and NBQX for AMPA and KA stimulation (IC50= 0.7 ± 0.1 and 0.7 ± 0.03 µM, respectively; n= 3). The gene expression profile of differentiated HIP-009 cells was distinct from that of undifferentiated cells and closely resembled that of the human adult hippocampus. Our results show that HIP-009 cells are a unique tool for obtaining human hippocampal neural cells and are applicable to systems for assay of ionotropic glutamate receptors as a physiologically relevant in vitro model. © 2014 Society for Laboratory Automation and Screening.

Optical diagnostics of osteoblast cells and osteogenic drug screening

NASA Astrophysics Data System (ADS)

Kolanti, Elayaraja; Veerla, Sarath C.; Khajuria, Deepak K.; Roy Mahapatra, D.

2016-02-01

Microfluidic device based diagnostics involving optical fibre path, in situ imaging and spectroscopy are gaining importance due to recent advances in diagnostics instrumentation and methods, besides other factors such as low amount of reagent required for analysis, short investigation times, and potential possibilities to replace animal model based study in near future. It is possible to grow and monitor tissues in vitro in microfluidic lab-on-chip. It may become a transformative way of studying how cells interact with drugs, pathogens and biomaterials in physiologically relevant microenvironments. To a large extent, progress in developing clinically viable solutions has been constrained because of (i) contradiction between in vitro and in vivo results and (ii) animal model based and clinical studies which is very expensive. Our study here aims to evaluate the usefulness of microfluidic device based 3D tissue growth and monitoring approach to better emulate physiologically and clinically relevant microenvironments in comparison to conventional in vitro 2D culture. Moreover, the microfluidic methodology permits precise high-throughput investigations through real-time imaging while using very small amounts of reagents and cells. In the present study, we report on the details of an osteoblast cell based 3D microfluidic platform which we employ for osteogenic drug screening. The drug formulation is functionalized with fluorescence and other biomarkers for imaging and spectroscopy, respectively. Optical fibre coupled paths are used to obtain insight regarding the role of stress/flow pressure fluctuation and nanoparticle-drug concentration on the osteoblast growth and osteogenic properties of bone.

The Ethanolamine Permease EutH Promotes Vacuole Adaptation of Salmonella enterica and Listeria monocytogenes during Macrophage Infection.

PubMed

Anderson, Christopher J; Satkovich, John; Köseoğlu, Volkan K; Agaisse, Hervé; Kendall, Melissa M

2018-05-01

Ethanolamine is a ubiquitous and essential molecule within a host. Significantly, bacterial pathogens exploit ethanolamine during infection to promote growth and regulate virulence. The ethanolamine permease EutH is dispensable for growth in vitro under standard conditions, whereas EutH is required for ethanolamine utilization at low pH. These findings suggested a model in which EutH facilitates diffusion of ethanolamine into the bacterial cell in acidic environments. To date, the ecological significance of this model has not been thoroughly investigated, and the importance of EutH to bacterial growth under physiologically relevant conditions is not known. During infection, immune cells internalize invading bacteria within an acidic, nutrient-depleted vacuole called the phagosome. Here, we investigated the hypothesis that EutH promotes bacterial survival following phagocytosis. Our findings indicate that EutH is important for survival and replication of the facultative intracellular pathogens Salmonella enterica serovar Typhimurium and Listeria monocytogenes during prolonged or transient exposure to the phagosome, respectively. Furthermore, in agreement with EutH being important in the acidic environment, neutralization of the vacuole abolished the requirement for EutH. Significantly, consistent with a role for EutH in promoting intramacrophage survival, EutH was not required during S Typhimurium local intestinal infection but specifically conferred an advantage upon dissemination to peripheral organs. These findings reveal a physiologically relevant and conserved role for EutH in spatiotemporal niche adaptation during infection. Copyright © 2018 American Society for Microbiology.

Physiological models to understand exercise fatigue and the adaptations that predict or enhance athletic performance.

PubMed

Noakes, T D

2000-06-01

A popular concept in the exercise sciences holds that fatigue develops during exercise of moderate to high intensity, when the capacity of the cardiorespiratory system to provide oxygen to the exercising muscles falls behind their demand inducing "anaerobic" metabolism. But this cardiovascular/anaerobic model is unsatisfactory because (i) a more rigorous analysis indicates that the first organ to be affected by anaerobiosis during maximal exercise would likely be the heart, not the skeletal muscles. This probability was fully appreciated by the pioneering exercise physiologists, A. V Hill, A. Bock and D. B. Dill, but has been systematically ignored by modern exercise physiologists; (ii) no study has yet definitely established the presence of either anaerobiosis, hypoxia or ischaemia in skeletal muscle during maximal exercise; (iii) the model is unable to explain why exercise terminates in a variety of conditions including prolonged exercise, exercise in the heat and at altitude, and in those with chronic diseases of the heart and lungs, without any evidence for skeletal muscle anaerobiosis, hypoxia or ischaemia, and before there is full activation of the total skeletal muscle mass, and (iv) cardiovascular and other measures believed to relate to skeletal muscle anaerobiosis, including the maximum oxygen consumption (VO2 max) and the "anaerobic threshold", are indifferent predictors of exercise capacity in athletes with similar abilities. This review considers four additional models that need to be considered when factors limiting either short duration, maximal or prolonged submaximal exercise are evaluated. These additional models are: (i) the energy supply/energy depletion model; (ii) the muscle power/muscle recruitment model; (iii) the biomechanical model and (iv) the psychological model. By reviewing features of these models, this review provides a broad overview of the physiological, metabolic and biomechanical factors that may limit exercise performance under different exercise conditions. A more complete understanding of fatigue during exercise, and the relevance of the adaptations that develop with training, requires that the potential relevance of each model to fatigue under different conditions of exercise must be considered.

Lysophosphatidic Acid (LPA) Signaling in Human and Ruminant Reproductive Tract

PubMed Central

Wocławek-Potocka, Izabela; Rawińska, Paulina; Kowalczyk-Zieba, Ilona; Boruszewska, Dorota; Sinderewicz, Emilia; Waśniewski, Tomasz; Skarzynski, Dariusz Jan

2014-01-01

Lysophosphatidic acid (LPA) through activating its G protein-coupled receptors (LPAR 1–6) exerts diverse cellular effects that in turn influence several physiological processes including reproductive function of the female. Studies in various species of animals and also in humans have identified important roles for the receptor-mediated LPA signaling in multiple aspects of human and animal reproductive tract function. These aspects range from ovarian and uterine function, estrous cycle regulation, early embryo development, embryo implantation, decidualization to pregnancy maintenance and parturition. LPA signaling can also have pathological consequences, influencing aspects of endometriosis and reproductive tissue associated tumors. The review describes recent progress in LPA signaling research relevant to human and ruminant reproduction, pointing at the cow as a relevant model to study LPA influence on the human reproductive performance. PMID:24744506

Anesthesia in Experimental Stroke Research

PubMed Central

Hoffmann, Ulrike; Sheng, Huaxin; Ayata, Cenk; Warner, David S.

2016-01-01

Anesthetics have enabled major advances in development of experimental models of human stroke. Yet their profound pharmacologic effects on neural function can confound the interpretation of experimental stroke research. Anesthetics have drug and dose-specific effects on cerebral blood flow and metabolism, neurovascular coupling, autoregulation, ischemic depolarizations, excitotoxicity, inflammation, neural networks, and numerous molecular pathways relevant for stroke outcome. Both pre- and post-conditioning properties have been described. Anesthetics also modulate systemic arterial blood pressure, lung ventilation, and thermoregulation, all of which may interact with the ischemic insult as well as the therapeutic interventions. These confounds present a dilemma. Here, we provide an overview of the anesthetic mechanisms of action and molecular and physiologic effects on factors relevant to stroke outcomes that can guide the choice and optimization of the anesthetic regimen in experimental stroke. PMID:27534542

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

PubMed

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

2013-09-01

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

Vascular structural and functional changes: their association with causality in hypertension: models, remodeling and relevance.

PubMed

Lee, Robert Mkw; Dickhout, Jeffrey G; Sandow, Shaun L

2017-04-01

Essential hypertension is a complex multifactorial disease process that involves the interaction of multiple genes at various loci throughout the genome, and the influence of environmental factors such as diet and lifestyle, to ultimately determine long-term arterial pressure. These factors converge with physiological signaling pathways to regulate the set-point of long-term blood pressure. In hypertension, structural changes in arteries occur and show differences within and between vascular beds, between species, models and sexes. Such changes can also reflect the development of hypertension, and the levels of circulating humoral and vasoactive compounds. The role of perivascular adipose tissue in the modulation of vascular structure under various disease states such as hypertension, obesity and metabolic syndrome is an emerging area of research, and is likely to contribute to the heterogeneity described in this review. Diversity in structure and related function is the norm, with morphological changes being causative in some beds and states, and in others, a consequence of hypertension. Specific animal models of hypertension have advantages and limitations, each with factors influencing the relevance of the model to the human hypertensive state/s. However, understanding the fundamental properties of artery function and how these relate to signalling mechanisms in real (intact) tissues is key for translating isolated cell and model data to have an impact and relevance in human disease etiology. Indeed, the ultimate aim of developing new treatments to correct vascular dysfunction requires understanding and recognition of the limitations of the methodologies used.

In vivo screening of modified siRNAs for non-specific antiviral effect in a small fish model: number and localization in the strands are important

PubMed Central

Schyth, Brian Dall; Bramsen, Jesper Bertram; Pakula, Malgorzata Maria; Larashati, Sekar; Kjems, Jørgen; Wengel, Jesper; Lorenzen, Niels

2012-01-01

Small interfering RNAs (siRNAs) are promising new active compounds in gene medicine but the induction of non-specific immune responses following their delivery continues to be a serious problem. With the purpose of avoiding such effects chemically modified siRNAs are tested in screening assay but often only examining the expression of specific immunologically relevant genes in selected cell populations typically blood cells from treated animals or humans. Assays using a relevant physiological state in biological models as read-out are not common. Here we use a fish model where the innate antiviral effect of siRNAs is functionally monitored as reduced mortality in challenge studies involving an interferon sensitive virus. Modifications with locked nucleic acid (LNA), altritol nucleic acid (ANA) and hexitol nucleic acid (HNA) reduced the antiviral protection in this model indicative of altered immunogenicity. For LNA modified siRNAs, the number and localization of modifications in the single strands was found to be important and a correlation between antiviral protection and the thermal stability of siRNAs was found. The previously published sisiRNA will in some sequences, but not all, increase the antiviral effect of siRNAs. The applied fish model represents a potent tool for conducting fast but statistically and scientifically relevant evaluations of chemically optimized siRNAs with respect to non-specific antiviral effects in vivo. PMID:22287630

Radio telemetry devices to monitor breathing in non-sedated animals.

PubMed

Samson, Nathalie; Dumont, Sylvain; Specq, Marie-Laure; Praud, Jean-Paul

2011-12-15

Radio telemetry equipment has significantly improved over the last 10-15 years and is increasingly being used in research for monitoring a variety of physiological parameters in non-sedated animals. The aim of this review is to provide an update on the current state of development of radio telemetry for recording respiration. Our literature review found only rare reports of respiratory studies via radio telemetry. Much of this article will hence report our experience with our custom-built radio telemetry devices designed for recording respiratory signals, together with numerous other physiological signals in lambs. Our current radio telemetry system allows to record 24 simultaneous signals 24h/day for several days. To our knowledge, this is the highest number of physiological signals, which can be recorded wirelessly. Our devices have been invaluable for studying respiration in our ovine models of preterm birth, reflux laryngitis, postnatal exposure to cigarette smoke, respiratory syncytial virus infection and nasal ventilation, all of which are relevant to neonatal respiratory problems. Copyright © 2011 Elsevier B.V. All rights reserved.

Mother-Adolescent Physiological Synchrony in Naturalistic Settings: Within-Family Cortisol Associations and Moderators

PubMed Central

Papp, Lauren M.; Pendry, Patricia; Adam, Emma K.

2010-01-01

In this study, the authors examined parent-adolescent cortisol associations in 45 families with adolescent children (24 girls; M age = 15.78 years, SD = 1.44 years). Family members’ salivary cortisol levels were measured 7 times a day on 2 typical weekdays. Family members provided reports of demographic and health variables, and adolescents rated parent-child relationship characteristics. After accounting for the effects of time of day and relevant demographic and health control variables on cortisol levels, hierarchical linear models indicated the presence of significant covariation over time in mother-adolescent cortisol (i.e., physiological synchrony). Furthermore, moderating tests revealed that mother-adolescent cortisol synchrony was strengthened among dyads characterized by mothers and adolescents spending more time together, and in families rated higher on levels of parent-youth shared activities and parental monitoring/supervision. Analysis of momentary characteristics indicated that maternal presence at the time of cortisol sampling lowered adolescent cortisol levels but did not account for mother-adolescent cortisol synchrony. Within-family physiological synchrony was amplified in momentary contexts of elevated maternal negative affect and elevated adolescent negative affect. PMID:20001147

Spouses’ Cortisol Associations and Moderators: Testing Physiological Synchrony and Connectedness in Everyday Life

PubMed Central

Papp, Lauren M.; Pendry, Patricia; Simon, Clarissa D.; Adam, Emma K.

2012-01-01

In this study, associations were examined between cortisol levels of wives and husbands in 47 heterosexual married couples. Both partners’ salivary cortisol levels were measured at the same moments seven times a day on 2 typical weekdays. After accounting for the effects of the diurnal rhythm of cortisol and relevant control variables, dyadic hierarchical linear modeling indicated significant positive linkages between partners’ cortisol levels, consistent with the hypothesized within-couple physiological synchrony. Variables reflecting more (spousal presence) or less connectedness (loneliness, being alone) were also collected at the time of each cortisol sample. Results indicated that husbands’ cortisol levels were higher at moments they reported feeling lonelier and lower at moments they were in the presence of their spouse. Wives’ cortisol levels were higher at moments they were alone. In addition, wife-husband cortisol synchrony was stronger for husbands who spent relatively more time with their spouse across the study period—even after accounting for time spent with others in general. These findings suggest that marital partners evidence positive within-couple cortisol associations, and that connectedness (particularly physical closeness) may underpin spouses’ physiological synchrony. PMID:23763687

Mother-adolescent physiological synchrony in naturalistic settings: within-family cortisol associations and moderators.

PubMed

Papp, Lauren M; Pendry, Patricia; Adam, Emma K

2009-12-01

In this study, the authors examined parent-adolescent cortisol associations in 45 families with adolescent children (24 girls; M age = 15.78 years, SD = 1.44 years). Family members' salivary cortisol levels were measured seven times a day on 2 typical weekdays. Family members provided reports of demographic and health variables, and adolescents rated parent-child relationship characteristics. After accounting for the effects of time of day and relevant demographic and health control variables on cortisol levels, hierarchical linear models indicated the presence of significant covariation over time in mother-adolescent cortisol (i.e., physiological synchrony). Furthermore, moderating tests revealed that mother-adolescent cortisol synchrony was strengthened among dyads characterized by mothers and adolescents spending more time together, and in families rated higher on levels of parent-youth shared activities and parental monitoring or supervision. Analysis of momentary characteristics indicated that maternal presence at the time of cortisol sampling lowered adolescent cortisol levels but did not account for mother-adolescent cortisol synchrony. Within-family physiological synchrony was amplified in momentary contexts of elevated maternal negative affect and elevated adolescent negative affect.

Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism.

PubMed

Dhamne, Sameer C; Silverman, Jill L; Super, Chloe E; Lammers, Stephen H T; Hameed, Mustafa Q; Modi, Meera E; Copping, Nycole A; Pride, Michael C; Smith, Daniel G; Rotenberg, Alexander; Crawley, Jacqueline N; Sahin, Mustafa

2017-01-01

Autism spectrum disorder (ASD) is a clinically and biologically heterogeneous condition characterized by social, repetitive, and sensory behavioral abnormalities. No treatments are approved for the core diagnostic symptoms of ASD. To enable the earliest stages of therapeutic discovery and development for ASD, robust and reproducible behavioral phenotypes and biological markers are essential to establish in preclinical animal models. The goal of this study was to identify electroencephalographic (EEG) and behavioral phenotypes that are replicable between independent cohorts in a mouse model of ASD. The larger goal of our strategy is to empower the preclinical biomedical ASD research field by generating robust and reproducible behavioral and physiological phenotypes in animal models of ASD, for the characterization of mechanistic underpinnings of ASD-relevant phenotypes, and to ensure reliability for the discovery of novel therapeutics. Genetic disruption of the SHANK3 gene, a scaffolding protein involved in the stability of the postsynaptic density in excitatory synapses, is thought to be responsible for a relatively large number of cases of ASD. Therefore, we have thoroughly characterized the robustness of ASD-relevant behavioral phenotypes in two cohorts, and for the first time quantified translational EEG activity in Shank3B null mutant mice. In vivo physiology and behavioral assays were conducted in two independently bred and tested full cohorts of Shank3B null mutant ( Shank3B KO) and wildtype littermate control (WT) mice. EEG was recorded via wireless implanted telemeters for 7 days of baseline followed by 20 min of recording following pentylenetetrazol (PTZ) challenge. Behaviors relevant to the diagnostic and associated symptoms of ASD were tested on a battery of established behavioral tests. Assays were designed to reproduce and expand on the original behavioral characterization of Shank3B KO mice. Two or more corroborative tests were conducted within each behavioral domain, including social, repetitive, cognitive, anxiety-related, sensory, and motor categories of assays. Relative to WT mice, Shank3B KO mice displayed a dramatic resistance to PTZ seizure induction and an enhancement of gamma band oscillatory EEG activity indicative of enhanced inhibitory tone. These findings replicated in two separate cohorts. Behaviorally, Shank3B KO mice exhibited repetitive grooming, deficits in aspects of reciprocal social interactions and vocalizations, and reduced open field activity, as well as variable deficits in sensory responses, anxiety-related behaviors, learning and memory. Robust animal models and quantitative, replicable biomarkers of neural dysfunction are needed to decrease risk and enable successful drug discovery and development for ASD and other neurodevelopmental disorders. Complementary to the replicated behavioral phenotypes of the Shank3B mutant mouse is the new identification of a robust, translational in vivo neurophysiological phenotype. Our findings provide strong evidence for robustness and replicability of key translational phenotypes in Shank3B mutant mice and support the usefulness of this mouse model of ASD for therapeutic discovery.

Self-Organized Cerebellar Tissue from Human Pluripotent Stem Cells and Disease Modeling with Patient-Derived iPSCs.

PubMed

Muguruma, Keiko

2018-02-01

Recent advances in the techniques that differentiate induced pluripotent stem cells (iPSCs) into specific types of cells enabled us to establish in vitro cell-based models as a platform for drug discovery. iPSC-derived disease models are advantageous to generation of a large number of cells required for high-throughput screening. Furthermore, disease-relevant cells differentiated from patient-derived iPSCs are expected to recapitulate the disorder-specific pathogenesis and physiology in vitro. Such disease-relevant cells will be useful for developing effective therapies. We demonstrated that cerebellar tissues are generated from human PSCs (hPSCs) in 3D culture systems that recapitulate the in vivo microenvironments associated with the isthmic organizer. Recently, we have succeeded in generation of spinocerebellar ataxia (SCA) patient-derived Purkinje cells by combining the iPSC technology and the self-organizing stem cell 3D culture technology. We demonstrated that SCA6-derived Purkinje cells exhibit vulnerability to triiodothyronine depletion, which is suppressed by treatment with thyrotropin-releasing hormone and Riluzole. We further discuss applications of patient-specific iPSCs to intractable cerebellar disease.

The Triandis model for the study of health and illness behavior: a social behavior theory with sensitivity to diversity.

PubMed

Facione, N C

1993-03-01

The Triandis model of social behavior offers exceptional promise to nurse researchers whose goal is to achieve cultural sensitivity in their research investigations. The model includes six components: consequential beliefs, affect, social influences, previous behavioral habits, physiologic arousal, and facilitating environmental resources. A directed methodology to include culture-relevant items in the measurement of each of these model components allows researchers to capture the diverse explanations of health and illness behavior that might pertain in diverse populations. Researchers utilizing the model can achieve theory-based explanations of differences they observe by gender, race/ethnicity, social class, and sexual orientation. The Triandis model can provide studies to target variables for future intervention studies, as well as highlight areas for needed political action to equalize access to and delivery of nursing care.

Human iPSC-derived myocardium-on-chip with capillary-like flow for personalized medicine.

PubMed

Ellis, Bradley W; Acun, Aylin; Can, U Isik; Zorlutuna, Pinar

2017-03-01

The heart wall tissue, or the myocardium, is one of the main targets in cardiovascular disease prevention and treatment. Animal models have not been sufficient in mimicking the human myocardium as evident by the very low clinical translation rates of cardiovascular drugs. Additionally, current in vitro models of the human myocardium possess several shortcomings such as lack of physiologically relevant co-culture of myocardial cells, lack of a 3D biomimetic environment, and the use of non-human cells. In this study, we address these shortcomings through the design and manufacture of a myocardium-on-chip (MOC) using 3D cell-laden hydrogel constructs and human induced pluripotent stem cell (hiPSC) derived myocardial cells. The MOC utilizes 3D spatially controlled co-culture of hiPSC derived cardiomyocytes (iCMs) and hiPSC derived endothelial cells (iECs) integrated among iCMs as well as in capillary-like side channels, to better mimic the microvasculature seen in native myocardium. We first fully characterized iCMs using immunostaining, genetic, and electrochemical analysis and iECs through immunostaining and alignment analysis to ensure their functionality, and then seeded these cells sequentially into the MOC device. We showed that iECs could be cultured within the microfluidic device without losing their phenotypic lineage commitment, and align with the flow upon physiological level shear stresses. We were able to incorporate iCMs within the device in a spatially controlled manner with the help of photocrosslinkable polymers. The iCMs were shown to be viable and functional within the device up to 7 days, and were integrated with the iECs. The iCMs and iECs in this study were derived from the same hiPSC cell line, essentially mimicking the myocardium of an individual human patient. Such devices are essential for personalized medicine studies where the individual drug response of patients with different genetic backgrounds can be tested in a physiologically relevant manner.

Human iPSC-derived myocardium-on-chip with capillary-like flow for personalized medicine

PubMed Central

Ellis, Bradley W.; Acun, Aylin; Can, U. Isik; Zorlutuna, Pinar

2017-01-01

The heart wall tissue, or the myocardium, is one of the main targets in cardiovascular disease prevention and treatment. Animal models have not been sufficient in mimicking the human myocardium as evident by the very low clinical translation rates of cardiovascular drugs. Additionally, current in vitro models of the human myocardium possess several shortcomings such as lack of physiologically relevant co-culture of myocardial cells, lack of a 3D biomimetic environment, and the use of non-human cells. In this study, we address these shortcomings through the design and manufacture of a myocardium-on-chip (MOC) using 3D cell-laden hydrogel constructs and human induced pluripotent stem cell (hiPSC) derived myocardial cells. The MOC utilizes 3D spatially controlled co-culture of hiPSC derived cardiomyocytes (iCMs) and hiPSC derived endothelial cells (iECs) integrated among iCMs as well as in capillary-like side channels, to better mimic the microvasculature seen in native myocardium. We first fully characterized iCMs using immunostaining, genetic, and electrochemical analysis and iECs through immunostaining and alignment analysis to ensure their functionality, and then seeded these cells sequentially into the MOC device. We showed that iECs could be cultured within the microfluidic device without losing their phenotypic lineage commitment, and align with the flow upon physiological level shear stresses. We were able to incorporate iCMs within the device in a spatially controlled manner with the help of photocrosslinkable polymers. The iCMs were shown to be viable and functional within the device up to 7 days, and were integrated with the iECs. The iCMs and iECs in this study were derived from the same hiPSC cell line, essentially mimicking the myocardium of an individual human patient. Such devices are essential for personalized medicine studies where the individual drug response of patients with different genetic backgrounds can be tested in a physiologically relevant manner. PMID:28396709

Adapting APSIM to model the physiology and genetics of complex adaptive traits in field crops.

PubMed

Hammer, Graeme L; van Oosterom, Erik; McLean, Greg; Chapman, Scott C; Broad, Ian; Harland, Peter; Muchow, Russell C

2010-05-01

Progress in molecular plant breeding is limited by the ability to predict plant phenotype based on its genotype, especially for complex adaptive traits. Suitably constructed crop growth and development models have the potential to bridge this predictability gap. A generic cereal crop growth and development model is outlined here. It is designed to exhibit reliable predictive skill at the crop level while also introducing sufficient physiological rigour for complex phenotypic responses to become emergent properties of the model dynamics. The approach quantifies capture and use of radiation, water, and nitrogen within a framework that predicts the realized growth of major organs based on their potential and whether the supply of carbohydrate and nitrogen can satisfy that potential. The model builds on existing approaches within the APSIM software platform. Experiments on diverse genotypes of sorghum that underpin the development and testing of the adapted crop model are detailed. Genotypes differing in height were found to differ in biomass partitioning among organs and a tall hybrid had significantly increased radiation use efficiency: a novel finding in sorghum. Introducing these genetic effects associated with plant height into the model generated emergent simulated phenotypic differences in green leaf area retention during grain filling via effects associated with nitrogen dynamics. The relevance to plant breeding of this capability in complex trait dissection and simulation is discussed.

PBPK models for the prediction of in vivo performance of oral dosage forms.

PubMed

Kostewicz, Edmund S; Aarons, Leon; Bergstrand, Martin; Bolger, Michael B; Galetin, Aleksandra; Hatley, Oliver; Jamei, Masoud; Lloyd, Richard; Pepin, Xavier; Rostami-Hodjegan, Amin; Sjögren, Erik; Tannergren, Christer; Turner, David B; Wagner, Christian; Weitschies, Werner; Dressman, Jennifer

2014-06-16

Drug absorption from the gastrointestinal (GI) tract is a highly complex process dependent upon numerous factors including the physicochemical properties of the drug, characteristics of the formulation and interplay with the underlying physiological properties of the GI tract. The ability to accurately predict oral drug absorption during drug product development is becoming more relevant given the current challenges facing the pharmaceutical industry. Physiologically-based pharmacokinetic (PBPK) modeling provides an approach that enables the plasma concentration-time profiles to be predicted from preclinical in vitro and in vivo data and can thus provide a valuable resource to support decisions at various stages of the drug development process. Whilst there have been quite a few successes with PBPK models identifying key issues in the development of new drugs in vivo, there are still many aspects that need to be addressed in order to maximize the utility of the PBPK models to predict drug absorption, including improving our understanding of conditions in the lower small intestine and colon, taking the influence of disease on GI physiology into account and further exploring the reasons behind population variability. Importantly, there is also a need to create more appropriate in vitro models for testing dosage form performance and to streamline data input from these into the PBPK models. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the current status of PBPK models available. The current challenges in PBPK set-ups for oral drug absorption including the composition of GI luminal contents, transit and hydrodynamics, permeability and intestinal wall metabolism are discussed in detail. Further, the challenges regarding the appropriate integration of results from in vitro models, such as consideration of appropriate integration/estimation of solubility and the complexity of the in vitro release and precipitation data, are also highlighted as important steps to advancing the application of PBPK models in drug development. It is expected that the "innovative" integration of in vitro data from more appropriate in vitro models and the enhancement of the GI physiology component of PBPK models, arising from the OrBiTo project, will lead to a significant enhancement in the ability of PBPK models to successfully predict oral drug absorption and advance their role in preclinical and clinical development, as well as for regulatory applications. Copyright © 2013 Elsevier B.V. All rights reserved.

Three-Dimensional Cell Culture Models for Infectious Disease and Drug Development

NASA Technical Reports Server (NTRS)

Nickerson, Cheryl A.; Honer zu Bentrup, Kerstin; Ott, C. Mark

2005-01-01

Three-dimensional (3-D) cell cultures hold enormous potential to advance our understanding of infectious disease and to effectively translate basic cellular research into clinical applications. Using novel NASA bioreactor technology, the rotating wall vessel (RWV), we have engineered physiologically relevant 3-D human tissue culture models for infectious disease studies. The design of the RWV is based on the understanding that organs and tissues function in a 3-D environment, and that this 3-D architecture is critical for the differentiated form and function of tissues in vivo. The RWV provides large numbers of cells which are amenable to a wide variety of experimental manipulations and provides an easy, reproducible, and cost-effective approach to enhance differentiated features of cell culture models.

Psychological Pathways Linking Social Support to Health Outcomes: A Visit with the “Ghosts” of Research Past, Present, and Future

PubMed Central

Uchino, Bert N.; Bowen, Kimberly; Carlisle, McKenzie; Birmingham, Wendy

2012-01-01

Contemporary models postulate the importance of psychological mechanisms linking perceived and received social support to physical health outcomes. In this review, we examine studies that directly tested the potential psychological mechanisms responsible for links between social support and health-relevant physiological processes (1980s to 2010). Inconsistent with existing theoretical models, no evidence was found that psychological mechanisms such as depression, perceived stress, and other affective processes are directly responsible for links between support and health. We discuss the importance of considering statistical/design issues, emerging conceptual perspectives, and limitations of our existing models for future research aimed at elucidating the psychological mechanisms responsible for links between social support and physical health outcomes. PMID:22326104

Industrial Relevance of Chromosomal Copy Number Variation in Saccharomyces Yeasts.

PubMed

Gorter de Vries, Arthur R; Pronk, Jack T; Daran, Jean-Marc G

2017-06-01

Chromosomal copy number variation (CCNV) plays a key role in evolution and health of eukaryotes. The unicellular yeast Saccharomyces cerevisiae is an important model for studying the generation, physiological impact, and evolutionary significance of CCNV. Fundamental studies of this yeast have contributed to an extensive set of methods for analyzing and introducing CCNV. Moreover, these studies provided insight into the balance between negative and positive impacts of CCNV in evolutionary contexts. A growing body of evidence indicates that CCNV not only frequently occurs in industrial strains of Saccharomyces yeasts but also is a key contributor to the diversity of industrially relevant traits. This notion is further supported by the frequent involvement of CCNV in industrially relevant traits acquired during evolutionary engineering. This review describes recent developments in genome sequencing and genome editing techniques and discusses how these offer opportunities to unravel contributions of CCNV in industrial Saccharomyce s strains as well as to rationally engineer yeast chromosomal copy numbers and karyotypes. Copyright © 2017 Gorter de Vries et al.

Interactions of hydroxyapatite surfaces: conditioning films of human whole saliva.

PubMed

Cárdenas, Marité; Valle-Delgado, Juan José; Hamit, Jildiz; Rutland, Mark W; Arnebrant, Thomas

2008-07-15

Hydroxyapatite is a very interesting material given that it is the main component in tooth enamel and because of its uses in bone implant applications. Therefore, not only the characterization of its surface is of high relevance but also designing reliable methods to study the interfacial properties of films adsorbed onto it. In this paper we apply the colloidal probe atomic force microscopy method to investigate the surface properties of commercially available hydroxyapatite surfaces (both microscopic particles and macroscopic discs) in terms of interfacial and frictional forces. In this way, we find that hydroxyapatite surfaces at physiological relevant conditions are slightly negatively charged. The surfaces were then exposed to human whole saliva, and the surface properties were re-evaluated. A thick film was formed that was very resistant to mechanical stress. The frictional measurements demonstrated that the film was indeed highly lubricating, supporting the argument that this system may prove to be a relevant model for evaluating dental and implant systems.

Industrial Relevance of Chromosomal Copy Number Variation in Saccharomyces Yeasts

PubMed Central

Gorter de Vries, Arthur R.; Pronk, Jack T.

2017-01-01

ABSTRACT Chromosomal copy number variation (CCNV) plays a key role in evolution and health of eukaryotes. The unicellular yeast Saccharomyces cerevisiae is an important model for studying the generation, physiological impact, and evolutionary significance of CCNV. Fundamental studies of this yeast have contributed to an extensive set of methods for analyzing and introducing CCNV. Moreover, these studies provided insight into the balance between negative and positive impacts of CCNV in evolutionary contexts. A growing body of evidence indicates that CCNV not only frequently occurs in industrial strains of Saccharomyces yeasts but also is a key contributor to the diversity of industrially relevant traits. This notion is further supported by the frequent involvement of CCNV in industrially relevant traits acquired during evolutionary engineering. This review describes recent developments in genome sequencing and genome editing techniques and discusses how these offer opportunities to unravel contributions of CCNV in industrial Saccharomyces strains as well as to rationally engineer yeast chromosomal copy numbers and karyotypes. PMID:28341679

Anatomy and physiology of the aging neck.

PubMed

Shadfar, Scott; Perkins, Stephen W

2014-05-01

This article discusses the surgically relevant anatomic and physiologic tenets of the aging neck. Procedures performed to rejuvenate and contour the aging neck can be challenging. A thorough understanding of the underlying neck anatomy, as well as the physiology associated with aging, is critical for surgical planning, execution, and achieving aesthetically pleasing outcomes. These topics are reviewed and used as the foundation for a discussion of various other techniques. Copyright © 2014 Elsevier Inc. All rights reserved.

How is physiology relevant to behavior analysis?

PubMed Central

Reese, Hayne W.

1996-01-01

Physiology is an important biological science; but behavior analysis is not a biological science, and behavior analysts can safely ignore biological processes. However, ignoring products of biological processes might be a serious mistake. The important products include behavior, instinctive drift, behavior potentials, hunger, and many developmental milestones and events. Physiology deals with the sources of such products; behavior analysis can deal with how the products affect behavior, which can be understood without understanding their sources. PMID:22478240

Lab-on-a-brane: nanofibrous polymer membranes to recreate organ-capillary interfaces

NASA Astrophysics Data System (ADS)

Budhwani, Karim I.; Thomas, Vinoy; Sethu, Palaniappan

2016-03-01

Drug discovery is a complex and time consuming process involving significant basic research and preclinical evaluation prior to testing in patients. Preclinical studies rely extensively on animal models which often fail in human trials. Biomimetic microphysiological systems (MPS) using human cells can be a promising alternative to animal models; where critical interactions between different organ systems are recreated to provide physiologically relevant in vitro human models. Central here are blood-vessel networks, the interface controlling transport of cellular and biomolecular components between the circulating fluid and underlying tissue. Here we present a novel lab-on-a-brane (or lab-on-a-membrane) nanofluidics MPS that combines the elegance of lab-on-a-chip with the more realistic morphology of 3D fibrous tissue-engineering constructs. Our blood-vessel lab-on-a-brane effectively simulates in vivo vessel-tissue interface for evaluating transendothelial transport in various pharmacokinetic and nanomedicine applications. Attributes of our platform include (a) nanoporous barrier interface enabling transmembrane molecular transport, (b) transformation of substrate into nanofibrous 3D tissue matrix, (c) invertible-sandwich architecture, and (d) simple co-culture mechanism for endothelial and smooth muscle layers to accurately mimic arterial anatomy. Structural, mechanical, and transport characterization using scanning electron microscopy, stress/strain analysis, infrared spectroscopy, immunofluorescence, and FITC-Dextran hydraulic permeability confirm viability of this in vitro system. Thus, our lab-on-a-brane provides an effective and efficient, yet considerably inexpensive, physiologically relevant alternative for pharmacokinetic evaluation; possibly reducing animals used in preclinical testing, costs from false starts, and time-to-market. Furthermore, it can be configured in multiple simultaneous arrays for personalized and precision medicine applications and for evaluating localized and targeted therapeutic delivery.

Prenatal cigarette smoke exposure: Pregnancy outcome and gestational changes in plasma nicotine concentration, hematocrit, and carboxyhemoglobin in a newly standardized rat model

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

Farkas, Svetlana; Hussein, Jabeen; Ariano, Robert E.

Epidemiological studies support an association between perinatal cigarette smoke (CS) exposure and a number of severe pre- and postnatal complications. However, the mechanisms through which CS enhances such risks largely remain unknown. One of the reasons for our inability to discover such mechanisms has been the unavailability of a clinically relevant and physiologically concordant animal model. A number of studies have previously used nicotine (Nic) as surrogate for CS. We sought to (1) establish the amount of CS exposure to achieve plasma Nic concentrations observed among moderate to heavy smokers (20-60 ng/ml) (2) investigate the temporal changes in plasma Nicmore » concentrations, carboxyhemoglobin, and hematocrit with advancing pregnancy, and (3) elucidate the effects of CS exposure on pregnancy outcome. Pregnant Sprague-Dawley rats were exposed to various doses of CS or room air (Sham) from days 6 to 21 of gestation. Exposure to 6000 ml/day of CS led to very high plasma Nic concentrations and increased maternal and fetal mortality (P < 0.001). The plasma Nic concentrations remained higher than those observed in moderate smokers until the CS dose was reduced to 1000 ml/day and showed dose-dependent temporal changes with advancing gestational age. Significant increases in carboxyhemoglobin and hematocrit were observed in the CS group as compared with the Sham group (P < 0.001). In addition, prenatally CS exposed fetuses had lower birth weight as compared with the Sham group (P = 0.04). Our current study establishes a newly standardized and physiologically relevant model to investigate the mechanisms of CS-mediated adverse effects during the critical period of fetal development.« less

A Biopsychosocial Conceptual Framework of Postpartum Depression Risk in Immigrant and U.S.-born Latina Mothers in the United States.

PubMed

Lara-Cinisomo, Sandraluz; Girdler, Susan S; Grewen, Karen; Meltzer-Brody, Samantha

2016-01-01

In this review, we offer a conceptual framework that identifies risk factors of postpartum depression (PPD) in immigrant and U.S.-born Latinas in the United States by focusing on psychosocial and neuroendocrine factors. Although the evidence of the impact psychosocial stressors have on the development of PPD has been well-documented, less is known about the biological etiology of PPD or how these complex stressors jointly increase the risk of PPD in immigrant and U.S.-born Latinas in the United States. Using PubMed, CINAHL, and Embase, we reviewed the literature from 2000 to 2015 regarding psychosocial and physiological risk factors associated with PPD to develop a conceptual model for Latinas. Our search yielded 16 relevant studies. Based on our review of the literature, we developed a biopsychosocial conceptual model of PPD for Latinas in the United States. We make arguments for an integrated model designed to assess psychosocial and physiological risk factors and PPD in a high-risk population. Our framework describes the hypothesized associations between culturally and contextually relevant psychosocial stressors, neurobiological factors (e.g., hypothalamic-pituitary-adrenal [HPA] axis response system and oxytocin signaling), and PPD in Latinas in the United States. Future studies should evaluate prospectively the impact psychosocial stressors identified here have on the development of PPD in both immigrant and U.S-born Latinas while examining neuroendocrine function, such as the HPA axis and oxytocin signaling. Our conceptual framework will allow for the reporting of main and indirect effects of psychosocial risk factors and biomarkers (e.g., HPA axis and oxytocin function) on PPD in foreign- and U.S.-born postpartum Latinas. Copyright © 2016 Jacobs Institute of Women's Health. Published by Elsevier Inc. All rights reserved.

Passing on the Legacy: Teaching Capillary Filtration and Developing Presentation Skills Using Classic Papers

ERIC Educational Resources Information Center

McGeown, J. Graham

2006-01-01

Capillary filtration is a key area in the understanding of cardiovascular function and has both physiological and pathophysiological relevance in nearly every organ system. This article describes how classic papers in the Legacy collection of American Physiological Society publications can be used in a teaching symposium exploring the evidence…

“Do-it-yourself in vitro vasculature that recapitulates in vivo geometries for investigating endothelial-blood cell interactions”

PubMed Central

Mannino, Robert G.; Myers, David R.; Ahn, Byungwook; Wang, Yichen; Margo Rollins; Gole, Hope; Lin, Angela S.; Guldberg, Robert E.; Giddens, Don P.; Timmins, Lucas H.; Lam, Wilbur A.

2015-01-01

Investigating biophysical cellular interactions in the circulation currently requires choosing between in vivo models, which are difficult to interpret due in part to the hemodynamic and geometric complexities of the vasculature; or in vitro systems, which suffer from non-physiologic assumptions and/or require specialized microfabrication facilities and expertise. To bridge that gap, we developed an in vitro “do-it-yourself” perfusable vasculature model that recapitulates in vivo geometries, such as aneurysms, stenoses, and bifurcations, and supports endothelial cell culture. These inexpensive, disposable devices can be created rapidly (<2 hours) with high precision and repeatability, using standard off-the-shelf laboratory supplies. Using these “endothelialized” systems, we demonstrate that spatial variation in vascular cell adhesion molecule (VCAM-1) expression correlates with the wall shear stress patterns of vascular geometries. We further observe that the presence of endothelial cells in stenoses reduces platelet adhesion but increases sickle cell disease (SCD) red blood cell (RBC) adhesion in bifurcations. Overall, our method enables researchers from all disciplines to study cellular interactions in physiologically relevant, yet simple-to-make, in vitro vasculature models. PMID:26202603

Computational Modeling of Pathophysiologic Responses to Exercise in Fontan Patients

PubMed Central

Kung, Ethan; Perry, James C.; Davis, Christopher; Migliavacca, Francesco; Pennati, Giancarlo; Giardini, Alessandro; Hsia, Tain-Yen; Marsden, Alison

2014-01-01

Reduced exercise capacity is nearly universal among Fontan patients. Although many factors have emerged as possible contributors, the degree to which each impacts the overall hemodynamics is largely unknown. Computational modeling provides a means to test hypotheses of causes of exercise intolerance via precisely controlled virtual experiments and measurements. We quantified the physiological impacts of commonly encountered, clinically relevant dysfunctions introduced to the exercising Fontan system via a previously developed lumped-parameter model of Fontan exercise. Elevated pulmonary arterial pressure was observed in all cases of dysfunction, correlated with lowered cardiac output, and often mediated by elevated atrial pressure. Pulmonary vascular resistance was not the most significant factor affecting exercise performance as measured by cardiac output. In the absence of other dysfunctions, atrioventricular valve insufficiency alone had significant physiological impact, especially under exercise demands. The impact of isolated dysfunctions can be linearly summed to approximate the combined impact of several dysfunctions occurring in the same system. A single dominant cause of exercise intolerance was not identified, though several hypothesized dysfunctions each led to variable decreases in performance. Computational predictions of performance improvement associated with various interventions should be weighed against procedural risks and potential complications, contributing to improvements in routine patient management protocol. PMID:25260878

Ultrathin Transparent Membranes for Cellular Barrier and Co-Culture Models

PubMed Central

Carter, Robert N.; Casillo, Stephanie M.; Mazzocchi, Andrea R.; DesOrmeaux, Jon-Paul S.; Roussie, James A.; Gaborski, Thomas R.

