Synaptic Plasticity In Vitro and In Silico: Insights into an Intracellular Signaling Maze

Physiology ◽  
2006 ◽  
Vol 21 (4) ◽  
pp. 289-296 ◽  
Author(s):  
Sriram M. Ajay ◽  
Upinder S. Bhalla
Keyword(s):  
Experimental Data ◽  
Synaptic Plasticity ◽  
Neuronal Activity ◽  
In Silico ◽  
Intracellular Signaling ◽  
Signaling Networks ◽  
Functional Roles ◽  
Current State ◽  
History Of

Synaptic plasticity provides a record of neuronal activity and is a likely basis for memory. The early apparent simplicity of the process of synaptic plasticity has been lost in a flood of experimental data that now implicates some 200 signaling molecules in cellular memory. It is now clear that these signaling networks perform surprisingly sophisticated cellular decisions that weigh factors such as input patterns, location of stimulus, history of activity, and context. Computer models have followed experiments into this maze of molecular detail, often matching closely with their experimental counterparts, but perhaps losing simplicity in the process. Here, we suggest that the merger of models and experiment have begun to restore the earlier simplicity by outlining a few key functional roles for signaling networks in synaptic plasticity. In this review, we discuss the current state of understanding of synaptic plasticity in terms of models and experiments.

scholarly journals Comparison of the Simulated Response of Three in Silico Human Stem Cell-Derived Cardiomyocytes Models and in Vitro Data Under 15 Drug Actions

2021 ◽  
Vol 12 ◽  
Author(s):  
Michelangelo Paci ◽  
Jussi T. Koivumäki ◽  
Hua Rong Lu ◽  
David J. Gallacher ◽  
Elisa Passini ◽  
...  
Keyword(s):  
Experimental Data ◽  
Stem Cell ◽  
In Silico ◽  
Drug Testing ◽  
Drug Application ◽  
Human Stem Cell ◽  
Drug Induced ◽  
Drug Actions ◽  
Experimental Findings

Objectives: Improvements in human stem cell-derived cardiomyocyte (hSC-CM) technology have promoted their use for drug testing and disease investigations. Several in silico hSC-CM models have been proposed to augment interpretation of experimental findings through simulations. This work aims to assess the response of three hSC-CM in silico models (Koivumäki2018, Kernik2019, and Paci2020) to simulated drug action, and compare simulation results against in vitro data for 15 drugs.Methods: First, simulations were conducted considering 15 drugs, using a simple pore-block model and experimental data for seven ion channels. Similarities and differences were analyzed in the in silico responses of the three models to drugs, in terms of Ca2+ transient duration (CTD90) and occurrence of arrhythmic events. Then, the sensitivity of each model to different degrees of blockage of Na+ (INa), L-type Ca2+ (ICaL), and rapid delayed rectifying K+ (IKr) currents was quantified. Finally, we compared the drug-induced effects on CTD90 against the corresponding in vitro experiments.Results: The observed CTD90 changes were overall consistent among the in silico models, all three showing changes of smaller magnitudes compared to the ones measured in vitro. For example, sparfloxacin 10 µM induced +42% CTD90 prolongation in vitro, and +17% (Koivumäki2018), +6% (Kernik2019), and +9% (Paci2020) in silico. Different arrhythmic events were observed following drug application, mainly for drugs affecting IKr. Paci2020 and Kernik2019 showed only repolarization failure, while Koivumäki2018 also displayed early and delayed afterdepolarizations. The spontaneous activity was suppressed by Na+ blockers and by drugs with similar effects on ICaL and IKr in Koivumäki2018 and Paci2020, while only by strong ICaL blockers, e.g. nisoldipine, in Kernik2019. These results were confirmed by the sensitivity analysis.Conclusion: To conclude, The CTD90 changes observed in silico are qualitatively consistent with our in vitro data, although our simulations show differences in drug responses across the hSC-CM models, which could stem from variability in the experimental data used in their construction.

