scholarly journals Systems-level neurophysiological state characteristics for drug evaluation in an animal model of levodopa-induced dyskinesia

2016 ◽  
Vol 115 (3) ◽  
pp. 1713-1729 ◽  
Author(s):  
Martin Tamtè ◽  
Ivani Brys ◽  
Ulrike Richter ◽  
Nedjeljka Ivica ◽  
Pär Halje ◽  
...  
Keyword(s):  
Large Scale ◽  
Drug Evaluation ◽  
Brain Structures ◽  
Significant Information ◽  
Animal Models Of Disease ◽  
Physiological Processes ◽  
Wide Range ◽  
The Central Nervous System ◽  
Neurophysiological Mechanisms ◽  
Models Of Disease

Disorders affecting the central nervous system have proven particularly hard to treat, and disappointingly few novel therapies have reached the clinics in recent decades. A better understanding of the physiological processes in the brain underlying various symptoms could therefore greatly improve the rate of progress in this field. We here show how systems-level descriptions of different brain states reliably can be obtained through a newly developed method based on large-scale recordings in distributed neural networks encompassing several different brain structures. Using this technology, we characterize the neurophysiological states associated with parkinsonism and levodopa-induced dyskinesia in a rodent model of Parkinson's disease together with pharmacological interventions aimed at reducing dyskinetic symptoms. Our results show that the obtained electrophysiological data add significant information to conventional behavioral evaluations and hereby elucidate the underlying effects of treatments in greater detail. Taken together, these results potentially open up for studies of neurophysiological mechanisms underlying symptoms in a wide range of neurological and psychiatric conditions that until now have been very hard to investigate in animal models of disease.

scholarly journals Drugs modulating the L-arginine:NO:cGMP pathway – current use in therapy

2016 ◽  
Vol 29 (1) ◽  
pp. 14-20 ◽  
Author(s):  
Magdalena Polakowska ◽  
Jolanta Orzelska-Gorka ◽  
Sylwia Talarek
Keyword(s):  
Nitric Oxide ◽  
Central Nervous System ◽  
Nervous System ◽  
Cardiovascular Diseases ◽  
Significant Role ◽  
Current Understanding ◽  
Physiological Processes ◽  
Wide Range ◽  
The Central Nervous System ◽  
Pharmacological Profiles

AbstractNitric oxide (NO) is a relatively novel messenger that plays a significant role in a wide range of physiological processes. Currently, it is known that, both, lack and excess of NO can cause diseases, thus a lot of substances have been discovered and utilized which can change the concentration of this molecule within the organism. The aim of the present work is to provide an overview of currently used agents modulating the L-arginine:NO:cGMP pathway, as well as to summarize current understanding of their pharmacological profiles. Nowadays, most of these agents are employed particularly in the treatment of cardiovascular diseases. Further studies can hold promise for enhancing the therapeutic equipment for a variety of other impairments, such as osteoporosis, and also in treatments of the central nervous system.

Spontaneous Collective Action: Peripheral Mobilization During the Arab Spring

2017 ◽  
Vol 111 (2) ◽  
pp. 379-403 ◽  
Author(s):  
ZACHARY C. STEINERT-THRELKELD
Keyword(s):  
Social Network ◽  
Collective Action ◽  
Information Diffusion ◽  
Large Scale ◽  
Authoritarian Regimes ◽  
Individual Level ◽  
The Core ◽  
Wide Range ◽  
Models Of Disease ◽  
The Arab Spring

Who is responsible for protest mobilization? Models of disease and information diffusion suggest that those central to a social network (the core) should have a greater ability to mobilize others than those who are less well-connected. To the contrary, this article argues that those not central to a network (the periphery) can generate collective action, especially in the context of large-scale protests in authoritarian regimes. To show that those in the core of a social network have no effect on levels of protest, this article develops a dataset of daily protests across 16 countries in the Middle East and North Africa over 14 months from 2010 through 2011. It combines that dataset with geocoded, individual-level communication from the same period and measures the number of connections of each person. Those on the periphery are shown to be responsible for changing levels of protest, with some evidence suggesting that the core’s mobilization efforts lead to fewer protests. These results have implications for a wide range of social choices that rely on interdependent decision making.