2017-01-01

Typical in vitro barrier and co-culture models rely upon thick semi-permeable polymeric membranes that physically separate two compartments. Polymeric track-etched membranes, while permeable to small molecules, are far from physiological with respect to physical interactions with co-cultured cells and are not compatible with high-resolution imaging due to light scattering and autofluorescence. Here we report on an optically transparent ultrathin membrane with porosity exceeding 20%. We optimize deposition and annealing conditions to create a tensile and robust porous silicon dioxide membrane that is comparable in thickness to the vascular basement membrane (100–300 nm). We demonstrate that human umbilical vein endothelial cells (HUVECs) spread and proliferate on these membranes similarly to control substrates. Additionally, HUVECs are able to transfer cytoplasmic cargo to adipose-derived stem cells when they are co-cultured on opposite sides of the membrane, demonstrating its thickness supports physiologically relevant cellular interactions. Lastly, we confirm that these porous glass membranes are compatible with lift-off processes yielding membrane sheets with an active area of many square centimeters. We believe that these membranes will enable new in vitro barrier and co-culture models while offering dramatically improved visualization compared to conventional alternatives. PMID:28140345

Mechanisms and disease relevance of neutrophil extracellular trap formation.

PubMed

Van Avondt, Kristof; Hartl, Dominik

2018-03-15

While the microscopic appearance of neutrophil extracellular traps (NETs) has fascinated basic researchers since its discovery, the (patho)physiological mechanisms triggering NET release, the disease relevance and clinical translatability of this unconventional cellular mechanism remained poorly understood. Here, we summarize and discuss current concepts of the mechanisms and disease relevance of NET formation. © 2018 Stichting European Society for Clinical Investigation Journal Foundation.

[Pain in humans: experimental facts and hypotheses].

PubMed

Cesaro, P

1994-09-15

The description of painful phenomena in humans has to take into account its different components: sensory component (relevant to nociception), affective and emotional components. Nociceptor's (physiology is best understood with electrophysiological and neurochemical methods allowing a clear description of hyperalgesia, with its peripheral and spinal mechanisms. A functional model is partly available to explain allodynia, spontaneous burning pain and lightning pain, the three main consequences following deafferentation. At the thalamo-cortical level, one can describe nociceptive pathways and other pathways or neuronal networks involved in the affective and emotional components of pain.

Food for Thought Look Back in Anger – What Clinical Studies Tell Us About Preclinical Work

PubMed Central

Hartung, Thomas

2013-01-01

Summary Misled by animal studies and basic research? Whenever we take a closer look at the outcome of clinical trials in a field such as, most recently, stroke or septic shock, we see how limited the value of our preclinical models was. For all indications, 95% of drugs that enter clinical trials do not make it to the market, despite all promise of the (animal) models used to develop them. Drug development has started already to decrease its reliance on animal models: In Europe, for example, despite increasing R&D expenditure, animal use by pharmaceutical companies dropped by more than 25% from 2005 to 2008. In vitro studies are likewise limited: questionable cell authenticity, over-passaging, mycoplasma infections, and lack of differentiation as well as non-homeostatic and non-physiologic culture conditions endanger the relevance of these models. The standards of statistics and reporting often are poor, further impairing reliability. Alarming studies from industry show miserable reproducibility of landmark studies. This paper discusses factors contributing to the lack of reproducibility and relevance of pre-clinical research. The conclusion: Publish less but of better quality and do not rely on the face value of animal studies. PMID:23861075

AGING AND TOXIC RESPONSE: ISSUES RELEVANT TO RISK ASSESSMENT (FINAL)

EPA Science Inventory

EPA has released a final report entitled, Aging and Toxic Response: Issues Relevant to Risk Assessment. This document contributes to the Agency's efforts to better understand the physiology of aging in order to protect the health of older persons, and identifies several d...

Heritability of climate-relevant traits in a rainforest skink.

PubMed

Martins, Felipe; Kruuk, Loeske; Llewelyn, John; Moritz, Craig; Phillips, Ben

2018-05-22

There is justified concern about the impact of global warming on the persistence of tropical ectotherms. There is also growing evidence for strong selection on climate-relevant physiological traits. Understanding the evolutionary potential of populations is especially important for low dispersal organisms in isolated populations, because these populations have little choice but to adapt. Despite this, direct estimates of heritability and genetic correlations for physiological traits in ectotherms-which will determine their evolutionary responses to selection-are sparse, especially for reptiles. Here we examine the heritabilities and genetic correlations for a set of four morphological and six climate-relevant physiological traits in an isolated population of an Australian rainforest lizard, Lampropholis coggeri. These traits show considerable variation across populations in this species, suggesting local adaptation. From laboratory crosses, we estimated very low to moderate heritability of temperature-related physiological traits (h 2  < 0.31), but significant and higher heritability of desiccation resistance (h 2 ~0.42). These values contrasted with uniformly higher heritabilities (h 2  > 0.51) for morphological traits. At the phenotypic level, there were positive associations among the morphological traits and between thermal limits. Growth rate was positively correlated with thermal limits, but there was no indication that morphology and physiology were linked in any other way. We found some support for a specialist-generalist trade-off in the thermal performance curve, but otherwise there was no evidence for evolutionary constraints, suggesting broadly labile multivariate trait structure. Our results indicate little potential to respond to selection on thermal traits in this population and provide new insights into the capacity of tropical ectotherms to adapt in situ to rapid climate change.

Physiological Parameters for Oral Delivery and In vitro Testing

PubMed Central

Mudie, Deanna M.; Amidon, Gordon L.; Amidon, Gregory E.

2010-01-01

Pharmaceutical solid oral dosage forms must undergo dissolution in the intestinal fluids of the gastrointestinal tract before they can be absorbed and reach the systemic circulation. Therefore, dissolution is a critical part of the drug-delivery process. The rate and extent of drug dissolution and absorption depend on the characteristics of the active ingredient as well as properties of the dosage form. Just as importantly, characteristics of the physiological environment such as buffer species, pH, bile salts, gastric emptying rate, intestinal motility, and hydrodynamics can significantly impact dissolution and absorption. While significant progress has been made since 1970 when the first compendial dissolution test was introduced (USP Apparatus 1), current dissolution testing does not take full advantage of the extensive physiologic information that is available. For quality control purposes, where the question is one of lot-to-lot consistency in performance, using nonphysiologic test conditions that match drug and dosage form properties with practical dissolution media and apparatus may be appropriate. However, where in vitro – in vivo correlations are desired, it is logical to consider and utilize knowledge of the in vivo condition. This publication critically reviews the literature that is relevant to oral human drug delivery. Physiologically relevant information must serve as a basis for the design of dissolution test methods and systems that are more representative of the human condition. As in vitro methods advance in their physiological relevance, better in vitro - in vivo correlations will be possible. This will, in turn, lead to in vitro systems that can be utilized to more effectively design dosage forms that have improved and more consistent oral bioperformance. PMID:20822152

Handheld Device Adapted to Smartphone Cameras for the Measurement of Sodium Ion Concentrations at Saliva-Relevant Levels via Fluorescence

PubMed Central

Lipowicz, Michelle; Garcia, Antonio

2015-01-01

The use of saliva sampling as a minimally-invasive means for drug testing and monitoring physiology is a subject of great interest to researchers and clinicians. This study describes a new optical method based on non-axially symmetric focusing of light using an oblate spheroid sample chamber. The device is simple, lightweight, low cost and is easily attached to several different brands/models of smartphones (Apple, Samsung, HTC and Nokia) for the measurement of sodium ion levels at physiologically-relevant saliva concentrations. The sample and fluorescent reagent solutions are placed in a specially-designed, lightweight device that excludes ambient light and concentrates 470-nm excitation light, from a low-power photodiode, within the sample through non-axially-symmetric refraction. The study found that smartphone cameras and post-image processing quantitated sodium ion concentration in water over the range of 0.5–10 mM, yielding best-fit regressions of the data that agree well with a data regression of microplate luminometer results. The data suggest that fluorescence can be used for the measurement of salivary sodium ion concentrations in low-resource or point-of-care settings. With further fluorescent assay testing, the device may find application in a variety of enzymatic or chemical assays. PMID:28955016

Estimation of the viscous properties of skin and subcutaneous tissue in uniaxial stress relaxation tests.

PubMed

Wu, John Z; Cutlip, Robert G; Welcome, Daniel; Dong, Ren G

2006-01-01

Knowledge of viscoelastic properties of soft tissues is essential for the finite element modelling of the stress/strain distributions in finger-pad during vibratory loading, which is important in exploring the mechanism of hand-arm vibration syndrome. In conventional procedures, skin and subcutaneous tissue have to be separated for testing the viscoelastic properties. In this study, a novel method has been proposed to simultaneously determine the viscoelastic properties of skin and subcutaneous tissue in uniaxial stress relaxation tests. A mathematical approach has been derived to obtain the creep and relaxation characteristics of skin and subcutaneous tissue using uniaxial stress relaxation data of skin/subcutaneous composite specimens. The micro-structures of collagen fiber networks in the soft tissue, which underline the tissue mechanical characteristics, will be intact in the proposed method. Therefore, the viscoelastic properties of soft tissues obtained using the proposed method would be more physiologically relevant than those obtained using the conventional method. The proposed approach has been utilized to measure the viscoelastic properties of soft tissues of pig. The relaxation curves of pig skin and subcutaneous tissue obtained in the current study agree well with those in literature. Using the proposed approach, reliable material properties of soft tissues can be obtained in a cost- and time-efficient manner, which simultaneously improves the physiological relevance.

An inside look at the sensory biology of triatomines.

PubMed

Barrozo, Romina B; Reisenman, Carolina E; Guerenstein, Pablo; Lazzari, Claudio R; Lorenzo, Marcelo G

Although kissing bugs (Triatominae: Reduviidae) are perhaps best known as vectors of Chagas disease, they are important experimental models in studies of insect sensory physiology, pioneered by the seminal studies of Wigglesworth and Gillet more than eighty years ago. Since then, many investigations have revealed that the thermal, hygric, visual and olfactory senses play critical roles in the orientation of these blood-sucking insects towards hosts. Here we review the current knowledge about the role of these sensory systems, focussing on relevant stimuli, sensory structures, receptor physiology and the molecular players involved in the complex and cryptic behavioural repertoire of these nocturnal insects. Odours are particularly relevant, as they are involved in host search and are used for sexual, aggregation and alarm communication. Tastants are critical for a proper recognition of hosts, food and conspecifics. Heat and relative humidity mediate orientation towards hosts and are also important for the selection of resting places. Vision, which mediates negative phototaxis and flight dispersion, is also critical for modulating shelter use and mediating escape responses. The molecular bases underlying the detection of sensory stimuli started to be uncovered by means of functional genetics due to both the recent publication of the genome sequence of Rhodnius prolixus and the availability of modern genome editing techniques. Copyright © 2016 Elsevier Ltd. All rights reserved.

A fluid membrane enhances the velocity of cargo transport by small teams of kinesin-1

NASA Astrophysics Data System (ADS)

Li, Qiaochu; Tseng, Kuo-Fu; King, Stephen J.; Qiu, Weihong; Xu, Jing

2018-03-01

Kinesin-1 (hereafter referred to as kinesin) is a major microtubule-based motor protein for plus-end-directed intracellular transport in live cells. While the single-molecule functions of kinesin are well characterized, the physiologically relevant transport of membranous cargos by small teams of kinesins remains poorly understood. A key experimental challenge remains in the quantitative control of the number of motors driving transport. Here we utilized "motile fraction" to overcome this challenge and experimentally accessed transport by a single kinesin through the physiologically relevant transport by a small team of kinesins. We used a fluid lipid bilayer to model the cellular membrane in vitro and employed optical trapping to quantify the transport of membrane-enclosed cargos versus traditional membrane-free cargos under identical conditions. We found that coupling motors via a fluid membrane significantly enhances the velocity of cargo transport by small teams of kinesins. Importantly, enclosing a cargo in a fluid lipid membrane did not impact single-kinesin transport, indicating that membrane-dependent velocity enhancement for team-based transport arises from altered interactions between kinesins. Our study demonstrates that membrane-based coupling between motors is a key determinant of kinesin-based transport. Enhanced velocity may be critical for fast delivery of cargos in live cells.

Coupling neutron reflectivity with cell-free protein synthesis to probe membrane protein structure in supported bilayers

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

Soranzo, Thomas; Martin, Donald K.; Lenormand, Jean -Luc

Here, the structure of the p7 viroporin, an oligomeric membrane protein ion channel involved in the assembly and release of the hepatitis C virus, was determined from proteins expressed and inserted directly into supported model lipid membranes using cell-free protein expression. Cell-free protein expression allowed (i) high protein concentration in the membrane, (ii) control of the protein’s isotopic constitution, and (iii) control over the lipid environment available to the protein. Here, we used cell-free protein synthesis to directly incorporate the hepatitis C virus (HCV) p7 protein into supported lipid bilayers formed from physiologically relevant lipids (POPC or asolectin) for bothmore » direct structural measurements using neutron reflectivity (NR) and conductance measurements using electrical impedance spectroscopy (EIS). We report that HCV p7 from genotype 1a strain H77 adopts a conical shape within lipid bilayers and forms a viroporin upon oligomerization, confirmed by EIS conductance measurements. This combination of techniques represents a novel approach to the study of membrane proteins and, through the use of selective deuteration of particular amino acids to enhance neutron scattering contrast, has the promise to become a powerful tool for characterizing the protein conformation in physiologically relevant environments and for the development of biosensor applications.« less

Automated patch clamp on mESC-derived cardiomyocytes for cardiotoxicity prediction.

PubMed

Stoelzle, Sonja; Haythornthwaite, Alison; Kettenhofen, Ralf; Kolossov, Eugen; Bohlen, Heribert; George, Michael; Brüggemann, Andrea; Fertig, Niels

2011-09-01

Cardiovascular side effects are critical in drug development and have frequently led to late-stage project terminations or even drug withdrawal from the market. Physiologically relevant and predictive assays for cardiotoxicity are hence strongly demanded by the pharmaceutical industry. To identify a potential impact of test compounds on ventricular repolarization, typically a variety of ion channels in diverse heterologously expressing cells have to be investigated. Similar to primary cells, in vitro-generated stem cell-derived cardiomyocytes simultaneously express cardiac ion channels. Thus, they more accurately represent the native situation compared with cell lines overexpressing only a single type of ion channel. The aim of this study was to determine if stem cell-derived cardiomyocytes are suited for use in an automated patch clamp system. The authors show recordings of cardiac ion currents as well as action potential recordings in readily available stem cell-derived cardiomyocytes. Besides monitoring inhibitory effects of reference compounds on typical cardiac ion currents, the authors revealed for the first time drug-induced modulation of cardiac action potentials in an automated patch clamp system. The combination of an in vitro cardiac cell model with higher throughput patch clamp screening technology allows for a cost-effective cardiotoxicity prediction in a physiologically relevant cell system.

Coupling neutron reflectivity with cell-free protein synthesis to probe membrane protein structure in supported bilayers

DOE PAGES

Soranzo, Thomas; Martin, Donald K.; Lenormand, Jean -Luc; ...

2017-06-13

Here, the structure of the p7 viroporin, an oligomeric membrane protein ion channel involved in the assembly and release of the hepatitis C virus, was determined from proteins expressed and inserted directly into supported model lipid membranes using cell-free protein expression. Cell-free protein expression allowed (i) high protein concentration in the membrane, (ii) control of the protein’s isotopic constitution, and (iii) control over the lipid environment available to the protein. Here, we used cell-free protein synthesis to directly incorporate the hepatitis C virus (HCV) p7 protein into supported lipid bilayers formed from physiologically relevant lipids (POPC or asolectin) for bothmore » direct structural measurements using neutron reflectivity (NR) and conductance measurements using electrical impedance spectroscopy (EIS). We report that HCV p7 from genotype 1a strain H77 adopts a conical shape within lipid bilayers and forms a viroporin upon oligomerization, confirmed by EIS conductance measurements. This combination of techniques represents a novel approach to the study of membrane proteins and, through the use of selective deuteration of particular amino acids to enhance neutron scattering contrast, has the promise to become a powerful tool for characterizing the protein conformation in physiologically relevant environments and for the development of biosensor applications.« less

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

PubMed

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

2015-12-15

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

Modelling radiation fluxes in simple and complex environments: basics of the RayMan model.

PubMed

Matzarakis, Andreas; Rutz, Frank; Mayer, Helmut

2010-03-01

Short- and long-wave radiation flux densities absorbed by people have a significant influence on their energy balance. The heat effect of the absorbed radiation flux densities is parameterised by the mean radiant temperature. This paper presents the physical basis of the RayMan model, which simulates the short- and long-wave radiation flux densities from the three-dimensional surroundings in simple and complex environments. RayMan has the character of a freely available radiation and human-bioclimate model. The aim of the RayMan model is to calculate radiation flux densities, sunshine duration, shadow spaces and thermo-physiologically relevant assessment indices using only a limited number of meteorological and other input data. A comparison between measured and simulated values for global radiation and mean radiant temperature shows that the simulated data closely resemble measured data.

Biomedical signal and image processing.

PubMed

Cerutti, Sergio; Baselli, Giuseppe; Bianchi, Anna; Caiani, Enrico; Contini, Davide; Cubeddu, Rinaldo; Dercole, Fabio; Rienzo, Luca; Liberati, Diego; Mainardi, Luca; Ravazzani, Paolo; Rinaldi, Sergio; Signorini, Maria; Torricelli, Alessandro

2011-01-01

Generally, physiological modeling and biomedical signal processing constitute two important paradigms of biomedical engineering (BME): their fundamental concepts are taught starting from undergraduate studies and are more completely dealt with in the last years of graduate curricula, as well as in Ph.D. courses. Traditionally, these two cultural aspects were separated, with the first one more oriented to physiological issues and how to model them and the second one more dedicated to the development of processing tools or algorithms to enhance useful information from clinical data. A practical consequence was that those who did models did not do signal processing and vice versa. However, in recent years,the need for closer integration between signal processing and modeling of the relevant biological systems emerged very clearly [1], [2]. This is not only true for training purposes(i.e., to properly prepare the new professional members of BME) but also for the development of newly conceived research projects in which the integration between biomedical signal and image processing (BSIP) and modeling plays a crucial role. Just to give simple examples, topics such as brain–computer machine or interfaces,neuroengineering, nonlinear dynamical analysis of the cardiovascular (CV) system,integration of sensory-motor characteristics aimed at the building of advanced prostheses and rehabilitation tools, and wearable devices for vital sign monitoring and others do require an intelligent fusion of modeling and signal processing competences that are certainly peculiar of our discipline of BME.

Microcirculation in the murine liver: a computational fluid dynamic model based on 3D reconstruction from in vivo microscopy.

PubMed

Piergiovanni, Monica; Bianchi, Elena; Capitani, Giada; Li Piani, Irene; Ganzer, Lucia; Guidotti, Luca G; Iannacone, Matteo; Dubini, Gabriele

2017-10-03

The liver is organized in hexagonal functional units - termed lobules - characterized by a rather peculiar blood microcirculation, due to the presence of a tangled network of capillaries - termed sinusoids. A better understanding of the hemodynamics that governs liver microcirculation is relevant to clinical and biological studies aimed at improving our management of liver diseases and transplantation. Herein, we built a CFD model of a 3D sinusoidal network, based on in vivo images of a physiological mouse liver obtained with a 2-photon microscope. The CFD model was developed with Fluent 16.0 (ANSYS Inc., Canonsburg, PA), particular care was taken in imposing the correct boundary conditions representing a physiological state. To account for the remaining branches of the sinusoids, a lumped parameter model was used to prescribe the correct pressure at each outlet. The effect of an adhered cell on local hemodynamics is also investigated for different occlusion degrees. The model here proposed accurately reproduces the fluid dynamics in a portion of the sinusoidal network in mouse liver. Mean velocities and mass flow rates are in agreement with literature values from in vivo measurements. Our approach provides details on local phenomena, hardly described by other computational studies, either focused on the macroscopic hepatic vasculature or based on homogeneous porous medium model. Copyright © 2017 Elsevier Ltd. All rights reserved.

Robust PBPK/PD-Based Model Predictive Control of Blood Glucose.

PubMed

Schaller, Stephan; Lippert, Jorg; Schaupp, Lukas; Pieber, Thomas R; Schuppert, Andreas; Eissing, Thomas

2016-07-01

Automated glucose control (AGC) has not yet reached the point where it can be applied clinically [3]. Challenges are accuracy of subcutaneous (SC) glucose sensors, physiological lag times, and both inter- and intraindividual variability. To address above issues, we developed a novel scheme for MPC that can be applied to AGC. An individualizable generic whole-body physiology-based pharmacokinetic and dynamics (PBPK/PD) model of the glucose, insulin, and glucagon metabolism has been used as the predictive kernel. The high level of mechanistic detail represented by the model takes full advantage of the potential of MPC and may make long-term prediction possible as it captures at least some relevant sources of variability [4]. Robustness against uncertainties was increased by a control cascade relying on proportional-integrative derivative-based offset control. The performance of this AGC scheme was evaluated in silico and retrospectively using data from clinical trials. This analysis revealed that our approach handles sensor noise with a MARD of 10%-14%, and model uncertainties and disturbances. The results suggest that PBPK/PD models are well suited for MPC in a glucose control setting, and that their predictive power in combination with the integrated database-driven (a priori individualizable) model framework will help overcome current challenges in the development of AGC systems. This study provides a new, generic, and robust mechanistic approach to AGC using a PBPK platform with extensive a priori (database) knowledge for individualization.

3D Bioprinting of Tissue/Organ Models.

PubMed

Pati, Falguni; Gantelius, Jesper; Svahn, Helene Andersson

2016-04-04

In vitro tissue/organ models are useful platforms that can facilitate systematic, repetitive, and quantitative investigations of drugs/chemicals. The primary objective when developing tissue/organ models is to reproduce physiologically relevant functions that typically require complex culture systems. Bioprinting offers exciting prospects for constructing 3D tissue/organ models, as it enables the reproducible, automated production of complex living tissues. Bioprinted tissues/organs may prove useful for screening novel compounds or predicting toxicity, as the spatial and chemical complexity inherent to native tissues/organs can be recreated. In this Review, we highlight the importance of developing 3D in vitro tissue/organ models by 3D bioprinting techniques, characterization of these models for evaluating their resemblance to native tissue, and their application in the prioritization of lead candidates, toxicity testing, and as disease/tumor models. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Zonal Articular Cartilage Possesses Complex Mechanical Behavior Spanning Multiple Length Scales: Dependence on Chemical Heterogeneity, Anisotropy, and Microstructure

NASA Astrophysics Data System (ADS)

Wahlquist, Joseph A.

This work focused on characterizing the mechanical behavior of biological material in physiologically relevant conditions and at sub millimeter length scales. Elucidating the time, length scale, and directionally dependent mechanical behavior of cartilage and other biological materials is critical to adequately recapitulate native mechanosensory cues for cells, create computational models that mimic native tissue behavior, and assess disease progression. This work focused on three broad aspects of characterizing the mechanical behavior of articular cartilage. First, we sought to reveal the causes of time-dependent deformation and variation of mechanical properties with distance from the articular surface. Second, we investigated size dependence of mechanical properties. Finally, we examined material anisotropy of both the calcified and uncalcified tissues of the osteochondral interface. This research provides insight into how articular cartilage serves to support physiologic loads and simultaneously sustain chondrocyte viability.

Complex biomembrane mimetics on the sub-nanometer scale

DOE PAGES

Heberle, Frederick A.; Pabst, Georg

2017-07-17

Biomimetic lipid vesicles are indispensable tools for gaining insight into the biophysics of cell physiology on the molecular level. The level of complexity of these model systems has steadily increased, and now spans from domain forming lipid mixtures to asymmetric lipid bilayers. We review recent progress in the development and application of elastic neutron and X-ray scattering techniques for studying these systems in situ and under physiologically relevant conditions on the nanometer to sub-nanometer length scales. Particularly we focus on: (i) structural details of coexisting liquid-ordered and liquid-disordered domains, including their thickness and lipid packing mismatch as a function ofmore » a size transition from nanoscopic to macroscopic domains; (ii) membrane-mediated protein partitioning into lipid domains; (iii) the role of the aqueous medium in tuning interactions between membranes and domains; and (iv) leaflet specific structure in asymmetric bilayers and passive lipid flip-flop.« less

Complex biomembrane mimetics on the sub-nanometer scale

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

Heberle, Frederick A.; Pabst, Georg

Biomimetic lipid vesicles are indispensable tools for gaining insight into the biophysics of cell physiology on the molecular level. The level of complexity of these model systems has steadily increased, and now spans from domain forming lipid mixtures to asymmetric lipid bilayers. We review recent progress in the development and application of elastic neutron and X-ray scattering techniques for studying these systems in situ and under physiologically relevant conditions on the nanometer to sub-nanometer length scales. Particularly we focus on: (i) structural details of coexisting liquid-ordered and liquid-disordered domains, including their thickness and lipid packing mismatch as a function ofmore » a size transition from nanoscopic to macroscopic domains; (ii) membrane-mediated protein partitioning into lipid domains; (iii) the role of the aqueous medium in tuning interactions between membranes and domains; and (iv) leaflet specific structure in asymmetric bilayers and passive lipid flip-flop.« less

Regulation of Hepatic Energy Metabolism and Gluconeogenesis by BAD

PubMed Central

Giménez-Cassina, Alfredo; Garcia-Haro, Luisa; Choi, Cheol Soo; Osundiji, Mayowa A.; Lane, Elizabeth; Huang, Hu; Yildirim, Muhammed A.; Szlyk, Benjamin; Fisher, Jill K.; Polak, Klaudia; Patton, Elaura; Wiwczar, Jessica; Godes, Marina; Lee, Dae Ho; Robertson, Kirsten; Kim, Sheene; Kulkarni, Ameya; Distefano, Alberto; Samuel, Varman; Cline, Gary; Kim, Young-Bum; Shulman, Gerald I.; Danial, Nika N.

2014-01-01

SUMMARY The homeostatic balance of hepatic glucose utilization, storage and production is exquisitely controlled by hormonal signals and hepatic carbon metabolism during fed and fasted states. How the liver senses extracellular glucose to cue glucose utilization versus production is not fully understood. Here, we show that the physiologic balance of hepatic glycolysis and gluconeogenesis is regulated by BAD, a dual function protein with roles in apoptosis and metabolism. BAD deficiency reprograms hepatic substrate and energy metabolism towards diminished glycolysis, excess fatty acid oxidation and exaggerated glucose production that escapes suppression by insulin. Genetic and biochemical evidence suggest that BAD’s suppression of gluconeogenesis is actuated by phosphorylation of its BH3 domain and subsequent activation of glucokinase. The physiologic relevance of these findings is evident from the ability of a BAD phospho-mimic variant to counteract unrestrained gluconeogenesis and improve glycemia in leptin resistant and high-fat diet models of diabetes and insulin resistance. PMID:24506868

Avian genomics lends insights into endocrine function in birds.

PubMed

Mello, C V; Lovell, P V

2018-01-15

The genomics era has brought along the completed sequencing of a large number of bird genomes that cover a broad range of the avian phylogenetic tree (>30 orders), leading to major novel insights into avian biology and evolution. Among recent findings, the discovery that birds lack a large number of protein coding genes that are organized in highly conserved syntenic clusters in other vertebrates is very intriguing, given the physiological importance of many of these genes. A considerable number of them play prominent endocrine roles, suggesting that birds evolved compensatory genetic or physiological mechanisms that allowed them to survive and thrive in spite of these losses. While further studies are needed to establish the exact extent of avian gene losses, these findings point to birds as potentially highly relevant model organisms for exploring the genetic basis and possible therapeutic approaches for a wide range of endocrine functions and disorders. Copyright © 2017 Elsevier Inc. All rights reserved.

Oxygen Tension Modulates Differentiation and Primary Macrophage Functions in the Human Monocytic THP-1 Cell Line

PubMed Central

Grodzki, Ana Cristina G.; Giulivi, Cecilia; Lein, Pamela J.

2013-01-01

The human THP-1 cell line is widely used as an in vitro model system for studying macrophage differentiation and function. Conventional culture conditions for these cells consist of ambient oxygen pressure (∼20% v/v) and medium supplemented with the thiol 2-mercaptoethanol (2-ME) and serum. In consideration of the redox activities of O2 and 2-ME, and the extensive experimental evidence supporting a role for reactive oxygen species (ROS) in the differentiation and function of macrophages, we addressed the question of whether culturing THP-1 cells under a more physiologically relevant oxygen tension (5% O2) in the absence of 2-ME and serum would alter THP-1 cell physiology. Comparisons of cultures maintained in 18% O2 versus 5% O2 indicated that reducing oxygen tension had no effect on the proliferation of undifferentiated THP-1 cells. However, decreasing the oxygen tension to 5% O2 significantly increased the rate of phorbol ester-induced differentiation of THP-1 cells into macrophage-like cells as well as the metabolic activity of both undifferentiated and PMA-differentiated THP-1 cells. Removal of both 2-ME and serum from the medium decreased the proliferation of undifferentiated THP-1 cells but increased metabolic activity and the rate of differentiation under either oxygen tension. In differentiated THP-1 cells, lowering the oxygen tension to 5% O2 decreased phagocytic activity, the constitutive release of β-hexosaminidase and LPS-induced NF-κB activation but enhanced LPS-stimulated release of cytokines. Collectively, these data demonstrate that oxygen tension influences THP-1 cell differentiation and primary macrophage functions, and suggest that culturing these cells under tightly regulated oxygen tension in the absence of exogenous reducing agent and serum is likely to provide a physiologically relevant baseline from which to study the role of the local redox environment in regulating THP-1 cell physiology. PMID:23355903

Behavioral and Physiological Changes during Benthic-Pelagic Transition in the Harmful Alga, Heterosigma akashiwo: Potential for Rapid Bloom Formation

PubMed Central

Tobin, Elizabeth D.; Grünbaum, Daniel; Patterson, Johnathan; Cattolico, Rose Ann

2013-01-01

Many species of harmful algae transition between a motile, vegetative stage in the water column and a non-motile, resting stage in the sediments. Physiological and behavioral traits expressed during benthic-pelagic transition potentially regulate the timing, location and persistence of blooms. The roles of key physiological and behavioral traits involved in resting cell emergence and bloom formation were examined in two geographically distinct strains of the harmful alga, Heterosigma akashiwo. Physiological measures of cell viability, division and population growth, and cell fatty acid content were made using flow cytometry and gas chromatography – mass spectrometry techniques as cells transitioned between the benthic resting stage and the vegetative pelagic stage. Video-based tracking was used to quantify cell-level swimming behaviors. Data show increased temperature and light triggered rapid emergence from the resting stage and initiated cell swimming. Algal strains varied in important physiological and behavioral traits, including survivorship during life-stage transitions, population growth rates and swimming velocities. Collectively, these traits function as “population growth strategies” that can influence bloom formation. Many resting cells regained the up-swimming capacity necessary to cross an environmentally relevant halocline and the ability to aggregate in near-surface waters within hours after vegetative growth supporting conditions were restored. Using a heuristic model, we illustrate how strain-specific population growth strategies can govern the timescales over which H. akashiwo blooms form. Our findings highlight the need for identification and quantification of strain-specific physiological and behavioral traits to improve mechanistic understanding of bloom formation and successful bloom prediction. PMID:24124586

HuPSON: the human physiology simulation ontology

PubMed Central

2013-01-01

Background Large biomedical simulation initiatives, such as the Virtual Physiological Human (VPH), are substantially dependent on controlled vocabularies to facilitate the exchange of information, of data and of models. Hindering these initiatives is a lack of a comprehensive ontology that covers the essential concepts of the simulation domain. Results We propose a first version of a newly constructed ontology, HuPSON, as a basis for shared semantics and interoperability of simulations, of models, of algorithms and of other resources in this domain. The ontology is based on the Basic Formal Ontology, and adheres to the MIREOT principles; the constructed ontology has been evaluated via structural features, competency questions and use case scenarios. The ontology is freely available at: http://www.scai.fraunhofer.de/en/business-research-areas/bioinformatics/downloads.html (owl files) and http://bishop.scai.fraunhofer.de/scaiview/ (browser). Conclusions HuPSON provides a framework for a) annotating simulation experiments, b) retrieving relevant information that are required for modelling, c) enabling interoperability of algorithmic approaches used in biomedical simulation, d) comparing simulation results and e) linking knowledge-based approaches to simulation-based approaches. It is meant to foster a more rapid uptake of semantic technologies in the modelling and simulation domain, with particular focus on the VPH domain. PMID:24267822

Microfluidic cardiac cell culture model (μCCCM).

PubMed

Giridharan, Guruprasad A; Nguyen, Mai-Dung; Estrada, Rosendo; Parichehreh, Vahidreza; Hamid, Tariq; Ismahil, Mohamed Ameen; Prabhu, Sumanth D; Sethu, Palaniappan

2010-09-15

Physiological heart development and cardiac function rely on the response of cardiac cells to mechanical stress during hemodynamic loading and unloading. These stresses, especially if sustained, can induce changes in cell structure, contractile function, and gene expression. Current cell culture techniques commonly fail to adequately replicate physical loading observed in the native heart. Therefore, there is a need for physiologically relevant in vitro models that recreate mechanical loading conditions seen in both normal and pathological conditions. To fulfill this need, we have developed a microfluidic cardiac cell culture model (μCCCM) that for the first time allows in vitro hemodynamic stimulation of cardiomyocytes by directly coupling cell structure and function with fluid induced loading. Cells are cultured in a small (1 cm diameter) cell culture chamber on a thin flexible silicone membrane. Integrating the cell culture chamber with a pump, collapsible pulsatile valve and an adjustable resistance element (hemostatic valve) in series allow replication of various loading conditions experienced in the heart. This paper details the design, modeling, fabrication and characterization of fluid flow, pressure and stretch generated at various frequencies to mimic hemodynamic conditions associated with the normal and failing heart. Proof-of-concept studies demonstrate successful culture of an embryonic cardiomyoblast line (H9c2 cells) and establishment of an in vivo like phenotype within this system.

Gaussian fitting for carotid and radial artery pressure waveforms: comparison between normal subjects and heart failure patients.

PubMed

Liu, Chengyu; Zheng, Dingchang; Zhao, Lina; Liu, Changchun

2014-01-01

It has been reported that Gaussian functions could accurately and reliably model both carotid and radial artery pressure waveforms (CAPW and RAPW). However, the physiological relevance of the characteristic features from the modeled Gaussian functions has been little investigated. This study thus aimed to determine characteristic features from the Gaussian functions and to make comparisons of them between normal subjects and heart failure patients. Fifty-six normal subjects and 51 patients with heart failure were studied with the CAPW and RAPW signals recorded simultaneously. The two signals were normalized first and then modeled by three positive Gaussian functions, with their peak amplitude, peak time, and half-width determined. Comparisons of these features were finally made between the two groups. Results indicated that the peak amplitude of the first Gaussian curve was significantly decreased in heart failure patients compared with normal subjects (P<0.001). Significantly increased peak amplitude of the second Gaussian curves (P<0.001) and significantly shortened peak times of the second and third Gaussian curves (both P<0.001) were also presented in heart failure patients. These results were true for both CAPW and RAPW signals, indicating the clinical significance of the Gaussian modeling, which should provide essential tools for further understanding the underlying physiological mechanisms of the artery pressure waveform.

Adrenomedullin and Pregnancy: Perspectives from Animal Models to Humans

PubMed Central

Lenhart, Patricia M.; Caron, Kathleen M.

2012-01-01

A healthy pregnancy requires strict coordination of genetic, physiologic, and environmental factors. The relatively common incidence of infertility and pregnancy complications has resulted in increased interest in understanding the mechanisms that underlie normal versus abnormal pregnancy. The peptide hormone adrenomedullin has recently been the focus of some exciting breakthroughs in the pregnancy field. Supported by mechanistic studies in genetic animal models, there continues to be a growing body of evidence demonstrating the importance of adrenomedullin protein levels in a variety of human pregnancy complications. With more extensive mechanistic studies and improved consistency in clinical measurements of adrenomedullin, there is great potential for the development of adrenomedullin as a clinically-relevant biomarker in pregnancy and pregnancy complications. PMID:22425034

Resilience in Aging Mice

PubMed Central

Kirkland, James L.; Stout, Michael B.

2016-01-01

Abstract Recently discovered interventions that target fundamental aging mechanisms have been shown to increase life span in mice and other species, and in some cases, these same manipulations have been shown to enhance health span and alleviate multiple age-related diseases and conditions. Aging is generally associated with decreases in resilience, the capacity to respond to or recover from clinically relevant stresses such as surgery, infections, or vascular events. We hypothesize that the age-related increase in susceptibility to those diseases and conditions is driven by or associated with the decrease in resilience. Thus, a test for resilience at middle age or even earlier could represent a surrogate approach to test the hypothesis that an intervention delays the process of aging itself. For this, animal models to test resilience accurately and predictably are needed. In addition, interventions that increase resilience might lead to treatments aimed at enhancing recovery following acute illnesses, or preventing poor outcomes from medical interventions in older, prefrail subjects. At a meeting of basic researchers and clinicians engaged in research on mechanisms of aging and care of the elderly, the merits and drawbacks of investigating effects of interventions on resilience in mice were considered. Available and potential stressors for assessing physiological resilience as well as the notion of developing a limited battery of such stressors and how to rank them were discussed. Relevant ranking parameters included value in assessing general health (as opposed to focusing on a single physiological system), ease of use, cost, reproducibility, clinical relevance, and feasibility of being repeated in the same animal longitudinally. During the discussions it became clear that, while this is an important area, very little is known or established. Much more research is needed in the near future to develop appropriate tests of resilience in animal models within an aging context. The preliminary set of tests ranked by the participants is discussed here, recognizing that this is a first attempt. PMID:27535963

High-Intensity Sweeteners and Energy Balance

PubMed Central

Swithers, Susan E.; Martin, Ashley A.; Davidson, Terry L.

2010-01-01

Recent epidemiological evidence points to a link between a variety of negative health outcomes (e.g. metabolic syndrome, diabetes and cardiovascular disease) and the consumption of both calorically sweetened beverages and beverages sweetened with high-intensity, non-caloric sweeteners. Research on the possibility that non-nutritive sweeteners promote food intake, body weight gain, and metabolic disorders has been hindered by the lack of a physiologically-relevant model that describes the mechanistic basis for these outcomes. We have suggested that based on Pavlovian conditioning principles, consumption of non-nutritive sweeteners could result in sweet tastes no longer serving as consistent predictors of nutritive postingestive consequences. This dissociation between the sweet taste cues and the caloric consequences could lead to a decrease in the ability of sweet tastes to evoke physiological responses that serve to regulate energy balance. Using a rodent model, we have found that intake of foods or fluids containing non-nutritive sweeteners was accompanied by increased food intake, body weight gain, accumulation of body fat, and weaker caloric compensation, compared to consumption of foods and fluids containing glucose. Our research also provided evidence consistent with the hypothesis that these effects of consuming saccharin may be associated with a decrement in the ability of sweet taste to evoke thermic responses, and perhaps other physiological, cephalic phase, reflexes that are thought to help maintain energy balance. PMID:20060008

Fabrication of a co-culture micro-bioreactor device for efficient hepatic differentiation of human induced pluripotent stem cells (hiPSCs).

PubMed

Kehtari, Mousa; Zeynali, Bahman; Soleimani, Masoud; Kabiri, Mahboubeh; Seyedjafari, Ehsan

2018-04-27

Primary hepatocytes, as the gold standard cell type for in vitro models, lose their characteristic morphology and functions after few days. There is an urgent need to develop physiologically relevant models that recapitulate liver microenvironment to obtain mature hepatocyte from stem cells. We designed and fabricated a micro-bioreactor device mimicking the physiological shear stress and cell-cell interaction in liver sinusoid microenvironment. Induced pluripotent stem cells (iPSCs) were co-cultured with human umbilical vein endothelial cells (HUVECs) in the micro-bioreactor device with continuous perfusion of hepatic differentiation medium (100 μL/h). Simulation results showed that flow field inside our perfusion device was uniform and shear stress was adjusted to physiological condition (<2 dyne/cm 2 ). IPSCs-derived hepatocytes (iPSCs-Heps) that were cultured in micro-bioreactor device showed a higher level of hepatic markers compared to those in static condition. Flow cytometry and immunocytochemistry analysis revealed iPSCs cultured in the device sequentially acquired characteristics of definitive endodermal cells (SOX17 positive), hepatoblasts (AFP positive) and mature hepatocyte (ALB positive). Moreover, the albumin and urea secretion were significantly higher in micro-bioreactor device than those cultured in culture dishes during experiment. Thus, based on our results, we propose our micro-bioreactor as a beneficial device to generate mature hepatocytes for drug screening and basic research.

Bringing in vitro analysis closer to in vivo: Studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling.