scholarly journals Application of in silico and in vitro methods in the development of adverse outcome pathway constructs in wildlife

2014 ◽  
Vol 369 (1656) ◽  
pp. 20130584 ◽  
Author(s):  
Judith C. Madden ◽  
Vera Rogiers ◽  
Mathieu Vinken
Keyword(s):  
In Silico ◽  
Adverse Outcome ◽  
Adverse Outcome Pathway ◽  
New Paradigm ◽  
Mechanisms Of Toxicity ◽  
In Vitro Methods ◽  
Diverse Species ◽  
History Of ◽  
Related Wild Species

There is a long history of using both in silico and in vitro methods to predict adverse effects in humans and environmental species where toxicity data are lacking. Currently, there is a great deal of interest in applying these methods to the development of so-called ‘adverse outcome pathway’ (AOP) constructs. The AOP approach provides a framework for organizing information at the chemical and biological level, allowing evidence from both in silico and in vitro studies to be rationally combined to fill gaps in knowledge concerning toxicological events. Fundamental to this new paradigm is a greater understanding of the mechanisms of toxicity and, in particular, where these mechanisms may be conserved across taxa, such as between model animals and related wild species. This presents an opportunity to make predictions across diverse species, where empirical data are unlikely to become available as is the case for most species of wildlife.

scholarly journals Metabolomic Laboratory-Developed Tests: Current Status and Perspectives

Metabolites ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 423
Author(s):  
Steven Lichtenberg ◽  
Oxana P. Trifonova ◽  
Dmitry L. Maslov ◽  
Elena E. Balashova ◽  
Petr G. Lokhov
Keyword(s):  
The United States ◽  
Legal Aspects ◽  
Current Status ◽  
Current State ◽  
The Us ◽  
Metabolomics Study ◽  
In Vitro Diagnostic ◽  
History Of ◽  
Characteristic Features

Laboratory-developed tests (LDTs) are a subset of in vitro diagnostic devices, which the US Food and Drug Administration defines as “tests that are manufactured by and used within a single laboratory”. The review describes the emergence and history of LDTs. The current state and development prospects of LDTs based on metabolomics are analyzed. By comparing LDTs with the scientific metabolomics study of human bio samples, the characteristic features of metabolomic LDT are shown, revealing its essence, strengths, and limitations. The possibilities for further developments and scaling of metabolomic LDTs and their potential significance for healthcare are discussed. The legal aspects of LDT regulation in the United States, European Union, and Singapore, demonstrating different approaches to this issue, are also provided. Based on the data presented in the review, recommendations were made on the feasibility and ways of further introducing metabolomic LDTs into practice.

scholarly journals An In Silico Cell Signaling-Based Approach for Exploring the Activities Involved in Pre-Metastasis and Metastasis

2017 ◽  
Vol 4 (1) ◽  
pp. 100046
Author(s):  
Pedro Pablo González-Pérez ◽  
Maura Cárdenas-García
Keyword(s):  
Cell Signaling ◽  
In Silico ◽  
Signaling Networks ◽  
Control Points ◽  
Intercellular Signaling ◽  
Bioinformatics Tool ◽  
A Cell

In order to understand, identify and explore the activities involved in metastasis, as well as possible control points, in this work we model and simulate the sequential steps that a cell must follow from its transformation to metastasis, using the Cellulat bioinformatics tool, an in silico experimentation environment that complements and guides in vitro experimentation concerning intra and intercellular signaling networks.

