scholarly journals isiKnock: in silico knockouts in biochemical pathways

2018 ◽  
Author(s):  
Jennifer Scheidel ◽  
Heiko Giese ◽  
Börje Schweizer ◽  
Leonie Amstein ◽  
Jörg Ackermann ◽  
...  
Keyword(s):  
Steady State ◽  
Mathematical Models ◽  
Open Source ◽  
Cell Response ◽  
In Silico ◽  
Receptor Activation ◽  
The Novel ◽  
Biochemical Pathways ◽  
Novel Concept ◽  
Microsoft Windows

AbstractSummaryisiKnock is a new software that automatically conducts in silico knockouts for mathematical models of biochemical pathways. The software allows for the prediction of the behavior of biological systems after single or multiple knockout. The implemented algorithm applies transition invariants and the novel concept of Manatee invariants. A knockout matrix visualizes the results. The tool enables the analysis of dependencies, for example, in signal flows from the receptor activation to the cell response at steady state.Availability and ImplementationisiKnock is an open-source tool, freely available at http://www.bioinformatik.uni-frankfurt.de/tools/isiKnock/index.php. It requires at least Java 8 and runs under Microsoft Windows, Linux, and Mac [email protected]

scholarly journals Subsynaptic positioning of AMPARs by LRRTM2 controls synaptic strength

2021 ◽  
Author(s):  
A.M. Ramsey ◽  
A.H. Tang ◽  
T.A. LeGates ◽  
X.Z. Gou ◽  
B.E. Carbone ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Ampa Receptors ◽  
Glutamate Release ◽  
Receptor Activation ◽  
Synaptic Strength ◽  
Synaptic Function ◽  
The Novel ◽  
Novel Concept ◽  
The Brain

AbstractRecent evidence suggests that nanoorganization of proteins within synapses may control the strength of communication between neurons in the brain. The unique subsynaptic distribution of glutamate receptors, which cluster in nanoalignment with presynaptic sites of glutamate release, supports this idea. However, testing it has been difficult because mechanisms controlling subsynaptic organization remain unknown. Reasoning that transcellular interactions could position AMPA receptors, we targeted a key transsynaptic adhesion molecule implicated in controlling AMPAR number, LRRTM2, using engineered, rapid proteolysis. Severing the LRRTM2 extracellular domain led quickly to nanoscale de-clustering of AMPARs away from release sites, not prompting their escape from synapses until much later. This rapid remodeling of AMPAR position produced significant deficits in evoked, but not spontaneous, postsynaptic receptor activation. These results dissociate receptor numbers from their nanopositioning in determination of synaptic function, and support the novel concept that adhesion molecules acutely position AMPA receptors to dynamically control synaptic strength.

scholarly journals Subsynaptic positioning of AMPARs by LRRTM2 controls synaptic strength

2021 ◽  
Vol 7 (34) ◽  
pp. eabf3126
Author(s):  
Austin M. Ramsey ◽  
Ai-Hui Tang ◽  
Tara A. LeGates ◽  
Xu-Zhuo Gou ◽  
Beatrice E. Carbone ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Ampa Receptors ◽  
Glutamate Release ◽  
Receptor Activation ◽  
Synaptic Strength ◽  
Synaptic Function ◽  
The Novel ◽  
Novel Concept ◽  
The Brain

Recent evidence suggests that nano-organization of proteins within synapses may control the strength of communication between neurons in the brain. The unique subsynaptic distribution of glutamate receptors, which cluster in nanoalignment with presynaptic sites of glutamate release, supports this hypothesis. However, testing it has been difficult because mechanisms controlling subsynaptic organization remain unknown. Reasoning that transcellular interactions could position AMPA receptors (AMPARs), we targeted a key transsynaptic adhesion molecule implicated in controlling AMPAR number, LRRTM2, using engineered, rapid proteolysis. Severing the LRRTM2 extracellular domain led quickly to nanoscale declustering of AMPARs away from release sites, not prompting their escape from synapses until much later. This rapid remodeling of AMPAR position produced significant deficits in evoked, but not spontaneous, postsynaptic receptor activation. These results dissociate receptor numbers from their nanopositioning in determination of synaptic function and support the novel concept that adhesion molecules acutely position receptors to dynamically control synaptic strength.