PubMed

Verheijen, Marcha; Schrooders, Yannick; Gmuender, Hans; Nudischer, Ramona; Clayton, Olivia; Hynes, James; Niederer, Steven; Cordes, Henrik; Kuepfer, Lars; Kleinjans, Jos; Caiment, Florian

2018-05-24

Doxorubicin (DOX) is a chemotherapeutic agent of which the medical use is limited due to cardiotoxicity. While acute cardiotoxicity is reversible, chronic cardiotoxicity is persistent or progressive, dose-dependent and irreversible. While DOX mechanisms of action are not fully understood yet, 3 toxicity processes are known to occur in vivo: cardiomyocyte dysfunction, mitochondrial dysfunction and cell death. We present an in vitro experimental design aimed at detecting DOX-induced cardiotoxicity by obtaining a global view of the induced molecular mechanisms through RNA-sequencing. To better reflect the in vivo situation, human 3D cardiac microtissues were exposed to physiologically-based pharmacokinetic (PBPK) relevant doses of DOX for 2 weeks. We analysed a therapeutic and a toxic dosing profile. Transcriptomics analysis revealed significant gene expression changes in pathways related to "striated muscle contraction" and "respiratory electron transport", thus suggesting mitochondrial dysfunction as an underlying mechanism for cardiotoxicity. Furthermore, expression changes in mitochondrial processes differed significantly between the doses. Therapeutic dose reflects processes resembling the phenotype of delayed chronic cardiotoxicity, while toxic doses resembled acute cardiotoxicity. Overall, these results demonstrate the capability of our innovative in vitro approach to detect the three known mechanisms of DOX leading to toxicity, thus suggesting its potential relevance for reflecting the patient situation. Our study also demonstrated the importance of applying physiologically relevant doses during toxicological research, since mechanisms of acute and chronic toxicity differ. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

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

De Vos, Winnok H., E-mail: winnok.devos@uantwerpen.be; Cell Systems and Imaging Research Group, Department of Molecular Biotechnology, Ghent University, Ghent; Beghuin, Didier

As commercial space flights have become feasible and long-term extraterrestrial missions are planned, it is imperative that the impact of space travel and the space environment on human physiology be thoroughly characterized. Scrutinizing the effects of potentially detrimental factors such as ionizing radiation and microgravity at the cellular and tissue level demands adequate visualization technology. Advanced light microscopy (ALM) is the leading tool for non-destructive structural and functional investigation of static as well as dynamic biological systems. In recent years, technological developments and advances in photochemistry and genetic engineering have boosted all aspects of resolution, readout and throughput, rendering ALMmore » ideally suited for biological space research. While various microscopy-based studies have addressed cellular response to space-related environmental stressors, biological endpoints have typically been determined only after the mission, leaving an experimental gap that is prone to bias results. An on-board, real-time microscopical monitoring device can bridge this gap. Breadboards and even fully operational microscope setups have been conceived, but they need to be rendered more compact and versatile. Most importantly, they must allow addressing the impact of gravity, or the lack thereof, on physiologically relevant biological systems in space and in ground-based simulations. In order to delineate the essential functionalities for such a system, we have reviewed the pending questions in space science, the relevant biological model systems, and the state-of-the art in ALM. Based on a rigorous trade-off, in which we recognize the relevance of multi-cellular systems and the cellular microenvironment, we propose a compact, but flexible concept for space-related cell biological research that is based on light sheet microscopy.« less

From Claude Bernard to the Batcave and Beyond: Using Batman as a Hook for Physiology Education

ERIC Educational Resources Information Center

Zehr, E. Paul

2011-01-01

Communicating physiology to the general public and popularizing science can be tremendously rewarding activities. Providing relevant and compelling points of linkage, however, between the scientific experiences and the interests of the general public can be challenging. One avenue for popularizing science is to link scientific concepts to images,…

The Emergent Coordination of Cognitive Function

ERIC Educational Resources Information Center

Kello, Christopher T.; Beltz, Brandon C.; Holden, John G.; Van Orden, Guy C.

2007-01-01

1/f scaling has been observed throughout human physiology and behavior, but its origins and meaning remain a matter of debate. Some argue that it is a byproduct of ongoing processes in the brain or body and therefore of limited relevance to psychological theory. Others argue that 1/f scaling reflects a fundamental aspect of all physiological and…

Challenges of physiological monitoring in a Navy operational setting

NASA Technical Reports Server (NTRS)

Banta, Guy R.

1988-01-01

Challenges to physiological monitoring in the Navy include environmental extremes, acceptance of use by test subjects, data transfer, data interpretation, and capability of relating collected data to valid operational relevant criterion measures. These problems are discussed with respect to diving, electrophysiological monitoring, in-flight monitoring, aircrew fatigue, in-flight cardiac stress, and in-flight monitoring devices.

Designing and implementing a physiology course for a new doctoral occupational therapy program with student feedback.

PubMed

Goodman, Barbara E; Ikiugu, Moses N

2017-09-01

Recently, the Occupational Therapy Department requested a custom-designed medical physiology course for the students in the new occupational therapy doctoral program. The first author, a physiologist with extensive experience in teaching both undergraduate preprofessional and medical students in human physiology, was recruited to design and implement the course. The course was designed to be consistent with the constructivist philosophy that guides the occupational therapy curriculum. The course was offered for the first time during fall/spring 2015/2016 and included both first- and second-year occupational therapy doctoral students. A number of anonymous assessment tools were used to evaluate students' perceptions regarding the effectiveness of various pedagogies used in the course in enhancing their learning. A summative course assessment survey with comments was used at the end of the course. This paper describes the model of course design and the student feedback, which generated some suggestions for improvement of the course. This approach in designing a new course for a new disciplinary group of students should be helpful to other faculty involved in developing courses for health career programs populated by students with variable physiology backgrounds and different educational needs. The final relevant feedback from the course would be to have the students evaluate the usefulness of the course to their future careers immediately following their certification examinations in a year or two and during their subsequent clinical experiences; however, that information will likely be more difficult to obtain. Copyright © 2017 the American Physiological Society.

Understanding Lymphatic Valve Function via Computational Modeling

NASA Astrophysics Data System (ADS)

Wolf, Ki; Nepiyushchikh, Zhanna; Razavi, Mohammad; Dixon, Brandon; Alexeev, Alexander

2017-11-01

The lymphatic system is a crucial part to the circulatory system with many important functions, such as transport of interstitial fluid, fatty acid, and immune cells. Lymphatic vessels' contractile walls and valves allow lymph flow against adverse pressure gradients and prevent back flow. Yet, the effect of lymphatic valves' geometric and mechanical properties to pumping performance and lymphatic dysfunctions like lymphedema is not well understood. Our coupled fluid-solid computational model based on lattice Boltzmann model and lattice spring model investigates the dynamics and effectiveness of lymphatic valves in resistance minimization, backflow prevention, and viscoelastic response under different geometric and mechanical properties, suggesting the range of lymphatic valve parameters with effective pumping performance. Our model also provides more physiologically relevant relations of the valve response under varied conditions to a lumped parameter model of the lymphatic system giving an integrative insight into lymphatic system performance, including its failure due to diseases. NSF CMMI-1635133.

Towards the quantitative evaluation of visual attention models.

PubMed

Bylinskii, Z; DeGennaro, E M; Rajalingham, R; Ruda, H; Zhang, J; Tsotsos, J K

2015-11-01

Scores of visual attention models have been developed over the past several decades of research. Differences in implementation, assumptions, and evaluations have made comparison of these models very difficult. Taxonomies have been constructed in an attempt at the organization and classification of models, but are not sufficient at quantifying which classes of models are most capable of explaining available data. At the same time, a multitude of physiological and behavioral findings have been published, measuring various aspects of human and non-human primate visual attention. All of these elements highlight the need to integrate the computational models with the data by (1) operationalizing the definitions of visual attention tasks and (2) designing benchmark datasets to measure success on specific tasks, under these definitions. In this paper, we provide some examples of operationalizing and benchmarking different visual attention tasks, along with the relevant design considerations. Copyright © 2015 Elsevier Ltd. All rights reserved.

The G protein-coupled receptor GPR34 - The past 20 years of a grownup.

PubMed

Schöneberg, Torsten; Meister, Jaroslawna; Knierim, Alexander Bernd; Schulz, Angela

2018-04-22

Research on GPR34, which was discovered in 1999 as an orphan G protein-coupled receptor of the rhodopsin-like class, disclosed its physiologic relevance only piece by piece. Being present in all recent vertebrate genomes analyzed so far it seems to improve the fitness of species although it is not essential for life and reproduction as GPR34-deficient mice demonstrate. However, closer inspection of macrophages and microglia, where it is mainly expressed, revealed its relevance in immune cell function. Recent data clearly demonstrate that GPR34 function is required to arrest microglia in the M0 homeostatic non-phagocytic phenotype. Herein, we summarize the current knowledge on its evolution, genomic and structural organization, physiology, pharmacology and relevance in human diseases including neurodegenerative diseases and cancer, which accumulated over the last 20 years. Copyright © 2018 Elsevier Inc. All rights reserved.

Modeling and Theories of Pathophysiology and Physiology of the Basal Ganglia–Thalamic–Cortical System: Critical Analysis

PubMed Central

Montgomery Jr., Erwin B.

2016-01-01

Theories impact the movement disorders clinic, not only affecting the development of new therapies but determining how current therapies are used. Models are theories that are procedural rather than declarative. Theories and models are important because, as argued by Kant, one cannot know the thing-in-itself (das Ding an sich) and only a model is knowable. Further, biological variability forces higher level abstraction relevant for all variants. It is that abstraction that is raison d’être of theories and models. Theories “connect the dots” to move from correlation to causation. The necessity of theory makes theories helpful or counterproductive. Theories and models of the pathophysiology and physiology of the basal ganglia–thalamic–cortical system do not spontaneously arise but have a history and consequently are legacies. Over the last 40 years, numerous theories and models of the basal ganglia have been proposed only to be forgotten or dismissed, rarely critiqued. It is not harsh to say that current popular theories positing increased neuronal activities in the Globus Pallidus Interna (GPi), excessive beta oscillations and increased synchronization not only fail to provide an adequate explication but are inconsistent with many observations. It is likely that their shared intellectual and epistemic inheritance plays a factor in their shared failures. These issues are critically examined. How one is to derive theories and models and have hope these will be better is explored as well. PMID:27708569

Depression-like behavior and stressor-induced neuroendocrine activation in female prairie voles exposed to chronic social isolation

PubMed Central

Grippo, Angela J.; Cushing, Bruce S.; Carter, C. Sue

2010-01-01

Objective Previous evidence suggests that responses to social stressors may play a mechanistic role in the behavioral and physiological changes associated with affective disorders such as depression. Prairie voles (Microtus ochrogaster) are socially monogamous rodents that share features of social behavior with humans, and therefore might provide a useful model for examining social regulation of behaviors and physiological responses related to depression. In the present study we hypothesized that social isolation in female prairie voles would induce depression-relevant behaviors and altered neuroendocrine responses to an acute social stressor. Methods Twenty adult female prairie voles were exposed to either 60 days of social isolation or paired (control) housing, and tested for a depression-like behavior (anhedonia), numbers of corticotropin-releasing factor- and oxytocin-immunoreactive cells in the paraventricular nucleus of the hypothalamus, and circulating levels of hormones and peptide in response to an acute social stressor (resident-intruder test). Results Chronic social isolation produced anhedonia, measured by a reduction in sucrose intake and sucrose preference relative to paired animals. Compared to paired animals, isolated prairie voles displayed increased plasma hormone and peptide levels (oxytocin, arginine vasopressin, and corticosterone) following a 5-minute resident-intruder test, mirrored by an increased number of oxytocin- and corticotropin-releasing factor-immunoreactive cells in the hypothalamic paraventricular nucleus. Conclusions These findings suggest that isolation in a socially monogamous rodent model induces both behavioral and neuroendocrine changes that are relevant to depression, and may provide insight into the mechanisms that underlie the development and/or maintenance of depressive disorders in humans. PMID:17289829

What are the origins and relevance of spontaneous bladder contractions? ICI-RS 2017.

PubMed

Drake, Marcus J; Fry, Christopher H; Hashitani, Hikaru; Kirschner-Hermanns, Ruth; Rahnama'i, Mohammad S; Speich, John E; Tomoe, Hikaru; Kanai, Anthony J; McCloskey, Karen D

2018-01-23

Storage phase bladder activity is a counter-intuitive observation of spontaneous contractions. They are potentially an intrinsic feature of the smooth muscle, but interstitial cells in the mucosa and the detrusor itself, as well as other muscular elements in the mucosa may substantially influence them. They are identified in several models explaining lower urinary tract dysfunction. A consensus meeting at the International Consultation on Incontinence Research Society (ICI-RS) 2017 congress considered the origins and relevance of spontaneous bladder contractions by debating which cell type(s) modulate bladder spontaneous activity, whether the methodologies are sufficiently robust, and implications for healthy and abnormal lower urinary tract function. The identified research priorities reflect a wide range of unknown aspects. Cellular contributions to spontaneous contractions in detrusor smooth muscle are still uncertain. Accordingly, insight into the cellular physiology of the bladder wall, particularly smooth muscle cells, interstitial cells, and urothelium, remains important. Upstream influences, such as innervation, endocrine, and paracrine factors, are particularly important. The cellular interactions represent the key understanding to derive the integrative physiology of organ function, notably the nature of signalling between mucosa and detrusor layers. Indeed, it is still not clear to what extent spontaneous contractions generated in isolated preparations mirror their normal and pathological counterparts in the intact bladder. Improved models of how spontaneous contractions influence pressure generation and sensory nerve function are also needed. Deriving approaches to robust evaluation of spontaneous contractions and their influences for experimental and clinical use could yield considerable progress in functional urology. © 2018 Wiley Periodicals, Inc.

Multiplexed fibre optic sensing in the distal lung (Conference Presentation)

NASA Astrophysics Data System (ADS)

Choudhary, Tushar R.; Tanner, Michael G.; Megia-Fernandez, Alicia; Harrington, Kerrianne; Wood, Harry A.; Chankeshwara, Sunay; Zhu, Patricia; Choudhury, Debaditya; Yu, Fei; Thomson, Robert R.; Duncan, Rory R.; Dhaliwal, Kevin; Bradley, Mark

2017-02-01

We present a toolkit for a multiplexed pH and oxygen sensing probe in the distal lung using multicore fibres. Measuring physiological relevant parameters like pH and oxygen is of significant importance in understanding changes associated with disease pathology. We present here, a single multicore fibre based pH and oxygen sensing probe which can be used with a standard bronchoscope to perform in vivo measurements in the distal lung. The multiplexed probe consists of fluorescent pH sensors (fluorescein based) and oxygen sensors (Palladium porphyrin complex based) covalently bonded to silica microspheres (10 µm) loaded on the distal facet of a 19 core (10 µm core diameter) multicore fibre (total diameter of 150 µm excluding coating). Pits are formed by selectively etching the cores using hydrofluoric acid, multiplexing is achieved through the self-location of individual probes on differing cores. This architecture can be expanded to include probes for further parameters. Robust measurements are demonstrated of self-referencing fluorophores, not limited by photobleaching, with short (100ms) measurement times at low ( 10µW) illumination powers. We have performed on bench calibration and tests of in vitro tissue models and in an ovine whole lung model to validate our sensors. The pH sensor is demonstrated in the physiologically relevant range of pH 5 to pH 8.5 and with an accuracy of ± 0.05 pH units. The oxygen sensor is demonstrated in gas mixtures downwards from 20% oxygen and in liquid saturated with 20% oxygen mixtures ( 8mg/L) down to full depletion (0mg/L) with 0.5mg/L accuracy.

In Vivo Predictive Dissolution: Comparing the Effect of Bicarbonate and Phosphate Buffer on the Dissolution of Weak Acids and Weak Bases.

PubMed

Krieg, Brian J; Taghavi, Seyed Mohammad; Amidon, Gordon L; Amidon, Gregory E

2015-09-01

Bicarbonate is the main buffer in the small intestine and it is well known that buffer properties such as pKa can affect the dissolution rate of ionizable drugs. However, bicarbonate buffer is complicated to work with experimentally. Finding a suitable substitute for bicarbonate buffer may provide a way to perform more physiologically relevant dissolution tests. The dissolution of weak acid and weak base drugs was conducted in bicarbonate and phosphate buffer using rotating disk dissolution methodology. Experimental results were compared with the predicted results using the film model approach of (Mooney K, Mintun M, Himmelstein K, Stella V. 1981. J Pharm Sci 70(1):22-32) based on equilibrium assumptions as well as a model accounting for the slow hydration reaction, CO2 + H2 O → H2 CO3 . Assuming carbonic acid is irreversible in the dehydration direction: CO2 + H2 O ← H2 CO3 , the transport analysis can accurately predict rotating disk dissolution of weak acid and weak base drugs in bicarbonate buffer. The predictions show that matching the dissolution of weak acid and weak base drugs in phosphate and bicarbonate buffer is possible. The phosphate buffer concentration necessary to match physiologically relevant bicarbonate buffer [e.g., 10.5 mM (HCO3 (-) ), pH = 6.5] is typically in the range of 1-25 mM and is very dependent upon drug solubility and pKa . © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Cellular and Physiological Effects of Anthrax Exotoxin and Its Relevance to Disease

PubMed Central

Lowe, David E.; Glomski, Ian J.

2012-01-01

Bacillus anthracis, the causative agent of anthrax, secretes a tri-partite exotoxin that exerts pleiotropic effects on the host. The purification of the exotoxin components, protective antigen, lethal factor, and edema factor allowed the rapid characterization of their physiologic effects on the host. As molecular biology matured, interest focused on the molecular mechanisms and cellular alterations induced by intoxication. Only recently have researchers begun to connect molecular and cellular knowledge back to the broader physiological effects of the exotoxin. This review focuses on the progress that has been made bridging molecular knowledge back to the exotoxin’s physiological effects on the host. PMID:22919667

Capillary response to skeletal muscle contraction: evidence that redundancy between vasodilators is physiologically relevant during active hyperaemia.

PubMed

Lamb, Iain R; Novielli, Nicole M; Murrant, Coral L

2018-04-15

The current theory behind matching blood flow to metabolic demand of skeletal muscle suggests redundant interactions between metabolic vasodilators. Capillaries play an important role in blood flow control given their ability to respond to muscle contraction by causing conducted vasodilatation in upstream arterioles that control their perfusion. We sought to determine whether redundancies occur between vasodilators at the level of the capillary by stimulating the capillaries with muscle contraction and vasodilators relevant to muscle contraction. We identified redundancies between potassium and both adenosine and nitric oxide, between nitric oxide and potassium, and between adenosine and both potassium and nitric oxide. During muscle contraction, we demonstrate redundancies between potassium and nitric oxide as well as between potassium and adenosine. Our data show that redundancy is physiologically relevant and involved in the coordination of the vasodilator response during muscle contraction at the level of the capillaries. We sought to determine if redundancy between vasodilators is physiologically relevant during active hyperaemia. As inhibitory interactions between vasodilators are indicative of redundancy, we tested whether vasodilators implicated in mediating active hyperaemia (potassium (K + ), adenosine (ADO) and nitric oxide (NO)) inhibit one another's vasodilatory effects through direct application of pharmacological agents and during muscle contraction. Using the hamster cremaster muscle and intravital microscopy, we locally stimulated capillaries with one vasodilator in the absence and the presence of a second vasodilator (10 -7 m S-nitroso-N-acetylpenicillamine (SNAP), 10 -7 m ADO, 10 mm KCl) applied sequentially and simultaneously, and observed the response in the associated upstream 4A arteriole controlling the perfusion of the stimulated capillary. We found that KCl significantly attenuated SNAP- and ADO-induced vasodilatations by ∼49.7% and ∼128.0% respectively and ADO significantly attenuated KCl- and SNAP-induced vasodilatations by ∼94.7% and ∼59.6%, respectively. NO significantly attenuated KCl vasodilatation by 93.8%. Further, during muscle contraction we found that inhibition of NO production using l-N G -nitroarginine methyl ester and inhibition of ADO receptors using xanthine amine congener was effective at inhibiting contraction-induced vasodilatation but only in the presence of K + release channel inhibition. Thus, only when the inhibiting vasodilator K + was blocked was the second vasodilator, NO or ADO, able to produce effective vasodilatation. Therefore, we show that there are inhibitory interactions between specific vasodilators at the level of the capillary. Further, these inhibitions can be observed during muscle contraction indicating that redundancies between vasodilators are physiologically relevant and influence vasodilatation during active hyperaemia. © 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.

Biosignals learning and synthesis using deep neural networks.

PubMed

Belo, David; Rodrigues, João; Vaz, João R; Pezarat-Correia, Pedro; Gamboa, Hugo

2017-09-25

Modeling physiological signals is a complex task both for understanding and synthesize biomedical signals. We propose a deep neural network model that learns and synthesizes biosignals, validated by the morphological equivalence of the original ones. This research could lead the creation of novel algorithms for signal reconstruction in heavily noisy data and source detection in biomedical engineering field. The present work explores the gated recurrent units (GRU) employed in the training of respiration (RESP), electromyograms (EMG) and electrocardiograms (ECG). Each signal is pre-processed, segmented and quantized in a specific number of classes, corresponding to the amplitude of each sample and fed to the model, which is composed by an embedded matrix, three GRU blocks and a softmax function. This network is trained by adjusting its internal parameters, acquiring the representation of the abstract notion of the next value based on the previous ones. The simulated signal was generated by forecasting a random value and re-feeding itself. The resulting generated signals are similar with the morphological expression of the originals. During the learning process, after a set of iterations, the model starts to grasp the basic morphological characteristics of the signal and later their cyclic characteristics. After training, these models' prediction are closer to the signals that trained them, specially the RESP and ECG. This synthesis mechanism has shown relevant results that inspire the use to characterize signals from other physiological sources.

Modeling road-cycling performance.

PubMed

Olds, T S; Norton, K I; Lowe, E L; Olive, S; Reay, F; Ly, S

1995-04-01

This paper presents a complete set of equations for a "first principles" mathematical model of road-cycling performance, including corrections for the effect of winds, tire pressure and wheel radius, altitude, relative humidity, rotational kinetic energy, drafting, and changed drag. The relevant physiological, biophysical, and environmental variables were measured in 41 experienced cyclists completing a 26-km road time trial. The correlation between actual and predicted times was 0.89 (P < or = 0.0001), with a mean difference of 0.74 min (1.73% of mean performance time) and a mean absolute difference of 1.65 min (3.87%). Multiple simulations were performed where model inputs were randomly varied using a normal distribution about the measured values with a SD equivalent to the estimated day-to-day variability or technical error of measurement in each of the inputs. This analysis yielded 95% confidence limits for the predicted times. The model suggests that the main physiological factors contributing to road-cycling performance are maximal O2 consumption, fractional utilization of maximal O2 consumption, mechanical efficiency, and projected frontal area. The model is then applied to some practical problems in road cycling: the effect of drafting, the advantage of using smaller front wheels, the effects of added mass, the importance of rotational kinetic energy, the effect of changes in drag due to changes in bicycle configuration, the normalization of performances under different conditions, and the limits of human performance.

A novel organotypic 3D sweat gland model with physiological functionality

PubMed Central

Grüdl, Sabine; Banowski, Bernhard; Giesen, Melanie; Sättler, Andrea; Proksch, Peter; Welss, Thomas; Förster, Thomas

2017-01-01

Dysregulated human eccrine sweat glands can negatively impact the quality-of-life of people suffering from disorders like hyperhidrosis. Inability of sweating can even result in serious health effects in humans affected by anhidrosis. The underlying mechanisms must be elucidated and a reliable in vitro test system for drug screening must be developed. Here we describe a novel organotypic three-dimensional (3D) sweat gland model made of primary human eccrine sweat gland cells. Initial experiments revealed that eccrine sweat gland cells in a two-dimensional (2D) culture lose typical physiological markers. To resemble the in vivo situation as close as possible, we applied the hanging drop cultivation technology regaining most of the markers when cultured in its natural spherical environment. To compare the organotypic 3D sweat gland model versus human sweat glands in vivo, we compared markers relevant for the eccrine sweat gland using transcriptomic and proteomic analysis. Comparing the marker profile, a high in vitro-in vivo correlation was shown. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), muscarinic acetylcholine receptor M3 (CHRM3), Na+-K+-Cl- cotransporter 1 (NKCC1), calcium-activated chloride channel anoctamin-1 (ANO1/TMEM16A), and aquaporin-5 (AQP5) are found at significant expression levels in the 3D model. Moreover, cholinergic stimulation with acetylcholine or pilocarpine leads to calcium influx monitored in a calcium flux assay. Cholinergic stimulation cannot be achieved with the sweat gland cell line NCL-SG3 used as a sweat gland model system. Our results show clear benefits of the organotypic 3D sweat gland model versus 2D cultures in terms of the expression of essential eccrine sweat gland key regulators and in the physiological response to stimulation. Taken together, this novel organotypic 3D sweat gland model shows a good in vitro-in vivo correlation and is an appropriate alternative for screening of potential bioactives regulating the sweat mechanism. PMID:28796813

Physiologically-Based Toxicokinetic Modeling of Zearalenone and Its Metabolites: Application to the Jersey Girl Study

PubMed Central

Mukherjee, Dwaipayan; Royce, Steven G.; Alexander, Jocelyn A.; Buckley, Brian; Isukapalli, Sastry S.; Bandera, Elisa V.; Zarbl, Helmut; Georgopoulos, Panos G.

2014-01-01

Zearalenone (ZEA), a fungal mycotoxin, and its metabolite zeranol (ZAL) are known estrogen agonists in mammals, and are found as contaminants in food. Zeranol, which is more potent than ZEA and comparable in potency to estradiol, is also added as a growth additive in beef in the US and Canada. This article presents the development and application of a Physiologically-Based Toxicokinetic (PBTK) model for ZEA and ZAL and their primary metabolites, zearalenol, zearalanone, and their conjugated glucuronides, for rats and for human subjects. The PBTK modeling study explicitly simulates critical metabolic pathways in the gastrointestinal and hepatic systems. Metabolic events such as dehydrogenation and glucuronidation of the chemicals, which have direct effects on the accumulation and elimination of the toxic compounds, have been quantified. The PBTK model considers urinary and fecal excretion and biliary recirculation and compares the predicted biomarkers of blood, urinary and fecal concentrations with published in vivo measurements in rats and human subjects. Additionally, the toxicokinetic model has been coupled with a novel probabilistic dietary exposure model and applied to the Jersey Girl Study (JGS), which involved measurement of mycoestrogens as urinary biomarkers, in a cohort of young girls in New Jersey, USA. A probabilistic exposure characterization for the study population has been conducted and the predicted urinary concentrations have been compared to measurements considering inter-individual physiological and dietary variability. The in vivo measurements from the JGS fall within the high and low predicted distributions of biomarker values corresponding to dietary exposure estimates calculated by the probabilistic modeling system. The work described here is the first of its kind to present a comprehensive framework developing estimates of potential exposures to mycotoxins and linking them with biologically relevant doses and biomarker measurements, including a systematic characterization of uncertainties in exposure and dose estimation for a vulnerable population. PMID:25474635

The application of physiologically based pharmacokinetic modelling to assess the impact of antiretroviral-mediated drug-drug interactions on piperaquine antimalarial therapy during pregnancy.

PubMed

Olafuyi, Olusola; Coleman, Michael; Badhan, Raj K S

2017-11-01

Antimalarial therapy during pregnancy poses important safety concerns due to potential teratogenicity and maternal physiological and biochemical changes during gestation. Piperaquine (PQ) has gained interest for use in pregnancy in response to increasing resistance towards sulfadoxine-pyrimethamine in sub-Saharan Africa. Coinfection with HIV is common in many developing countries, however, little is known about the impact of antiretroviral (ARV) mediated drug-drug interaction (DDI) on piperaquine pharmacokinetics during pregnancy. This study applied mechanistic pharmacokinetic modelling to predict pharmacokinetics in non-pregnant and pregnant patients, which was validated in distinct customised population groups from Thailand, Sudan and Papua New Guinea. In each population group, no significant differences in day 7 concentrations were observed during different gestational weeks (GW) (weeks 10-40), supporting the notion that piperaquine is safe throughout pregnancy with consistent pharmacokinetics, although possible teratogenicity may limit this. Antiretroviral-mediated DDIs (efavirenz and ritonavir) had moderate effects on piperaquine during different gestational weeks with a predicted AUC ratio in the range 0.56-0.8 and 1.64-1.79 for efavirenz and ritonavir, respectively, over GW 10-40, with a reduction in circulating human serum albumin significantly reducing the number of subjects attaining the day 7 (post-dose) therapeutic efficacy concentrations under both efavirenz and ritonavir DDIs. This present model successfully mechanistically predicted the pharmacokinetics of piperaquine in pregnancy to be unchanged with respect to non-pregnant women, in the light of factors such as malaria/HIV co-infection. However, antiretroviral-mediated DDIs could significantly alter piperaquine pharmacokinetics. Further model refinement will include collation of relevant physiological and biochemical alterations common to HIV/malaria patients. Copyright © 2017 John Wiley & Sons, Ltd.

Comprehensive evaluation of poly(I:C) induced inflammatory response in an airway epithelial model

PubMed Central

Lever, Amanda R; Park, Hyoungshin; Mulhern, Thomas J; Jackson, George R; Comolli, James C; Borenstein, Jeffrey T; Hayden, Patrick J; Prantil-Baun, Rachelle

2015-01-01

Respiratory viruses invade the upper airway of the lung, triggering a potent immune response that often exacerbates preexisting conditions such as asthma and COPD. Poly(I:C) is a synthetic analog of viral dsRNA that induces the characteristic inflammatory response associated with viral infection, such as loss of epithelial integrity, and increased production of mucus and inflammatory cytokines. Here, we explore the mechanistic responses to poly(I:C) in a well-defined primary normal human bronchial epithelial (NHBE) model that recapitulates in vivo functions and responses. We developed functional and quantifiable methods to evaluate the physiology of our model in both healthy and inflamed states. Through gene and protein expression, we validated the differentiation state and population of essential cell subtypes (i.e., ciliated, goblet, club, and basal cells) as compared to the human lung. Assays for total mucus production, cytokine secretion, and barrier function were used to evaluate in vitro physiology and response to viral insult. Cells were treated apically with poly(I:C) and evaluated 48 h after induction. Results revealed a dose-dependent increase in goblet cell differentiation, as well as, an increase in mucus production relative to controls. There was also a dose-dependent increase in secretion of IL-6, IL-8, TNF-α, and RANTES. Epithelial barrier function, as measured by TEER, was maintained at 1501 ± 355 Ω*cm² postdifferentiation, but dropped significantly when challenged with poly(I:C). This study provides first steps toward a well-characterized model with defined functional methods for understanding dsRNA stimulated inflammatory responses in a physiologically relevant manner. PMID:25847914

Stem cells in pharmaceutical biotechnology.

PubMed

Zuba-Surma, Ewa K; Józkowicz, Alicja; Dulak, Józef

2011-11-01

Multiple populations of stem cells have been indicated to potentially participate in regeneration of injured organs. Especially, embryonic stem cells (ESC) and recently inducible pluripotent stem cells (iPS) receive a marked attention from scientists and clinicians for regenerative medicine because of their high proliferative and differentiation capacities. Despite that ESC and iPS cells are expected to give rise into multiple regenerative applications when their side effects are overcame during appropriate preparation procedures, in fact their most recent application of human ESC may, however, reside in their use as a tool in drug development and disease modeling. This review focuses on the applications of stem cells in pharmaceutical biotechnology. We discuss possible relevance of pluripotent cell stem populations in developing physiological models for any human tissue cell type useful for pharmacological, metabolic and toxicity evaluation necessary in the earliest steps of drug development. The present models applied for preclinical drug testing consist of primary cells or immortalized cell lines that show limitations in terms of accessibility or relevance to their in vivo counterparts. The availability of renewable human cells with functional similarities to their in vivo counterparts is the first landmark for a new generation of cell-based assays. We discuss the approaches for using stem cells as valuable physiological targets of drug activity which may increase the strength of target validation and efficacy potentially resulting in introducing new safer remedies into clinical trials and the marketplace. Moreover, we discuss the possible applications of stem cells for elucidating mechanisms of disease pathogenesis. The knowledge about the mechanisms governing the development and progression of multitude disorders which would come from the cellular models established based on stem cells, may give rise to new therapeutical strategies for such diseases. All together, the applications of various cell types derived from patient specific pluripotent stem cells may lead to targeted drug and cellular therapies for certain individuals.

Temperature Effects on Kinetics of KV11.1 Drug Block Have Important Consequences for In Silico Proarrhythmic Risk Prediction.

PubMed

Windley, Monique J; Mann, Stefan A; Vandenberg, Jamie I; Hill, Adam P

2016-07-01

Drug block of voltage-gated potassium channel subtype 11.1 human ether-a-go-go related gene (Kv11.1) (hERG) channels, encoded by the KCNH2 gene, is associated with reduced repolarization of the cardiac action potential and is the predominant cause of acquired long QT syndrome that can lead to fatal cardiac arrhythmias. Current safety guidelines require that potency of KV11.1 block is assessed in the preclinical phase of drug development. However, not all drugs that block KV11.1 are proarrhythmic, meaning that screening on the basis of equilibrium measures of block can result in high attrition of potentially low-risk drugs. The basis of the next generation of drug-screening approaches is set to be in silico risk prediction, informed by in vitro mechanistic descriptions of drug binding, including measures of the kinetics of block. A critical issue in this regard is characterizing the temperature dependence of drug binding. Specifically, it is important to address whether kinetics relevant to physiologic temperatures can be inferred or extrapolated from in vitro data gathered at room temperature in high-throughout systems. Here we present the first complete study of the temperature-dependent kinetics of block and unblock of a proarrhythmic drug, cisapride, to KV11.1. Our data highlight a complexity to binding that manifests at higher temperatures and can be explained by accumulation of an intermediate, non-blocking encounter-complex. These results suggest that for cisapride, physiologically relevant kinetic parameters cannot be simply extrapolated from those measured at lower temperatures; rather, data gathered at physiologic temperatures should be used to constrain in silico models that may be used for proarrhythmic risk prediction. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Coding of spatial attention priorities and object features in the macaque lateral intraparietal cortex.

PubMed

Levichkina, Ekaterina; Saalmann, Yuri B; Vidyasagar, Trichur R

2017-03-01

Primate posterior parietal cortex (PPC) is known to be involved in controlling spatial attention. Neurons in one part of the PPC, the lateral intraparietal area (LIP), show enhanced responses to objects at attended locations. Although many are selective for object features, such as the orientation of a visual stimulus, it is not clear how LIP circuits integrate feature-selective information when providing attentional feedback about behaviorally relevant locations to the visual cortex. We studied the relationship between object feature and spatial attention properties of LIP cells in two macaques by measuring the cells' orientation selectivity and the degree of attentional enhancement while performing a delayed match-to-sample task. Monkeys had to match both the location and orientation of two visual gratings presented separately in time. We found a wide range in orientation selectivity and degree of attentional enhancement among LIP neurons. However, cells with significant attentional enhancement had much less orientation selectivity in their response than cells which showed no significant modulation by attention. Additionally, orientation-selective cells showed working memory activity for their preferred orientation, whereas cells showing attentional enhancement also synchronized with local neuronal activity. These results are consistent with models of selective attention incorporating two stages, where an initial feature-selective process guides a second stage of focal spatial attention. We suggest that LIP contributes to both stages, where the first stage involves orientation-selective LIP cells that support working memory of the relevant feature, and the second stage involves attention-enhanced LIP cells that synchronize to provide feedback on spatial priorities. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

A mathematical model of coronary blood flow control: simulation of patient-specific three-dimensional hemodynamics during exercise

PubMed Central

Lau, Kevin D.; Asrress, Kaleab N.; Redwood, Simon R.; Figueroa, C. Alberto

2016-01-01

This work presents a mathematical model of the metabolic feedback and adrenergic feedforward control of coronary blood flow that occur during variations in the cardiac workload. It is based on the physiological observations that coronary blood flow closely follows myocardial oxygen demand, that myocardial oxygen debts are repaid, and that control oscillations occur when the system is perturbed and so are phenomenological in nature. Using clinical data, we demonstrate that the model can provide patient-specific estimates of coronary blood flow changes between rest and exercise, requiring only the patient's heart rate and peak aortic pressure as input. The model can be used in zero-dimensional lumped parameter network studies or as a boundary condition for three-dimensional multidomain Navier-Stokes blood flow simulations. For the first time, this model provides feedback control of the coronary vascular resistance, which can be used to enhance the physiological accuracy of any hemodynamic simulation, which includes both a heart model and coronary arteries. This has particular relevance to patient-specific simulation for which heart rate and aortic pressure recordings are available. In addition to providing a simulation tool, under our assumptions, the derivation of our model shows that β-feedforward control of the coronary microvascular resistance is a mathematical necessity and that the metabolic feedback control must be dependent on two error signals: the historical myocardial oxygen debt, and the instantaneous myocardial oxygen deficit. PMID:26945076

An Age-Dependent Physiologically-Based Pharmacokinetic/Pharmacodynamic Model for the Organophosphorus Insecticide Chlorpyrifos in the Preweanling Rat

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

Timchalk, Chuck; Kousba, Ahmed A.; Poet, Torka S.

2007-08-01

Juvenile rats are more susceptible than adults to the acute toxicity of organophosphorus insecticides like chlorpyrifos (CPF). Age- and dose-dependent differences in metabolism may be responsible. Of importance is CYP450 activation and detoxification of CPF to chlorpyrifos-oxon (CPF-oxon) and trichloropyridinol (TCP), as well as B-esterase (cholinesterase; ChE) and A-esterase (PON-1) detoxification of CPF-oxon to TCP. In the current study, a modified physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model incorporating age-dependent changes in CYP450, PON-1, and tissue ChE levels for rats was developed. In this model, age was used as a dependent function to estimate body weight which was then used to allometricallymore » scale both metabolism and tissue ChE levels. Model simulations suggest that preweanling rats are particularly sensitive to CPF toxicity, with levels of CPF-oxon in blood and brain disproportionately increasing, relative to the response in adult rats. This age-dependent non-linear increase in CPF-oxon concentration may potentially result from the depletion of non-target B-esterases, and a lower PON-1 metabolic capacity in younger animals. These results indicate that the PBPK/PD model behaves consistently with the general understanding of CPF toxicity, pharmacokinetics and tissue ChE inhibition in neonatal and adult rats. Hence, this model represents an important starting point for developing a computational model to assess the neurotoxic potential of environmentally relevant organophosphate exposures in infants and children.« less

Placenta-on-a-chip: a novel platform to study the biology of the human placenta.

PubMed

Lee, Ji Soo; Romero, Roberto; Han, Yu Mi; Kim, Hee Chan; Kim, Chong Jai; Hong, Joon-Seok; Huh, Dongeun

2016-01-01

Studying the biology of the human placenta represents a major experimental challenge. Although conventional cell culture techniques have been used to study different types of placenta-derived cells, current in vitro models have limitations in recapitulating organ-specific structure and key physiological functions of the placenta. Here we demonstrate that it is possible to leverage microfluidic and microfabrication technologies to develop a microengineered biomimetic model that replicates the architecture and function of the placenta. A "Placenta-on-a-Chip" microdevice was created by using a set of soft elastomer-based microfabrication techniques known as soft lithography. This microsystem consisted of two polydimethylsiloxane (PDMS) microfluidic channels separated by a thin extracellular matrix (ECM) membrane. To reproduce the placental barrier in this model, human trophoblasts (JEG-3) and human umbilical vein endothelial cells (HUVECs) were seeded onto the opposite sides of the ECM membrane and cultured under dynamic flow conditions to form confluent epithelial and endothelial layers in close apposition. We tested the physiological function of the microengineered placental barrier by measuring glucose transport across the trophoblast-endothelial interface over time. The permeability of the barrier study was analyzed and compared to that obtained from acellular devices and additional control groups that contained epithelial or endothelial layers alone. Our microfluidic cell culture system provided a tightly controlled fluidic environment conducive to the proliferation and maintenance of JEG-3 trophoblasts and HUVECs on the ECM scaffold. Prolonged culture in this model produced confluent cellular monolayers on the intervening membrane that together formed the placental barrier. This in vivo-like microarchitecture was also critical for creating a physiologically relevant effective barrier to glucose transport. Quantitative investigation of barrier function was conducted by calculating permeability coefficients and metabolic rates in varying conditions of barrier structure. The rates of glucose transport and metabolism were consistent with previously reported in vivo observations. The "Placenta-on-a-Chip" microdevice described herein provides new opportunities to simulate and analyze critical physiological responses of the placental barrier. This system may be used to address the major limitations of existing placenta model systems and serve to enable research platforms for reproductive biology and medicine.

Physiology undergraduate degree requirements in the U.S.

PubMed

VanRyn, Valerie S; Poteracki, James M; Wehrwein, Erica A

2017-12-01

Course-level learning objectives and core concepts for undergraduate physiology teaching exist. The next step is to consider how these resources fit into generalizable program-level guidelines for Bachelor of Science (BS) degrees in Physiology. In the absence of program-level guidelines for Physiology degree programs, we compiled a selective internal report to review degree requirements from 18 peer BS programs entitled "Physiology" in the United States (U.S.). There was a range of zero to three required semesters of math, physics, physics laboratory, general biology, biology laboratory, general chemistry, chemistry laboratory, organic chemistry, organic chemistry laboratory, biochemistry, biochemistry laboratory, anatomy, anatomy laboratory, core systems physiology, and physiology laboratory. Required upper division credits ranged from 11 to 31 and included system-specific, exercise and environmental, clinically relevant, pathology/disease-related, and basic science options. We hope that this information will be useful for all programs that consider themselves to be physiology, regardless of name. Reports such as this can serve as a starting point for collaboration among BS programs to improve physiology undergraduate education and best serve our students. Copyright © 2017 the American Physiological Society.

Understanding essential tremor: progress on the biological front.

PubMed

Louis, Elan D

2014-06-01

For many years, little was written about the underlying biology of ET, despite its high prevalence. Discussions of disease mechanisms were dominated by a focus on tremor physiology. The traditional model of ET, the olivary model, was proposed in the 1970s. The model suffers from several critical problems, and its relevance to ET has been questioned. Recent mechanistic research has focused on the cerebellum. Clinical and neuroimaging studies strongly implicate the importance of this brain region in ET. Recent mechanistic research has been grounded more in tissue-based changes (i.e., postmortem studies of the brain). These studies have collectively and systematically identified a sizable number of changes in the ET cerebellum, and have led to a new model of ET, referred to as the cerebellar degenerative model. Hence, there is a renewed interest in the science behind the biology of ET. How the new understanding of ET will translate into treatment changes is an open question.

Egg and Soy-Derived Peptides and Hydrolysates: A Review of Their Physiological Actions against Diabetes and Obesity.

PubMed

C de Campos Zani, Stepheny; Wu, Jianping; B Chan, Catherine

2018-04-28

Type 2 diabetes and obesity are two chronic conditions associated with the metabolic syndrome and their prevalences are increasing worldwide. The investigation of food protein-derived bioactive peptides that can improve the pathophysiology of diabetes or obesity while causing minimal side effects is desired. Egg and soy proteins generate bioactive peptides with multiple biological effects, exerting nutritional and physiological benefits. This review focuses on the anti-diabetic and anti-obesity effects of egg- and soy-derived peptides and hydrolysates in vivo and in vitro relevant to these conditions. Studies using the intact protein were considered only when comparing the results with the hydrolysate or peptides. In vivo evidence suggests that bioactive peptides from egg and soy can potentially be used to manage elements of glucose homeostasis in metabolic syndrome; however, the mechanisms of action on glucose and insulin metabolism, and the interaction between peptides and their molecular targets remain unclear. Optimizing the production of egg- and soy-derived peptides and standardizing the physiological models to study their effects on diabetes and obesity could help to clarify the effects of these bioactive peptides in metabolic syndrome-related conditions.

A physiologically required G protein-coupled receptor (GPCR)-regulator of G protein signaling (RGS) interaction that compartmentalizes RGS activity.