scholarly journals A modular computational framework for medical digital twins

2021 ◽  
Vol 118 (20) ◽  
pp. e2024287118
Author(s):  
J. Masison ◽  
J. Beezley ◽  
Y. Mei ◽  
HAL Ribeiro ◽  
A. C. Knapp ◽  
...  
Keyword(s):  
Large Scale ◽  
Computational Models ◽  
Model Building ◽  
Heterogeneous Data ◽  
Distributed Model ◽  
Modular Software ◽  
Digital Twins ◽  
Building Process ◽  
Wide Range ◽  
Models Of Disease

This paper presents a modular software design for the construction of computational modeling technology that will help implement precision medicine. In analogy to a common industrial strategy used for preventive maintenance of engineered products, medical digital twins are computational models of disease processes calibrated to individual patients using multiple heterogeneous data streams. They have the potential to help improve diagnosis, prognosis, and personalized treatment for a wide range of medical conditions. Their large-scale development relies on both mechanistic and data-driven techniques and requires the integration and ongoing update of multiple component models developed across many different laboratories. Distributed model building and integration requires an open-source modular software platform for the integration and simulation of models that is scalable and supports a decentralized, community-based model building process. This paper presents such a platform, including a case study in an animal model of a respiratory fungal infection.

scholarly journals In Vivo Imaging With Confirmation by Histopathology for Increased Rigor and Reproducibility in Translational Research: A Review of Examples, Options, and Resources

ILAR Journal ◽  
2018 ◽  
Vol 59 (1) ◽  
pp. 80-98 ◽  
Author(s):  
Kathleen Gabrielson ◽  
Robert Maronpot ◽  
Sébastien Monette ◽  
Coraline Mlynarczyk ◽  
Yuval Ramot ◽  
...  
Keyword(s):  
Animal Model ◽  
In Vivo Imaging ◽  
Image Interpretation ◽  
Imaging Data ◽  
Case Examples ◽  
Animal Models Of Disease ◽  
Molecular Features ◽  
Wide Range ◽  
Models Of Disease

Abstract Preclinical noninvasive imaging can be an indispensable tool for studying animal models of disease. In vivo imaging to assess anatomical, functional, and molecular features requires verification by a comparison to the macroscopic and microscopic morphological features, since all noninvasive in vivo imaging methods have much lower resolution than standard histopathology. Comprehensive pathological evaluation of the animal model is underutilized; yet, many institutions have veterinary or human pathologists with necessary comparative pathology expertise. By performing a rigorous comparison to gross or histopathology for image interpretation, these trained individuals can assist scientists with the development of the animal model, experimental design, and evaluation of the in vivo imaging data. These imaging and pathology corroboration studies undoubtedly increase scientific rigor and reproducibility in descriptive and hypothesis-driven research. A review of case examples including ultrasound, nuclear, optical, and MRI is provided to illustrate how a wide range of imaging modalities data can be confirmed by gross or microscopic pathology. This image confirmation and authentication will improve characterization of the model and may contribute to decreasing costs and number of animals used and to more rapid translation from preclinical animal model to the clinic.

scholarly journals Harnessing the microbiota to treat neurological diseases

2019 ◽  
Vol 21 (2) ◽  
pp. 159-165 ◽  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neurological Diseases ◽  
Clinical Samples ◽  
Pathogenic Role ◽  
Animal Models Of Disease ◽  
The Central Nervous System ◽  
Microbe Interactions ◽  
Host Microbe Interactions ◽  
Models Of Disease

Studies over the last decade have transformed our previously simplistic view of microbes, having only a pathogenic role in disease to a more robust understanding that they are critical for maintaining human health. Indeed, our microbiota—the collection of commensal organisms that live in and on each of us—contributes to nearly every facet of host physiology, from ontogeny of the immune system to neurological function to metabolism. Although the specific details of these host–microbe interactions are still being elucidated for most diseases, the coupling of clinical samples with animal models of disease have provided key insights. This review provides some general background on the microbiota, highlights a few examples of how the microbiota influences diseases of the central nervous system, and provides a perspective for how these findings may be clinically translatable.