DRUG REPOSITIONING FOR THERAPY OF COVID-19

2021 ◽  
Vol 1 (19) ◽  
pp. 209-211
Author(s):  
D.S. Druzhilovskiy ◽  
P.I. Savosina ◽  
O.A. Gomazkov ◽  
B.N. Sobolev ◽  
A.V. Veselovsky ◽  
...  
Keyword(s):  
Research And Development ◽  
Viral Infection ◽  
In Silico ◽  
Drug Repositioning ◽  
In Vitro Methods ◽  
Current State ◽  
Natural Response ◽  
State Of Research

Drug repositioning – the discovery of new indications for the launched drugs – is the rapid natural response to viral infection SARS-CoV-2/COVID-19. We will consider the current state of research and development of repositioned pharmaceuticals for the therapy of COVID-19 using in silico and in vitro methods.

scholarly journals Multi-fractal characterization of bacterial swimming dynamics: a case study on real and simulated Serratia marcescens

2017 ◽  
Vol 473 (2203) ◽  
pp. 20170154 ◽  
Author(s):  
Hana Koorehdavoudi ◽  
Paul Bogdan ◽  
Guopeng Wei ◽  
Radu Marculescu ◽  
Jiang Zhuang ◽  
...  
Keyword(s):  
Serratia Marcescens ◽  
In Silico ◽  
Fractal Characteristic ◽  
Bacterial Dynamics ◽  
Current State ◽  
Bacterial Swimming ◽  
Dynamics Of Populations

To add to the current state of knowledge about bacterial swimming dynamics, in this paper, we study the fractal swimming dynamics of populations of Serratia marcescens bacteria both in vitro and in silico , while accounting for realistic conditions like volume exclusion, chemical interactions, obstacles and distribution of chemoattractant in the environment. While previous research has shown that bacterial motion is non-ergodic, we demonstrate that, besides the non-ergodicity, the bacterial swimming dynamics is multi-fractal in nature. Finally, we demonstrate that the multi-fractal characteristic of bacterial dynamics is strongly affected by bacterial density and chemoattractant concentration.

scholarly journals Use of the Polo-like kinase 4 (PLK4) inhibitor centrinone to investigate intracellular signaling networks using SILAC-based phosphoproteomics

2020 ◽  
Author(s):  
Dominic P Byrne ◽  
Christopher J Clarke ◽  
Philip J Brownridge ◽  
Anton Kalyuzhnyy ◽  
Simon Perkins ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Kinase Inhibitors ◽  
Cellular Protein ◽  
Human Cells ◽  
Signaling Networks ◽  
Sequence Motifs ◽  
Inhibitory Effects ◽  
Centriole Duplication ◽  
Tightly Coupled

ABSTRACTPolo-like kinase 4 (PLK4) is the master regulator of centriole duplication in metazoan organisms. Catalytic activity and protein turnover of PLK4 are tightly coupled in human cells, since changes in PLK4 concentration and catalysis have profound effects on centriole duplication and supernumerary centrosomes, which are associated with aneuploidy and cancer. Recently, PLK4 has been targeted with a variety of small molecule kinase inhibitors exemplified by centrinone, which rapidly induces inhibitory effects on PLK4 and leads to on-target centrosome depletion. Despite this, relatively few PLK4 substrates have been identified unequivocally in human cells, and PLK4 signaling outside centriolar networks remains poorly characterised. We report an unbiased mass spectrometry (MS)-based quantitative analysis of cellular protein phosphorylation in stable PLK4-expressing U2OS human cells exposed to centrinone. PLK4 phosphorylation was itself sensitive to brief exposure to the compound, resulting in PLK4 stabilization. Analysing asynchronous cell populations, we report hundreds of centrinone-regulated cellular phosphoproteins, including centrosomal and cell cycle proteins and a variety of likely ‘non-canonical’ substrates. Surprisingly, sequence interrogation of ~300 significantly down-regulated phosphoproteins reveals an extensive network of centrinone-sensitive [Ser/Thr]Pro phosphorylation sequence motifs, which based on our analysis might be either direct or indirect targets of PLK4. In addition, we confirm that NMYC and PTPN12 are PLK4 substrates, both in vitro and in human cells. Our findings suggest that PLK4 catalytic output directly controls the phosphorylation of a diverse set of cellular proteins, including Pro-directed targets that are likely to be important in PLK4-mediated cell signaling.

Sign in / Sign up

Export Citation Format

Share Document