PubMed

Croft, Wayne; Hill, Claire; McCann, Eilish; Bond, Michael; Esparza-Franco, Manuel; Bennett, Jeannette; Rand, David; Davey, John; Ladds, Graham

2013-09-20

G protein-coupled receptors (GPCRs) can interact with regulator of G protein signaling (RGS) proteins. However, the effects of such interactions on signal transduction and their physiological relevance have been largely undetermined. Ligand-bound GPCRs initiate by promoting exchange of GDP for GTP on the Gα subunit of heterotrimeric G proteins. Signaling is terminated by hydrolysis of GTP to GDP through intrinsic GTPase activity of the Gα subunit, a reaction catalyzed by RGS proteins. Using yeast as a tool to study GPCR signaling in isolation, we define an interaction between the cognate GPCR (Mam2) and RGS (Rgs1), mapping the interaction domains. This reaction tethers Rgs1 at the plasma membrane and is essential for physiological signaling response. In vivo quantitative data inform the development of a kinetic model of the GTPase cycle, which extends previous attempts by including GPCR-RGS interactions. In vivo and in silico data confirm that GPCR-RGS interactions can impose an additional layer of regulation through mediating RGS subcellular localization to compartmentalize RGS activity within a cell, thus highlighting their importance as potential targets to modulate GPCR signaling pathways.

[Clinical, morphological and molecular biological characteristics of the aging eye].

PubMed

Böhm, M R R; Thomasen, H; Parnitzke, F; Steuhl, K-P

2017-02-01

The physiological aging of the eye is associated with loss of visual function. Age-related changes of the eye can result in ophthalmological diseases. The aim of this article is to display morphological, histological and molecular biological alterations of the aging eye. A web-based search and review of the literature for aging of the visual system including cornea, lens, vitreous humor, retina, retinal pigment epithelium (RPE), choroidea and optic nerve were carried out. The most important results related to morphological, histological and molecular biological changes are summarized. Age-related, morphological alterations can be found in preretinal structures, e. g. cornea, lens and vitreous humor, as well as neuronal structures, such as the retina. In addition to negligible clinical signs of the aging eye, there are clinically relevant changes which can develop into pathological ophthalmological diseases. These transitions from age-related alterations to relevant ophthalmological diseases, e. g. age-related macular degeneration and glaucoma are continuous. An understanding of aging could provide predictive factors to detect the conversion of physiological aging into pathological conditions. The derivation of physiological markers or new approaches to detection and treatment of disease-related entities associated with the risk factor aging are desirable. Translational approaches in clinical and basic science are necessary to provide new therapeutic options for relevant ophthalmological diseases in the future.

Identification of novel inhibitors of non-replicating Mycobacterium tuberculosis using a carbon starvation model

PubMed Central

Grant, Sarah Schmidt; Kawate, Tomohiko; Nag, Partha P.; Silvis, Melanie R.; Gordon, Katherine; Stanley, Sarah A.; Kazyanskaya, Ed; Nietupski, Ray; Golas, Aaron; Fitzgerald, Michael; Cho, Sanghyun; Franzblau, Scott G.; Hung, Deborah T.

2013-01-01

During Mycobacterium tuberculosis infection, a population of bacteria is thought to exist in a non-replicating state, refractory to antibiotics, which may contribute to the need for prolonged antibiotic therapy. The identification of inhibitors of the non-replicating state provides tools that can be used to probe this hypothesis and the physiology of this state. The development of such inhibitors also has the potential to shorten the duration of antibiotic therapy required. Here we describe the development of a novel non-replicating assay amenable to high-throughput chemical screening coupled with secondary assays that use carbon starvation as the in vitro model. Together these assays identify compounds with activity against replicating and non-replicating M. tuberculosis as well as compounds that inhibit the transition from non-replicating to replicating stages of growth. Using these assays we successfully screened over 300,000 compounds and identified 786 inhibitors of non-replicating M. tuberculosis. In order to understand the relationship among different non-replicating models, we teste 52 of these molecules in a hypoxia model and four different chemical scaffolds in a stochastic persist model and a streptomycin dependent model. We found that compounds display varying levels of activity in different models for the non-replicating state, suggesting important differences in bacterial physiology between models. Therefore, chemical tools identified in this assay may be useful for determining the relevance of different non-replicating in vitro models to in vivo M. tuberculosis infection. Given our current limited understanding, molecules that are active across multiple models may represent more promising candidates for further development. PMID:23898841

An energy budget agent-based model of earthworm populations and its application to study the effects of pesticides

PubMed Central

Johnston, A.S.A.; Hodson, M.E.; Thorbek, P.; Alvarez, T.; Sibly, R.M.

2014-01-01

Earthworms are important organisms in soil communities and so are used as model organisms in environmental risk assessments of chemicals. However current risk assessments of soil invertebrates are based on short-term laboratory studies, of limited ecological relevance, supplemented if necessary by site-specific field trials, which sometimes are challenging to apply across the whole agricultural landscape. Here, we investigate whether population responses to environmental stressors and pesticide exposure can be accurately predicted by combining energy budget and agent-based models (ABMs), based on knowledge of how individuals respond to their local circumstances. A simple energy budget model was implemented within each earthworm Eisenia fetida in the ABM, based on a priori parameter estimates. From broadly accepted physiological principles, simple algorithms specify how energy acquisition and expenditure drive life cycle processes. Each individual allocates energy between maintenance, growth and/or reproduction under varying conditions of food density, soil temperature and soil moisture. When simulating published experiments, good model fits were obtained to experimental data on individual growth, reproduction and starvation. Using the energy budget model as a platform we developed methods to identify which of the physiological parameters in the energy budget model (rates of ingestion, maintenance, growth or reproduction) are primarily affected by pesticide applications, producing four hypotheses about how toxicity acts. We tested these hypotheses by comparing model outputs with published toxicity data on the effects of copper oxychloride and chlorpyrifos on E. fetida. Both growth and reproduction were directly affected in experiments in which sufficient food was provided, whilst maintenance was targeted under food limitation. Although we only incorporate toxic effects at the individual level we show how ABMs can readily extrapolate to larger scales by providing good model fits to field population data. The ability of the presented model to fit the available field and laboratory data for E. fetida demonstrates the promise of the agent-based approach in ecology, by showing how biological knowledge can be used to make ecological inferences. Further work is required to extend the approach to populations of more ecologically relevant species studied at the field scale. Such a model could help extrapolate from laboratory to field conditions and from one set of field conditions to another or from species to species. PMID:25844009

Overcoming the challenges of studying conservation physiology in large whales: a review of available methods

PubMed Central

Hunt, Kathleen E.; Moore, Michael J.; Rolland, Rosalind M.; Kellar, Nicholas M.; Hall, Ailsa J.; Kershaw, Joanna; Raverty, Stephen A.; Davis, Cristina E.; Yeates, Laura C.; Fauquier, Deborah A.; Rowles, Teresa K.; Kraus, Scott D.

2013-01-01

Large whales are subjected to a variety of conservation pressures that could be better monitored and managed if physiological information could be gathered readily from free-swimming whales. However, traditional approaches to studying physiology have been impractical for large whales, because there is no routine method for capture of the largest species and there is presently no practical method of obtaining blood samples from free-swimming whales. We review the currently available techniques for gathering physiological information on large whales using a variety of non-lethal and minimally invasive (or non-invasive) sample matrices. We focus on methods that should produce information relevant to conservation physiology, e.g. measures relevant to stress physiology, reproductive status, nutritional status, immune response, health, and disease. The following four types of samples are discussed: faecal samples, respiratory samples (‘blow’), skin/blubber samples, and photographs. Faecal samples have historically been used for diet analysis but increasingly are also used for hormonal analyses, as well as for assessment of exposure to toxins, pollutants, and parasites. Blow samples contain many hormones as well as respiratory microbes, a diverse array of metabolites, and a variety of immune-related substances. Biopsy dart samples are widely used for genetic, contaminant, and fatty-acid analyses and are now being used for endocrine studies along with proteomic and transcriptomic approaches. Photographic analyses have benefited from recently developed quantitative techniques allowing assessment of skin condition, ectoparasite load, and nutritional status, along with wounds and scars from ship strikes and fishing gear entanglement. Field application of these techniques has the potential to improve our understanding of the physiology of large whales greatly, better enabling assessment of the relative impacts of many anthropogenic and ecological pressures. PMID:27293590

Cancer cell motility: lessons from migration in confined spaces

PubMed Central

Paul, Colin D.; Mistriotis, Panagiotis; Konstantopoulos, Konstantinos

2017-01-01

Time-lapse, deep-tissue imaging made possible by advances in intravital microscopy has demonstrated the importance of tumour cell migration through confining tracks in vivo. These tracks may either be endogenous features of tissues or be created by tumour or tumour-associated cells. Importantly, migration mechanisms through confining microenvironments are not predicted by 2D migration assays. Engineered in vitro models have been used to delineate the mechanisms of cell motility through confining spaces encountered in vivo. Understanding cancer cell locomotion through physiologically relevant confining tracks could be useful in developing therapeutic strategies to combat metastasis. PMID:27909339

Mucosal wrinkling in animal antra induced by volumetric growth

NASA Astrophysics Data System (ADS)

Li, Bo; Cao, Yan-Ping; Feng, Xi-Qiao; Yu, Shou-Wen

2011-04-01

Surface wrinkling of animal mucosas is crucial for the biological functions of some tissues, and the change in their surface patterns is a phenotypic characteristic of certain diseases. Here we develop a biomechanical model to study the relationship between morphogenesis and volumetric growth, either physiological or pathological, of mucosas. Theoretical analysis and numerical simulations are performed to unravel the critical characteristics of mucosal wrinkling in a spherical antrum. It is shown that the thicknesses and elastic moduli of mucosal and submucosal layers dictate the surface buckling morphology. The results hold clinical relevance for such diseases as inflammation and gastritis.

Cu-Click Compatible Triazabutadienes To Expand the Scope of Aryl Diazonium Ion Chemistry.

PubMed

Cornali, Brandon M; Kimani, Flora W; Jewett, John C

2016-10-07

Triazabutadienes can be used to readily generate reactive aryl diazonium ions under mild, physiologically relevant conditions. These conditions are compatible with a range of functionalities that do not tolerate traditional aryl diazonium ion generation. To increase the utility of this aryl diazonium ion releasing chemistry an alkyne-containing triazabutadiene was synthesized. The copper-catalyzed azide-alkyne cycloaddition ("Cu-click") reaction was utilized to modify the alkyne-containing triazabutadiene and shown to be compatible with the nitrogen-rich triazabutadiene. One of the triazole products was tethered to a fluorophore, thus enabling the direct fluorescent labeling of a model protein.

State-of-the-Art Review on Physiologically Based Pharmacokinetic Modeling in Pediatric Drug Development.

PubMed

Yellepeddi, Venkata; Rower, Joseph; Liu, Xiaoxi; Kumar, Shaun; Rashid, Jahidur; Sherwin, Catherine M T

2018-05-18

Physiologically based pharmacokinetic modeling and simulation is an important tool for predicting the pharmacokinetics, pharmacodynamics, and safety of drugs in pediatrics. Physiologically based pharmacokinetic modeling is applied in pediatric drug development for first-time-in-pediatric dose selection, simulation-based trial design, correlation with target organ toxicities, risk assessment by investigating possible drug-drug interactions, real-time assessment of pharmacokinetic-safety relationships, and assessment of non-systemic biodistribution targets. This review summarizes the details of a physiologically based pharmacokinetic modeling approach in pediatric drug research, emphasizing reports on pediatric physiologically based pharmacokinetic models of individual drugs. We also compare and contrast the strategies employed by various researchers in pediatric physiologically based pharmacokinetic modeling and provide a comprehensive overview of physiologically based pharmacokinetic modeling strategies and approaches in pediatrics. We discuss the impact of physiologically based pharmacokinetic models on regulatory reviews and product labels in the field of pediatric pharmacotherapy. Additionally, we examine in detail the current limitations and future directions of physiologically based pharmacokinetic modeling in pediatrics with regard to the ability to predict plasma concentrations and pharmacokinetic parameters. Despite the skepticism and concern in the pediatric community about the reliability of physiologically based pharmacokinetic models, there is substantial evidence that pediatric physiologically based pharmacokinetic models have been used successfully to predict differences in pharmacokinetics between adults and children for several drugs. It is obvious that the use of physiologically based pharmacokinetic modeling to support various stages of pediatric drug development is highly attractive and will rapidly increase, provided the robustness and reliability of these techniques are well established.

DigitalHuman (DH): An Integrative Mathematical Model ofHuman Physiology

NASA Technical Reports Server (NTRS)

Hester, Robert L.; Summers, Richard L.; lIescu, Radu; Esters, Joyee; Coleman, Thomas G.

2010-01-01

Mathematical models and simulation are important tools in discovering the key causal relationships governing physiological processes and improving medical intervention when physiological complexity is a central issue. We have developed a model of integrative human physiology called DigitalHuman (DH) consisting of -5000 variables modeling human physiology describing cardiovascular, renal, respiratory, endocrine, neural and metabolic physiology. Users can view time-dependent solutions and interactively introduce perturbations by altering numerical parameters to investigate new hypotheses. The variables, parameters and quantitative relationships as well as all other model details are described in XML text files. All aspects of the model, including the mathematical equations describing the physiological processes are written in XML open source, text-readable files. Model structure is based upon empirical data of physiological responses documented within the peer-reviewed literature. The model can be used to understand proposed physiological mechanisms and physiological interactions that may not be otherwise intUitively evident. Some of the current uses of this model include the analyses of renal control of blood pressure, the central role of the liver in creating and maintaining insulin resistance, and the mechanisms causing orthostatic hypotension in astronauts. Additionally the open source aspect of the modeling environment allows any investigator to add detailed descriptions of human physiology to test new concepts. The model accurately predicts both qualitative and more importantly quantitative changes in clinically and experimentally observed responses. DigitalHuman provides scientists a modeling environment to understand the complex interactions of integrative physiology. This research was supported by.NIH HL 51971, NSF EPSCoR, and NASA

Physiologically Based Pharmacokinetic (PBPK) Modeling of Interstrain Variability in Trichloroethylene Metabolism in the Mouse

PubMed Central

Campbell, Jerry L.; Clewell, Harvey J.; Zhou, Yi-Hui; Wright, Fred A.; Guyton, Kathryn Z.

2014-01-01

Background: Quantitative estimation of toxicokinetic variability in the human population is a persistent challenge in risk assessment of environmental chemicals. Traditionally, interindividual differences in the population are accounted for by default assumptions or, in rare cases, are based on human toxicokinetic data. Objectives: We evaluated the utility of genetically diverse mouse strains for estimating toxicokinetic population variability for risk assessment, using trichloroethylene (TCE) metabolism as a case study. Methods: We used data on oxidative and glutathione conjugation metabolism of TCE in 16 inbred and 1 hybrid mouse strains to calibrate and extend existing physiologically based pharmacokinetic (PBPK) models. We added one-compartment models for glutathione metabolites and a two-compartment model for dichloroacetic acid (DCA). We used a Bayesian population analysis of interstrain variability to quantify variability in TCE metabolism. Results: Concentration–time profiles for TCE metabolism to oxidative and glutathione conjugation metabolites varied across strains. Median predictions for the metabolic flux through oxidation were less variable (5-fold range) than that through glutathione conjugation (10-fold range). For oxidative metabolites, median predictions of trichloroacetic acid production were less variable (2-fold range) than DCA production (5-fold range), although the uncertainty bounds for DCA exceeded the predicted variability. Conclusions: Population PBPK modeling of genetically diverse mouse strains can provide useful quantitative estimates of toxicokinetic population variability. When extrapolated to lower doses more relevant to environmental exposures, mouse population-derived variability estimates for TCE metabolism closely matched population variability estimates previously derived from human toxicokinetic studies with TCE, highlighting the utility of mouse interstrain metabolism studies for addressing toxicokinetic variability. Citation: Chiu WA, Campbell JL Jr, Clewell HJ III, Zhou YH, Wright FA, Guyton KZ, Rusyn I. 2014. Physiologically based pharmacokinetic (PBPK) modeling of interstrain variability in trichloroethylene metabolism in the mouse. Environ Health Perspect 122:456–463; http://dx.doi.org/10.1289/ehp.1307623 PMID:24518055

Media Ion Composition Controls Regulatory and Virulence Response of Salmonella in Spaceflight

PubMed Central

Wilson, James W.; Ott, C. Mark; Quick, Laura; Davis, Richard; zu Bentrup, Kerstin Höner; Crabbé, Aurélie; Richter, Emily; Sarker, Shameema; Barrila, Jennifer; Porwollik, Steffen; Cheng, Pui; McClelland, Michael; Tsaprailis, George; Radabaugh, Timothy; Hunt, Andrea; Shah, Miti; Nelman-Gonzalez, Mayra; Hing, Steve; Parra, Macarena; Dumars, Paula; Norwood, Kelly; Bober, Ramona; Devich, Jennifer; Ruggles, Ashleigh; CdeBaca, Autumn; Narayan, Satro; Benjamin, Joseph; Goulart, Carla; Rupert, Mark; Catella, Luke; Schurr, Michael J.; Buchanan, Kent; Morici, Lisa; McCracken, James; Porter, Marc D.; Pierson, Duane L.; Smith, Scott M.; Mergeay, Max; Leys, Natalie; Stefanyshyn-Piper, Heidemarie M.; Gorie, Dominic; Nickerson, Cheryl A.

2008-01-01

The spaceflight environment is relevant to conditions encountered by pathogens during the course of infection and induces novel changes in microbial pathogenesis not observed using conventional methods. It is unclear how microbial cells sense spaceflight-associated changes to their growth environment and orchestrate corresponding changes in molecular and physiological phenotypes relevant to the infection process. Here we report that spaceflight-induced increases in Salmonella virulence are regulated by media ion composition, and that phosphate ion is sufficient to alter related pathogenesis responses in a spaceflight analogue model. Using whole genome microarray and proteomic analyses from two independent Space Shuttle missions, we identified evolutionarily conserved molecular pathways in Salmonella that respond to spaceflight under all media compositions tested. Identification of conserved regulatory paradigms opens new avenues to control microbial responses during the infection process and holds promise to provide an improved understanding of human health and disease on Earth. PMID:19079590

γ-Secretase Heterogeneity in the Aph1 Subunit: Relevance for Alzheimer’s Disease

PubMed Central

Serneels, Lutgarde; Van Biervliet, Jérôme; Craessaerts, Katleen; Dejaegere, Tim; Horré, Katrien; Van Houtvin, Tine; Esselmann, Hermann; Paul, Sabine; Schäfer, Martin K.; Berezovska, Oksana; Hyman, Bradley T.; Sprangers, Ben; Sciot, Raf; Moons, Lieve; Jucker, Mathias; Yang, Zhixiang; May, Patrick C.; Karran, Eric; Wiltfang, Jens; D’Hooge, Rudi; De Strooper, Bart

2009-01-01

The γ-secretase complex plays a role in Alzheimer’s disease (AD) and cancer progression. The development of clinical useful inhibitors, however, is complicated by the role of the γ-secretase complex in regulated intramembrane proteolysis of Notch and other essential proteins. Different γ-secretase complexes containing different Presenilin or Aph1 protein subunits are present in various tissues. Here we show that these complexes have heterogeneous biochemical and physiological properties. Specific inactivation of the Aph1B γ-secretase in a murine Alzheimer’s disease model led to improvements of Alzheimer’s disease-relevant phenotypic features without any Notch-related side effects. The Aph1B complex contributes to total γ-secretase activity in the human brain, thus specific targeting of Aph1B-containing γ-secretase complexes may be helpful in generating less toxic therapies for Alzheimer’s disease. PMID:19299585

Dynamic optical imaging of vascular and metabolic reactivity in rheumatoid joints.

PubMed

Lasker, Joseph M; Fong, Christopher J; Ginat, Daniel T; Dwyer, Edward; Hielscher, Andreas H

2007-01-01

Dynamic optical imaging is increasingly applied to clinically relevant areas such as brain and cancer imaging. In this approach, some external stimulus is applied and changes in relevant physiological parameters (e.g., oxy- or deoxyhemoglobin concentrations) are determined. The advantage of this approach is that the prestimulus state can be used as a reference or baseline against which the changes can be calibrated. Here we present the first application of this method to the problem of characterizing joint diseases, especially effects of rheumatoid arthritis (RA) in the proximal interphalangeal finger joints. Using a dual-wavelength tomographic imaging system together with previously implemented model-based iterative image reconstruction schemes, we have performed initial dynamic imaging case studies on a limited number of healthy volunteers and patients diagnosed with RA. Focusing on three cases studies, we illustrated our major finds. These studies support our hypothesis that differences in the vascular reactivity exist between affected and unaffected joints.

Design of a framework for modeling, integration and simulation of physiological models.

PubMed

Erson, E Zeynep; Cavuşoğlu, M Cenk

2012-09-01

Multiscale modeling and integration of physiological models carry challenges due to the complex nature of physiological processes. High coupling within and among scales present a significant challenge in constructing and integrating multiscale physiological models. In order to deal with such challenges in a systematic way, there is a significant need for an information technology framework together with related analytical and computational tools that will facilitate integration of models and simulations of complex biological systems. Physiological Model Simulation, Integration and Modeling Framework (Phy-SIM) is an information technology framework providing the tools to facilitate development, integration and simulation of integrated models of human physiology. Phy-SIM brings software level solutions to the challenges raised by the complex nature of physiological systems. The aim of Phy-SIM, and this paper is to lay some foundation with the new approaches such as information flow and modular representation of the physiological models. The ultimate goal is to enhance the development of both the models and the integration approaches of multiscale physiological processes and thus this paper focuses on the design approaches that would achieve such a goal. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Generative models for clinical applications in computational psychiatry.

PubMed

Frässle, Stefan; Yao, Yu; Schöbi, Dario; Aponte, Eduardo A; Heinzle, Jakob; Stephan, Klaas E

2018-05-01

Despite the success of modern neuroimaging techniques in furthering our understanding of cognitive and pathophysiological processes, translation of these advances into clinically relevant tools has been virtually absent until now. Neuromodeling represents a powerful framework for overcoming this translational deadlock, and the development of computational models to solve clinical problems has become a major scientific goal over the last decade, as reflected by the emergence of clinically oriented neuromodeling fields like Computational Psychiatry, Computational Neurology, and Computational Psychosomatics. Generative models of brain physiology and connectivity in the human brain play a key role in this endeavor, striving for computational assays that can be applied to neuroimaging data from individual patients for differential diagnosis and treatment prediction. In this review, we focus on dynamic causal modeling (DCM) and its use for Computational Psychiatry. DCM is a widely used generative modeling framework for functional magnetic resonance imaging (fMRI) and magneto-/electroencephalography (M/EEG) data. This article reviews the basic concepts of DCM, revisits examples where it has proven valuable for addressing clinically relevant questions, and critically discusses methodological challenges and recent methodological advances. We conclude this review with a more general discussion of the promises and pitfalls of generative models in Computational Psychiatry and highlight the path that lies ahead of us. This article is categorized under: Neuroscience > Computation Neuroscience > Clinical Neuroscience. © 2018 Wiley Periodicals, Inc.

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

Nguyen, Thao D.; Grazier, John Mark; Boyce, Brad Lee

Biological tissues are uniquely structured materials with technologically appealing properties. Soft tissues such as skin, are constructed from a composite of strong fibrils and fluid-like matrix components. This was the first coordinated experimental/modeling project at Sandia or in the open literature to consider the mechanics of micromechanically-based anisotropy and viscoelasticity of soft biological tissues. We have exploited and applied Sandia's expertise in experimentation and mechanics modeling to better elucidate the behavior of collagen fibril-reinforced soft tissues. The purpose of this project was to provide a detailed understanding of the deformation of ocular tissues, specifically the highly structured skin-like tissue inmore » the cornea. This discovery improved our knowledge of soft/complex materials testing and modeling. It also provided insight into the way that cornea tissue is bio-engineered such that under physiologically-relevant conditions it has a unique set of properties which enhance functionality. These results also provide insight into how non-physiologic loading conditions, such as corrective surgeries, may push the cornea outside of its natural design window, resulting in unexpected non-linear responses. Furthermore, this project created a clearer understanding of the mechanics of soft tissues that could lead to bio-inspired materials, such as highly supple and impact resistant body armor, and improve our design of human-machine interfaces, such as micro-electrical-mechanical (MEMS) based prosthetics.« less

Raman spectroscopy: in vivo quick response code of skin physiological status

NASA Astrophysics Data System (ADS)

Vyumvuhore, Raoul; Tfayli, Ali; Piot, Olivier; Le Guillou, Maud; Guichard, Nathalie; Manfait, Michel; Baillet-Guffroy, Arlette

2014-11-01

Dermatologists need to combine different clinically relevant characteristics for a better understanding of skin health. These characteristics are usually measured by different techniques, and some of them are highly time consuming. Therefore, a predicting model based on Raman spectroscopy and partial least square (PLS) regression was developed as a rapid multiparametric method. The Raman spectra collected from the five uppermost micrometers of 11 healthy volunteers were fitted to different skin characteristics measured by independent appropriate methods (transepidermal water loss, hydration, pH, relative amount of ceramides, fatty acids, and cholesterol). For each parameter, the obtained PLS model presented correlation coefficients higher than R2=0.9. This model enables us to obtain all the aforementioned parameters directly from the unique Raman signature. In addition to that, in-depth Raman analyses down to 20 μm showed different balances between partially bound water and unbound water with depth. In parallel, the increase of depth was followed by an unfolding process of the proteins. The combinations of all these information led to a multiparametric investigation, which better characterizes the skin status. Raman signal can thus be used as a quick response code (QR code). This could help dermatologic diagnosis of physiological variations and presents a possible extension to pathological characterization.

Raman spectroscopy: in vivo quick response code of skin physiological status.

PubMed

Vyumvuhore, Raoul; Tfayli, Ali; Piot, Olivier; Le Guillou, Maud; Guichard, Nathalie; Manfait, Michel; Baillet-Guffroy, Arlette

2014-01-01

Dermatologists need to combine different clinically relevant characteristics for a better understanding of skin health. These characteristics are usually measured by different techniques, and some of them are highly time consuming. Therefore, a predicting model based on Raman spectroscopy and partial least square (PLS) regression was developed as a rapid multiparametric method. The Raman spectra collected from the five uppermost micrometers of 11 healthy volunteers were fitted to different skin characteristics measured by independent appropriate methods (transepidermal water loss, hydration, pH, relative amount of ceramides, fatty acids, and cholesterol). For each parameter, the obtained PLS model presented correlation coefficients higher than R2=0.9. This model enables us to obtain all the aforementioned parameters directly from the unique Raman signature. In addition to that, in-depth Raman analyses down to 20 μm showed different balances between partially bound water and unbound water with depth. In parallel, the increase of depth was followed by an unfolding process of the proteins. The combinations of all these information led to a multiparametric investigation, which better characterizes the skin status. Raman signal can thus be used as a quick response code (QR code). This could help dermatologic diagnosis of physiological variations and presents a possible extension to pathological characterization.

Keeping pace with climate change: what is wrong with the evolutionary potential of upper thermal limits?

PubMed Central

Santos, Mauro; Castañeda, Luis E; Rezende, Enrico L

2012-01-01

The potential of populations to evolve in response to ongoing climate change is partly conditioned by the presence of heritable genetic variation in relevant physiological traits. Recent research suggests that Drosophila melanogaster exhibits negligible heritability, hence little evolutionary potential in heat tolerance when measured under slow heating rates that presumably mimic conditions in nature. Here, we study the effects of directional selection for increased heat tolerance using Drosophila as a model system. We combine a physiological model to simulate thermal tolerance assays with multilocus models for quantitative traits. Our simulations show that, whereas the evolutionary response of the genetically determined upper thermal limit (CTmax) is independent of methodological context, the response in knockdown temperatures varies with measurement protocol and is substantially (up to 50%) lower than for CTmax. Realized heritabilities of knockdown temperature may grossly underestimate the true heritability of CTmax. For instance, assuming that the true heritability of CTmax in the base population is h2 = 0.25, realized heritabilities of knockdown temperature are around 0.08–0.16 depending on heating rate. These effects are higher in slow heating assays, suggesting that flawed methodology might explain the apparently limited evolutionary potential of cosmopolitan D. melanogaster. PMID:23170220

Frailty and cardiac rehabilitation: A call to action from the EAPC Cardiac Rehabilitation Section.

PubMed

Vigorito, Carlo; Abreu, Ana; Ambrosetti, Marco; Belardinelli, Romualdo; Corrà, Ugo; Cupples, Margaret; Davos, Constantinos H; Hoefer, Stefan; Iliou, Marie-Christine; Schmid, Jean-Paul; Voeller, Heinz; Doherty, Patrick

2017-04-01

Frailty is a geriatric syndrome characterised by a vulnerability status associated with declining function of multiple physiological systems and loss of physiological reserves. Two main models of frailty have been advanced: the phenotypic model (primary frailty) or deficits accumulation model (secondary frailty), and different instruments have been proposed and validated to measure frailty. However measured, frailty correlates to medical outcomes in the elderly, and has been shown to have prognostic value for patients in different clinical settings, such as in patients with coronary artery disease, after cardiac surgery or transvalvular aortic valve replacement, in patients with chronic heart failure or after left ventricular assist device implantation. The prevalence, clinical and prognostic relevance of frailty in a cardiac rehabilitation setting has not yet been well characterised, despite the increasing frequency of elderly patients in cardiac rehabilitation, where frailty is likely to influence the onset, type and intensity of the exercise training programme and the design of tailored rehabilitative interventions for these patients. Therefore, we need to start looking for frailty in elderly patients entering cardiac rehabilitation programmes and become more familiar with some of the tools to recognise and evaluate the severity of this condition. Furthermore, we need to better understand whether exercise-based cardiac rehabilitation may change the course and the prognosis of frailty in cardiovascular patients.

Development of a computational model of glucose toxicity in the progression of diabetes mellitus.

PubMed

Perez-Rivera, Danilo T; Torres-Torres, Veronica L; Torres-Colon, Abraham E; Cruz-Aponte, Maytee

2016-10-01

Diabetes mellitus is a disease characterized by a range of metabolic complications involving an individual's blood glucose levels, and its main regulator, insulin. These complications can vary largely from person to person depending on their current biophysical state. Biomedical research day-by-day makes strides to impact the lives of patients of a variety of diseases, including diabetes. One large stride that is being made is the generation of techniques to assist physicians to ``personalize medicine''. From available physiological data, biological understanding of the system, and dimensional analysis, a differential equation-based mathematical model was built in a sequential matter, to be able to elucidate clearly how each parameter correlates to the patient's current physiological state. We developed a simple mathematical model that accurately simulates the dynamics between glucose, insulin, and pancreatic $\\beta$-cells throughout disease progression with constraints to maintain biological relevance. The current framework is clearly capable of tracking the patient's current progress through the disease, dependent on factors such as latent insulin resistance or an attrite $\\beta$-cell population. Further interests would be to develop tools that allow the direct and feasible testing of how effective a given plan of treatment would be at returning the patient to a desirable biophysical state.

Sorafenib metabolism, transport, and enterohepatic recycling: physiologically based modeling and simulation in mice.

PubMed

Edginton, Andrea N; Zimmerman, Eric I; Vasilyeva, Aksana; Baker, Sharyn D; Panetta, John C

2016-05-01

This study used uncertainty and sensitivity analysis to evaluate a physiologically based pharmacokinetic (PBPK) model of the complex mechanisms of sorafenib and its two main metabolites, sorafenib glucuronide and sorafenib N-oxide in mice. A PBPK model for sorafenib and its two main metabolites was developed to explain disposition in mice. It included relevant influx (Oatp) and efflux (Abcc2 and Abcc3) transporters, hepatic metabolic enzymes (CYP3A4 and UGT1A9), and intestinal β-glucuronidase. Parameterization of drug-specific processes was based on in vitro, ex vivo, and in silico data along with plasma and liver pharmacokinetic data from single and multiple transporter knockout mice. Uncertainty analysis demonstrated that the model structure and parameter values could explain the observed variability in the pharmacokinetic data. Global sensitivity analysis demonstrated the global effects of metabolizing enzymes on sorafenib and metabolite disposition and the local effects of transporters on their respective substrate exposures. In addition, through hypothesis testing, the model supported that the influx transporter Oatp is a weak substrate for sorafenib and a strong substrate for sorafenib glucuronide and that the efflux transporter Abcc2 is not the only transporter affected in the Abcc2 knockout mouse. Translation of the mouse model to humans for the purpose of explaining exceptionally high human pharmacokinetic variability and its relationship with exposure-dependent dose-limiting toxicities will require delineation of the importance of these processes on disposition.

Kernel-Based Relevance Analysis with Enhanced Interpretability for Detection of Brain Activity Patterns

PubMed Central

Alvarez-Meza, Andres M.; Orozco-Gutierrez, Alvaro; Castellanos-Dominguez, German

2017-01-01

We introduce Enhanced Kernel-based Relevance Analysis (EKRA) that aims to support the automatic identification of brain activity patterns using electroencephalographic recordings. EKRA is a data-driven strategy that incorporates two kernel functions to take advantage of the available joint information, associating neural responses to a given stimulus condition. Regarding this, a Centered Kernel Alignment functional is adjusted to learning the linear projection that best discriminates the input feature set, optimizing the required free parameters automatically. Our approach is carried out in two scenarios: (i) feature selection by computing a relevance vector from extracted neural features to facilitating the physiological interpretation of a given brain activity task, and (ii) enhanced feature selection to perform an additional transformation of relevant features aiming to improve the overall identification accuracy. Accordingly, we provide an alternative feature relevance analysis strategy that allows improving the system performance while favoring the data interpretability. For the validation purpose, EKRA is tested in two well-known tasks of brain activity: motor imagery discrimination and epileptic seizure detection. The obtained results show that the EKRA approach estimates a relevant representation space extracted from the provided supervised information, emphasizing the salient input features. As a result, our proposal outperforms the state-of-the-art methods regarding brain activity discrimination accuracy with the benefit of enhanced physiological interpretation about the task at hand. PMID:29056897

Multisite Ion Model in Concentrated Solutions of Divalent Cations (MgCl2 and CaCl2): Osmotic Pressure Calculations

PubMed Central

2015-01-01

Accurate force field parameters for ions are essential for meaningful simulation studies of proteins and nucleic acids. Currently accepted models of ions, especially for divalent ions, do not necessarily reproduce the right physiological behavior of Ca2+ and Mg2+ ions. Saxena and Sept (J. Chem. Theor. Comput.2013, 9, 3538–3542) described a model, called the multisite-ion model, where instead of treating the ions as an isolated sphere, the charge was split into multiple sites with partial charge. This model provided accurate inner shell coordination of the ion with biomolecules and predicted better free energies for proteins and nucleic acids. Here, we expand and refine the multisite model to describe the behavior of divalent ions in concentrated MgCl2 and CaCl2 electrolyte solutions, eliminating the unusual ion–ion pairing and clustering of ions which occurred in the original model. We calibrate and improve the parameters of the multisite model by matching the osmotic pressure of concentrated solutions of MgCl2 to the experimental values and then use these parameters to test the behavior of CaCl2 solutions. We find that the concentrated solutions of both divalent ions exhibit the experimentally observed behavior with correct osmotic pressure, the presence of solvent separated ion pairs instead of direct ion pairs, and no aggregation of ions. The improved multisite model for (Mg2+ and Ca2+) can be used in classical simulations of biomolecules at physiologically relevant salt concentrations. PMID:25482831

A computational analysis of the long-term regulation of arterial pressure.

PubMed

Beard, Daniel A; Pettersen, Klas H; Carlson, Brian E; Omholt, Stig W; Bugenhagen, Scott M

2013-01-01

The asserted dominant role of the kidneys in the chronic regulation of blood pressure and in the etiology of hypertension has been debated since the 1970s. At the center of the theory is the observation that the acute relationships between arterial pressure and urine production-the acute pressure-diuresis and pressure-natriuresis curves-physiologically adapt to perturbations in pressure and/or changes in the rate of salt and volume intake. These adaptations, modulated by various interacting neurohumoral mechanisms, result in chronic relationships between water and salt excretion and pressure that are much steeper than the acute relationships. While the view that renal function is the dominant controller of arterial pressure has been supported by computer models of the cardiovascular system known as the "Guyton-Coleman model", no unambiguous description of a computer model capturing chronic adaptation of acute renal function in blood pressure control has been presented. Here, such a model is developed with the goals of: 1. representing the relevant mechanisms in an identifiable mathematical model; 2. identifying model parameters using appropriate data; 3. validating model predictions in comparison to data; and 4. probing hypotheses regarding the long-term control of arterial pressure and the etiology of primary hypertension. The developed model reveals: long-term control of arterial blood pressure is primarily through the baroreflex arc and the renin-angiotensin system; and arterial stiffening provides a sufficient explanation for the etiology of primary hypertension associated with ageing. Furthermore, the model provides the first consistent explanation of the physiological response to chronic stimulation of the baroreflex.

Diffusion in Single Supported Lipid Bilayers

NASA Astrophysics Data System (ADS)

Armstrong, C. L.; Trapp, M.; Rheinstädter, M. C.

2011-03-01

Despite their potential relevance for the development of functionalized surfaces and biosensors, the study of single supported membranes using neutron scattering has been limited by the challenge of obtaining relevant dynamic information from a sample with minimal material. Using state of the art neutron instrumentation we have, for the first time, modeled lipid diffusion in single supported lipid bilayers. While we find that the diffusion coefficient for the single bilayer system is comparable to a multi-lamellar lipid system, the molecular mechanism for lipid motion in the single bilayer is a continuous diffusion process with no sign of the flow-like ballistic motion reported in the stacked membrane system. In the future, these membranes will be used to hold and align proteins, mimicking physiological conditions enabling the study of protein structure, function and interactions in relevant and highly topical membrane/protein systems with minimal sample material. C.L. Armstrong, M.D. Kaye, M. Zamponi, E. Mamontov, M. Tyagi, T. Jenkins and M.C. Rheinstädter, Soft Matter Communication, 2010, Advance Article, DOI: 10.1039/C0SM00637H

Toxicity challenges in environmental chemicals: Prediction of ...

EPA Pesticide Factsheets

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 structure-activity relationships (QSAR) serve as a vital tool for the high-throughput prediction of chemical-specific PBPK parameters, such as the fraction of a chemical unbound by plasma protein (Fub). The presented work explores the merit of utilizing experimental pharmaceutical Fub data for the construction of a universal QSAR model, in order to compensate for the limited range of high-quality experimental Fub data for environmentally relevant chemicals, such as pollutants, pesticides, and consumer products. Independent QSAR models were constructed with three machine-learning algorithms, k nearest neighbors (kNN), random forest (RF), and support vector machine (SVM) regression, from a large pharmaceutical training set (~1000) and assessed with independent test sets of pharmaceuticals (~200) and environmentally relevant chemicals in the ToxCast program (~400). Small descriptor sets yielded the optimal balance of model complexity and performance, providing insight into the biochemical factors of plasma protein binding, while preventing over fitting to the training set. Overlaps in chemical space between pharmaceutical and environmental compounds were considered through applicability of do

Research on Infancy of Special Relevance for Mental Health. Matrix No. 11A.

ERIC Educational Resources Information Center

Provence, Sally

Research relevant to planning and practice in the area of infant mental health is discussed in this paper. First, three examples of research approaches that reflect current attitudes are given. The first example represents those studies in which there is an effort to closely coordinate physiological and behavioral studies. The second example…

Sleep mechanisms: Sleep deprivation and detection of changing levels of consciousness

NASA Technical Reports Server (NTRS)

Dement, W. C.; Barchas, J. D.

1972-01-01

An attempt was made to obtain information relevant to assessing the need to sleep and make up for lost sleep. Physiological and behavioral parameters were used as measuring parameters. Sleep deprivation in a restricted environment, derivation of data relevant to determining sleepiness from EEG, and the development of the Sanford Sleepiness Scale were discussed.

Medicating the environment: assessing risks of pharmaceuticals to wildlife and ecosystems

PubMed Central

Arnold, Kathryn E.; Brown, A. Ross; Ankley, Gerald T.; Sumpter, John P.

2014-01-01

Global pharmaceutical consumption is rising with the growing and ageing human population and more intensive food production. Recent studies have revealed pharmaceutical residues in a wide range of ecosystems and organisms. Environmental concentrations are often low, but pharmaceuticals typically are designed to have biological effects at low doses, acting on physiological systems that can be evolutionarily conserved across taxa. This Theme Issue introduces the latest research investigating the risks of environmentally relevant concentrations of pharmaceuticals to vertebrate wildlife. We take a holistic, global view of environmental exposure to pharmaceuticals encompassing terrestrial, freshwater and marine ecosystems in high- and low-income countries. Based on both field and laboratory data, the evidence for and relevance of changes to physiology and behaviour, in addition to mortality and reproductive effects, are examined in terms of the population- and community-level consequences of pharmaceutical exposure on wildlife. Studies on uptake, trophic transfer and indirect effects of pharmaceuticals acting via food webs are presented. Given the logistical and ethical complexities of research in this area, several papers focus on techniques for prioritizing which compounds are most likely to harm wildlife and how modelling approaches can make predictions about the bioavailability, metabolism and toxicity of pharmaceuticals in non-target species. This Theme Issue aims to help clarify the uncertainties, highlight opportunities and inform ongoing scientific and policy debates on the impacts of pharmaceuticals in the environment. PMID:25405959

Managing fatigue in operational settings. 1: Physiological considerations and countermeasures

NASA Technical Reports Server (NTRS)

Rosekind, M. R.; Gander, P. H.; Gregory, K. B.; Smith, R. M.; Miller, D. L.; Oyung, R.; Webbon, L. L.; Johnson, J. M.

1996-01-01

The authors consider three aspects of managing fatigue in the workplace. They provide a brief overview of important scientific findings related to sleep and circadian physiology that establish the psychobiological foundation of fatigue. Their major focus is on the relevance of these findings to operational settings. In addition, they provide examples to describe practical fatigue countermeasures that can be used in operational settings.

A physiologically based pharmacokinetic model for atrazine and its main metabolites in the adult male C57BL/6 mouse

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

Lin Zhoumeng; Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602; Fisher, Jeffrey W.