scholarly journals Improving preclinical studies through replications

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Natascha Ingrid Drude ◽  
Lorena Martinez Gamboa ◽  
Meggie Danziger ◽  
Ulrich Dirnagl ◽  
Ulf Toelch
Keyword(s):  
Clinical Trials ◽  
Animal Models ◽  
Large Scale ◽  
Preclinical Studies ◽  
Efficient Allocation ◽  
Allocation Of Resources ◽  
Preclinical Research ◽  
Replication Studies ◽  
Animal Models Of Disease ◽  
Models Of Disease

The purpose of preclinical research is to inform the development of novel diagnostics or therapeutics, and the results of experiments on animal models of disease often inform the decision to conduct studies in humans. However, a substantial number of clinical trials fail, even when preclinical studies have apparently demonstrated the efficacy of a given intervention. A number of large-scale replication studies are currently trying to identify the factors that influence the robustness of preclinical research. Here, we discuss replications in the context of preclinical research trajectories, and argue that increasing validity should be a priority when selecting experiments to replicate and when performing the replication. We conclude that systematically improving three domains of validity – internal, external and translational – will result in a more efficient allocation of resources, will be more ethical, and will ultimately increase the chances of successful translation.

The endocannabinoid system

2020 ◽  
Vol 64 (3) ◽  
pp. 485-499
Author(s):  
Aruna Kilaru ◽  
Kent D. Chapman
Keyword(s):  
Signaling Pathways ◽  
Membrane Lipids ◽  
Endocannabinoid System ◽  
Physiological Processes ◽  
Therapeutic Value ◽  
Wide Range ◽  
Therapeutic Development ◽  
The Central Nervous System ◽  
Psychotropic Effects ◽  
Signaling Process

Abstract Thirty years ago, the discovery of a cannabinoid (CB) receptor that interacts with the psychoactive compound in Cannabis led to the identification of anandamide, an endogenous receptor ligand or endocannabinoid. Research on endocannabinoids has since exploded, and additional receptors along with their lipid mediators and signaling pathways continue to be revealed. Specifically, in humans, the release of endocannabinoids from membrane lipids occurs on demand and the signaling process is rapidly attenuated by the breakdown of the ligand suggesting a tight regulation of the endocannabinoid system (ECS). Additionally, the varying distribution of CB receptors between the central nervous system and other tissues allows for the ECS to participate in a wide range of cognitive and physiological processes. Select plant-derived ‘phyto’cannabinoids such as Δ-9-tetrahydrocannabinol (Δ9-THC) bind to the CB receptors and trigger the ECS, and in the case of Δ9-THC, while it has therapeutic value, can also produce detrimental effects. Current research is aimed at the identification of additional phytocannabinoids with minimal psychotropic effects with potential for therapeutic development. Although decades of research on the ECS and its components have expanded our understanding of the mechanisms and implications of endocannabinoid signaling in mammals, it continues to evolve. Here, we provide a brief overview of the ECS and its overlap with other related lipid-mediated signaling pathways.

scholarly journals Use eco-physiological modelling to investigate Potassium limitation of wood productivity in tropical eucalypt plantations

2021 ◽  
Author(s):  
Ivan Cornut ◽  
Nicolas Delpierre ◽  
Guerric Le Maire ◽  
Joannès Guillemot ◽  
Yann Nouvellon ◽  
...  
Keyword(s):  
Large Scale ◽  
Eucalyptus Grandis ◽  
Mechanistic Modeling ◽  
Generation Model ◽  
P Availability ◽  
Leaf Ontogeny ◽  
Physiological Processes ◽  
Eucalypt Plantations ◽  
Wide Range ◽  
K Deficiency