Critical Review on the Chemical Aspects of Cannabidiol (CBD) and Harmonization of Computational Bioactivity Data

2020 ◽  
Vol 28 (2) ◽  
pp. 213-237 ◽  
Author(s):  
Andrea Mastinu ◽  
Giovanni Ribaudo ◽  
Alberto Ongaro ◽  
Sara Anna Bonini ◽  
Maurizio Memo ◽  
...  
Keyword(s):  
In Silico ◽  
Cannabis Sativa ◽  
Therapeutic Potential ◽  
The Novel ◽  
In Silico Studies ◽  
Computational Data ◽  
Synthetic Approaches ◽  
Analytical Approaches ◽  
Yield Sensitivity ◽  
Therapeutic Profile

: Cannabidiol (CBD) is a non-psychotropic phytocannabinoid which represents one of the constituents of the “phytocomplex” of Cannabis sativa. This natural compound is attracting growing interest since when CBD-based remedies and commercial products were marketed. This review aims to exhaustively address the extractive and analytical approaches that have been developed for the isolation and quantification of CBD. Recent updates on cutting-edge technologies were critically examined in terms of yield, sensitivity, flexibility and performances in general, and are reviewed alongside original representative results. As an add-on to currently available contributions in the literature, the evolution of the novel, efficient synthetic approaches for the preparation of CBD, a procedure which is appealing for the pharmaceutical industry, is also discussed. Moreover, with the increasing interest on the therapeutic potential of CBD and the limited understanding of the undergoing biochemical pathways, the reader will be updated about recent in silico studies on the molecular interactions of CBD towards several different targets attempting to fill this gap. Computational data retrieved from the literature have been integrated with novel in silico experiments, critically discussed to provide a comprehensive and updated overview on the undebatable potential of CBD and its therapeutic profile.

The Antiviral and Antimalarial Drug Repurposing in Quest of Chemotherapeutics to Combat COVID-19 Utilizing Structure-Based Molecular Docking

2020 ◽  
Vol 23 ◽  
Author(s):  
Sisir Nandi ◽  
Mohit Kumar ◽  
Mridula Saxena ◽  
Anil Kumar Saxena
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Drug Repurposing ◽  
Clinical Settings ◽  
The Novel ◽  
In Silico Docking ◽  
Biochemical Mechanisms ◽  
Novel Coronavirus ◽  
In Silico Molecular Docking

Background: The novel coronavirus disease (COVID-19) is caused by a new strain (SARS-CoV-2) erupted in 2019. Nowadays, it is a great threat that claims uncountable lives worldwide. There is no specific chemotherapeutics developed yet to combat COVID-19. Therefore, scientists have been devoted in the quest of the medicine that can cure COVID- 19. Objective: Existing antivirals such as ASC09/ritonavir, lopinavir/ritonavir with or without umifenovir in combination with antimalarial chloroquine or hydroxychloroquine have been repurposed to fight the current coronavirus epidemic. But exact biochemical mechanisms of these drugs towards COVID-19 have not been discovered to date. Method: In-silico molecular docking can predict the mode of binding to sort out the existing chemotherapeutics having a potential affinity towards inhibition of the COVID-19 target. An attempt has been made in the present work to carry out docking analyses of 34 drugs including antivirals and antimalarials to explain explicitly the mode of interactions of these ligands towards the COVID-19protease target. Results: 13 compounds having good binding affinity have been predicted towards protease binding inhibition of COVID-19. Conclusion: Our in silico docking results have been confirmed by current reports from clinical settings through the citation of suitable experimental in vitro data available in the published literature.

Steady-state mathematical models of convertors with biparametric regulation

1993 ◽  
Vol 140 (2) ◽  
pp. 105
Author(s):  
G. Carpinelli ◽  
F. Gagliardi ◽  
A. Sturchio ◽  
M. Russo
Keyword(s):  
Steady State ◽  
Mathematical Models

scholarly journals Receptor-operated Ca2+ channels in gastric parietal cells: gastrin and carbachol induce Ca2+ influx in depleting intracellular Ca2+ stores

1993 ◽  
Vol 289 (1) ◽  
pp. 117-124 ◽  
Author(s):  
S Roche ◽  
J P Bali ◽  
R Magous
Keyword(s):  
Steady State ◽  
Receptor Activation ◽  
Parietal Cells ◽  
The Other ◽  
Bivalent Cation ◽  
Gtp Binding ◽  
Gastric Parietal Cells ◽  
Type Receptor ◽  
Ca2 Channels ◽  
Stimulation Of