Atrazine (ATR) is a chlorotriazine herbicide that is widely used and relatively persistent in the environment. In laboratory rodents, excessive exposure to ATR is detrimental to the reproductive, immune, and nervous systems. To better understand the toxicokinetics of ATR and to fill the need for a mouse model, a physiologically based pharmacokinetic (PBPK) model for ATR and its main chlorotriazine metabolites (Cl-TRIs) desethyl atrazine (DE), desisopropyl atrazine (DIP), and didealkyl atrazine (DACT) was developed for the adult male C57BL/6 mouse. Taking advantage of all relevant and recently made available mouse-specific data, a flow-limited PBPK model was constructed. The ATR andmore » DACT sub-models included blood, brain, liver, kidney, richly and slowly perfused tissue compartments, as well as plasma protein binding and red blood cell binding, whereas the DE and DIP sub-models were constructed as simple five-compartment models. The model adequately simulated plasma levels of ATR and Cl-TRIs and urinary dosimetry of Cl-TRIs at four single oral dose levels (250, 125, 25, and 5 mg/kg). Additionally, the model adequately described the dose dependency of brain and liver ATR and DACT concentrations. Cumulative urinary DACT amounts were accurately predicted across a wide dose range, suggesting the model's potential use for extrapolation to human exposures by performing reverse dosimetry. The model was validated using previously reported data for plasma ATR and DACT in mice and rats. Overall, besides being the first mouse PBPK model for ATR and its Cl-TRIs, this model, by analogy, provides insights into tissue dosimetry for rats. The model could be used in tissue dosimetry prediction and as an aid in the exposure assessment to this widely used herbicide.« less

Adsorption of doxorubicin on citrate-capped gold nanoparticles: insights into engineering potent chemotherapeutic delivery systems

NASA Astrophysics Data System (ADS)

Curry, Dennis; Cameron, Amanda; MacDonald, Bruce; Nganou, Collins; Scheller, Hope; Marsh, James; Beale, Stefanie; Lu, Mingsheng; Shan, Zhi; Kaliaperumal, Rajendran; Xu, Heping; Servos, Mark; Bennett, Craig; Macquarrie, Stephanie; Oakes, Ken D.; Mkandawire, Martin; Zhang, Xu

2015-11-01

Gold nanomaterials have received great interest for their use in cancer theranostic applications over the past two decades. Many gold nanoparticle-based drug delivery system designs rely on adsorbed ligands such as DNA or cleavable linkers to load therapeutic cargo. The heightened research interest was recently demonstrated in the simple design of nanoparticle-drug conjugates wherein drug molecules are directly adsorbed onto the as-synthesized nanoparticle surface. The potent chemotherapeutic, doxorubicin often serves as a model drug for gold nanoparticle-based delivery platforms; however, the specific interaction facilitating adsorption in this system remains understudied. Here, for the first time, we propose empirical and theoretical evidence suggestive of the main adsorption process where (1) hydrophobic forces drive doxorubicin towards the gold nanoparticle surface before (2) cation-π interactions and gold-carbonyl coordination between the drug molecule and the cations on AuNP surface facilitate DOX adsorption. In addition, biologically relevant compounds, such as serum albumin and glutathione, were shown to enhance desorption of loaded drug molecules from AuNP at physiologically relevant concentrations, providing insight into the drug release and in vivo stability of such drug conjugates.Gold nanomaterials have received great interest for their use in cancer theranostic applications over the past two decades. Many gold nanoparticle-based drug delivery system designs rely on adsorbed ligands such as DNA or cleavable linkers to load therapeutic cargo. The heightened research interest was recently demonstrated in the simple design of nanoparticle-drug conjugates wherein drug molecules are directly adsorbed onto the as-synthesized nanoparticle surface. The potent chemotherapeutic, doxorubicin often serves as a model drug for gold nanoparticle-based delivery platforms; however, the specific interaction facilitating adsorption in this system remains understudied. Here, for the first time, we propose empirical and theoretical evidence suggestive of the main adsorption process where (1) hydrophobic forces drive doxorubicin towards the gold nanoparticle surface before (2) cation-π interactions and gold-carbonyl coordination between the drug molecule and the cations on AuNP surface facilitate DOX adsorption. In addition, biologically relevant compounds, such as serum albumin and glutathione, were shown to enhance desorption of loaded drug molecules from AuNP at physiologically relevant concentrations, providing insight into the drug release and in vivo stability of such drug conjugates. Electronic supplementary information (ESI) available: DOX-AuNP absorption spectra and colored solution images, citrate displacement data, original DOX-AuNP loading isotherm, XPS data and TEM micrographs, modelling data. See DOI: 10.1039/c5nr05826k

Age-Related Change in Mobility: Perspectives From Life Course Epidemiology and Geroscience

PubMed Central

Cooper, Rachel; Shardell, Michelle; Simonsick, Eleanor M.; Schrack, Jennifer A.; Kuh, Diana

2016-01-01

Mobility is the most studied and most relevant physical ability affecting quality of life with strong prognostic value for disability and survival. Natural selection has built the “engine” of mobility with great robustness, redundancy, and functional reserve. Efficient patterns of mobility can be acquired during development even by children affected by severe impairments. Analogously, age-associated impairments in mobility-related physiological systems are compensated and overt limitations of mobility only occur when the severity can no longer be compensated. Mobility loss in older persons usually results from multiple impairments in the central nervous system, muscles, joints, and energetic and sensory physiological systems. Early preclinical changes in these physiological systems that precede mobility loss have been poorly studied. Peak performance, rate of decline, compensatory behaviors, or subclinical deterioration of physiological resources may cumulatively influence both timing of mobility loss and chances of recovery, but their role as risk factors has not been adequately characterized. Understanding the natural history of these early changes and intervening on them would likely be the most effective strategy to reduce the burden of disability in the population. For example, young women with low bone peak mass could be counseled to start strength resistance exercise to reduce their high risk of developing osteoporosis and fracture later in life. Expanding this approach to other physiological domains requires collecting and interpreting data from life course epidemiological studies, establishing normative measures of mobility, physical function, and physical activity, and connecting them with life course trajectories of the mobility-relevant physiological domains. PMID:26975983

Performance of first-year health sciences students in a large, diverse, multidisciplinary, first-semester, physiology service module.

PubMed

Higgins-Opitz, Susan B; Tufts, Mark

2014-06-01

Health Science students at the University of KwaZulu-Natal perform better in their professional modules compared with their physiology modules. The pass rates of physiology service modules have steadily declined over the years. While a system is in place to identify "at-risk" students, it is only activated after the first semester. As a result, it is only from the second semester of their first year studies onward that at-risk students can be formally assisted. The challenge is thus to devise an appropriate strategy to identify struggling students earlier in the semester. Using questionnaires, students were asked about attendance, financing of their studies, and relevance of physiology. After the first class test, failing students were invited to complete a second questionnaire. In addition, demographic data were also collected and analyzed. Correlation analyses were undertaken of performance indicators based on the demographical data collected. The 2011 class comprised mainly sport science students (57%). The pass rate of sport science students was lower than the pass rates of other students (42% vs. 70%, P < 0.001). Most students were positive about physiology and recognized its relevance. Key issues identified were problems understanding concepts and terminology, poor study environment and skills, and lack of matriculation biology. The results of the first class test and final module marks correlated well. It is clear from this study that student performance in the first class test is a valuable tool to identify struggling students and that appropriate testing should be held as early as possible. Copyright © 2014 The American Physiological Society.

Physiologically Based Pharmacokinetic and Absorption Modeling for Osmotic Pump Products.

PubMed

Ni, Zhanglin; Talattof, Arjang; Fan, Jianghong; Tsakalozou, Eleftheria; Sharan, Satish; Sun, Dajun; Wen, Hong; Zhao, Liang; Zhang, Xinyuan

2017-07-01

Physiologically based pharmacokinetic (PBPK) and absorption modeling approaches were employed for oral extended-release (ER) drug products based on an osmotic drug delivery system (osmotic pumps). The purpose was to systemically evaluate the in vivo relevance of in vitro dissolution for this type of formulation. As expected, in vitro dissolution appeared to be generally predictive of in vivo PK profiles, because of the unique feature of this delivery system that the in vitro and in vivo release of osmotic pump drug products is less susceptible to surrounding environment in the gastrointestinal (GI) tract such as pH, hydrodynamic, and food effects. The present study considered BCS (Biopharmaceutics Classification System) class 1, 2, and 3 drug products with half-lives ranging from 2 to greater than 24 h. In some cases, the colonic absorption models needed to be adjusted to account for absorption in the colon. C max (maximum plasma concentration) and AUCt (area under the concentration curve) of the studied drug products were sensitive to changes in colon permeability and segmental GI transit times in a drug product-dependent manner. While improvement of the methodology is still warranted for more precise prediction (e.g., colonic absorption and dynamic movement in the GI tract), the results from the present study further emphasized the advantage of using PBPK modeling in addressing product-specific questions arising from regulatory review and drug development.

Invited review article: Advanced light microscopy for biological space research.

PubMed

De Vos, Winnok H; Beghuin, Didier; Schwarz, Christian J; Jones, David B; van Loon, Jack J W A; Bereiter-Hahn, Juergen; Stelzer, Ernst H K

2014-10-01

As commercial space flights have become feasible and long-term extraterrestrial missions are planned, it is imperative that the impact of space travel and the space environment on human physiology be thoroughly characterized. Scrutinizing the effects of potentially detrimental factors such as ionizing radiation and microgravity at the cellular and tissue level demands adequate visualization technology. Advanced light microscopy (ALM) is the leading tool for non-destructive structural and functional investigation of static as well as dynamic biological systems. In recent years, technological developments and advances in photochemistry and genetic engineering have boosted all aspects of resolution, readout and throughput, rendering ALM ideally suited for biological space research. While various microscopy-based studies have addressed cellular response to space-related environmental stressors, biological endpoints have typically been determined only after the mission, leaving an experimental gap that is prone to bias results. An on-board, real-time microscopical monitoring device can bridge this gap. Breadboards and even fully operational microscope setups have been conceived, but they need to be rendered more compact and versatile. Most importantly, they must allow addressing the impact of gravity, or the lack thereof, on physiologically relevant biological systems in space and in ground-based simulations. In order to delineate the essential functionalities for such a system, we have reviewed the pending questions in space science, the relevant biological model systems, and the state-of-the art in ALM. Based on a rigorous trade-off, in which we recognize the relevance of multi-cellular systems and the cellular microenvironment, we propose a compact, but flexible concept for space-related cell biological research that is based on light sheet microscopy.

Invited Review Article: Advanced light microscopy for biological space research

NASA Astrophysics Data System (ADS)

De Vos, Winnok H.; Beghuin, Didier; Schwarz, Christian J.; Jones, David B.; van Loon, Jack J. W. A.; Bereiter-Hahn, Juergen; Stelzer, Ernst H. K.

2014-10-01

As commercial space flights have become feasible and long-term extraterrestrial missions are planned, it is imperative that the impact of space travel and the space environment on human physiology be thoroughly characterized. Scrutinizing the effects of potentially detrimental factors such as ionizing radiation and microgravity at the cellular and tissue level demands adequate visualization technology. Advanced light microscopy (ALM) is the leading tool for non-destructive structural and functional investigation of static as well as dynamic biological systems. In recent years, technological developments and advances in photochemistry and genetic engineering have boosted all aspects of resolution, readout and throughput, rendering ALM ideally suited for biological space research. While various microscopy-based studies have addressed cellular response to space-related environmental stressors, biological endpoints have typically been determined only after the mission, leaving an experimental gap that is prone to bias results. An on-board, real-time microscopical monitoring device can bridge this gap. Breadboards and even fully operational microscope setups have been conceived, but they need to be rendered more compact and versatile. Most importantly, they must allow addressing the impact of gravity, or the lack thereof, on physiologically relevant biological systems in space and in ground-based simulations. In order to delineate the essential functionalities for such a system, we have reviewed the pending questions in space science, the relevant biological model systems, and the state-of-the art in ALM. Based on a rigorous trade-off, in which we recognize the relevance of multi-cellular systems and the cellular microenvironment, we propose a compact, but flexible concept for space-related cell biological research that is based on light sheet microscopy.

Reproductive investment is connected to innate immunity in a long-lived animal.

PubMed

Neggazi, Sara A; Noreikiene, Kristina; Öst, Markus; Jaatinen, Kim

2016-10-01

Life-history theory predicts that organisms optimize their resource allocation strategy to maximize lifetime reproductive success. Individuals can flexibly reallocate resources depending on their life-history stage, and environmental and physiological factors, which lead to variable life-history strategies even within species. Physiological trade-offs between immunity and reproduction are particularly relevant for long-lived species that need to balance current reproduction against future survival and reproduction, but their underlying mechanisms are poorly understood. A major unresolved issue is whether the first-line innate immune function is suppressed by reproductive investment. In this paper, we tested if reproductive investment is associated with the suppression of innate immunity, and how this potential trade-off is resolved depending on physiological state and residual reproductive value. We used long-lived capital-breeding female eiders (Somateria mollissima) as a model. We showed that the innate immune response, measured by plasma bacteria-killing capacity (BKC), was negatively associated with increasing reproductive investment, i.e., with increasing clutch size and advancing incubation stage. Females in a better physiological state, as indexed by low heterophil-to-lymphocyte (H/L) ratios, showed higher BKC during early incubation, but this capacity decreased as incubation progressed, whereas females in poorer state showed low BKC capacity throughout incubation. Although plasma BKC generally declined with increasing H/L ratios, this decrease was most pronounced in young females. Our results demonstrate that reproductive investment can suppress constitutive first-line immune defence in a long-lived bird, but the degree of immunosuppression depends on physiological state and age.

Cue-reactivity in behavioral addictions: A meta-analysis and methodological considerations.

PubMed

Starcke, Katrin; Antons, Stephanie; Trotzke, Patrick; Brand, Matthias

2018-05-23

Background and aims Recent research has applied cue-reactivity paradigms to behavioral addictions. The aim of the current meta-analysis is to systematically analyze the effects of learning-based cue-reactivity in behavioral addictions. Methods The current meta-analysis includes 18 studies (29 data sets, 510 participants) that have used a cue-reactivity paradigm in persons with gambling (eight studies), gaming (nine studies), or buying (one study) disorders. We compared subjective, peripheral physiological, electroencephal, and neural responses toward addiction-relevant cues in patients versus control participants and toward addiction-relevant cues versus control cues in patients. Results Persons with behavioral addictions showed higher cue-reactivity toward addiction-relevant cues compared with control participants: subjective cue-reactivity (d = 0.84, p = .01) and peripheral physiological and electroencephal measures of cue-reactivity (d = 0.61, p < .01). Increased neural activation was found in the caudate nucleus, inferior frontal gyrus, median cingulate cortex, subgenual cingulate, and precentral gyrus. Persons with gambling, gaming, or buying disorders also showed higher cue-reactivity toward addiction-relevant cues compared with control cues: subjective cue-reactivity (d = 0.39, p = .11) and peripheral physiological and electroencephal measures of cue-reactivity (d = 0.47, p = .05). Increased neural activation was found in the caudate nucleus, inferior frontal gyrus, angular gyrus, inferior network, and precuneus. Discussion and conclusions Cue-reactivity not only exists in substance-use disorders but also in gambling, gaming, and buying disorders. Future research should differentiate between cue-reactivity in addictive behaviors and cue-reactivity in functional excessive behaviors such as passions, hobbies, or professions.

Overtraining and exercise motivation: A research prospectus

NASA Technical Reports Server (NTRS)

Hackney, Anthony C.

1989-01-01

The problems of exercise overtraining has recently become one of great interest to professionals in the field of human performance assessment. Quite obviously, the ultimate goal of the training process is to improve physical performance. However, excessive training can result in the opposite effect, that is, a performance decline and an impairment in the functional work capacity of the body. Research indicates that both psychological as well as physiological disturbances are quite common in overtrained individuals. For example, psychological changes include increased levels of depression, fatigue, and a lack of motivation. Similarly, impairment of the physiological function of the cardiovascular, metabolic, and endocrine systems also have been found. Some similarities may be found in the psychological and physiological states of crew members exposed to extended space flight and overtrained individuals. Therefore, the possibility exists that the crew members subjected to extended missions in space may develop overstressed or overtrained or both states during their flights. If such states do develop within the crew members, mission performance may be impaired. With these points as a background, the intent is to address potential research directions that NASA may consider viable and of a mutual interest to the researcher. A clear framework by which to begin discussion of research topics is needed; therefore, working definitions of overtraining and exercise motivation are presented. Subsequently, a proposed conceptional model of how exercise overtraining and motivation interact is presented. In support of the proposed model is a brief literature review of relevant areas. Potential research projects are presented and discussed.

Trauma-related dissociation and altered states of consciousness: a call for clinical, treatment, and neuroscience research

PubMed Central

Lanius, Ruth A.

2015-01-01

The primary aim of this commentary is to describe trauma-related dissociation and altered states of consciousness in the context of a four-dimensional model that has recently been proposed (Frewen & Lanius, 2015). This model categorizes symptoms of trauma-related psychopathology into (1) those that occur within normal waking consciousness and (2) those that are dissociative and are associated with trauma-related altered states of consciousness (TRASC) along four dimensions: (1) time; (2) thought; (3) body; and (4) emotion. Clinical applications and future research directions relevant to each dimension are discussed. Conceptualizing TRASC across the dimensions of time, thought, body, and emotion has transdiagnostic implications for trauma-related disorders described in both the Diagnostic Statistical Manual and the International Classifications of Diseases. The four-dimensional model provides a framework, guided by existing models of dissociation, for future research examining the phenomenological, neurobiological, and physiological underpinnings of trauma-related dissociation. PMID:25994026

Genesis of Preeclampsia: An Epidemiological Approach

PubMed Central

Salvador-Moysén, Jaime; Martínez-López, Yolanda; Ramírez-Aranda, José M.; Aguilar-Durán, Marisela; Terrones-González, Alberto

2012-01-01

There are analyzed some of the main aspects related to the causality of preeclampsia, privileging two types of models: the clinic model and the epidemiologic model, first one represented by the hypothesis of the reduced placental perfusion and the second one considering the epidemiologic findings related to the high levels of psychosocial stress and its association with preeclampsia. It is reasoned out the relevance of raising the causality of the disease from an interdisciplinary perspective, integrating the valuable information generated from both types, clinical and epidemiologic, and finally a tentative explanatory model of preeclampsia is proposed, the subclinical and sociocultural aspects that predispose and trigger the disease are emphasized making aspects to stand out: the importance of reduced placental perfusion as an indicator of individual risk, and the high levels of physiological stress, as a result of the unfavorable conditions of the psychosocial surroundings (indicator of population risk) of the pregnant women. PMID:22462008

Physiological Reactivity in a Community Sample of Sexually Aggressive Young Men: A Test of Competing Hypotheses

PubMed Central

Peterson, Zoë D.; Janssen, Erick; Goodrich, David; Heiman, Julia R.

2015-01-01

Men’s sexually aggressive behavior potentially could relate to either physiological hyporeactivity or hyperreactivity, and these two different physiological profiles could be associated with different underlying causes of sexual aggression. Thus, measurement of physiological reactivity could provide insight into mechanisms relevant to the etiology of sexual aggression. The relationship between sexual aggression and physiological reactivity was investigated in 78 community men (38 sexually aggressive and 40 non-aggressive men). In a laboratory protocol, the men were exposed to neutral, negative-affect-inducing, and positive-affect-inducing stimuli. Men’s salivary cortisol concentrations and electrodermal activity (EDA) were measured throughout the laboratory procedure. Sexually aggressive men demonstrated (1) lower overall cortisol levels and (2) lower EDA reactivity in some conditions as compared to non-aggressive men. Results of this study were consistent with the idea that men’s sexual aggression is associated with physiological hyporeactivity, a physiological profile that has been found to be associated with externalizing behaviors and psychopathic traits. PMID:24310818

Physiological reactivity in a community sample of sexually aggressive young men: a test of competing hypotheses.

PubMed

Peterson, Zoë D; Janssen, Erick; Goodrich, David; Heiman, Julia R

2014-01-01

Men's sexually aggressive behavior potentially could relate to either physiological hyporeactivity or hyperreactivity, and these two different physiological profiles could be associated with different underlying causes of sexual aggression. Thus, measurement of physiological reactivity could provide insight into mechanisms relevant to the etiology of sexual aggression. The relationship between sexual aggression and physiological reactivity was investigated in 78 community men (38 sexually aggressive and 40 non-aggressive men). In a laboratory protocol, the men were exposed to neutral, negative-affect-inducing, and positive-affect-inducing stimuli. Men's salivary cortisol concentrations and electrodermal activity (EDA) were measured throughout the laboratory procedure. Sexually aggressive men demonstrated (1) lower overall cortisol levels and (2) lower EDA reactivity in some conditions as compared to non-aggressive men. Results of this study were consistent with the idea that men's sexual aggression is associated with physiological hyporeactivity, a physiological profile that has been found to be associated with externalizing behaviors and psychopathic traits. © 2013 Wiley Periodicals, Inc.

A computational analysis of the long-term regulation of arterial pressure

PubMed Central

Beard, Daniel A.

2013-01-01

The asserted dominant role of the kidneys in the chronic regulation of blood pressure and in the etiology of hypertension has been debated since the 1970s. At the center of the theory is the observation that the acute relationships between arterial pressure and urine production—the acute pressure-diuresis and pressure-natriuresis curves—physiologically adapt to perturbations in pressure and/or changes in the rate of salt and volume intake. These adaptations, modulated by various interacting neurohumoral mechanisms, result in chronic relationships between water and salt excretion and pressure that are much steeper than the acute relationships. While the view that renal function is the dominant controller of arterial pressure has been supported by computer models of the cardiovascular system known as the “Guyton-Coleman model”, no unambiguous description of a computer model capturing chronic adaptation of acute renal function in blood pressure control has been presented. Here, such a model is developed with the goals of: 1. representing the relevant mechanisms in an identifiable mathematical model; 2. identifying model parameters using appropriate data; 3. validating model predictions in comparison to data; and 4. probing hypotheses regarding the long-term control of arterial pressure and the etiology of primary hypertension. The developed model reveals: long-term control of arterial blood pressure is primarily through the baroreflex arc and the renin-angiotensin system; and arterial stiffening provides a sufficient explanation for the etiology of primary hypertension associated with ageing. Furthermore, the model provides the first consistent explanation of the physiological response to chronic stimulation of the baroreflex. PMID:24555102

A physiologically-inspired model reproducing the speech intelligibility benefit in cochlear implant listeners with residual acoustic hearing.

PubMed

Zamaninezhad, Ladan; Hohmann, Volker; Büchner, Andreas; Schädler, Marc René; Jürgens, Tim

2017-02-01

This study introduces a speech intelligibility model for cochlear implant users with ipsilateral preserved acoustic hearing that aims at simulating the observed speech-in-noise intelligibility benefit when receiving simultaneous electric and acoustic stimulation (EA-benefit). The model simulates the auditory nerve spiking in response to electric and/or acoustic stimulation. The temporally and spatially integrated spiking patterns were used as the final internal representation of noisy speech. Speech reception thresholds (SRTs) in stationary noise were predicted for a sentence test using an automatic speech recognition framework. The model was employed to systematically investigate the effect of three physiologically relevant model factors on simulated SRTs: (1) the spatial spread of the electric field which co-varies with the number of electrically stimulated auditory nerves, (2) the "internal" noise simulating the deprivation of auditory system, and (3) the upper bound frequency limit of acoustic hearing. The model results show that the simulated SRTs increase monotonically with increasing spatial spread for fixed internal noise, and also increase with increasing the internal noise strength for a fixed spatial spread. The predicted EA-benefit does not follow such a systematic trend and depends on the specific combination of the model parameters. Beyond 300 Hz, the upper bound limit for preserved acoustic hearing is less influential on speech intelligibility of EA-listeners in stationary noise. The proposed model-predicted EA-benefits are within the range of EA-benefits shown by 18 out of 21 actual cochlear implant listeners with preserved acoustic hearing. Copyright © 2016 Elsevier B.V. All rights reserved.

Emulating Host-Microbiome Ecosystem of Human Gastrointestinal Tract in Vitro.

PubMed

Park, Gun-Seok; Park, Min Hee; Shin, Woojung; Zhao, Connie; Sheikh, Sameer; Oh, So Jung; Kim, Hyun Jung

2017-06-01

The human gut microbiome performs prodigious physiological functions such as production of microbial metabolites, modulation of nutrient digestion and drug metabolism, control of immune system, and prevention of infection. Paradoxically, gut microbiome can also negatively orchestrate the host responses in diseases or chronic disorders, suggesting that the regulated and balanced host-gut microbiome crosstalk is a salient prerequisite in gastrointestinal physiology. To understand the pathophysiological role of host-microbiome crosstalk, it is critical to recreate in vivo relevant models of the host-gut microbiome ecosystem in human. However, controlling the multi-species microbial communities and their uncontrolled growth has remained a notable technical challenge. Furthermore, conventional two-dimensional (2D) or 3D culture systems do not recapitulate multicellular microarchitectures, mechanical dynamics, and tissue-specific functions. Here, we review recent advances and current pitfalls of in vitro and ex vivo models that display human GI functions. We also discuss how the disruptive technologies such as 3D organoids or a human organ-on-a-chip microphysiological system can contribute to better emulate host-gut microbiome crosstalks in health and disease. Finally, the medical and pharmaceutical significance of the gut microbiome-based personalized interventions is underlined as a future perspective.

Abnormal illness behaviour: physiological, psychological and social dimensions of coping with distress.

PubMed

Kirmayer, Laurence J; Looper, Karl J

2006-01-01

Pilowsky introduced the term 'abnormal illness behaviour' to characterize syndromes of excessive or inadequate response to symptoms, including hypochondriasis, somatization, and denial of illness. This review summarizes recent work from sociology, health psychology and psychiatry that contributes to an understanding of the processes that may underlie abnormal illness behaviour. Disturbances in the regulation of physiological systems may account for many 'unexplained' symptoms and sickness behaviour. Increased attention to bodily sensations, sensitivity to pain and catastrophizing play important roles in illness behaviour in medical illness. Developmental adversities and parental modelling of illness behaviour in childhood may increase bodily preoccupation and health care utilization. Apparent cross-national differences in illness behaviour may reflect differences in health care systems, but cultural models of illness and social stigma remain important determinants of illness denial and avoidance of mental health services. Research into illness behaviour is relevant to efforts to rethink the psychiatric nosology of somatoform disorders. The discrete somatoform disorders might well be replaced by a dimensional framework that identifies specific pathological processes in cognition, perception and social behaviour that contribute to bodily distress, impaired coping, inappropriate use of health services, chronicity and disability.

Towards an animal model of callousness.

PubMed

Hernandez-Lallement, Julen; van Wingerden, Marijn; Kalenscher, Tobias

2016-12-28

Callous-unemotional traits - the insensitivity to other's welfare and well-being - are characterized by a lack of empathy. They are characteristic of psychopathy and can be found in other anti-social disorders, such as conduct disorder. Because of the increasing prevalence of anti-social disorders and the rising societal costs of violence and aggression, it is of great importance to elucidate the psychological and physiological mechanisms underlying callousness in the search for pharmacological treatments. One promising avenue is to create a relevant animal model to explore the neural bases of callousness. Here, we review recent advances in rodent models of pro-social choice that could be applied to probe the absence of pro-sociality as a proxy of callous behavior, and provide future directions for the exploration of the neural substrates of callousness. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

PubMed Central

Ju, Wenjun; Brosius, Frank C.

2010-01-01

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

Ras Dimer Formation as a New Signaling Mechanism and Potential Cancer Therapeutic Target

PubMed Central

Chen, Mo; Peters, Alec; Huang, Tao; Nan, Xiaolin

2016-01-01

The K-, N-, and HRas small GTPases are key regulators of cell physiology and are frequently mutated in human cancers. Despite intensive research, previous efforts to target hyperactive Ras based on known mechanisms of Ras signaling have been met with little success. Several studies have provided compelling evidence for the existence and biological relevance of Ras dimers, establishing a new mechanism for regulating Ras activity in cells additionally to GTP-loading and membrane localization. Existing data also start to reveal how Ras proteins dimerize on the membrane. We propose a dimer model to describe Ras-mediated effector activation, which contrasts existing models of Ras signaling as a monomer or as a 5-8 membered multimer. We also discuss potential implications of this model in both basic and translational Ras biology. PMID:26423697

Comparisons between the attitudes of medical and dental students toward the clinical importance of gross anatomy and physiology.

PubMed

Olowo-Ofayoku, Anthony; Moxham, Bernard John

2014-10-01

Marked changes are occurring within both the medical and dental curricula and new ways of teaching the basic sciences have been devised and traditional methods (e.g., dissection for gross anatomy and of bench-based animal preparations for physiology) are increasingly no longer the norm. Although there is much anecdotal evidence that students are not in favor of such changes, there is little evidence for this based on quantitative analyses of students' attitudes. Using Thurstone and Chave attitude analyses, we assessed the attitudes of first year medical and dental students at Cardiff University toward gross anatomy and physiology in terms of their perceived clinical importance. In addition, we investigated the appropriateness ("fitness for purpose") of teaching methodologies used for anatomy and physiology. The hypotheses tested recognized the possibility that medical and dental students differed in their opinions, but that they had a preference to being taught gross anatomy through the use of dissection and had no preference for physiology teaching. It was found that both medical and dental students displayed positive attitudes toward the clinical relevance of gross anatomy and that they preferred to be taught by means of dissection. Although both medical and dental students displayed positives attitudes toward the clinical relevance of physiology, this was greater for the medical students. Both medical and dental students showed a preference for being taught physiology through didactic teaching in small groups but the medical students also appreciated being taught by means of practicals. Overall, this study highlights the expectations that students have for the basic science foundation teaching within their professional training and signals a preference for being taught experientially/practically. Differences were discerned between medical and dental students that might reflect the direct association between systems physiology and pathophysiology and the application of this knowledge within the medical field in comparison to the dental field, which is heavily skill-based. © 2014 Wiley Periodicals, Inc.

Are more complex physiological models of forest ecosystems better choices for plot and regional predictions?

Treesearch

Wenchi Jin; Hong S. He; Frank R. Thompson

2016-01-01

Process-based forest ecosystem models vary from simple physiological, complex physiological, to hybrid empirical-physiological models. Previous studies indicate that complex models provide the best prediction at plot scale with a temporal extent of less than 10 years, however, it is largely untested as to whether complex models outperform the other two types of models...

The Graphical Representation of the Digital Astronaut Physiology Backbone

NASA Technical Reports Server (NTRS)

Briers, Demarcus

2010-01-01

This report summarizes my internship project with the NASA Digital Astronaut Project to analyze the Digital Astronaut (DA) physiology backbone model. The Digital Astronaut Project (DAP) applies integrated physiology models to support space biomedical operations, and to assist NASA researchers in closing knowledge gaps related to human physiologic responses to space flight. The DA physiology backbone is a set of integrated physiological equations and functions that model the interacting systems of the human body. The current release of the model is HumMod (Human Model) version 1.5 and was developed over forty years at the University of Mississippi Medical Center (UMMC). The physiology equations and functions are scripted in an XML schema specifically designed for physiology modeling by Dr. Thomas G. Coleman at UMMC. Currently it is difficult to examine the physiology backbone without being knowledgeable of the XML schema. While investigating and documenting the tags and algorithms used in the XML schema, I proposed a standard methodology for a graphical representation. This standard methodology may be used to transcribe graphical representations from the DA physiology backbone. In turn, the graphical representations can allow examination of the physiological functions and equations without the need to be familiar with the computer programming languages or markup languages used by DA modeling software.

A biomimetic hydrogel functionalized with adipose ECM components as a microenvironment for the 3D culture of human and murine adipocytes.

PubMed

Louis, Fiona; Pannetier, Pauline; Souguir, Zied; Le Cerf, Didier; Valet, Philippe; Vannier, Jean-Pierre; Vidal, Guillaume; Demange, Elise

2017-08-01

The lack of relevant in vitro models for adipose tissue makes necessary the development of a more physiological environment providing spatial and chemical cues for the effective maturation of adipocytes. We developed a biofunctionalized hydrogel with components of adipose extracellular matrix: collagen I, collagen VI, and the cell binding domain of fibronectin and we compared it to usual 2D cultures on plastic plates. This scaffold allowed 3D culture of mature adipocytes from the preadipocytes cell lines 3T3-L1 and 3T3-F442A, as well as primary Human White Preadipocytes (HWP), acquiring in vivo-like organization, with spheroid shaped adipocytes forming multicellular aggregates. The size of these aggregates increased with time up to 120 μm in diameter after 4 weeks of maturation, with good viability. Significantly higher lipogenic activity (up to 20-fold at day 28 for HWP cultures) and differentiation rates were also observed compared to 2D. Gene expression analyses highlighted earlier differentiation and complete maturation of 3D HWP compared to 2D, reinforced by the expression of Perilipin protein after 21 days of nutrition. This increase in adipocytes phenotypic and genotypic markers made this scaffold-driven culture as a robust adipose 3D model. Retinoic acid inhibition of lipogenesis in HWP or isoprenalin and caffeine induction of lipolysis performed on mouse 3T3-F442A cells, showed higher doses of molecules than typically used in 2D, underlying the physiologic relevance of this 3D culture system. Biotechnol. Bioeng. 2017;114: 1813-1824. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Transport of benzo[alpha]pyrene in the dually perfused human placenta perfusion model: effect of albumin in the perfusion medium.

PubMed

Mathiesen, Line; Rytting, Erik; Mose, Tina; Knudsen, Lisbeth E

2009-09-01

Transport of benzo[alpha]pyrene (BaP) across the placenta was examined because it is a ubiquitous and highly carcinogenic substance found in tobacco smoke, polluted air and certain foods. Foetal exposure to this substance is highly relevant but is difficult to estimate. The human placenta is unique compared to other species; since it is available without major ethical obstacles, we have used the human placenta perfusion model to study transport from mother to foetus. Placentas were donated after births at Rigshospitalet in Copenhagen from pregnant mothers who signed an informed consent. BaP is lipophilic and studies using cell culture medium in 6-hr placenta perfusions showed minimal transport through the placenta. To increase the solubility of BaP in perfusion medium and to increase physiological relevance, perfusions were also performed with albumin added to the perfusion medium [2 and 30 mg/ml bovine serum albumin (BSA) and 30 mg/ml human serum albumin (HSA)]. The addition of albumin resulted in increased transfer of BaP from maternal to foetal reservoirs. The transfer was even higher in the presence of an HSA formulation containing acetyltryptophanate and caprylate, resulting in a foetal-maternal concentration (FM) ratio of 0.71 +/- 0.10 after 3 hr and 0.78 +/- 0.11 after 6 hr, whereas the FM ratio in perfusions without albumin was only 0.05 +/- 0.03 after 6 hr of perfusion. Less BaP accumulated in placental tissue in perfusions with added albumin. This shows that transplacental transport of the pro-carcinogenic substance BaP occurs, and emphasizes the importance of adding physiological concentrations of albumin when studying the transport of lipophilic substances.

Development of a Physiologically Relevant Population Pharmacokinetic in Vitro-in Vivo Correlation Approach for Designing Extended-Release Oral Dosage Formulation.

PubMed

Kim, Tae Hwan; Shin, Soyoung; Bulitta, Jürgen B; Youn, Yu Seok; Yoo, Sun Dong; Shin, Beom Soo

2017-01-03

Establishing a level A in vitro-in vivo correlation (IVIVC) for a drug with complex absorption kinetics is challenging. The objective of the present study was to develop an IVIVC approach based on population pharmacokinetic (POP-PK) modeling that incorporated physiologically relevant absorption kinetics. To prepare three extended release (ER) tablets of loxoprofen, three types of hydroxypropyl methylcellulose (HPMC 100, 4000, and 15000 cps) were used as drug release modifiers, while lactose and magnesium stearate were used as the diluent and lubricant, respectively. An in vitro dissolution test in various pH conditions showed that loxoprofen dissolution was faster at higher pH. The in vivo pharmacokinetics of loxoprofen was assessed following oral administration of the different loxoprofen formulations to Beagle dogs (n = 22 in total). Secondary peaks or shoulders were observed in many of the individual plasma concentration vs time profiles after ER tablet administration, which may result from secondary absorption in the intestine due to a dissolution rate increase under intestinal pH compared to that observed at stomach pH. In addition, in vivo oral bioavailability was found to decrease with prolonged drug dissolution, indicating site-specific absorption. Based on the in vitro dissolution and in vivo absorption data, a POP-PK IVIVC model was developed using S-ADAPT software. pH-dependent biphasic dissolution kinetics, described using modified Michaelis-Menten kinetics with varying V max , and site-specific absorption, modeled using a changeable absorbed fraction parameter, were applied to the POP-PK IVIVC model. To experimentally determine the biphasic dissolution profiles of the ER tablets, another in vitro dissolution test was conducted by switching dissolution medium pH based on an in vivo estimate of gastric emptying time. The model estimated, using linear regression, that in vivo initial maximum dissolution rate (V max (0) in vivo ) was highly correlated (r 2 > 0.998) with in vitro (V max (0) in vitro ), indicating that in vivo dissolution profiles obtained from POP-PK modeling could be converted to in vitro dissolution profiles and vice versa. Monte Carlo simulations were performed for model validation, and prediction errors for C max and AUC were all within the acceptable range (90 to 110%) according to the FDA guidelines. The developed model was successfully applied for the prediction of in vivo pharmacokinetics of a loxoprofen double-layered tablet using the in vitro dissolution profile. In conclusion, a level A IVIVC approach was developed and validated using population modeling that accounted for pH-dependent dissolution and site-specific absorption. Excellent correlations were observed between in vitro and in vivo dissolution profiles. This new approach holds great promise for the establishment of IVIVCs for drug and formulation development where absorption kinetics strongly depend on complex physiologically absorption processes.

[Satellite glial cells in sensory ganglia: its role in pain].

PubMed

Costa, Filipa Alexandra Leite; Moreira Neto, Fani Lourença

2015-01-01

Satellite glial cells in sensory ganglia are a recent subject of research in the field of pain and a possible therapeutic target in the future. Therefore, the aim of this study was to summarize some of the important physiological and morphological characteristics of these cells and gather the most relevant scientific evidence about its possible role in the development of chronic pain. In the sensory ganglia, each neuronal body is surrounded by satellite glial cells forming distinct functional units. This close relationship enables bidirectional communication via a paracrine signaling between those two cell types. There is a growing body of evidence that glial satellite cells undergo structural and biochemical changes after nerve injury, which influence neuronal excitability and consequently the development and/or maintenance of pain in different animal models of chronic pain. Satellite glial cells are important in the establishment of physiological pain, in addition to being a potential target for the development of new pain treatments. Copyright © 2014 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

Mechanical stress activates NMDA receptors in the absence of agonists.

PubMed

Maneshi, Mohammad Mehdi; Maki, Bruce; Gnanasambandam, Radhakrishnan; Belin, Sophie; Popescu, Gabriela K; Sachs, Frederick; Hua, Susan Z

2017-01-03

While studying the physiological response of primary rat astrocytes to fluid shear stress in a model of traumatic brain injury (TBI), we found that shear stress induced Ca 2+ entry. The influx was inhibited by MK-801, a specific pore blocker of N-Methyl-D-aspartic acid receptor (NMDAR) channels, and this occurred in the absence of agonists. Other NMDA open channel blockers ketamine and memantine showed a similar effect. The competitive glutamate antagonists AP5 and GluN2B-selective inhibitor ifenprodil reduced NMDA-activated currents, but had no effect on the mechanically induced Ca 2+ influx. Extracellular Mg 2+ at 2 mM did not significantly affect the shear induced Ca 2+ influx, but at 10 mM it produced significant inhibition. Patch clamp experiments showed mechanical activation of NMDAR and inhibition by MK-801. The mechanical sensitivity of NMDARs may play a role in the normal physiology of fluid flow in the glymphatic system and it has obvious relevance to TBI.

Mechanical stress activates NMDA receptors in the absence of agonists

PubMed Central

Maneshi, Mohammad Mehdi; Maki, Bruce; Gnanasambandam, Radhakrishnan; Belin, Sophie; Popescu, Gabriela K.; Sachs, Frederick; Hua, Susan Z.

2017-01-01

While studying the physiological response of primary rat astrocytes to fluid shear stress in a model of traumatic brain injury (TBI), we found that shear stress induced Ca2+ entry. The influx was inhibited by MK-801, a specific pore blocker of N-Methyl-D-aspartic acid receptor (NMDAR) channels, and this occurred in the absence of agonists. Other NMDA open channel blockers ketamine and memantine showed a similar effect. The competitive glutamate antagonists AP5 and GluN2B-selective inhibitor ifenprodil reduced NMDA-activated currents, but had no effect on the mechanically induced Ca2+ influx. Extracellular Mg2+ at 2 mM did not significantly affect the shear induced Ca2+ influx, but at 10 mM it produced significant inhibition. Patch clamp experiments showed mechanical activation of NMDAR and inhibition by MK-801. The mechanical sensitivity of NMDARs may play a role in the normal physiology of fluid flow in the glymphatic system and it has obvious relevance to TBI. PMID:28045032

A novel Minimalist Cell-Free MHC Class II Antigen Processing System Identifies Immunodominant Epitopes

PubMed Central

Hartman, Isamu Z.; Kim, AeRyon; Cotter, Robert J.; Walter, Kimberly; Dalai, Sarat K.; Boronina, Tatiana; Griffith, Wendell; Schwenk, Robert; Lanar, David E.; Krzych, Urszula; Cole, Robert N.; Sadegh-Nasseri, Scheherazade

2010-01-01

Immunodominance is defined as restricted responsiveness of T cells to a few selected epitopes from complex antigens. Strategies currently used for elucidating CD4+ T cell epitopes are inadequate. To understand the mechanism of epitope selection for helper T cells, we established a cell-free antigen processing system composed of defined proteins: MHC class II, cathepsins, and HLA-DM. Our minimalist system successfully identified the physiologically selected immunodominant epitopes of model antigens, HA1 from influenza virus (A/Texas/1/77) and type II collagen. When applied for de novo epitope identification to a malaria antigen, or HA1 from H5N1 virus (Avian Flu), the system selected a single epitope from each protein that were confirmed to be immunodominant by their capacity to activate CD4+ T cells in HLA-DR1 positive human volunteers or transgenic mice immunized with the corresponding proteins. Thus, we provide a powerful new tool for the identification of physiologically relevant helper T cell epitopes from antigens. PMID:21037588

Peptidase inhibitors in tick physiology.