<p>Potassium (K) is essential for a wide range of physiological functions in plants, and a limiting element for wood productivity in numerous forest ecosystems. However, the contribution of each of the K-sensitive physiological processes to the limitation of wood productivity is poorly known. In trees, K deficiency acts both on the source and the sinks of carbon making it difficult to disentangle its effects on wood productivity. The literature dealing with the influence of K-limitation on tree physiologywhile disparate, shows some converging results. Furthermore, K-limited tropical <em>Eucalyptus</em> plantations have been studied extensively over the last 2 decades. Large scale fertilization experiments, run over multiple rotations, allow us to gain insight into the ecosystem’s K-cycle as a whole and the physiological processes that are impacted the most by K deficiency. Mechanistic modeling of this system should allow us to quantify the relative contribution of each process when it comes to wood productivity limitation by K. We have thus adapted an eco-physiological model (CASTANEA-CNP), previously used in temperate forest settings, to use in tropical eucalypt plantations. This has led us to adapt existing nutrient (N and P) eco-physiological modeling frameworks specifically for K as well as focus on processes that are little impacted by N and P availability but greatly by K availability. The biological K-cycle model was calibrated using the comprehensive experimental data. Carbon and water fluxes were calibrated using data from a flux tower site (Eucflux) with the same environmental conditions as the experimental plots. The development of a new canopy generation model was mandated by both the continuous nature of leaf generation in <em>Eucalyptus grandis </em>and the major interaction between leaf ontogeny and the K-cycle. At first we focus mainly on carbon assimilation at the canopy level. Here we present the preliminary results obtained by this model.</p>

scholarly journals Animal Models of Cardiovascular Diseases

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Carlos Zaragoza ◽  
Carmen Gomez-Guerrero ◽  
Jose Luis Martin-Ventura ◽  
Luis Blanco-Colio ◽  
Begoña Lavin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiovascular Diseases ◽  
Animal Models ◽  
Developed Countries ◽  
Cardiovascular Complications ◽  
Cardiac Diseases ◽  
Animal Models Of Disease ◽  
Wide Range ◽  
Genetic And Environmental Factors ◽  
Models Of Disease

Cardiovascular diseases are the first leading cause of death and morbidity in developed countries. The use of animal models have contributed to increase our knowledge, providing new approaches focused to improve the diagnostic and the treatment of these pathologies. Several models have been developed to address cardiovascular complications, including atherothrombotic and cardiac diseases, and the same pathology have been successfully recreated in different species, including small and big animal models of disease. However, genetic and environmental factors play a significant role in cardiovascular pathophysiology, making difficult to match a particular disease, with a single experimental model. Therefore, no exclusive method perfectly recreates the human complication, and depending on the model, additional considerations of cost, infrastructure, and the requirement for specialized personnel, should also have in mind. Considering all these facts, and depending on the budgets available, models should be selected that best reproduce the disease being investigated. Here we will describe models of atherothrombotic diseases, including expanding and occlusive animal models, as well as models of heart failure. Given the wide range of models available, today it is possible to devise the best strategy, which may help us to find more efficient and reliable solutions against human cardiovascular diseases.

Electron microscopy study of reactively sputter-deposited Ti/N films on silicon

1992 ◽  
Vol 50 (2) ◽  
pp. 1362-1363
Author(s):  
V. C. Kannan ◽  
A. K. Singh ◽  
R. B. Irwin ◽  
S. Chittipeddi ◽  
F. D. Nkansah ◽  
...  
Keyword(s):  
Integrated Circuits ◽  
Large Scale ◽  
Hexagonal Phase ◽  
Microscopy Study ◽  
Electron Microscopy Study ◽  
Process Conditions ◽  
Tin Films ◽  
Wide Range ◽  
Fcc Phase ◽  
Circuits Vlsi

Titanium nitride (TiN) films have historically been used as diffusion barrier between silicon and aluminum, as an adhesion layer for tungsten deposition and as an interconnect material etc. Recently, the role of TiN films as contact barriers in very large scale silicon integrated circuits (VLSI) has been extensively studied. TiN films have resistivities on the order of 20μ Ω-cm which is much lower than that of titanium (nearly 66μ Ω-cm). Deposited TiN films show resistivities which vary from 20 to 100μ Ω-cm depending upon the type of deposition and process conditions. TiNx is known to have a NaCl type crystal structure for a wide range of compositions. Change in color from metallic luster to gold reflects the stabilization of the TiNx (FCC) phase over the close packed Ti(N) hexagonal phase. It was found that TiN (1:1) ideal composition with the FCC (NaCl-type) structure gives the best electrical property.

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