PubMed

Parizi, L F; Ali, A; Tirloni, L; Oldiges, D P; Sabadin, G A; Coutinho, M L; Seixas, A; Logullo, C; Termignoni, C; DA Silva Vaz, I

2018-06-01

Peptidase inhibitors regulate a wide range of physiological processes involved in the interaction between hematophagous parasites and their hosts, including tissue remodeling, the immune response and blood coagulation. In tick physiology, peptidase inhibitors have a crucial role in adaptation to improve parasitism mechanisms, facilitating blood feeding by interfering with defense-related host peptidases. Recently, a larger number of studies on this topic led to the description of several new tick inhibitors displaying interesting novel features, for example a role in pathogen transmission to the host. A comprehensive review discussing these emerging concepts can therefore shed light on peptidase inhibitor functions, their relevance to tick physiology and their potential applications. Here, we summarize and examine the general characteristics, functional diversity and action of tick peptidase inhibitors with known physiological roles in the tick-host-pathogen interaction. © 2017 The Royal Entomological Society.

Quantifying the roles of random motility and directed motility using advection-diffusion theory for a 3T3 fibroblast cell migration assay stimulated with an electric field.

PubMed

Simpson, Matthew J; Lo, Kai-Yin; Sun, Yung-Shin

2017-03-17

Directed cell migration can be driven by a range of external stimuli, such as spatial gradients of: chemical signals (chemotaxis); adhesion sites (haptotaxis); or temperature (thermotaxis). Continuum models of cell migration typically include a diffusion term to capture the undirected component of cell motility and an advection term to capture the directed component of cell motility. However, there is no consensus in the literature about the form that the advection term takes. Some theoretical studies suggest that the advection term ought to include receptor saturation effects. However, others adopt a much simpler constant coefficient. One of the limitations of including receptor saturation effects is that it introduces several additional unknown parameters into the model. Therefore, a relevant research question is to investigate whether directed cell migration is best described by a simple constant tactic coefficient or a more complicated model incorporating saturation effects. We study directed cell migration using an experimental device in which the directed component of the cell motility is driven by a spatial gradient of electric potential, which is known as electrotaxis. The electric field (EF) is proportional to the spatial gradient of the electric potential. The spatial variation of electric potential across the experimental device varies in such a way that there are several subregions on the device in which the EF takes on different values that are approximately constant within those subregions. We use cell trajectory data to quantify the motion of 3T3 fibroblast cells at different locations on the device to examine how different values of the EF influences cell motility. The undirected (random) motility of the cells is quantified in terms of the cell diffusivity, D, and the directed motility is quantified in terms of a cell drift velocity, v. Estimates D and v are obtained under a range of four different EF conditions, which correspond to normal physiological conditions. Our results suggest that there is no anisotropy in D, and that D appears to be approximately independent of the EF and the electric potential. The drift velocity increases approximately linearly with the EF, suggesting that the simplest linear advection term, with no additional saturation parameters, provides a good explanation of these physiologically relevant data. We find that the simplest linear advection term in a continuum model of directed cell motility is sufficient to describe a range of different electrotaxis experiments for 3T3 fibroblast cells subject to normal physiological values of the electric field. This is useful information because alternative models that include saturation effects involve additional parameters that need to be estimated before a partial differential equation model can be applied to interpret or predict a cell migration experiment.

Predicting the oral pharmacokinetic profiles of multiple-unit (pellet) dosage forms using a modeling and simulation approach coupled with biorelevant dissolution testing: case example diclofenac sodium.

PubMed

Kambayashi, Atsushi; Blume, Henning; Dressman, Jennifer B

2014-07-01

The objective of this research was to characterize the dissolution profile of a poorly soluble drug, diclofenac, from a commercially available multiple-unit enteric coated dosage form, Diclo-Puren® capsules, and to develop a predictive model for its oral pharmacokinetic profile. The paddle method was used to obtain the dissolution profiles of this dosage form in biorelevant media, with the exposure to simulated gastric conditions being varied in order to simulate the gastric emptying behavior of pellets. A modified Noyes-Whitney theory was subsequently fitted to the dissolution data. A physiologically-based pharmacokinetic (PBPK) model for multiple-unit dosage forms was designed using STELLA® software and coupled with the biorelevant dissolution profiles in order to simulate the plasma concentration profiles of diclofenac from Diclo-Puren® capsule in both the fasted and fed state in humans. Gastric emptying kinetics relevant to multiple-units pellets were incorporated into the PBPK model by setting up a virtual patient population to account for physiological variations in emptying kinetics. Using in vitro biorelevant dissolution coupled with in silico PBPK modeling and simulation it was possible to predict the plasma profile of this multiple-unit formulation of diclofenac after oral administration in both the fasted and fed state. This approach might be useful to predict variability in the plasma profiles for other drugs housed in multiple-unit dosage forms. Copyright © 2014 Elsevier B.V. All rights reserved.

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

PubMed Central

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

2012-01-01

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

An in-vitro scaffold-free epithelial-fibroblast coculture model for the larynx

PubMed Central

Walimbe, Tanaya; Panitch, Alyssa; Sivasankar, M. Preeti

2017-01-01

Objective Physiologically relevant, well-characterized in vitro vocal fold coculture models are needed to test the effects of various challenges and therapeutics on vocal fold physiology. We characterize a healthy state coculture model, created by using bronchial/tracheal epithelial cells and immortalized vocal fold fibroblasts. We also demonstrate that this model can be induced into a fibroplastic state to overexpress stress fibers using TGFβ1. Method Cell metabolic activity of immortalized human vocal fold fibroblasts incubated in different media combinations were confirmed with MTT assay. Fibroblasts were grown to confluence and primary bronchial/tracheal epithelial cells suspended in coculture media were seeded directly over the base layer of the fibroblasts. Cells were treated with TGFβ1 to induce myofibroblast formation. Cell shape and position was confirmed by live cell tracking, fibrosis was confirmed by probing for α smooth muscle actin (α-SMA) and phenotype was confirmed by immunostaining for vimentin and E-cadherin. Results Fibroblasts retain metabolic activity in coculture epithelial media. Live cell imaging revealed a layer of epithelial cells atop fibroblasts. α-SMA expression was enhanced in TGFβ1 treated cells, confirming that both cell types maintained a healthy phenotype in coculture, and can be induced into overexpressing stress fibers. Vimentin and E-cadherin immunostaining show that cells retain phenotype in coculture. Conclusion These data lay effective groundwork for a functional coculture model that retains the reproducibility necessary to serve as a viable diagnostic and therapeutic screening platform. Level of Evidence NA PMID:27859361

Evaluation of Drug-Drug Interaction Potential Between Sacubitril/Valsartan (LCZ696) and Statins Using a Physiologically Based Pharmacokinetic Model.

PubMed

Lin, Wen; Ji, Tao; Einolf, Heidi; Ayalasomayajula, Surya; Lin, Tsu-Han; Hanna, Imad; Heimbach, Tycho; Breen, Christopher; Jarugula, Venkateswar; He, Handan

2017-05-01

Sacubitril/valsartan (LCZ696) has been approved for the treatment of heart failure. Sacubitril is an in vitro inhibitor of organic anion-transporting polypeptides (OATPs). In clinical studies, LCZ696 increased atorvastatin C max by 1.7-fold and area under the plasma concentration-time curve by 1.3-fold, but had little or no effect on simvastatin or simvastatin acid exposure. A physiologically based pharmacokinetics modeling approach was applied to explore the underlying mechanisms behind the statin-specific LCZ696 drug interaction observations. The model incorporated OATP-mediated clearance (CL int,T ) for simvastatin and simvastatin acid to successfully describe the pharmacokinetic profiles of either analyte in the absence or presence of LCZ696. Moreover, the model successfully described the clinically observed drug effect with atorvastatin. The simulations clarified the critical parameters responsible for the observation of a low, yet clinically relevant, drug-drug interaction DDI between sacubitril and atorvastatin and the lack of effect with simvastatin acid. Atorvastatin is administered in its active form and rapidly achieves C max that coincide with the low C max of sacubitril. In contrast, simvastatin requires a hydrolysis step to the acid form and therefore is not present at the site of interactions at sacubitril concentrations that are inhibitory. Similar models were used to evaluate the drug-drug interaction risk for additional OATP-transported statins which predicted to maximally result in a 1.5-fold exposure increase. Copyright © 2017. Published by Elsevier Inc.

Studying Host-Pathogen Interactions In 3-D: Organotypic Models For Infectious Disease And Drug Development

NASA Technical Reports Server (NTRS)

Nickerson, Cheryl A.; Richter, Emily G.; Ott, C. Mark

2006-01-01

Representative, reproducible and high-throughput models of human cells and tissues are critical for a meaningful evaluation of host-pathogen interactions and are an essential component of the research developmental pipeline. The most informative infection models - animals, organ explants and human trials - are not suited for extensive evaluation of pathogenesis mechanisms and screening of candidate drugs. At the other extreme, more cost effective and accessible infection models such as conventional cell culture and static co-culture may not capture physiological and three-dimensional aspects of tissue biology that are important in assessing pathogenesis, and effectiveness and cytotoxicity of therapeutics. Our lab has used innovative bioengineering technology to establish biologically meaningful 3-D models of human tissues that recapitulate many aspects of the differentiated structure and function of the parental tissue in vivo, and we have applied these models to study infectious disease. We have established a variety of different 3-D models that are currently being used in infection studies - including small intestine, colon, lung, placenta, bladder, periodontal ligament, and neuronal models. Published work from our lab has shown that our 3-D models respond to infection with bacterial and viral pathogens in ways that reflect the infection process in vivo. By virtue of their physiological relevance, 3-D cell cultures may also hold significant potential as models to provide insight into the neuropathogenesis of HIV infection. Furthermore, the experimental flexibility, reproducibility, cost-efficiency, and high throughput platform afforded by these 3-D models may have important implications for the design and development of drugs with which to effectively treat neurological complications of HIV infection.

Endogenous Opioid Antagonism in Physiological Experimental Pain Models: A Systematic Review

PubMed Central

Werner, Mads U.; Pereira, Manuel P.; Andersen, Lars Peter H.; Dahl, Jørgen B.

2015-01-01

Opioid antagonists are pharmacological tools applied as an indirect measure to detect activation of the endogenous opioid system (EOS) in experimental pain models. The objective of this systematic review was to examine the effect of mu-opioid-receptor (MOR) antagonists in placebo-controlled, double-blind studies using ʻinhibitoryʼ or ʻsensitizingʼ, physiological test paradigms in healthy human subjects. The databases PubMed and Embase were searched according to predefined criteria. Out of a total of 2,142 records, 63 studies (1,477 subjects [male/female ratio = 1.5]) were considered relevant. Twenty-five studies utilized ʻinhibitoryʼ test paradigms (ITP) and 38 studies utilized ʻsensitizingʼ test paradigms (STP). The ITP-studies were characterized as conditioning modulation models (22 studies) and repetitive transcranial magnetic stimulation models (rTMS; 3 studies), and, the STP-studies as secondary hyperalgesia models (6 studies), ʻpainʼ models (25 studies), summation models (2 studies), nociceptive reflex models (3 studies) and miscellaneous models (2 studies). A consistent reversal of analgesia by a MOR-antagonist was demonstrated in 10 of the 25 ITP-studies, including stress-induced analgesia and rTMS. In the remaining 14 conditioning modulation studies either absence of effects or ambiguous effects by MOR-antagonists, were observed. In the STP-studies, no effect of the opioid-blockade could be demonstrated in 5 out of 6 secondary hyperalgesia studies. The direction of MOR-antagonist dependent effects upon pain ratings, threshold assessments and somatosensory evoked potentials (SSEP), did not appear consistent in 28 out of 32 ʻpainʼ model studies. In conclusion, only in 2 experimental human pain models, i.e., stress-induced analgesia and rTMS, administration of MOR-antagonist demonstrated a consistent effect, presumably mediated by an EOS-dependent mechanisms of analgesia and hyperalgesia. PMID:26029906

Precision-cut rat, mouse, and human intestinal slices as novel models for the early-onset of intestinal fibrosis.

PubMed

Pham, Bao Tung; van Haaften, Wouter Tobias; Oosterhuis, Dorenda; Nieken, Judith; de Graaf, Inge Anne Maria; Olinga, Peter

2015-04-01

Intestinal fibrosis (IF) is a major complication of inflammatory bowel disease. IF research is limited by the lack of relevant in vitro and in vivo models. We evaluated precision-cut intestinal slices (PCIS) prepared from human, rat, and mouse intestine as ex vivo models mimicking the early-onset of (human) IF. Precision-cut intestinal slices prepared from human (h), rat (r), and mouse (m) jejunum, were incubated up to 72 h, the viability of PCIS was assessed by ATP content and morphology, and the gene expression of several fibrosis markers was determined. The viability of rPCIS decreased after 24 h of incubation, whereas mPCIS and hPCIS were viable up to 72 h of culturing. Furthermore, during this period, gene expression of heat shock protein 47 and plasminogen activator inhibitor 1 increased in all PCIS in addition to augmented expression of synaptophysin in hPCIS, fibronectin (Fn2) and TGF-β1 in rPCIS, and Fn2 and connective tissue growth factor (Ctgf) in mPCIS. Addition of TGF-β1 to rPCIS or mPCIS induced the gene expression of the fibrosis markers Pro-collagen1a1, Fn2, and Ctgf in both species. However, none of the fibrosis markers was further elevated in hPCIS. We successfully developed a novel ex vivo model that can mimic the early-onset of fibrosis in the intestine using human, rat, and mouse PCIS. Furthermore, in rat and mouse PCIS, TGF-β1 was able to even further increase the gene expression of fibrosis markers. This indicates that PCIS can be used as a model for the early-onset of IF. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Magnesium degradation under physiological conditions - Best practice.

PubMed

Gonzalez, Jorge; Hou, Rui Qing; Nidadavolu, Eshwara P S; Willumeit-Römer, Regine; Feyerabend, Frank

2018-06-01

This review focusses on the application of physiological conditions for the mechanistic understanding of magnesium degradation. Despite the undisputed relevance of simplified laboratory setups for alloy screening purposes, realistic and predictive in vitro setups are needed. Due to the complexity of these systems, the review gives an overview about technical measures, defines some caveats and can be used as a guideline for the establishment of harmonized laboratory approaches.

The Behavior-Physiology Nexus: Behavioral and Physiological Compensation Are Relied on to Different Extents between Seasons.

PubMed

Basson, Christine H; Clusella-Trullas, Susana

2015-01-01

Environmental variability occurring at different timescales can significantly reduce performance, resulting in evolutionary fitness costs. Shifts in thermoregulatory behavior, metabolism, and water loss via phenotypic plasticity can compensate for thermal variation, but the relative contribution of each mechanism and how they may influence each other are largely unknown. Here, we take an ecologically relevant experimental approach to dissect these potential responses at two temporal scales: weather transients and seasons. Using acclimation to cold, average, or warm conditions in summer and winter, we measure the direction and magnitude of plasticity of resting metabolic rate (RMR), water loss rate (WLR), and preferred body temperature (Tpref) in the lizard Cordylus oelofseni within and between seasons. In summer, lizards selected lower Tpref when acclimated to warm versus cold but had no plasticity of either RMR or WLR. By contrast, winter lizards showed partial compensation of RMR but no behavioral compensation. Between seasons, both behavioral and physiological shifts took place. By integrating ecological reality into laboratory assays, we demonstrate that behavioral and physiological responses of C. oelofseni can be contrasting, depending on the timescale investigated. Incorporating ecologically relevant scenarios and the plasticity of multiple traits is thus essential when attempting to forecast extinction risk to climate change.

Distribution and Biological Effects of Nanoparticles in the Reproductive System.

PubMed

Liu, Ying; Li, Hongxia; Xiao, Kai

2016-01-01

Nanoparticles have shown great potential in biomedical applications such as imaging probes and drug delivery. However, the increasing use of nanoparticles has raised concerns about their adverse effects on human health and environment. Reproductive tissues and gametes represent highly delicate biological systems with the essential function of transmitting genetic information to the offspring, which is highly sensitive to environmental toxicants. This review aims to summarzie the penetration of physiological barriers (blood-testis barrier and placental barrier), distribution and biological effects of nanoparticles in the reproductive system, which is essential to control the beneficial effects of nanoparticles applications and to avoid their adverse effects on the reproductive system. We referred to a large number of relevant peer-reviewed research articles about the reproductive toxicity of nanoparticles. The comprehensive information was summarized into two parts: physiological barrier penetration and biological effects of nanoparticles in male or female reproductive system; distribution and metabolism of nanoparticles in the reproductive system. The representative examples were also presented in four tables. The in vitro and in vivo studies imply that some nanoparticles are able to cross the blood-testis barrier or placental barrier, and their penetration depends on the physicochemical characteristics of nanoparticles (e.g., composition, shape, particle size and surface coating). The toxicity assays indicate that nanoparticles might induce adverse physiological effects and impede fertility or embryogenesis. The barrier penetration, adverse physiological effects, distribution and metabolism are closely related to physicochemical characteristics of nanoparticles. Further systematic and mechanistic studies using well-characterized nanoparticles, relevant administration routes, and doses relevant to the expected exposure level are required to improve our understanding of biological effects of nanoparticles on the reproductive system.

A physiologically-based plant hydraulics scheme for ESMs: impacts of hydraulic trait variability for tropical forests under drought

NASA Astrophysics Data System (ADS)

Christoffersen, B. O.; Xu, C.; Fisher, R.; Fyllas, N.; Gloor, M.; Fauset, S.; Galbraith, D.; Koven, C.; Knox, R. G.; Kueppers, L. M.; Chambers, J. Q.; Meir, P.; McDowell, N. G.

2016-12-01

A major challenge of Earth System Models (ESMs) is to capture the diversity of individual-level responses to changes in water availability. Yet, decades of research in plant physiological ecology have given us a means to quantify central tendencies and variances of plant hydraulic traits. If ESMs possessed the relevant hydrodynamic process structure, these traits could be incorporated into improved predictions of community- and ecosystem-level processes such as tree mortality. We present a model of plant hydraulics in which all parameters are biologically-interpretable and measurable traits, such as turgor loss point πtlp, bulk elastic modulus ɛ, hydraulic capacitance Cft, xylem hydraulic conductivity ks,max, water potential at 50 % loss of conductivity for both xylem (P50,x) and stomata (P50,gs). We applied this scheme to tropical forests by incorporating it into both an individual-based model `Trait Forest Simulator' (TFS) and the `Functionally Assembled Terrestrial Ecosystem Simulator' (FATES; derived from CLM(ED)), and explore the consequences of variability in plant hydraulic traits on simulated leaf water potential, a potentially powerful predictor of tree mortality. We show that, independent of the difference between P50,gs and P50,x, or the hydraulic safety margin (HSM), diversity in hydraulic traits can increase or decrease whole-ecosystem resistance to hydraulic failure, and thus ecosystem-level responses to drought. Key uncertainties remaining concern how coordination and trade-offs in hydraulic traits are parameterized. We conclude that inclusion of such a physiologically-based plant hydraulics scheme in ESMs will greatly improve the capability of ESMs to predict functional trait filtering within ecosystems in responding to environmental change.

Optimization of physiological parameter for macroscopic modeling of reacted singlet oxygen concentration in an in-vivo model

NASA Astrophysics Data System (ADS)

Wang, Ken Kang-Hsin; Busch, Theresa M.; Finlay, Jarod C.; Zhu, Timothy C.

2009-02-01

Singlet oxygen (1O2) is generally believed to be the major cytotoxic agent during photodynamic therapy (PDT), and the reaction between 1O2 and tumor cells define the treatment efficacy. From a complete set of the macroscopic kinetic equations which describe the photochemical processes of PDT, we can express the reacted 1O2 concentration, [1O2]rx, in a form related to time integration of the product of 1O2 quantum yield and the PDT dose rate. The production of [1O2]rx involves physiological and photophysical parameters which need to be determined explicitly for the photosensitizer of interest. Once these parameters are determined, we expect the computed [1O2]rx to be an explicit dosimetric indicator for clinical PDT. Incorporating the diffusion equation governing the light transport in turbid medium, the spatially and temporally-resolved [1O2]rx described by the macroscopic kinetic equations can be numerically calculated. A sudden drop of the calculated [1O2]rx along with the distance following the decrease of light fluence rate is observed. This suggests that a possible correlation between [1O2]rx and necrosis boundary may occur in the tumor subject to PDT irradiation. In this study, we have theoretically examined the sensitivity of the physiological parameter from two clinical related conditions: (1) collimated light source on semi-infinite turbid medium and (2) linear light source in turbid medium. In order to accurately determine the parameter in a clinical relevant environment, the results of the computed [1O2]rx are expected to be used to fit the experimentally-measured necrosis data obtained from an in vivo animal model.

Effects of spinal cord injury-induced changes in muscle activation on foot drag in a computational rat ankle model.

PubMed

Hillen, Brian K; Jindrich, Devin L; Abbas, James J; Yamaguchi, Gary T; Jung, Ranu

2015-04-01

Spinal cord injury (SCI) can lead to changes in muscle activation patterns and atrophy of affected muscles. Moderate levels of SCI are typically associated with foot drag during the swing phase of locomotion. Foot drag is often used to assess locomotor recovery, but the causes remain unclear. We hypothesized that foot drag results from inappropriate muscle coordination preventing flexion at the stance-to-swing transition. To test this hypothesis and to assess the relative contributions of neural and muscular changes on foot drag, we developed a two-dimensional, one degree of freedom ankle musculoskeletal model with gastrocnemius and tibialis anterior muscles. Anatomical data collected from sham-injured and incomplete SCI (iSCI) female Long-Evans rats as well as physiological data from the literature were used to implement an open-loop muscle dynamics model. Muscle insertion point motion was calculated with imposed ankle trajectories from kinematic analysis of treadmill walking in sham-injured and iSCI animals. Relative gastrocnemius deactivation and tibialis anterior activation onset times were varied within physiologically relevant ranges based on simplified locomotor electromyogram profiles. No-atrophy and moderate muscle atrophy as well as normal and injured muscle activation profiles were also simulated. Positive moments coinciding with the transition from stance to swing phase were defined as foot swing and negative moments as foot drag. Whereas decreases in activation delay caused by delayed gastrocnemius deactivation promote foot drag, all other changes associated with iSCI facilitate foot swing. Our results suggest that even small changes in the ability to precisely deactivate the gastrocnemius could result in foot drag after iSCI. Copyright © 2015 the American Physiological Society.

Topographic variations of water supply and plant hydraulics in a mountainous forest

NASA Astrophysics Data System (ADS)

Tai, X.; Mackay, D. S.; Ewers, B. E.; Parsekian, A.; Sperry, J.; Beverly, D.; Speckman, H. N.; Ohara, N.; Fantello, N.; Kelleners, T.; Fullhart, A. T.

2017-12-01

How plants respond to variable local water supply in complex soil-topography systems is not clear although critical. This has been attributed to a lack of integrated models that can resolve relevant hydrological and physiological mechanisms and intensive field monitoring to inform/evaluate such a model. This research addresses these knowledge gaps by leveraging a newly developed distributed plant hydraulics model, ParFlow-TREES, and detailed geophysical and physiological measurements. Observations of sap flow, leaf water potentials, micrometeorology, and electrical resistivity tomography (ERT) are combined with the model to examine the key mechanisms affecting the spatial distribution of soil water and tree water stress. Modeling results showed higher soil water condition at bottom of the hillslope on average, corroborating the ERT-derived soil moisture observations. Hydraulic traits are critical to capture the sap flux dynamics of species with contrasting leaf water potential regulation strategies and heterogeneous soil drying at different hillslope positions. These results suggested the integrated effect of topography and plants on the evolvement of soil moisture distribution. Furthermore, sensitivity analysis demonstrated the importance of using distributed observations to validate/calibrate distributed models. Focusing on lumped variables or only one particular variable might give misleading conclusions. Co-located observations improve the characterization of plant traits and local living environment, providing key information needed as a first step in resolving the form and function of the critical zone from bedrock to atmosphere. We will discuss the broader implications and potential applications of this intensive data-model comparison at other sites and greater spatial extent.

Evaluation of a computer-based approach to teaching acid/base physiology.

PubMed

Rawson, Richard E; Quinlan, Kathleen M

2002-12-01

Because acid/base physiology is a difficult subject for most medical and veterinary students, the first author designed a software program, Acid/Base Primer, that would help students with this topic. The Acid/Base Primer was designed and evaluated within a conceptual framework of basic educational principles. Seventy-five first-year veterinary students (of 81; 93% response rate) participated in this study. Students took both a pre- and posttest of content understanding. After completing the Acid/Base Primer in pairs, each student filled out a survey evaluating the features of the program and describing his/her use and experience of it. Four pairs of students participated in interviews that elaborated on the surveys. Scores improved from 53 +/- 2% on the pretest to 74 +/- 1% on an immediate posttest. On surveys and in interviews, students reported that the program helped them construct their own understanding of acid/base physiology and prompted discussions in pairs of students when individual understandings differed. The case-based format provided anchors and a high degree of relevance. Repetition of concepts helped students develop a more complex network of understanding. Questions in the program served to scaffold the learning process by providing direction, accentuating the relevant features of the cases, and provoking discussion. Guidelines for software development were generated on the basis of the findings and relevant educational literature.

A conceptual framework for homeostasis: development and validation.

PubMed

McFarland, Jenny; Wenderoth, Mary Pat; Michael, Joel; Cliff, William; Wright, Ann; Modell, Harold

2016-06-01

We have developed and validated a conceptual framework for understanding and teaching organismal homeostasis at the undergraduate level. The resulting homeostasis conceptual framework details critical components and constituent ideas underlying the concept of homeostasis. It has been validated by a broad range of physiology faculty members from community colleges, primarily undergraduate institutions, research universities, and medical schools. In online surveys, faculty members confirmed the relevance of each item in the framework for undergraduate physiology and rated the importance and difficulty of each. The homeostasis conceptual framework was constructed as a guide for teaching and learning of this critical core concept in physiology, and it also paves the way for the development of a concept inventory for homeostasis. Copyright © 2016 The American Physiological Society.

Cell-oriented modeling of angiogenesis.

PubMed

Guidolin, Diego; Rebuffat, Piera; Albertin, Giovanna

2011-01-01

Due to its significant involvement in various physiological and pathological conditions, angiogenesis (the development of new blood vessels from an existing vasculature) represents an important area of the actual biological research and a field in which mathematical modeling proved particularly useful in supporting the experimental work. In this paper, we focus on a specific modeling strategy, known as "cell-centered" approach. This type of mathematical models work at a "mesoscopic scale," assuming the cell as the natural level of abstraction for computational modeling of development. They treat cells phenomenologically, considering their essential behaviors to study how tissue structure and organization emerge from the collective dynamics of multiple cells. The main contributions of the cell-oriented approach to the study of the angiogenic process will be described. From one side, they have generated "basic science understanding" about the process of capillary assembly during development, growth, and pathology. On the other side, models were also developed supporting "applied biomedical research" for the purpose of identifying new therapeutic targets and clinically relevant approaches for either inhibiting or stimulating angiogenesis.

Drug-induced cholestasis: mechanisms, models, and markers.

PubMed

Chatterjee, Sagnik; Annaert, Pieter

2018-04-27

Drug-induced cholestasis is a risk factor in progression of drug candidates, and poses serious health hazard if not detected before going into human. Intrahepatic accumulation of bile acids (BAs) represents a characteristic phenomenon associated with drug-induced cholestasis. The major challenges in obtaining a complete understanding of drug-induced cholestasis lies in the complexity of BA-mediated toxicity mechanisms and the impact of bile acids at different 'targets' such as transporters, enzymes and nuclear receptors. At the same time, it is not trivial to have a relevant in vitro system that recapitulates these features. In addition, lack of sensitive and early preclinical biomarkers, relevant to the clinical situation, complicates proper detection of drug-induced cholestasis. Significant overlap in biomarker signatures between different mechanisms of drug-induced liver injury (DILI) precludes identification of specific mechanisms. Over the last decade the knowledge gaps in drug-induced cholestasis are closing due to growing mechanistic understanding of BA-mediated toxicity at (patho)physiologically relevant BA concentrations. Significant progress has been made in the mechanistic understanding of drug-induced cholestasis and associated toxicity, biomarkers and susceptibility factors. In addition, novel in vitro models are evolving which provide a holistic understanding of processes underlying drug-induced cholestasis. This review summarizes the challenges and recent understandings about drug-induced cholestasis with a potential path forward. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A Laboratory Program for Bioinorganic Chemistry

ERIC Educational Resources Information Center

Ochiai, Ei-ichiro

1973-01-01

Outlines a laboratory course entitled Inorganic Chemistry for Biological Sciences'' which is designed primarily for juniors in biochemistry, physiology, and soil sciences. Inclusion of relevant environmental topics is indicated. (CC)

Waveform shape analysis: extraction of physiologically relevant information from Doppler recordings.

PubMed

Ramsay, M M; Broughton Pipkin, F; Rubin, P C; Skidmore, R

1994-05-01

1. Doppler recordings were made from the brachial artery of healthy female subjects during a series of manoeuvres which altered the pressure-flow characteristics of the vessel. 2. Changes were induced in the peripheral circulation of the forearm by the application of heat or ice-packs. A sphygmomanometer cuff was used to create graded occlusion of the vessel above and below the point of measurement. Recordings were also made whilst the subjects performed a standardized Valsalva manoeuvre. 3. The Doppler recordings were analysed both with the standard waveform indices (systolic/diastolic ratio, pulsatility index and resistance index) and by the method of Laplace transform analysis. 4. The waveform parameters obtained by Laplace transform analysis distinguished the different changes in flow conditions; they thus had direct physiological relevance, unlike the standard waveform indices.

[Signaling mechanisms involved in resolution of inflammation].

PubMed

Cervantes-Villagrana, Rodolfo Daniel; Cervantes-Villagrana, Alberto Rafael; Presno-Bernal, José Miguel

2014-01-01

Inflammation is a physiological process, which eliminates pathogens and induces repair of damaged tissue. This process is controlled by negative feedback mechanisms, but if the inflammation persists, it generates a deleterious autoimmune process or can to contribute with diseases such as obesity or cancer. The inflammation resolution involves mechanisms such as decrease of proliferation and maturation of immune cells, phagocytosis and apoptosis of immune cells, and decrease of proinflammatory mediators. Therefore, is relevant to study the physiological effects of specific receptors that participate in inflammation resolution and the design of specific agonists as conventional anti-inflammatory therapeutics, without dramatic collateral effects. In this review, we study some mechanisms associated with inflammation inhibition, particularly the transduction of receptors for ligands with anti-inflammatory effects and that are relevant for their potential therapeutic.

A Novel, Ecologically Relevant, Highly Preferred, and Non-invasive Means of Oral Substance Administration for Rodents

PubMed Central

Sobolewski, Marissa; Allen, Joshua L.; Morris-Schaffer, Keith; Klocke, Carolyn; Conrad, Katherine; Cory-Slechta, Deborah A.

2017-01-01

Prenatal stress and nutrition are well-known to alter a broad range of physiological systems, notably metabolic, endocrine and neurobehavioral function. Commonly used methods for oral administration of xenobiotics can, by acting as a stressor or altering normal nutrition intake, alter these physiological systems as well. Taken together, oral administration methods may unintentionally introduce confounding physiological effects that can mask or enhance toxicity of xenobiotics, particularly if they share biological targets. Consequently, it should be preferable to develop alternative methods without these potential confounds. The aim of this study was to determine the suitability of mealworms as an alternative treat-based method to deliver xenobiotics via the orogastric route. Accurate oral administration is contingent on motivation and preference; mice reliably preferred mealworms over wafer cookie treats. Further, ingestion of wafer cookies significantly increased mouse blood glucose levels, whereas unaltered mealworms produced no such change. Mealworms functioned effectively to orally administer glucose, as glucose-spiked mealworms produced a rise in blood glucose equivalent to the ingestion of the wafer cookie. Mealworms did not interfere with the physiological function of orally administered d-amphetamine, as both mealworm and oral gavage administered d-amphetamine showed similar alterations in locomotor behavior (mice did not fully consume d-amphetamine-dosed cookies and thus could not be compared). Collectively, the findings indicate that mealworms are a preferred and readily consumed treat, which importantly mimics environmental-relevant nutritional intake, and mealworms per se do not alter glucose metabolic pathways. Additionally, mealworms accurately delivered xenobiotics into blood circulation and did not interfere with the physiological function of administered xenobiotics. Thus mealworm-based oral administration may be a preferable and accurate route of xenobiotic administration that eliminates physiological alterations associated with other methods of delivery. PMID:27094606

A novel, ecologically relevant, highly preferred, and non-invasive means of oral substance administration for rodents.

PubMed

Sobolewski, Marissa; Allen, Joshua L; Morris-Schaffer, Keith; Klocke, Carolyn; Conrad, Katherine; Cory-Slechta, Deborah A

2016-01-01

Prenatal stress and nutrition are well-known to alter a broad range of physiological systems, notably metabolic, endocrine and neurobehavioral function. Commonly used methods for oral administration of xenobiotics can, by acting as a stressor or altering normal nutrition intake, alter these physiological systems as well. Taken together, oral administration methods may unintentionally introduce confounding physiological effects that can mask or enhance toxicity of xenobiotics, particularly if they share biological targets. Consequently, it should be preferable to develop alternative methods without these potential confounds. The aim of this study was to determine the suitability of mealworms as an alternative treat-based method to deliver xenobiotics via the orogastric route. Accurate oral administration is contingent on motivation and preference; mice reliably preferred mealworms over wafer cookie treats. Further, ingestion of wafer cookies significantly increased mouse blood glucose levels, whereas unaltered mealworms produced no such change. Mealworms functioned effectively to orally administer glucose, as glucose-spiked mealworms produced a rise in blood glucose equivalent to the ingestion of the wafer cookie. Mealworms did not interfere with the physiological function of orally administered d-amphetamine, as both mealworm and oral gavage administered d-amphetamine showed similar alterations in locomotor behavior (mice did not fully consume d-amphetamine-dosed cookies and thus could not be compared). Collectively, the findings indicate that mealworms are a preferred and readily consumed treat, which importantly mimics environmental-relevant nutritional intake, and mealworms per se do not alter glucose metabolic pathways. Additionally, mealworms accurately delivered xenobiotics into blood circulation and did not interfere with the physiological function of administered xenobiotics. Thus mealworm-based oral administration may be a preferable and accurate route of xenobiotic administration that eliminates physiological alterations associated with other methods of delivery. Copyright © 2016. Published by Elsevier Inc.

Microbial ecology and host-microbiota interactions during early life stages

PubMed Central

Collado, Maria Carmen; Cernada, Maria; Baüerl, Christine; Vento, Máximo; Pérez-Martínez, Gaspar

2012-01-01

The role of human microbiota has been redefined during recent years and its physiological role is now much more important than earlier understood. Intestinal microbial colonization is essential for the maturation of immune system and for the developmental regulation of the intestinal physiology. Alterations in this process of colonization have been shown to predispose and increase the risk to disease later in life. The first contact of neonates with microbes is provided by the maternal microbiota. Moreover, mode of delivery, type of infant feeding and other perinatal factors can influence the establishment of the infant microbiota. Taken into consideration all the available information it could be concluded that the exposure to the adequate microbes early in gestation and neonatal period seems to have a relevant role in health. Maternal microbial environment affects maternal and fetal immune physiology and, of relevance, this interaction with microbes at the fetal-maternal interface could be modulated by specific microbes administered to the pregnant mother. Indeed, probiotic interventions aiming to reduce the risk of immune-mediated diseases may appear effective during early life. PMID:22743759

Bio-integrated electronics and sensor systems

NASA Astrophysics Data System (ADS)

Yeo, Woon-Hong; Webb, R. Chad; Lee, Woosik; Jung, Sungyoung; Rogers, John A.

2013-05-01

Skin-mounted epidermal electronics, a strategy for bio-integrated electronics, provide an avenue to non-invasive monitoring of clinically relevant physiological signals for healthcare applications. Current conventional systems consist of single-point sensors fastened to the skin with adhesives, and sometimes with conducting gels, which limits their use outside of clinical settings due to loss of adhesion and irritation to the user. In order to facilitate extended use of skin-mounted healthcare sensors without disrupting everyday life, we envision electronic monitoring systems that integrate seamlessly with the skin below the notice of the user. This manuscript reviews recent significant results towards our goal of wearable electronic sensor systems for long-term monitoring of physiological signals. Ultra-thin epidermal electronic systems (EES) are demonstrated for extended use on the skin, in a conformal manner, including during everyday bathing and sleeping activities. We describe the assessment of clinically relevant physiological parameters, such as electrocardiograms (ECG), electromyograms (EMG), electroencephalograms (EEG), temperature, mechanical strain and thermal conductivity, using examples of multifunctional EES devices. Additionally, we demonstrate capability for real life application of EES by monitoring the system functionality, which has no discernible change, during cyclic fatigue testing.

Development of a Promising Fish Model (Oryzias melastigma) for Assessing Multiple Responses to Stresses in the Marine Environment

PubMed Central

Dong, Sijun; Kang, Mei; Wu, Xinlong; Ye, Ting

2014-01-01

With the increasing number of contaminants in the marine environment, various experimental organisms have been “taken into labs” by investigators to find the most suitable environmentally relevant models for toxicity testing. The marine medaka, Oryzias melastigma, has a number of advantages that make it a prime candidate for these tests. Recently, many studies have been conducted on marine medaka, especially in terms of their physiological, biochemical, and molecular responses after exposure to contaminants and other environmental stressors. This review provides a literature survey highlighting the steady increase of ecotoxicological research on marine medaka, summarizes the advantages of using O. melastigma as a tool for toxicological research, and promotes the utilization of this organism in future studies. PMID:24724087

Neurobiology of Caenorhabditis elegans Locomotion: Where Do We Stand?

PubMed Central

Gjorgjieva, Julijana; Biron, David; Haspel, Gal

2014-01-01

Animals use a nervous system for locomotion in some stage of their life cycle. The nematode Caenorhabditis elegans, a major animal model for almost all fields of experimental biology, has long been used for detailed studies of genetic and physiological locomotion mechanisms. Of its 959 somatic cells, 302 are neurons that are identifiable by lineage, location, morphology, and neurochemistry in every adult hermaphrodite. Of those, 75 motoneurons innervate body wall muscles that provide the thrust during locomotion. In this Overview, we concentrate on the generation of either forward- or backward-directed motion during crawling and swimming. We describe locomotion behavior, the parts constituting the locomotion system, and the relevant neuronal connectivity. Because it is not yet fully understood how these components combine to generate locomotion, we discuss competing hypotheses and models. PMID:26955070

An open-access microfluidic model for lung-specific functional studies at an air-liquid interface.

PubMed

Nalayanda, Divya D; Puleo, Christopher; Fulton, William B; Sharpe, Leilani M; Wang, Tza-Huei; Abdullah, Fizan

2009-10-01

In an effort to improve the physiologic relevance of existing in vitro models for alveolar cells, we present a microfluidic platform which provides an air-interface in a dynamic system combining microfluidic and suspended membrane culture systems. Such a system provides the ability to manipulate multiple parameters on a single platform along with ease in cell seeding and manipulation. The current study presents a comparison of the efficacy of the hybrid system with conventional platforms using assays analyzing the maintenance of function and integrity of A549 alveolar epithelial cell monolayer cultures. The hybrid system incorporates bio-mimetic nourishment on the basal side of the epithelial cells along with an open system on the apical side of the cells exposed to air allowing for easy access for assays.

Using guinea pigs in studies relevant to asthma and COPD

PubMed Central

Canning, Brendan J.; Chou, Yangling

2010-01-01

The guinea pig has been the most commonly used small animal species in preclinical studies related to asthma and COPD. The primary advantages of the guinea pig are the similar potencies and efficacies of agonists and antagonists in human and guinea pig airways and the many similarities in physiological processes, especially airway autonomic control and the response to allergen. The primary disadvantages to using guinea pigs are the lack of transgenic methods, limited numbers of guinea pig strains for comparative studies and a prominent axon reflex that is unlikely to be present in human airways. These attributes and various models developed in guinea pigs are discussed. PMID:18462968

Comparison of Caenorhabditis elegans NLP peptides with arthropod neuropeptides.

PubMed

Husson, Steven J; Lindemans, Marleen; Janssen, Tom; Schoofs, Liliane

2009-04-01

Neuropeptides are small messenger molecules that can be found in all metazoans, where they govern a diverse array of physiological processes. Because neuropeptides seem to be conserved among pest species, selected peptides can be considered as attractive targets for drug discovery. Much can be learned from the model system Caenorhabditis elegans because of the availability of a sequenced genome and state-of-the-art postgenomic technologies that enable characterization of endogenous peptides derived from neuropeptide-like protein (NLP) precursors. Here, we provide an overview of the NLP peptide family in C. elegans and discuss their resemblance with arthropod neuropeptides and their relevance for anthelmintic discovery.

Resilience in Aging Mice.

PubMed

Kirkland, James L; Stout, Michael B; Sierra, Felipe

2016-11-01

Recently discovered interventions that target fundamental aging mechanisms have been shown to increase life span in mice and other species, and in some cases, these same manipulations have been shown to enhance health span and alleviate multiple age-related diseases and conditions. Aging is generally associated with decreases in resilience, the capacity to respond to or recover from clinically relevant stresses such as surgery, infections, or vascular events. We hypothesize that the age-related increase in susceptibility to those diseases and conditions is driven by or associated with the decrease in resilience. Thus, a test for resilience at middle age or even earlier could represent a surrogate approach to test the hypothesis that an intervention delays the process of aging itself. For this, animal models to test resilience accurately and predictably are needed. In addition, interventions that increase resilience might lead to treatments aimed at enhancing recovery following acute illnesses, or preventing poor outcomes from medical interventions in older, prefrail subjects. At a meeting of basic researchers and clinicians engaged in research on mechanisms of aging and care of the elderly, the merits and drawbacks of investigating effects of interventions on resilience in mice were considered. Available and potential stressors for assessing physiological resilience as well as the notion of developing a limited battery of such stressors and how to rank them were discussed. Relevant ranking parameters included value in assessing general health (as opposed to focusing on a single physiological system), ease of use, cost, reproducibility, clinical relevance, and feasibility of being repeated in the same animal longitudinally. During the discussions it became clear that, while this is an important area, very little is known or established. Much more research is needed in the near future to develop appropriate tests of resilience in animal models within an aging context. The preliminary set of tests ranked by the participants is discussed here, recognizing that this is a first attempt. Published by Oxford University Press on behalf of The Gerontological Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

A physiologically based pharmacokinetic model for ionic silver and silver nanoparticles

PubMed Central

Bachler, Gerald; von Goetz, Natalie; Hungerbühler, Konrad

2013-01-01

Silver is a strong antibiotic that is increasingly incorporated into consumer products as a bulk, salt, or nanosilver, thus potentially causing side-effects related to human exposure. However, the fate and behavior of (nano)silver in the human body is presently not well understood. In order to aggregate the existing experimental information, a physiologically based pharmacokinetic model (PBPK) was developed in this study for ionic silver and nanosilver. The structure of the model was established on the basis of toxicokinetic data from intravenous studies. The number of calibrated parameters was minimized in order to enhance the predictive capability of the model. We validated the model structure for both silver forms by reproducing exposure conditions (dermal, oral, and inhalation) of in vivo experiments and comparing simulated and experimentally assessed organ concentrations. Therefore, the percutaneous, intestinal, or pulmonary absorption fraction was estimated based on the blood silver concentration of the respective experimental data set. In all of the cases examined, the model could successfully predict the biodistribution of ionic silver and 15–150 nm silver nanoparticles, which were not coated with substances designed to prolong the circulatory time (eg, polyethylene glycol). Furthermore, the results of our model indicate that: (1) within the application domain of our model, the particle size and coating had a minor influence on the biodistribution; (2) in vivo, it is more likely that silver nanoparticles are directly stored as insoluble salt particles than dissolve into Ag+; and (3) compartments of the mononuclear phagocytic system play a minor role in exposure levels that are relevant for human consumers. We also give an example of how the model can be used in exposure and risk assessments based on five different exposure scenarios, namely dietary intake, use of three separate consumer products, and occupational exposure. PMID:24039420

Assessing Airflow Sensitivity to Healthy and Diseased Lung Conditions in a Computational Fluid Dynamics Model Validated In Vitro.

PubMed

Sul, Bora; Oppito, Zachary; Jayasekera, Shehan; Vanger, Brian; Zeller, Amy; Morris, Michael; Ruppert, Kai; Altes, Talissa; Rakesh, Vineet; Day, Steven; Robinson, Risa; Reifman, Jaques; Wallqvist, Anders

2018-05-01

Computational models are useful for understanding respiratory physiology. Crucial to such models are the boundary conditions specifying the flow conditions at truncated airway branches (terminal flow rates). However, most studies make assumptions about these values, which are difficult to obtain in vivo. We developed a computational fluid dynamics (CFD) model of airflows for steady expiration to investigate how terminal flows affect airflow patterns in respiratory airways. First, we measured in vitro airflow patterns in a physical airway model, using particle image velocimetry (PIV). The measured and computed airflow patterns agreed well, validating our CFD model. Next, we used the lobar flow fractions from a healthy or chronic obstructive pulmonary disease (COPD) subject as constraints to derive different terminal flow rates (i.e., three healthy and one COPD) and computed the corresponding airflow patterns in the same geometry. To assess airflow sensitivity to the boundary conditions, we used the correlation coefficient of the shape similarity (R) and the root-mean-square of the velocity magnitude difference (Drms) between two velocity contours. Airflow patterns in the central airways were similar across healthy conditions (minimum R, 0.80) despite variations in terminal flow rates but markedly different for COPD (minimum R, 0.26; maximum Drms, ten times that of healthy cases). In contrast, those in the upper airway were similar for all cases. Our findings quantify how variability in terminal and lobar flows contributes to airflow patterns in respiratory airways. They highlight the importance of using lobar flow fractions to examine physiologically relevant airflow characteristics.

Application of Biologically-Based Lumping To Investigate the ...

EPA Pesticide Factsheets

People are often exposed to complex mixtures of environmental chemicals such as gasoline, tobacco smoke, water contaminants, or food additives. However, investigators have often considered complex mixtures as one lumped entity. Valuable information can be obtained from these experiments, though this simplification provides little insight into the impact of a mixture's chemical composition on toxicologically-relevant metabolic interactions that may occur among its constituents. We developed an approach that applies chemical lumping methods to complex mixtures, in this case gasoline, based on biologically relevant parameters used in physiologically-based pharmacokinetic (PBPK) modeling. Inhalation exposures were performed with rats to evaluate performance of our PBPK model. There were 109 chemicals identified and quantified in the vapor in the chamber. The time-course kinetic profiles of 10 target chemicals were also determined from blood samples collected during and following the in vivo experiments. A general PBPK model was used to compare the experimental data to the simulated values of blood concentration for the 10 target chemicals with various numbers of lumps, iteratively increasing from 0 to 99. Large reductions in simulation error were gained by incorporating enzymatic chemical interactions, in comparison to simulating the individual chemicals separately. The error was further reduced by lumping the 99 non-target chemicals. Application of this biologic

Computational models of the pulmonary circulation: Insights and the move towards clinically directed studies

PubMed Central

Tawhai, Merryn H.; Clark, Alys R.; Burrowes, Kelly S.

2011-01-01

Biophysically-based computational models provide a tool for integrating and explaining experimental data, observations, and hypotheses. Computational models of the pulmonary circulation have evolved from minimal and efficient constructs that have been used to study individual mechanisms that contribute to lung perfusion, to sophisticated multi-scale and -physics structure-based models that predict integrated structure-function relationships within a heterogeneous organ. This review considers the utility of computational models in providing new insights into the function of the pulmonary circulation, and their application in clinically motivated studies. We review mathematical and computational models of the pulmonary circulation based on their application; we begin with models that seek to answer questions in basic science and physiology and progress to models that aim to have clinical application. In looking forward, we discuss the relative merits and clinical relevance of computational models: what important features are still lacking; and how these models may ultimately be applied to further increasing our understanding of the mechanisms occurring in disease of the pulmonary circulation. PMID:22034608

Biochemical activity and multiple locations of particulate guanylate cyclase in Rhyacophila dorsalis acutidens (Insecta: Trichoptera) provide insights into the cGMP signalling pathway in Malpighian tubules.

PubMed

Secca, T; Sciaccaluga, M; Marra, A; Barberini, L; Bicchierai, M C

2011-04-01

In insect renal physiology, cGMP and cAMP have important regulatory roles. In Drosophila melanogaster, considered a good model for molecular physiology studies, and in other insects, cGMP and cAMP act as signalling molecules in the Malpighian tubules (MTs). However, many questions related to cyclic nucleotide functions are unsolved in principal cells (PC) and stellate cells (SC), the two cell types that compose the MT. In PC, despite the large body of information available on soluble guanylate cyclase (sGC) in the cGMP pathway, the functional circuit of particulate guanylate cyclase (pGC) remains obscure. In SC, on the other side, the synthesis and physiological role of the cGMP are still unknown. Our biochemical data regarding the presence of cyclic nucleotides in the MTs of Rhyacophila dorsalis acutidens revealed a cGMP level above the 50%, in comparison with the cAMP. The specific activity values for the membrane-bound guanylate cyclase were also recorded, implying that, besides the sGC, pGC is a physiologically relevant source of cGMP in MTs. Cytochemical studies showed ultrastructurally that there was a great deal of pGC on the basolateral membranes of both the principal and stellate cells. In addition, pGC was also detected in the contact zone between the two cell types and in the apical microvillar region of the stellate cells bordering the tubule lumen. The pGC signal is so well represented in PC and, unexpectedly in SC of MTs, that it is possible to hypothesize the existence of still uncharacterized physiological processes regulated by the pGC-cGMP system. Copyright © 2011 Elsevier Ltd. All rights reserved.

Demand for interdisciplinary laboratories for physiology research by undergraduate students in biosciences and biomedical engineering.

PubMed

Clase, Kari L; Hein, Patrick W; Pelaez, Nancy J

2008-12-01

Physiology as a discipline is uniquely positioned to engage undergraduate students in interdisciplinary research in response to the 2006-2011 National Science Foundation Strategic Plan call for innovative transformational research, which emphasizes multidisciplinary projects. To prepare undergraduates for careers that cross disciplinary boundaries, students need to practice interdisciplinary communication in academic programs that connect students in diverse disciplines. This report surveys policy documents relevant to this emphasis on interdisciplinary training and suggests a changing role for physiology courses in bioscience and engineering programs. A role for a physiology course is increasingly recommended for engineering programs, but the study of physiology from an engineering perspective might differ from the study of physiology as a basic science. Indeed, physiology laboratory courses provide an arena where biomedical engineering and bioscience students can apply knowledge from both fields while cooperating in multidisciplinary teams under specified technical constraints. Because different problem-solving approaches are used by students of engineering and bioscience, instructional innovations are needed to break down stereotypes between the disciplines and create an educational environment where interdisciplinary teamwork is used to bridge differences.

Enhancement of non-invasive trans-membrane drug delivery using ultrasound and microbubbles during physiologically relevant flow.

PubMed

Shamout, Farah E; Pouliopoulos, Antonios N; Lee, Patrizia; Bonaccorsi, Simone; Towhidi, Leila; Krams, Rob; Choi, James J

2015-09-01

Sonoporation has been associated with drug delivery across cell membranes and into target cells, yet several limitations have prohibited further advancement of this technology. Higher delivery rates were associated with increased cellular death, thus implying a safety-efficacy trade-off. Meanwhile, there has been no reported study of safe in vitro sonoporation in a physiologically relevant flow environment. The objective of our study was not only to evaluate sonoporation under physiologically relevant flow conditions, such as fluid velocity, shear stress and temperature, but also to design ultrasound parameters that exploit the presence of flow to maximize sonoporation efficacy while minimizing or avoiding cellular damage. Human umbilical vein endothelial cells (EA.hy926) were seeded in flow chambers as a monolayer to mimic the endothelium. A peristaltic pump maintained a constant fluid velocity of 12.5 cm/s. A focused 0.5 MHz transducer was used to sonicate the cells, while an inserted focused 7.5 MHz passive cavitation detector monitored microbubble-seeded cavitation emissions. Under these conditions, propidium iodide, which is normally impermeable to the cell membrane, was traced to determine whether it could enter cells after sonication. Meanwhile, calcein-AM was used as a cell viability marker. A range of focused ultrasound parameters was explored, with several unique bioeffects observed: cell detachment, preservation of cell viability with no membrane penetration, cell death and preservation of cell viability with sonoporation. The parameters were then modified further to produce safe sonoporation with minimal cell death. To increase the number of favourable cavitation events, we lowered the ultrasound exposure pressure to 40 kPapk-neg and increased the number of cavitation nuclei by 50 times to produce a trans-membrane delivery rate of 62.6% ± 4.3% with a cell viability of 95% ± 4.2%. Furthermore, acoustic cavitation analysis showed that the low pressure sonication produced stable and non-inertial cavitation throughout the pulse sequence. To our knowledge, this is the first study to demonstrate a high drug delivery rate coupled with high cell viability in a physiologically relevant in vitro flow system. Copyright © 2015. Published by Elsevier Inc.

I.M. Sechenov (1829 - 1905) and the scientific self-understanding for medical sciences.

PubMed

Kofler, Walter

2007-01-01

There is no discussion about the historic relevance of I. Sechenov for physiology and neurosciences as the "father of Russian modern physiology". But he is relevant for modern natural science too because of his basic epistemological and ontological work. He did not accept the up to now basic paradigm of "Ignorabimus" which can be seen as the reason to exclude even the generalizable aspects of individuality, creativity and spontaneity from natural science. He developed techniques for empirical based science to deal with materialistic and idealistic aspects of the comprehensive person the "ignoramus" according to the actual stay of knowledge and the acceptable ontologies. He demonstrated that ontologies ("paradigms") can be used as tools according to the given problem which should be solved. So Sechenov can be seen as a precursor of the so efficient philosophical positions of Einstein and Th. Kuhn. The stay of the art in physiology and neurosciences changed since the time of Sechenov dramatically. Therefore the philosophical positions of the 19th century should be discussed. Maybe this is indispensable for the needed linkage between materialistic and idealistic aspects of a person. For this the proposals of Sechenov are helpful up to now but nearly unknown. There is no discussion about the historic relevance of I. Sechenov as the "father of Russian physiology." But he is relevant for modern natural science too because of his epistemological and ontological work. He did not accept the up to now basic paradigm of "Ignorabimus" that can be seen as the reason to exclude even the generalizable aspects of individuality, creativity, and spontaneity from natural science. He demonstrated that ontologies ("paradigms") and epistemology can be used as tools according to the given problem. So Sechenov can be seen as a precursor of the so efficient philosophical positions of Einstein and Th. Kuhn. The state of the art changed dramatically. Therefore, the philosophical positions of the nineteenth century should be questioned. Maybe this is indispensable for the needed link between materialistic and idealistic aspects of a person as a whole. In this respect the proposals of Sechenov are helpful for medical science in the twenty-first century too but nearly unknown.

Salicylate toxicity model of tinnitus

PubMed Central

Stolzberg, Daniel; Salvi, Richard J.; Allman, Brian L.

2012-01-01

Salicylate, the active component of the common drug aspirin, has mild analgesic, antipyretic, and anti-inflammatory effects at moderate doses. At higher doses, however, salicylate temporarily induces moderate hearing loss and the perception of a high-pitch ringing in humans and animals. This phantom perception of sound known as tinnitus is qualitatively similar to the persistent subjective tinnitus induced by high-level noise exposure, ototoxic drugs, or aging, which affects ∼14% of the general population. For over a quarter century, auditory scientists have used the salicylate toxicity model to investigate candidate biochemical and neurophysiological mechanisms underlying phantom sound perception. In this review, we summarize some of the intriguing biochemical and physiological effects associated with salicylate-induced tinnitus, some of which occur in the periphery and others in the central nervous system. The relevance and general utility of the salicylate toxicity model in understanding phantom sound perception in general are discussed. PMID:22557950

Spectroscopic and molecular modeling studies of the interaction between cytidine and human serum albumin and its analytical application.

PubMed

Cui, Fengling; Wang, Junli; Yao, Xiaojun; Wang, Li; Zhang, Qiangzhai; Qu, Guirong

In this study, the interaction between cytidine and human serum albumin (HSA) was investigated for the first time by fluorescence spectroscopy in combination with UV absorption spectrum and molecular modeling under simulative physiological conditions. Experimental results indicated that cytidine had a strong ability to quench the intrinsic fluorescence of human serum albumin. The binding constants (K) at different temperatures, thermodynamic parameter enthalpy changes (DeltaH) and entropy changes (DeltaS) of HSA-cytidine had been calculated according to the relevant fluorescence data, which indicated that the hydrophobic and electrostatic interactions played a major role, which was in agreement with the results of molecular modeling study. In addition, the effects of other ions on the binding constants were also studied. Furthermore, synchronous fluorescence technology was successfully applied to the determination of human serum albumin added into the cytidine solution.

Are animal models useful for studying human disc disorders/degeneration?

PubMed Central

Eisenstein, Stephen M.; Ito, Keita; Little, Christopher; Kettler, A. Annette; Masuda, Koichi; Melrose, James; Ralphs, Jim; Stokes, Ian; Wilke, Hans Joachim

2007-01-01

Intervertebral disc (IVD) degeneration is an often investigated pathophysiological condition because of its implication in causing low back pain. As human material for such studies is difficult to obtain because of ethical and government regulatory restriction, animal tissue, organs and in vivo models have often been used for this purpose. However, there are many differences in cell population, tissue composition, disc and spine anatomy, development, physiology and mechanical properties, between animal species and human. Both naturally occurring and induced degenerative changes may differ significantly from those seen in humans. This paper reviews the many animal models developed for the study of IVD degeneration aetiopathogenesis and treatments thereof. In particular, the limitations and relevance of these models to the human condition are examined, and some general consensus guidelines are presented. Although animal models are invaluable to increase our understanding of disc biology, because of the differences between species, care must be taken when used to study human disc degeneration and much more effort is needed to facilitate research on human disc material. PMID:17632738

Effect of surfactants, gastric emptying, and dosage form on supersaturation of dipyridamole in an in vitro model simulating the stomach and duodenum.

PubMed

Mitra, A; Fadda, H M

2014-08-04

The purpose of this study was to investigate the influence of gastric emptying patterns, surfactants, and dosage form on the supersaturation of a poorly soluble weakly basic drug, dipyridamole, using an in vitro model mimicking the dynamic environment of the upper gastrointestinal tract, and, furthermore, to evaluate the usefulness of this model in establishing correlations to in vivo bioavailability for drugs with solubility/dissolution limited absorption. A simulated stomach duodenum model comprising four compartments was used to assess supersaturation and precipitation kinetics as a function of time. It integrates physiologically relevant fluid volumes, fluid transfer rates, and pH changes of the upper GI tract. Monoexponential gastric emptying patterns simulating the fasted state were compared to linear gastric emptying patterns simulating the fed state. The effect of different surfactants commonly used in oral preparations, specifically, sodium lauryl sulfate (SLS), poloxamer-188, and polysorbate-80, on dipyridamole supersaturation was investigated while maintaining surface tension of the simulated gastric fluids at physiological levels and without obtaining artificial micellar solubilization of the drug. The supersaturation behavior of different dose strengths of dipyridamole was explored. Significant levels of dipyridamole supersaturation were observed in the duodenal compartment under all the different in vivo relevant conditions explored. Dipyridamole supersaturation ratios of up to 11-fold have been observed, and supersaturation has been maintained for up to 120 min. Lower duodenal concentrations of dipyridamole were observed under linear gastric emptying patterns compared to mononexponential gastric emptying. The mean duodenal area under concentration-time curves (AUC60min) for the dipyridamole concentration profile in the duodenal compartment is significantly different for all the surfactants explored (P < 0.05). Our investigations with the different surfactants and comparison of dosage form (solution versus suspension) on the precipitation of dipyridamole revealed that crystal growth, rather than nucleation, is the rate-limiting step for the precipitation of dipyridamole. A linear dose-response relationship was found for the mean in vitro duodenal area under concentration-time curves (AUC∞) in the dose range of 25 mg to 100 mg (R(2) = 0.886). This is in agreement with the pharmacokinetic data of dipyridamole reported in the literature. The simulated stomach duodenum model can provide a reliable and discriminative screening tool for exploring the effect of different physiological variables or formulations on the supersaturation/precipitation kinetics of weakly basic drugs with solubility limited absorption. The amount of drug in solution in the duodenal compartment of the SSD correlates to bioavailability for the weakly basic drug, dipyridamole, which has solubility limited absorption and undergoes supersaturation/precipitation.

Homology Modeling, Validation and Dynamics of the G Protein-coupled Estrogen Receptor 1 (GPER-1).

PubMed

Bruno, Agostino; Aiello, Francesca; Costantino, Gabriele; Radi, Marco

2016-09-01

Estrogens exert their action mainly by binding three receptors, namely estrogen receptors α and β (ERα and ERβ) and GPER-1 (G-protein coupled estrogen receptor 1). While the patho-physiological role of both ERα and ERβ has been deeply investigated, the role of GPER-1 in estrogens' signaling has not been clearly defined yet. Unfortunately, only few GPER-1 selective ligands were discovered so far, and the real efficiency of such compounds is still matter of debate. To better understand the physiological relevance of GPER-1, new selective chemical probes are higly needed. In this scenario, we report herein the generation and validation of a three-dimensional (3-D) GPER-1 homology model by means of docking studies and molecular dynamics simulations. The model thus generated was employed to (i) decipher the structural basis underlying the ability of estrogens and some Selective Estrogen Receptor Modulators (SERMs) to bind GPER-1 and classical ERα and ERβ, and (ii) generate a reliable G1/GPER-1 complex useful in rationalizing the pharmacological profile of G1 reported in the literature. The G1/GPER-1 complex herein reported could be further exploited in drug design approaches aimed at improving the pharmacological profile of G1 or at identifying new chemical entities (NCEs) as potential modulators of GPER-1. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Biomechanical responses due to discitis infection of a juvenile thoracolumbar spine using finite element modeling.

PubMed

Davidson Jebaseelan, D; Jebaraj, C; Yoganandan, N; Rajasekaran, S; Yerramshetty, J

2014-07-01

Growth modulation changes occur in pediatric spines and lead to kyphotic deformity during discitis infection from mechanical forces. The present study was done to understand the consequences of discitis by simulating inflammatory puss at the T12/L1 disc space using a validated eight-year-old thoracolumbar spine finite element model. Changes in the biomechanical responses of the bone, disc and ligaments were determined under physiological compression and flexion loads in the intact and discitis models. During flexion, the angular-displacement increased by 3.33 times the intact spine and localized at the infected junction (IJ). The IJ became a virtual hinge. During compression loading, higher stresses occurred in the growth plate superior to the IJ. The components of the principal stresses in the growth plates at the T12/L1 junction indicated differential stresses. The strain increased by 143% during flexion loading in the posterior ligaments. The study indicates that the flexible pediatric spine increases the motion of the infected spine during physiological loadings. Understanding intrinsic responses around growth plates is important within the context of growth modulation in children. These results are clinically relevant as it might help surgeons to come up with better decisions while developing treatment protocols or performing surgeries. Copyright © 2014 IPEM. Published by Elsevier Ltd. All rights reserved.

Functional metabolic interactions of human neuron-astrocyte 3D in vitro networks

PubMed Central

Simão, Daniel; Terrasso, Ana P.; Teixeira, Ana P.; Brito, Catarina; Sonnewald, Ursula; Alves, Paula M.

2016-01-01

The generation of human neural tissue-like 3D structures holds great promise for disease modeling, drug discovery and regenerative medicine strategies. Promoting the establishment of complex cell-cell interactions, 3D culture systems enable the development of human cell-based models with increased physiological relevance, over monolayer cultures. Here, we demonstrate the establishment of neuronal and astrocytic metabolic signatures and shuttles in a human 3D neural cell model, namely the glutamine-glutamate-GABA shuttle. This was indicated by labeling of neuronal GABA following incubation with the glia-specific substrate [2-13C]acetate, which decreased by methionine sulfoximine-induced inhibition of the glial enzyme glutamine synthetase. Cell metabolic specialization was further demonstrated by higher pyruvate carboxylase-derived labeling in glutamine than in glutamate, indicating its activity in astrocytes and not in neurons. Exposure to the neurotoxin acrylamide resulted in intracellular accumulation of glutamate and decreased GABA synthesis. These results suggest an acrylamide-induced impairment of neuronal synaptic vesicle trafficking and imbalanced glutamine-glutamate-GABA cycle, due to loss of cell-cell contacts at synaptic sites. This work demonstrates, for the first time to our knowledge, that neural differentiation of human cells in a 3D setting recapitulates neuronal-astrocytic metabolic interactions, highlighting the relevance of these models for toxicology and better understanding the crosstalk between human neural cells. PMID:27619889

Functional metabolic interactions of human neuron-astrocyte 3D in vitro networks.

PubMed

Simão, Daniel; Terrasso, Ana P; Teixeira, Ana P; Brito, Catarina; Sonnewald, Ursula; Alves, Paula M

2016-09-13

The generation of human neural tissue-like 3D structures holds great promise for disease modeling, drug discovery and regenerative medicine strategies. Promoting the establishment of complex cell-cell interactions, 3D culture systems enable the development of human cell-based models with increased physiological relevance, over monolayer cultures. Here, we demonstrate the establishment of neuronal and astrocytic metabolic signatures and shuttles in a human 3D neural cell model, namely the glutamine-glutamate-GABA shuttle. This was indicated by labeling of neuronal GABA following incubation with the glia-specific substrate [2-(13)C]acetate, which decreased by methionine sulfoximine-induced inhibition of the glial enzyme glutamine synthetase. Cell metabolic specialization was further demonstrated by higher pyruvate carboxylase-derived labeling in glutamine than in glutamate, indicating its activity in astrocytes and not in neurons. Exposure to the neurotoxin acrylamide resulted in intracellular accumulation of glutamate and decreased GABA synthesis. These results suggest an acrylamide-induced impairment of neuronal synaptic vesicle trafficking and imbalanced glutamine-glutamate-GABA cycle, due to loss of cell-cell contacts at synaptic sites. This work demonstrates, for the first time to our knowledge, that neural differentiation of human cells in a 3D setting recapitulates neuronal-astrocytic metabolic interactions, highlighting the relevance of these models for toxicology and better understanding the crosstalk between human neural cells.

Imatinib attenuates inflammation and vascular leak in a clinically relevant two-hit model of acute lung injury.

PubMed

Rizzo, Alicia N; Sammani, Saad; Esquinca, Adilene E; Jacobson, Jeffrey R; Garcia, Joe G N; Letsiou, Eleftheria; Dudek, Steven M

2015-12-01

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), an illness characterized by life-threatening vascular leak, is a significant cause of morbidity and mortality in critically ill patients. Recent preclinical studies and clinical observations have suggested a potential role for the chemotherapeutic agent imatinib in restoring vascular integrity. Our prior work demonstrates differential effects of imatinib in mouse models of ALI, namely attenuation of LPS-induced lung injury but exacerbation of ventilator-induced lung injury (VILI). Because of the critical role of mechanical ventilation in the care of patients with ARDS, in the present study we pursued an assessment of the effectiveness of imatinib in a "two-hit" model of ALI caused by combined LPS and VILI. Imatinib significantly decreased bronchoalveolar lavage protein, total cells, neutrophils, and TNF-α levels in mice exposed to LPS plus VILI, indicating that it attenuates ALI in this clinically relevant model. In subsequent experiments focusing on its protective role in LPS-induced lung injury, imatinib attenuated ALI when given 4 h after LPS, suggesting potential therapeutic effectiveness when given after the onset of injury. Mechanistic studies in mouse lung tissue and human lung endothelial cells revealed that imatinib inhibits LPS-induced NF-κB expression and activation. Overall, these results further characterize the therapeutic potential of imatinib against inflammatory vascular leak. Copyright © 2015 the American Physiological Society.

Characterization of blunt chest trauma in a long-term porcine model of severe multiple trauma

PubMed Central

Horst, K.; Simon, T. P.; Pfeifer, R.; Teuben, M.; Almahmoud, K.; Zhi, Q.; Santos, S. Aguiar; Wembers, C. Castelar; Leonhardt, S.; Heussen, N.; Störmann, P.; Auner, B.; Relja, B.; Marzi, I.; Haug, A. T.; van Griensven, M.; Kalbitz, M.; Huber-Lang, M.; Tolba, R.; Reiss, L. K.; Uhlig, S.; Marx, G.; Pape, H. C.; Hildebrand, F.

2016-01-01

Chest trauma has a significant relevance on outcome after severe trauma. Clinically, impaired lung function typically occurs within 72 hours after trauma. However, the underlying pathophysiological mechanisms are still not fully elucidated. Therefore, we aimed to establish an experimental long-term model to investigate physiological, morphologic and inflammatory changes, after severe trauma. Male pigs (sus scrofa) sustained severe trauma (including unilateral chest trauma, femur fracture, liver laceration and hemorrhagic shock). Additionally, non-injured animals served as sham controls. Chest trauma resulted in severe lung damage on both CT and histological analyses. Furthermore, severe inflammation with a systemic increase of IL-6 (p = 0.0305) and a local increase of IL-8 in BAL (p = 0.0009) was observed. The pO2/FiO2 ratio in trauma animals decreased over the observation period (p < 0.0001) but not in the sham group (p = 0.2967). Electrical Impedance Tomography (EIT) revealed differences between the traumatized and healthy lung (p < 0.0001). In conclusion, a clinically relevant, long-term model of blunt chest trauma with concomitant injuries has been developed. This reproducible model allows to examine local and systemic consequences of trauma and is valid for investigation of potential diagnostic or therapeutic options. In this context, EIT might represent a radiation-free method for bedside diagnostics. PMID:28000769

Perioperative abstinence from cigarettes: physiologic and clinical consequences.

PubMed

Warner, David O

2006-02-01

Chronic exposure to cigarette smoke produces profound changes in physiology that may alter responses to perioperative interventions and contribute to perioperative morbidity. Because of smoke-free policies in healthcare facilities, all smokers undergoing surgery are abstinent from cigarettes for at least some period of time so that all are in various stages of recovery from the effects of smoke. Understanding this recovery process will help perioperative physicians better treat these patients. This review examines current knowledge regarding how both short-term (duration ranging from hours to weeks) and long-term smoking cessation affects selected physiology and pathophysiology of particular relevance to perioperative outcomes and how these changes affect perioperative risk. It will also consider current evidence regarding how nicotine replacement therapy, a valuable adjunct to help patients maintain abstinence, may affect perioperative physiology.

Bivalent O-glycoside mimetics with S/disulfide/Se substitutions and aromatic core: Synthesis, molecular modeling and inhibitory activity on biomedically relevant lectins in assays of increasing physiological relevance.

PubMed

Kaltner, Herbert; Szabó, Tamás; Fehér, Krisztina; André, Sabine; Balla, Sára; Manning, Joachim C; Szilágyi, László; Gabius, Hans-Joachim

2017-06-15

The emerging significance of recognition of cellular glycans by lectins for diverse aspects of pathophysiology is a strong incentive for considering development of bioactive and non-hydrolyzable glycoside derivatives, for example by introducing S/Se atoms and the disulfide group instead of oxygen into the glycosidic linkage. We report the synthesis of 12 bivalent thio-, disulfido- and selenoglycosides attached to benzene/naphthalene cores. They present galactose, for blocking a plant toxin, or lactose, the canonical ligand of adhesion/growth-regulatory galectins. Modeling reveals unrestrained flexibility and inter-headgroup distances too small to bridge two sites in the same lectin. Inhibitory activity was first detected by solid-phase assays using a surface-presented glycoprotein, with relative activity enhancements per sugar unit relative to free cognate sugar up to nearly 10fold. Inhibitory activity was also seen on lectin binding to surfaces of human carcinoma cells. In order to proceed to characterize this capacity in the tissue context monitoring of lectin binding in the presence of inhibitors was extended to sections of three types of murine organs as models. This procedure proved to be well-suited to determine relative activity levels of the glycocompounds to block binding of the toxin and different human galectins to natural glycoconjugates at different sites in sections. The results on most effective inhibition by two naphthalene-based disulfides and a selenide raise the perspective for broad applicability of the histochemical assay in testing glycoclusters that target biomedically relevant lectins. Copyright © 2017 Elsevier Ltd. All rights reserved.

Systematic Review of Ossicular Chain Anatomy: Strategic Planning for Development of Novel Middle Ear Prostheses.

PubMed

Kamrava, Brandon; Roehm, Pamela C

2017-08-01

Objective To systematically review the anatomy of the ossicular chain. Data Sources Google Scholar, PubMed, and otologic textbooks. Review Methods A systematic literature search was performed on January 26, 2015. Search terms used to discover articles consisted of combinations of 2 keywords. One keyword from both groups was used: [ ossicular, ossicle, malleus, incus, stapes] and [ morphology, morphometric, anatomy, variation, physiology], yielding more than 50,000 hits. Articles were then screened by title and abstract if they did not contain information relevant to human ossicular chain anatomy. In addition to this search, references of selected articles were studied as well as suggested relevant articles from publication databases. Standard otologic textbooks were screened using the search criteria. Results Thirty-three sources were selected for use in this review. From these studies, data on the composition, physiology, morphology, and morphometrics were acquired. In addition, any correlations or lack of correlations between features of the ossicular chain and other features of the ossicular chain or patient were noted, with bilateral symmetry between ossicles being the only important correlation reported. Conclusion There was significant variation in all dimensions of each ossicle between individuals, given that degree of variation, custom fitting, or custom manufacturing of prostheses for each patient could optimize prosthesis fit. From published data, an accurate 3-dimensional model of the malleus, incus, and stapes can be created, which can then be further modified for each patient's individual anatomy.

Sulforaphane prevents microcystin-LR-induced oxidative damage and apoptosis in BALB/c mice

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

Sun Xiaoyun; Mi Lixin; Liu Jin

2011-08-15

Microcystins (MCs), the products of blooming algae Microcystis, are waterborne environmental toxins that have been implicated in the development of liver cancer, necrosis, and even fatal intrahepatic bleeding. Alternative protective approaches in addition to complete removal of MCs in drinking water are urgently needed. In our previous work, we found that sulforaphane (SFN) protects against microcystin-LR (MC-LR)-induced cytotoxicity by activating the NF-E2-related factor 2 (Nrf2)-mediated defensive response in human hepatoma (HepG2) and NIH 3T3 cells. The purpose of this study was to investigate and confirm efficacy the SFN-induced multi-mechanistic defense system against MC-induced hepatotoxicity in an animal model. We reportmore » that SFN protected against MC-LR-induced liver damage and animal death at a nontoxic and physiologically relevant dose in BALB/c mice. The protection by SFN included activities of anti-cytochrome P450 induction, anti-oxidation, anti-inflammation, and anti-apoptosis. Our results suggest that SFN may protect mice against MC-induced hepatotoxicity. This raises the possibility of a similar protective effect in human populations, particularly in developing countries where freshwaters are polluted by blooming algae. - Graphical abstract: Display Omitted Research Highlights: > SFN protected against MC-LR-induced liver damage and animal death in BALB/c mice. > The dose of SFN is at a nontoxic and physiologically relevant dose. > The protection included activities of anti-oxidation, anti-inflammation, and anti-apoptosis. > SFN may protect mice against MC-induced hepatotoxicity.« less

Medicating the environment: assessing risks of pharmaceuticals to wildlife and ecosystems.

PubMed

Arnold, Kathryn E; Brown, A Ross; Ankley, Gerald T; Sumpter, John P

2014-11-19

Global pharmaceutical consumption is rising with the growing and ageing human population and more intensive food production. Recent studies have revealed pharmaceutical residues in a wide range of ecosystems and organisms. Environmental concentrations are often low, but pharmaceuticals typically are designed to have biological effects at low doses, acting on physiological systems that can be evolutionarily conserved across taxa. This Theme Issue introduces the latest research investigating the risks of environmentally relevant concentrations of pharmaceuticals to vertebrate wildlife. We take a holistic, global view of environmental exposure to pharmaceuticals encompassing terrestrial, freshwater and marine ecosystems in high- and low-income countries. Based on both field and laboratory data, the evidence for and relevance of changes to physiology and behaviour, in addition to mortality and reproductive effects, are examined in terms of the population- and community-level consequences of pharmaceutical exposure on wildlife. Studies on uptake, trophic transfer and indirect effects of pharmaceuticals acting via food webs are presented. Given the logistical and ethical complexities of research in this area, several papers focus on techniques for prioritizing which compounds are most likely to harm wildlife and how modelling approaches can make predictions about the bioavailability, metabolism and toxicity of pharmaceuticals in non-target species. This Theme Issue aims to help clarify the uncertainties, highlight opportunities and inform ongoing scientific and policy debates on the impacts of pharmaceuticals in the environment. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Dynamic physiological modeling for functional diffuse optical tomography

PubMed Central

Diamond, Solomon Gilbert; Huppert, Theodore J.; Kolehmainen, Ville; Franceschini, Maria Angela; Kaipio, Jari P.; Arridge, Simon R.; Boas, David A.

2009-01-01

Diffuse optical tomography (DOT) is a noninvasive imaging technology that is sensitive to local concentration changes in oxy- and deoxyhemoglobin. When applied to functional neuroimaging, DOT measures hemodynamics in the scalp and brain that reflect competing metabolic demands and cardiovascular dynamics. The diffuse nature of near-infrared photon migration in tissue and the multitude of physiological systems that affect hemodynamics motivate the use of anatomical and physiological models to improve estimates of the functional hemodynamic response. In this paper, we present a linear state-space model for DOT analysis that models the physiological fluctuations present in the data with either static or dynamic estimation. We demonstrate the approach by using auxiliary measurements of blood pressure variability and heart rate variability as inputs to model the background physiology in DOT data. We evaluate the improvements accorded by modeling this physiology on ten human subjects with simulated functional hemodynamic responses added to the baseline physiology. Adding physiological modeling with a static estimator significantly improved estimates of the simulated functional response, and further significant improvements were achieved with a dynamic Kalman filter estimator (paired t tests, n = 10, P < 0.05). These results suggest that physiological modeling can improve DOT analysis. The further improvement with the Kalman filter encourages continued research into dynamic linear modeling of the physiology present in DOT. Cardiovascular dynamics also affect the blood-oxygen-dependent (BOLD) signal in functional magnetic resonance imaging (fMRI). This state-space approach to DOT analysis could be extended to BOLD fMRI analysis, multimodal studies and real-time analysis. PMID:16242967

Behavior of human gastrocnemius muscle fascicles during ramped submaximal isometric contractions.

PubMed

Héroux, Martin E; Stubbs, Peter W; Herbert, Robert D

2016-09-01

Precise estimates of muscle architecture are necessary to understand and model muscle mechanics. The primary aim of this study was to estimate continuous changes in fascicle length and pennation angle in human gastrocnemius muscles during ramped plantar flexor contractions at two ankle angles. The secondary aim was to determine whether these changes differ between proximal and distal fascicles. Fifteen healthy subjects performed ramped contractions (0-25% MVC) as ultrasound images were recorded from the medial (MG, eight sites) and lateral (LG, six sites) gastrocnemius muscle with the ankle at 90° and 120° (larger angles correspond to shorter muscle lengths). In all subjects, fascicles progressively shortened with increasing torque. MG fascicles shortened 5.8 mm (11.1%) at 90° and 4.5 mm (12.1%) at 120°, whereas LG muscle fascicles shortened 5.1 mm (8.8%) at both ankle angles. MG pennation angle increased 1.4° at 90° and 4.9° at 120°, and LG pennation angle decreased 0.3° at 90° and increased 2.6° at 120°. Muscle architecture changes were similar in proximal and distal fascicles at both ankle angles. This is the first study to describe continuous changes in fascicle length and pennation angle in the human gastrocnemius muscle during ramped isometric contractions. Very similar changes occurred in proximal and distal muscle regions. These findings are relevant to studies modeling active muscle mechanics. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Contextual processing in unpredictable auditory environments: the limited resource model of auditory refractoriness in the rhesus

PubMed Central

Gurnsey, Kate; Salisbury, Dean; Sweet, Robert A.

2016-01-01

Auditory refractoriness refers to the finding of smaller electroencephalographic (EEG) responses to tones preceded by shorter periods of silence. To date, its physiological mechanisms remain unclear, limiting the insights gained from findings of abnormal refractoriness in individuals with schizophrenia. To resolve this roadblock, we studied auditory refractoriness in the rhesus, one of the most important animal models of auditory function, using grids of up to 32 chronically implanted cranial EEG electrodes. Four macaques passively listened to sounds whose identity and timing was random, thus preventing animals from forming valid predictions about upcoming sounds. Stimulus onset asynchrony ranged between 0.2 and 12.8 s, thus encompassing the clinically relevant timescale of refractoriness. Our results show refractoriness in all 8 previously identified middle- and long-latency components that peaked between 14 and 170 ms after tone onset. Refractoriness may reflect the formation and gradual decay of a basic sensory memory trace that may be mirrored by the expenditure and gradual recovery of a limited physiological resource that determines generator excitability. For all 8 components, results were consistent with the assumption that processing of each tone expends ∼65% of the available resource. Differences between components are caused by how quickly the resource recovers. Recovery time constants of different components ranged between 0.5 and 2 s. This work provides a solid conceptual, methodological, and computational foundation to dissect the physiological mechanisms of auditory refractoriness in the rhesus. Such knowledge may, in turn, help develop novel pharmacological, mechanism-targeted interventions. PMID:27512021

Impedance Spectrum in Cortical Tissue: Implications for Propagation of LFP Signals on the Microscopic Level

PubMed Central

Miceli, Stéphanie

2017-01-01

Brain research investigating electrical activity within neural tissue is producing an increasing amount of physiological data including local field potentials (LFPs) obtained via extracellular in vivo and in vitro recordings. In order to correctly interpret such electrophysiological data, it is vital to adequately understand the electrical properties of neural tissue itself. An ongoing controversy in the field of neuroscience is whether such frequency-dependent effects bias LFP recordings and affect the proper interpretation of the signal. On macroscopic scales and with large injected currents, previous studies have found various grades of frequency dependence of cortical tissue, ranging from negligible to strong, within the frequency band typically considered relevant for neuroscience (less than a few thousand hertz). Here, we performed a detailed investigation of the frequency dependence of the conductivity within cortical tissue at microscopic distances using small current amplitudes within the typical (neuro)physiological micrometer and sub-nanoampere range. We investigated the propagation of LFPs, induced by extracellular electrical current injections via patch-pipettes, in acute rat brain slice preparations containing the somatosensory cortex in vitro using multielectrode arrays. Based on our data, we determined the cortical tissue conductivity over a 100-fold increase in signal frequency (5–500 Hz). Our results imply at most very weak frequency-dependent effects within the frequency range of physiological LFPs. Using biophysical modeling, we estimated the impact of different putative impedance spectra. Our results indicate that frequency dependencies of the order measured here and in most other studies have negligible impact on the typical analysis and modeling of LFP signals from extracellular brain recordings. PMID:28197543

Coordinated three-dimensional motion of the head and torso by dynamic neural networks.

PubMed

Kim, J; Hemami, H

1998-01-01

The problem of trajectory tracking control of a three dimensional (3D) model of the human upper torso and head is considered. The torso and the head are modeled as two rigid bodies connected at one point, and the Newton-Euler method is used to derive the nonlinear differential equations that govern the motion of the system. The two-link system is driven by six pairs of muscle like actuators that possess physiologically inspired alpha like and gamma like inputs, and spindle like and Golgi tendon organ like outputs. These outputs are utilized as reflex feedback for stability and stiffness control, in a long loop feedback for the purpose of estimating the state of the system (somesthesis), and as part of the input to the controller. Ideal delays of different duration are included in the feedforward and feedback paths of the system to emulate such delays encountered in physiological systems. Dynamical neural networks are trained to learn effective control of the desired maneuvers of the system. The feasibility of the controller is demonstrated by computer simulation of the successful execution of the desired maneuvers. This work demonstrates the capabilities of neural circuits in controlling highly nonlinear systems with multidelays in their feedforward and feedback paths. The ultimate long range goal of this research is toward understanding the working of the central nervous system in controlling movement. It is an interdisciplinary effort relying on mechanics, biomechanics, neuroscience, system theory, physiology and anatomy, and its short range relevance to rehabilitation must be noted.

Impedance Spectrum in Cortical Tissue: Implications for Propagation of LFP Signals on the Microscopic Level.

PubMed

Miceli, Stéphanie; Ness, Torbjørn V; Einevoll, Gaute T; Schubert, Dirk

2017-01-01

Brain research investigating electrical activity within neural tissue is producing an increasing amount of physiological data including local field potentials (LFPs) obtained via extracellular in vivo and in vitro recordings. In order to correctly interpret such electrophysiological data, it is vital to adequately understand the electrical properties of neural tissue itself. An ongoing controversy in the field of neuroscience is whether such frequency-dependent effects bias LFP recordings and affect the proper interpretation of the signal. On macroscopic scales and with large injected currents, previous studies have found various grades of frequency dependence of cortical tissue, ranging from negligible to strong, within the frequency band typically considered relevant for neuroscience (less than a few thousand hertz). Here, we performed a detailed investigation of the frequency dependence of the conductivity within cortical tissue at microscopic distances using small current amplitudes within the typical (neuro)physiological micrometer and sub-nanoampere range. We investigated the propagation of LFPs, induced by extracellular electrical current injections via patch-pipettes, in acute rat brain slice preparations containing the somatosensory cortex in vitro using multielectrode arrays. Based on our data, we determined the cortical tissue conductivity over a 100-fold increase in signal frequency (5-500 Hz). Our results imply at most very weak frequency-dependent effects within the frequency range of physiological LFPs. Using biophysical modeling, we estimated the impact of different putative impedance spectra. Our results indicate that frequency dependencies of the order measured here and in most other studies have negligible impact on the typical analysis and modeling of LFP signals from extracellular brain recordings.

Physiology education in North American dental schools: the basic science survey series.

PubMed

Gautam, Medha; Shaw, David H; Pate, Ted D; Lambert, H Wayne

2014-06-01

As part of the Basic Science Survey Series for Dentistry, members of the American Dental Education Association (ADEA) Physiology, Pharmacology, and Therapeutics Section surveyed directors of physiology courses in North American dental schools. The survey was designed to assess, among other things, faculty affiliation and experience of course directors, teaching methods, general course content and emphasis, extent of interdisciplinary (shared) instruction, and impact of recent curricular changes. Responses were received from forty-four of sixty-seven (65.7 percent) U.S. and Canadian dental schools. The findings suggest the following: substantial variation exists in instructional hours, faculty affiliation, class size, and interdisciplinary nature of physiology courses; physiology course content emphasis is similar between schools; student contact hours in physiology, which have remained relatively stable in the past fifteen years, are starting to be reduced; recent curricular changes have often been directed towards enhancing the integrative and clinically relevant aspects of physiology instruction; and a trend toward innovative content delivery, such as use of computer-assisted instruction, is evident. Data from this study may be useful to physiology course directors, curriculum committees, and other dental educators with an interest in integrative and interprofessional education.

Animal Models in Genomic Research: Techniques, Applications, and Roles for Nurses

PubMed Central

Osier, Nicole D.; Pham, Lan; Savarese, Amanda; Sayles, Kendra

2016-01-01

Animal research has been conducted by scientists for over two millennia resulting in a better understanding of human anatomy, physiology, and pathology, as well as testing of novel therapies. In the molecular genomic era, pre-clinical models represent a key tool for understanding the genomic underpinnings of health and disease and are relevant to precision medicine initiatives. Nurses contribute to improved health by collecting and translating evidence from clinically relevant pre-clinical models. Using animal models, nurses can ask questions that would not be feasible or ethical to address in humans, and establish the safety and efficacy of interventions before translating them to clinical trials. Two advantages of using pre-clinical models are reduced variability between test subjects and the opportunity for precisely controlled experimental exposures. Standardized care controls the effects of diet and environment, while the availability of inbred strains significantly reduces the confounding effects of genetic differences. Outside the laboratory, nurses can contribute to the approval and oversight of animal studies, as well as translation to clinical trials and, ultimately, patient care. This review is intended as a primer on the use of animal models to advance nursing science; specifically, the paper discusses the utility of preclinical models for studying the pathophysiologic and genomic contributors to health and disease, testing interventions, and evaluating effects of environmental exposures. Considerations specifically geared to nurse researchers are also introduced, including discussion of how to choose an appropriate model and controls, potential confounders, as well as legal and ethical concerns. Finally, roles for nurse clinicians in pre-clinical research are also highlighted. PMID:27969037

Animal models in genomic research: Techniques, applications, and roles for nurses.

PubMed

Osier, Nicole D; Pham, Lan; Savarese, Amanda; Sayles, Kendra; Alexander, Sheila A

2016-11-01

Animal research has been conducted by scientists for over two millennia resulting in a better understanding of human anatomy, physiology, and pathology, as well as testing of novel therapies. In the molecular genomic era, pre-clinical models represent a key tool for understanding the genomic underpinnings of health and disease and are relevant to precision medicine initiatives. Nurses contribute to improved health by collecting and translating evidence from clinically relevant pre-clinical models. Using animal models, nurses can ask questions that would not be feasible or ethical to address in humans, and establish the safety and efficacy of interventions before translating them to clinical trials. Two advantages of using pre-clinical models are reduced variability between test subjects and the opportunity for precisely controlled experimental exposures. Standardized care controls the effects of diet and environment, while the availability of inbred strains significantly reduces the confounding effects of genetic differences. Outside the laboratory, nurses can contribute to the approval and oversight of animal studies, as well as translation to clinical trials and, ultimately, patient care. This review is intended as a primer on the use of animal models to advance nursing science; specifically, the paper discusses the utility of preclinical models for studying the pathophysiologic and genomic contributors to health and disease, testing interventions, and evaluating effects of environmental exposures. Considerations specifically geared to nurse researchers are also introduced, including discussion of how to choose an appropriate model and controls, potential confounders, as well as legal and ethical concerns. Finally, roles for nurse clinicians in pre-clinical research are also highlighted. Copyright © 2016 Elsevier Inc. All rights reserved.

High monetary reward rates and caloric rewards decrease temporal persistence

PubMed Central

Bode, Stefan; Murawski, Carsten

2017-01-01

Temporal persistence refers to an individual's capacity to wait for future rewards, while forgoing possible alternatives. This requires a trade-off between the potential value of delayed rewards and opportunity costs, and is relevant to many real-world decisions, such as dieting. Theoretical models have previously suggested that high monetary reward rates, or positive energy balance, may result in decreased temporal persistence. In our study, 50 fasted participants engaged in a temporal persistence task, incentivised with monetary rewards. In alternating blocks of this task, rewards were delivered at delays drawn randomly from distributions with either a lower or higher maximum reward rate. During some blocks participants received either a caloric drink or water. We used survival analysis to estimate participants' probability of quitting conditional on the delay distribution and the consumed liquid. Participants had a higher probability of quitting in blocks with the higher reward rate. Furthermore, participants who consumed the caloric drink had a higher probability of quitting than those who consumed water. Our results support the predictions from the theoretical models, and importantly, suggest that both higher monetary reward rates and physiologically relevant rewards can decrease temporal persistence, which is a crucial determinant for survival in many species. PMID:28228517

High monetary reward rates and caloric rewards decrease temporal persistence.

PubMed

Fung, Bowen J; Bode, Stefan; Murawski, Carsten

2017-02-22

Temporal persistence refers to an individual's capacity to wait for future rewards, while forgoing possible alternatives. This requires a trade-off between the potential value of delayed rewards and opportunity costs, and is relevant to many real-world decisions, such as dieting. Theoretical models have previously suggested that high monetary reward rates, or positive energy balance, may result in decreased temporal persistence. In our study, 50 fasted participants engaged in a temporal persistence task, incentivised with monetary rewards. In alternating blocks of this task, rewards were delivered at delays drawn randomly from distributions with either a lower or higher maximum reward rate. During some blocks participants received either a caloric drink or water. We used survival analysis to estimate participants' probability of quitting conditional on the delay distribution and the consumed liquid. Participants had a higher probability of quitting in blocks with the higher reward rate. Furthermore, participants who consumed the caloric drink had a higher probability of quitting than those who consumed water. Our results support the predictions from the theoretical models, and importantly, suggest that both higher monetary reward rates and physiologically relevant rewards can decrease temporal persistence, which is a crucial determinant for survival in many species. © 2017 The Authors.

Performance of first-year health sciences students in a large, diverse, multidisciplinary, first-semester, physiology service module

PubMed Central

Tufts, Mark

2014-01-01

Health Science students at the University of KwaZulu-Natal perform better in their professional modules compared with their physiology modules. The pass rates of physiology service modules have steadily declined over the years. While a system is in place to identify “at-risk” students, it is only activated after the first semester. As a result, it is only from the second semester of their first year studies onward that at-risk students can be formally assisted. The challenge is thus to devise an appropriate strategy to identify struggling students earlier in the semester. Using questionnaires, students were asked about attendance, financing of their studies, and relevance of physiology. After the first class test, failing students were invited to complete a second questionnaire. In addition, demographic data were also collected and analyzed. Correlation analyses were undertaken of performance indicators based on the demographical data collected. The 2011 class comprised mainly sport science students (57%). The pass rate of sport science students was lower than the pass rates of other students (42% vs. 70%, P < 0.001). Most students were positive about physiology and recognized its relevance. Key issues identified were problems understanding concepts and terminology, poor study environment and skills, and lack of matriculation biology. The results of the first class test and final module marks correlated well. It is clear from this study that student performance in the first class test is a valuable tool to identify struggling students and that appropriate testing should be held as early as possible. PMID:24913452

Mammalian lipoxygenases and their biological relevance.

PubMed

Kuhn, Hartmut; Banthiya, Swathi; van Leyen, Klaus

2015-04-01

Lipoxygenases (LOXs) form a heterogeneous class of lipid peroxidizing enzymes, which have been implicated not only in cell proliferation and differentiation but also in the pathogenesis of various diseases with major public health relevance. As other fatty acid dioxygenases LOXs oxidize polyunsaturated fatty acids to their corresponding hydroperoxy derivatives, which are further transformed to bioactive lipid mediators (eicosanoids and related substances). On the other hand, lipoxygenases are key players in the regulation of the cellular redox homeostasis, which is an important element in gene expression regulation. Although the first mammalian lipoxygenases were discovered 40 years ago and although the enzymes have been well characterized with respect to their structural and functional properties the biological roles of the different lipoxygenase isoforms are not completely understood. This review is aimed at summarizing the current knowledge on the physiological roles of different mammalian LOX-isoforms and their patho-physiological function in inflammatory, metabolic, hyperproliferative, neurodegenerative and infectious disorders. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance". Copyright © 2014 Elsevier B.V. All rights reserved.

Dynamic analysis of Lactobacillus delbrueckii subsp. bulgaricus CFL1 physiological characteristics during fermentation.

PubMed

Rault, Aline; Bouix, Marielle; Béal, Catherine

2008-12-01

This study aimed at examining and comparing the relevance of various methods in order to discriminate different cellular states of Lactobacillus bulgaricus CFL1 and to improve knowledge on the dynamics of the cellular physiological state during growth and acidification. By using four fluorescent probes combined with multiparametric flow cytometry, membrane integrity, intracellular esterase activity, cellular vitality, membrane depolarization, and intracellular pH were quantified throughout fermentations. Results were compared and correlated with measurements of cultivability, acidification activity (Cinac system), and cellular ability to recover growth in fresh medium (Bioscreen system). The Cinac system and flow cytometry were relevant to distinguish different physiological states throughout growth. Lb. bulgaricus cells maintained their high viability, energetic state, membrane potential, and pH gradient in the late stationary phase, despite the gradual decrease of both cultivability and acidification activity. Viability and membrane integrity were maintained during acidification, at the expense of their cultivability and acidification activity. Finally, this study demonstrated that the physiological state during fermentation was strongly affected by intracellular pH and the pH gradient. The critical pHi of Lb. bulgaricus CFL1 was found to be equal to pH 5.8. Through linear relationships between dpH and cultivability and pHi and acidification activity, pHi and dpH well described the time course of metabolic activity, cultivability, and viability in a single analysis.

TRI-Worthy Projects for the Deep Space Gateway

NASA Astrophysics Data System (ADS)

Wotring, V. E.; Strangman, G. E.; Donoviel, D.

2018-02-01

Preparations for exploration will require exposure to the actual deep space environment. The new TRI for Space Health proposes innovative projects using real space radiation to make medically-relevant measurements affecting human physiology.

The relevance of phylogeny to studies of global change.

PubMed

Edwards, Erika J; Still, Christopher J; Donoghue, Michael J

2007-05-01

Phylogenetic thinking has infiltrated many areas of biological research, but has had little impact on studies of global ecology or climate change. Here, we illustrate how phylogenetic information can be relevant to understanding vegetation-atmosphere dynamics at ecosystem or global scales by re-analyzing a data set of carbonic anhydrase (CA) activity in leaves that was used to estimate terrestrial gross primary productivity. The original calculations relied on what appeared to be low CA activity exclusively in C4 grasses, but our analyses indicate that such activity might instead characterize the PACCAD grass lineage, which includes many widespread C3 species. We outline how phylogenetics can guide better taxon sampling of key physiological traits, and discuss how the emerging field of phyloinformatics presents a promising new framework for scaling from organism physiology to global processes.

Pathways of the Maillard reaction under physiological conditions.

PubMed

Henning, Christian; Glomb, Marcus A

2016-08-01

Initially investigated as a color formation process in thermally treated foods, nowadays, the relevance of the Maillard reaction in vivo is generally accepted. Many chronic and age-related diseases such as diabetes, uremia, atherosclerosis, cataractogenesis and Alzheimer's disease are associated with Maillard derived advanced glycation endproducts (AGEs) and α-dicarbonyl compounds as their most important precursors in terms of reactivity and abundance. However, the situation in vivo is very challenging, because Maillard chemistry is paralleled by enzymatic reactions which can lead to both, increases and decreases in certain AGEs. In addition, mechanistic findings established under the harsh conditions of food processing might not be valid under physiological conditions. The present review critically discusses the relevant α-dicarbonyl compounds as central intermediates of AGE formation in vivo with a special focus on fragmentation pathways leading to formation of amide-AGEs.

Anthocyanins and their gut metabolites reduce the adhesion of monocyte to TNFα-activated endothelial cells at physiologically relevant concentrations.

PubMed

Krga, Irena; Monfoulet, Laurent-Emmanuel; Konic-Ristic, Aleksandra; Mercier, Sylvie; Glibetic, Maria; Morand, Christine; Milenkovic, Dragan

2016-06-01

An increasing number of evidence suggests a protective role of dietary anthocyanins against cardiovascular diseases. Anthocyanins' extensive metabolism indicates that their metabolites could be responsible for the protective effects associated with consumption of anthocyanin-rich foods. The aim of this work was to investigate the effect of plasma anthocyanins and their metabolites on the adhesion of monocytes to TNFα-activated endothelial cells and on the expression of genes encoding cell adhesion molecules. Human umbilical vein endothelial cells (HUVECs) were exposed to circulating anthocyanins: cyanidin-3-arabinoside, cyanidin-3-galactoside, cyanidin-3-glucoside, delphinidin-3-glucoside, peonidin-3-glucoside, anthocyanin degradation product: 4-hydroxybenzaldehyde, or to their gut metabolites: protocatechuic, vanillic, ferulic and hippuric acid, at physiologically-relevant concentrations (0.1-2 μM) and time of exposure. Both anthocyanins and gut metabolites decreased the adhesion of monocytes to HUVECs, with a magnitude ranging from 18.1% to 47%. The mixture of anthocyanins and that of gut metabolites also reduced monocyte adhesion. However, no significant effect on the expression of genes encoding E-selectin, ICAM1 and VCAM1 was observed, suggesting that other molecular targets are involved in the observed effect. In conclusion, this study showed the potency of anthocyanins and their gut metabolites to modulate the adhesion of monocytes to endothelial cells, the initial step in atherosclerosis development, under physiologically-relevant conditions. Copyright © 2016 Elsevier Inc. All rights reserved.

Understanding the Onset of Health Impacts Caused by Disturbances

DTIC Science & Technology

2015-09-30

will define the PCoD Health stage in a way that we can start to integrate ecological and physiological PCoD research. OBJECTIVES In order to...for the first time assess the relevance of adipose transcriptomic and metabolomic biomarkers as measures relevant to PCoD in cetaceans. We aim to...individuals. APPROACH The Population Consequences of Disturbances ( PCoD ) paradigm provides a mean to link perturbations of individual phenotypic

Physiological responses to short-term thermal stress in mayfly (Neocloeon triangulifer) larvae in relation to upper thermal limits.

PubMed

Kim, Kyoung Sun; Chou, Hsuan; Funk, David H; Jackson, John K; Sweeney, Bernard W; Buchwalter, David B

2017-07-15

Understanding species' thermal limits and their physiological determinants is critical in light of climate change and other human activities that warm freshwater ecosystems. Here, we ask whether oxygen limitation determines the chronic upper thermal limits in larvae of the mayfly Neocloeon triangulifer , an emerging model for ecological and physiological studies. Our experiments are based on a robust understanding of the upper acute (∼40°C) and chronic thermal limits of this species (>28°C, ≤30°C) derived from full life cycle rearing experiments across temperatures. We tested two related predictions derived from the hypothesis that oxygen limitation sets the chronic upper thermal limits: (1) aerobic scope declines in mayfly larvae as they approach and exceed temperatures that are chronically lethal to larvae; and (2) genes indicative of hypoxia challenge are also responsive in larvae exposed to ecologically relevant thermal limits. Neither prediction held true. We estimated aerobic scope by subtracting measurements of standard oxygen consumption rates from measurements of maximum oxygen consumption rates, the latter of which was obtained by treating with the metabolic uncoupling agent carbonyl cyanide-4-(trifluoromethoxy) pheylhydrazone (FCCP). Aerobic scope was similar in larvae held below and above chronic thermal limits. Genes indicative of oxygen limitation (LDH, EGL-9) were only upregulated under hypoxia or during exposure to temperatures beyond the chronic (and more ecologically relevant) thermal limits of this species (LDH). Our results suggest that the chronic thermal limits of this species are likely not driven by oxygen limitation, but rather are determined by other factors, e.g. bioenergetics costs. We caution against the use of short-term thermal ramping approaches to estimate critical thermal limits (CT max ) in aquatic insects because those temperatures are typically higher than those that occur in nature. © 2017. Published by The Company of Biologists Ltd.

Application of dynamic metabolomics to examine in vivo skeletal muscle glucose metabolism in the chronically high-fat fed mouse

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

Kowalski, Greg M., E-mail: greg.kowalski@deakin.edu.au; De Souza, David P.; Burch, Micah L.

Rationale: Defects in muscle glucose metabolism are linked to type 2 diabetes. Mechanistic studies examining these defects rely on the use of high fat-fed rodent models and typically involve the determination of muscle glucose uptake under insulin-stimulated conditions. While insightful, they do not necessarily reflect the physiology of the postprandial state. In addition, most studies do not examine aspects of glucose metabolism beyond the uptake process. Here we present an approach to study rodent muscle glucose and intermediary metabolism under the dynamic and physiologically relevant setting of the oral glucose tolerance test (OGTT). Methods and results: In vivo muscle glucose andmore » intermediary metabolism was investigated following oral administration of [U-{sup 13}C] glucose. Quadriceps muscles were collected 15 and 60 min after glucose administration and metabolite flux profiling was determined by measuring {sup 13}C mass isotopomers in glycolytic and tricarboxylic acid (TCA) cycle intermediates via gas chromatography–mass spectrometry. While no dietary effects were noted in the glycolytic pathway, muscle from mice fed a high fat diet (HFD) exhibited a reduction in labelling in TCA intermediates. Interestingly, this appeared to be independent of alterations in flux through pyruvate dehydrogenase. In addition, our findings suggest that TCA cycle anaplerosis is negligible in muscle during an OGTT. Conclusions: Under the dynamic physiologically relevant conditions of the OGTT, skeletal muscle from HFD fed mice exhibits alterations in glucose metabolism at the level of the TCA cycle. - Highlights: • Dynamic metabolomics was used to investigate muscle glucose metabolism in vivo. • Mitochondrial TCA cycle metabolism is altered in muscle of HFD mice. • This defect was not pyruvate dehydrogenase mediated, as has been previously thought. • Mitochondrial TCA cycle anaplerosis in muscle is virtually absent during the OGTT.« less

Cell autonomous regulation of hippocampal circuitry via Aph1b-γ-secretase/neuregulin 1 signalling

PubMed Central

Fazzari, Pietro; Snellinx, An; Sabanov, Victor; Ahmed, Tariq; Serneels, Lutgarde; Gartner, Annette; Shariati, S Ali M; Balschun, Detlef; De Strooper, Bart

2014-01-01

Neuregulin 1 (NRG1) and the γ-secretase subunit APH1B have been previously implicated as genetic risk factors for schizophrenia and schizophrenia relevant deficits have been observed in rodent models with loss of function mutations in either gene. Here we show that the Aph1b-γ-secretase is selectively involved in Nrg1 intracellular signalling. We found that Aph1b-deficient mice display a decrease in excitatory synaptic markers. Electrophysiological recordings show that Aph1b is required for excitatory synaptic transmission and plasticity. Furthermore, gain and loss of function and genetic rescue experiments indicate that Nrg1 intracellular signalling promotes dendritic spine formation downstream of Aph1b-γ-secretase in vitro and in vivo. In conclusion, our study sheds light on the physiological role of Aph1b-γ-secretase in brain and provides a new mechanistic perspective on the relevance of NRG1 processing in schizophrenia. DOI: http://dx.doi.org/10.7554/eLife.02196.001 PMID:24891237

Love and emotional well-being in people with intellectual disabilities.

PubMed

Arias, Benito; Ovejero, Anastasio; Morentin, Raquel

2009-05-01

Love has been a recurrent topic throughout history, and especially, literature. Moreover, there is generalized agreement about its relevance for health emotional well-being, and quality of life. This study was carried out with a sample of 376 persons with ID. The goals of the work were to analyze a theoretical model of love in people with intellectual disabilities by means of the methodology of structural equations, and to analyze their perception of love and of amorous relations with regard to other aspects such as amorous satisfaction, perceived satisfaction, absence of family interference, self-determination, and emotional well-being. The results revealed that (a) the construct under study has three factors: Commitment, stability, and idealization, Passion and physiological excitement, and Intimacy and romanticism; (b) the perception of love in this collective is, in general, idealized and affected by the context; and (c) self-determination and the lack of family interference are relevant variables to explain both love and emotional well-being.

Comparison of the Mortality Probability Admission Model III, National Quality Forum, and Acute Physiology and Chronic Health Evaluation IV hospital mortality models: implications for national benchmarking*.

PubMed

Kramer, Andrew A; Higgins, Thomas L; Zimmerman, Jack E

2014-03-01

To examine the accuracy of the original Mortality Probability Admission Model III, ICU Outcomes Model/National Quality Forum modification of Mortality Probability Admission Model III, and Acute Physiology and Chronic Health Evaluation IVa models for comparing observed and risk-adjusted hospital mortality predictions. Retrospective paired analyses of day 1 hospital mortality predictions using three prognostic models. Fifty-five ICUs at 38 U.S. hospitals from January 2008 to December 2012. Among 174,001 intensive care admissions, 109,926 met model inclusion criteria and 55,304 had data for mortality prediction using all three models. None. We compared patient exclusions and the discrimination, calibration, and accuracy for each model. Acute Physiology and Chronic Health Evaluation IVa excluded 10.7% of all patients, ICU Outcomes Model/National Quality Forum 20.1%, and Mortality Probability Admission Model III 24.1%. Discrimination of Acute Physiology and Chronic Health Evaluation IVa was superior with area under receiver operating curve (0.88) compared with Mortality Probability Admission Model III (0.81) and ICU Outcomes Model/National Quality Forum (0.80). Acute Physiology and Chronic Health Evaluation IVa was better calibrated (lowest Hosmer-Lemeshow statistic). The accuracy of Acute Physiology and Chronic Health Evaluation IVa was superior (adjusted Brier score = 31.0%) to that for Mortality Probability Admission Model III (16.1%) and ICU Outcomes Model/National Quality Forum (17.8%). Compared with observed mortality, Acute Physiology and Chronic Health Evaluation IVa overpredicted mortality by 1.5% and Mortality Probability Admission Model III by 3.1%; ICU Outcomes Model/National Quality Forum underpredicted mortality by 1.2%. Calibration curves showed that Acute Physiology and Chronic Health Evaluation performed well over the entire risk range, unlike the Mortality Probability Admission Model and ICU Outcomes Model/National Quality Forum models. Acute Physiology and Chronic Health Evaluation IVa had better accuracy within patient subgroups and for specific admission diagnoses. Acute Physiology and Chronic Health Evaluation IVa offered the best discrimination and calibration on a large common dataset and excluded fewer patients than Mortality Probability Admission Model III or ICU Outcomes Model/National Quality Forum. The choice of ICU performance benchmarks should be based on a comparison of model accuracy using data for identical patients.

Growth of Coccolithophores Controlled by Internal Nutrient Stores in Light- and Nutrient-Limited Batch Reactors: Relevance for the BIOSOPE Deep Ecological Niche of Coccolithophores.

NASA Astrophysics Data System (ADS)

Laura, P.; Probert, I.; Langer, G.; Aloisi, G.

2016-02-01

Coccolithophores are unicellular, calcifying marine algae that play a fundamental role in the oceanic carbon cycle. Recent research has focused on investigating the effect of ocean acidification on cellular calcification. However, the success of this important phytoplankton group in the future ocean will depend on how cellular growth reacts to changes in a combination of environmental variables. We carried out batch culture experiments in conditions of light- and nutrient- (nitrate and phosphate) limitation that reproduce the in situ conditions of a deep ecological niche of coccolithophores in the South Pacific Gyre (BIOSOPE cruise, 2004). We modelled nutrient acquisition and cellular growth in our batch experiments using a Droop internal-stores model. We show that nutrient acquisition and growth are decoupled in coccolithophores; this ability may be key in making life possible in oligotrophic conditions such as the deep BIOSOPE biological niche. Combining the results of our culture experiments with those of Langer et al. (2013), we used the model to obtain estimates of fundamental physiological parameters such as the Monod constant for nutrient uptake, the maximum growth rate and the minimum cellular nutrient quota. These parameters are characteristic of different phytoplankton groups and are needed to simulate phytoplankton growth in biogeochemical models. Our results suggest that growth of coccolithophores in the BIOSOPE deep ecological niche is light-limited rather than nutrient-limited. Our work also shows that simple batch experiments and straightforward numerical modelling are capable of providing estimates of physiological parameters usually obtained in more costly and complicated chemostat experiments.

Disease modeling using human induced pluripotent stem cells: lessons from the liver.

PubMed

Gieseck, Richard L; Colquhoun, Jennifer; Hannan, Nicholas R F

2015-01-01

Human pluripotent stem cells (hPSCs) have the capacity to differentiate into any of the hundreds of distinct cell types that comprise the human body. This unique characteristic has resulted in considerable interest in the field of regenerative medicine, given the potential for these cells to be used to protect, repair, or replace diseased, injured, and aged cells within the human body. In addition to their potential in therapeutics, hPSCs can be used to study the earliest stages of human development and to provide a platform for both drug screening and disease modeling using human cells. Recently, the description of human induced pluripotent stem cells (hIPSCs) has allowed the field of disease modeling to become far more accessible and physiologically relevant, as pluripotent cells can be generated from patients of any genetic background. Disease models derived from hIPSCs that manifest cellular disease phenotypes have been established to study several monogenic diseases; furthermore, hIPSCs can be used for phenotype-based drug screens to investigate complex diseases for which the underlying genetic mechanism is unknown. As a result, the use of stem cells as research tools has seen an unprecedented growth within the last decade as researchers look for in vitro disease models which closely mimic in vivo responses in humans. Here, we discuss the beginnings of hPSCs, starting with isolation of human embryonic stem cells, moving into the development and optimization of hIPSC technology, and ending with the application of hIPSCs towards disease modeling and drug screening applications, with specific examples highlighting the modeling of inherited metabolic disorders of the liver. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. Crown Copyright © 2014. Published by Elsevier B.V. All rights reserved.

Predicting the effect of cytochrome P450 inhibitors on substrate drugs: analysis of physiologically based pharmacokinetic modeling submissions to the US Food and Drug Administration.

PubMed

Wagner, Christian; Pan, Yuzhuo; Hsu, Vicky; Grillo, Joseph A; Zhang, Lei; Reynolds, Kellie S; Sinha, Vikram; Zhao, Ping

2015-01-01

The US Food and Drug Administration (FDA) has seen a recent increase in the application of physiologically based pharmacokinetic (PBPK) modeling towards assessing the potential of drug-drug interactions (DDI) in clinically relevant scenarios. To continue our assessment of such approaches, we evaluated the predictive performance of PBPK modeling in predicting cytochrome P450 (CYP)-mediated DDI. This evaluation was based on 15 substrate PBPK models submitted by nine sponsors between 2009 and 2013. For these 15 models, a total of 26 DDI studies (cases) with various CYP inhibitors were available. Sponsors developed the PBPK models, reportedly without considering clinical DDI data. Inhibitor models were either developed by sponsors or provided by PBPK software developers and applied with minimal or no modification. The metric for assessing predictive performance of the sponsors' PBPK approach was the R predicted/observed value (R predicted/observed = [predicted mean exposure ratio]/[observed mean exposure ratio], with the exposure ratio defined as [C max (maximum plasma concentration) or AUC (area under the plasma concentration-time curve) in the presence of CYP inhibition]/[C max or AUC in the absence of CYP inhibition]). In 81 % (21/26) and 77 % (20/26) of cases, respectively, the R predicted/observed values for AUC and C max ratios were within a pre-defined threshold of 1.25-fold of the observed data. For all cases, the R predicted/observed values for AUC and C max were within a 2-fold range. These results suggest that, based on the submissions to the FDA to date, there is a high degree of concordance between PBPK-predicted and observed effects of CYP inhibition, especially CYP3A-based, on the exposure of drug substrates.

Effects of Hydrostatic Loading on a Self-Aggregating, Suspension Culture–Derived Cartilage Tissue Analog

PubMed Central

Kraft, Jeffrey J.; Jeong, Changhoon; Novotny, John E.; Seacrist, Thomas; Chan, Gilbert; Domzalski, Marcin; Turka, Christina M.; Richardson, Dean W.; Dodge, George R.

2011-01-01

Objective: Many approaches are being taken to generate cartilage replacement materials. The goal of this study was to use a self-aggregating suspension culture model of chondrocytes with mechanical preconditioning. Design: Our model differs from others in that it is based on a scaffold-less, self-aggregating culture model that produces a cartilage tissue analog that has been shown to share many similarities with the natural cartilage phenotype. Owing to the known loaded environment under which chondrocytes function in vivo, we hypothesized that applying force to the suspension culture–derived chondrocyte biomass would improve its cartilage-like characteristics and provide a new model for engineering cartilage tissue analogs. Results: In this study, we used a specialized hydrostatic pressure bioreactor system to apply mechanical forces during the growth phase to improve biochemical and biophysical properties of the biomaterial formed. We demonstrated that using this high-density suspension culture, a biomaterial more consistent with the hyaline cartilage phenotype was produced without any foreign material added. Unpassaged chondrocytes responded to a physiologically relevant hydrostatic load by significantly increasing gene expression of critical cartilage molecule collagen and aggrecan along with other cartilage relevant genes, CD44, perlecan, decorin, COMP, and iNOS. Conclusions: This study describes a self-aggregating bioreactor model without foreign material or scaffold in which chondrocytes form a cartilage tissue analog with many features similar to native cartilage. This study represents a promising scaffold-less, methodological advancement in cartilage tissue engineering with potential translational applications to cartilage repair. PMID:26069584

Effects of Hydrostatic Loading on a Self-Aggregating, Suspension Culture-Derived Cartilage Tissue Analog.

PubMed

Kraft, Jeffrey J; Jeong, Changhoon; Novotny, John E; Seacrist, Thomas; Chan, Gilbert; Domzalski, Marcin; Turka, Christina M; Richardson, Dean W; Dodge, George R

2011-07-01

Many approaches are being taken to generate cartilage replacement materials. The goal of this study was to use a self-aggregating suspension culture model of chondrocytes with mechanical preconditioning. Our model differs from others in that it is based on a scaffold-less, self-aggregating culture model that produces a cartilage tissue analog that has been shown to share many similarities with the natural cartilage phenotype. Owing to the known loaded environment under which chondrocytes function in vivo, we hypothesized that applying force to the suspension culture-derived chondrocyte biomass would improve its cartilage-like characteristics and provide a new model for engineering cartilage tissue analogs. In this study, we used a specialized hydrostatic pressure bioreactor system to apply mechanical forces during the growth phase to improve biochemical and biophysical properties of the biomaterial formed. We demonstrated that using this high-density suspension culture, a biomaterial more consistent with the hyaline cartilage phenotype was produced without any foreign material added. Unpassaged chondrocytes responded to a physiologically relevant hydrostatic load by significantly increasing gene expression of critical cartilage molecule collagen and aggrecan along with other cartilage relevant genes, CD44, perlecan, decorin, COMP, and iNOS. This study describes a self-aggregating bioreactor model without foreign material or scaffold in which chondrocytes form a cartilage tissue analog with many features similar to native cartilage. This study represents a promising scaffold-less, methodological advancement in cartilage tissue engineering with potential translational applications to cartilage repair.

Gene Expression Analysis to Assess the Relevance of Rodent Models to Human Lung Injury.

PubMed

Sweeney, Timothy E; Lofgren, Shane; Khatri, Purvesh; Rogers, Angela J

2017-08-01

The relevance of animal models to human diseases is an area of intense scientific debate. The degree to which mouse models of lung injury recapitulate human lung injury has never been assessed. Integrating data from both human and animal expression studies allows for increased statistical power and identification of conserved differential gene expression across organisms and conditions. We sought comprehensive integration of gene expression data in experimental acute lung injury (ALI) in rodents compared with humans. We performed two separate gene expression multicohort analyses to determine differential gene expression in experimental animal and human lung injury. We used correlational and pathway analyses combined with external in vitro gene expression data to identify both potential drivers of underlying inflammation and therapeutic drug candidates. We identified 21 animal lung tissue datasets and three human lung injury bronchoalveolar lavage datasets. We show that the metasignatures of animal and human experimental ALI are significantly correlated despite these widely varying experimental conditions. The gene expression changes among mice and rats across diverse injury models (ozone, ventilator-induced lung injury, LPS) are significantly correlated with human models of lung injury (Pearson r = 0.33-0.45, P < 1E -16 ). Neutrophil signatures are enriched in both animal and human lung injury. Predicted therapeutic targets, peptide ligand signatures, and pathway analyses are also all highly overlapping. Gene expression changes are similar in animal and human experimental ALI, and provide several physiologic and therapeutic insights to the disease.

Vascular physiology and protein disposition in a preclinical model of neurodegeneration.

PubMed

Boswell, C Andrew; Mundo, Eduardo E; Johnstone, Bernadette; Ulufatu, Sheila; Schweiger, Michelle G; Bumbaca, Daniela; Fielder, Paul J; Prabhu, Saileta; Khawli, Leslie A

2013-05-06

The development of clinically relevant preclinical models that mimic the hallmarks of neurodegenerative disease is an ongoing pursuit in early drug development. In particular, robust physiological characterization of central nervous system (CNS) disease models is necessary to predict drug delivery to target tissues and to correctly interpret pharmacodynamic responses to disease-modifying therapeutic candidates. Efficient drug delivery across the blood-CNS barrier is a particularly daunting task, prompting our strategy to evaluate the biodistribution of five distinct molecular probes in a well-characterized mouse model of neurodegeneration. A transgenic mouse model of amyotrophic lateral sclerosis was selected based on a phenotype resembling clinical symptoms, including loss of motor neurons from the spinal cord and paralysis in one or more limbs, due to expression of a G93A mutant form of human superoxide dismutase (SOD1). The tissue distributions of two proteins, albumin and a representative immunoglobulin G antibody, as well as two blood flow markers, the lipophilic blood flow marker Ceretec (i.e., (99m)Tc-HMPAO) and the polar ionic tracer, rubidium-86 chloride ((86)RbCl), were measured following intravenous injection in SOD1(G93A) and age-matched control mice. The radiopharmaceutical TechneScan PYP was also used to measure the distribution of (99m)Tc-labeled red blood cells as a blood pool marker. Both the antibody and (86)Rb were able to cross the blood-spinal cord barrier in SOD1(G93A) mice to a greater extent than in control mice. Although the biodistribution patterns of antibody, albumin, and RBCs were largely similar, notable differences were detected in muscle and skin. Moreover, vastly different biodistribution patterns were observed for a lipophilic and polar perfusion agent, with SOD1(G93A) mutation resulting in reduced renal filtration rates for the former but not the latter. Overall, the multiprobe strategy provided an opportunity to efficiently collect an abundance of physiological information, including the degree and regional extent of blood-CNS barrier permeability, in a preclinical model of neurodegeneration.

The hydrodynamic and ultrasound-induced forces on microbubbles under high Reynolds number flow representative of the human systemic circulation

NASA Astrophysics Data System (ADS)

Clark, Alicia; Aliseda, Alberto

2016-11-01

Ultrasound contrast agents (UCAs) are micron-sized bubbles that are used in conjunction with ultrasound (US) in medical applications such as thrombolysis and targeted intravenous drug delivery. Previous work has shown that the Bjerknes force, due to the phase difference between the incoming US pressure wave and the bubble volume oscillations, can be used to manipulate the trajectories of microbubbles. Our work explores the behavior of microbubbles in medium sized blood vessels under both uniform and pulsatile flows at a range of physiologically relevant Reynolds and Womersley numbers. High speed images were taken of the microbubbles in an in-vitro flow loop that replicates physiological flow conditions. During the imaging, the microbubbles were insonified at different diagnostic ultrasound settings (varying center frequency, PRF, etc.). An in-house Lagrangian particle tracking code was then used to determine the trajectories of the microbubbles and, thus, a dynamic model for the microbubbles including the Bjerknes forces acting on them, as well as drag, lift, and added mass. Preliminary work has also explored the behavior of the microbubbles in a patient-specific model of a carotid artery bifurcation to demonstrate the feasibility of preferential steering of microbubbles towards the intracranial circulation with US.

Neuronal activity-regulated gene transcription: how are distant synaptic signals conveyed to the nucleus?

PubMed Central

Matamales, Miriam

2012-01-01

Synaptic activity can trigger gene expression programs that are required for the stable change of neuronal properties, a process that is essential for learning and memory. Currently, it is still unclear how the stimulation of dendritic synapses can be coupled to transcription in the nucleus in a timely way given that large distances can separate these two cellular compartments. Although several mechanisms have been proposed to explain long distance communication between synapses and the nucleus, the possible co-existence of these models and their relevance in physiological conditions remain elusive. One model suggests that synaptic activation triggers the translocation to the nucleus of certain transcription regulators localised at postsynaptic sites that function as synapto-nuclear messengers. Alternatively, it has been hypothesised that synaptic activity initiates propagating regenerative intracellular calcium waves that spread through dendrites into the nucleus where nuclear transcription machinery is thereby regulated. It has also been postulated that membrane depolarisation of voltage-gated calcium channels on the somatic membrane is sufficient to increase intracellular calcium concentration and activate transcription without the need for transported signals from distant synapses. Here I provide a critical overview of the suggested mechanisms for coupling synaptic stimulation to transcription, the underlying assumptions behind them and their plausible physiological significance. PMID:24327840

Neuronal activity-regulated gene transcription: how are distant synaptic signals conveyed to the nucleus?

PubMed

Matamales, Miriam

2012-12-19

Synaptic activity can trigger gene expression programs that are required for the stable change of neuronal properties, a process that is essential for learning and memory. Currently, it is still unclear how the stimulation of dendritic synapses can be coupled to transcription in the nucleus in a timely way given that large distances can separate these two cellular compartments. Although several mechanisms have been proposed to explain long distance communication between synapses and the nucleus, the possible co-existence of these models and their relevance in physiological conditions remain elusive. One model suggests that synaptic activation triggers the translocation to the nucleus of certain transcription regulators localised at postsynaptic sites that function as synapto-nuclear messengers. Alternatively, it has been hypothesised that synaptic activity initiates propagating regenerative intracellular calcium waves that spread through dendrites into the nucleus where nuclear transcription machinery is thereby regulated. It has also been postulated that membrane depolarisation of voltage-gated calcium channels on the somatic membrane is sufficient to increase intracellular calcium concentration and activate transcription without the need for transported signals from distant synapses. Here I provide a critical overview of the suggested mechanisms for coupling synaptic stimulation to transcription, the underlying assumptions behind them and their plausible physiological significance.

Neuronal activity-regulated gene transcription: how are distant synaptic signals conveyed to the nucleus?

PubMed

Matamales, Miriam

2012-01-01

Synaptic activity can trigger gene expression programs that are required for the stable change of neuronal properties, a process that is essential for learning and memory. Currently, it is still unclear how the stimulation of dendritic synapses can be coupled to transcription in the nucleus in a timely way given that large distances can separate these two cellular compartments. Although several mechanisms have been proposed to explain long distance communication between synapses and the nucleus, the possible co-existence of these models and their relevance in physiological conditions remain elusive. One model suggests that synaptic activation triggers the translocation to the nucleus of certain transcription regulators localised at postsynaptic sites that function as synapto-nuclear messengers. Alternatively, it has been hypothesised that synaptic activity initiates propagating regenerative intracellular calcium waves that spread through dendrites into the nucleus where nuclear transcription machinery is thereby regulated. It has also been postulated that membrane depolarisation of voltage-gated calcium channels on the somatic membrane is sufficient to increase intracellular calcium concentration and activate transcription without the need for transported signals from distant synapses. Here I provide a critical overview of the suggested mechanisms for coupling synaptic stimulation to transcription, the underlying assumptions behind them and their plausible physiological significance.

Shaping long-term primate development: Telomere length trajectory as an indicator of early maternal maltreatment and predictor of future physiologic regulation.

PubMed

Drury, Stacy S; Howell, Brittany R; Jones, Christopher; Esteves, Kyle; Morin, Elyse; Schlesinger, Reid; Meyer, Jerrold S; Baker, Kate; Sanchez, Mar M

2017-12-01

The molecular, neurobiological, and physical health impacts of child maltreatment are well established, yet mechanistic pathways remain inadequately defined. Telomere length (TL) decline is an emerging molecular indicator of stress exposure with definitive links to negative health outcomes in maltreated individuals. The multiple confounders endemic to human maltreatment research impede the identification of causal pathways. This study leverages a unique randomized, cross-foster, study design in a naturalistic translational nonhuman primate model of infant maltreatment. At birth, newborn macaques were randomly assigned to either a maltreating or a competent control mother, balancing for sex, biological mother parenting history, and social rank. Offspring TL was measured longitudinally across the first 6 months of life (infancy) from peripheral blood. Hair cortisol accumulation was also determined at 6, 12, and 18 months of age. TL decline was greater in animals randomized to maltreatment, but also interacted with biological mother group. Shorter TL at 6 months was associated with higher mean cortisol levels through 18 months (juvenile period) when controlling for relevant covariates. These results suggest that even under the equivalent social, nutritional, and environmental conditions feasible in naturalistic translational nonhuman primate models, early adverse caregiving results in lasting molecular scars that foreshadow elevated health risk and physiologic dysregulation.