The mechanism whereby gastrin-type receptor and muscarinic M3-type receptor regulate free intracellular Ca2+ concentration ([Ca2+]i) was studied in rabbit gastric parietal cells stimulated by either gastrin or carbachol. Both agonists induced a biphasic [Ca2+]i response: a transient [Ca2+]i rise, followed by a sustained steady state depending on extracellular Ca2+. Gastrin and carbachol also caused a rapid and transient increase in Mn2+ influx (a tracer for bivalent-cation entry). Pre-stimulation of cells with one agonist drastically decreased both [Ca2+]i increase and Mn2+ influx induced by the other. Neither diltiazem nor pertussistoxin treatment had any effect on agonist-stimulated Mn2+ entry. Thapsigargin, a Ca(2+)-pump inhibitor, induced a biphasic [Ca2+]i increase, and enhanced the rate of Mn2+ entry. Preincubation of cells with thapsigargin inhibits the [Ca2+]i increase as well as Mn2+ entry stimulated by gastrin or by carbachol. Thapsigargin induced a weak but significant increase in Ins(1,4,5)P3 content, but this agent had no effect on the agonist-evoked Ins(1,4,5)P3 response. In permeabilized parietal cells, Ins(1,4,5)P3 and caffeine caused an immediate Ca2+ release from intracellular pools, followed by a reloading of Ca2+ pools which can be prevented in the presence of thapsigargin. We conclude that (i) gastrin and carbachol mobilize common Ca2+ intracellular stores, (ii) Ca2+ permeability secondary to receptor activation involves neither a voltage-sensitive Ca2+ channel nor a GTP-binding protein from the G1 family, and (iii) agonists regulate common Ca2+ channels in depleting intracellular Ca2+ stores.

scholarly journals Racism and Antiracism in the Liberal International Order

2020 ◽  
pp. 1-24
Author(s):  
Zoltán I. Búzás
Keyword(s):  
International Relations ◽  
Racial Inequality ◽  
Racial Diversity ◽  
International Order ◽  
Interdisciplinary Studies ◽  
Racial Equality ◽  
The Novel ◽  
Current Regime ◽  
Novel Concept ◽  
Comprehensive Framework

Abstract Formal racial equality is a key aspect of the current Liberal International Order (LIO). It is subject to two main challenges: resurgent racial nationalism and substantive racial inequality. Combining work in International Relations with interdisciplinary studies on race, I submit that these challenges are the latest iteration of struggles between two transnational coalitions over the LIO's central racial provisions, which I call racial diversity regimes (RDRs). The traditional coalition has historically favored RDRs based on racial inequality and racial nationalism. The transformative coalition has favored RDRs based on racial equality and nonracial nationalism. I illustrate the argument by tracing the development of the liberal order's RDR as a function of intercoalitional struggles from one based on racial nationalism and inequality in 1919 to the current regime based on nonracial nationalism and limited equality. Today, racial nationalists belong to the traditional coalition and critics of racial inequality are part of the transformative coalition. The stakes of their struggles are high because they will determine whether we will live in a more racist or a more antiracist world. This article articulates a comprehensive framework that places race at the heart of the liberal order, offers the novel concept of “embedded racism” to capture how sovereignty shields domestic racism from foreign interference, and proposes an agenda for mainstream International Relations that takes race seriously.

scholarly journals Using green infrastructure to stimulate discourse with and for planning practice: experiences with fuzzy concepts from a pan-European, a national and a local perspective

2021 ◽  
Author(s):  
Rieke Hansen ◽  
Martina van Lierop ◽  
Werner Rolf ◽  
Damjana Gantar ◽  
Ina Šuklje Erjavec ◽  
...  
Keyword(s):  
Green Infrastructure ◽  
Regional Cooperation ◽  
Knowledge Exchange ◽  
Stakeholder Involvement ◽  
The Novel ◽  
Planning Practice ◽  
Regional Project ◽  
Development Processes ◽  
Guidance Documents ◽  
Novel Concept

AbstractConcepts such as green infrastructure, nature-based solutions, and ecosystem services gained popularity in recent discourses on urban planning. Despite their recognition as innovative concepts, all of them share a degree of ambiguity. Fuzziness can be a weakness but also an opportunity to shape novel concepts together with the stakeholders that are supposed to implement them in the planning practice. The paper traces concept development processes of green infrastructure through transdisciplinary knowledge exchange in three different projects, a European and a national research project and a local city-regional project as part of an EU regional cooperation project. In all projects, the green infrastructure concept evolved in different stages. Stakeholder involvement during these stages span from consultation to co-creation. The cases reveal two different approaches: concepts that are developed “for planning practice” might be based on a plethora of insight via consultation, while those “with planning practice” foster co-creation and might result in high acceptance among the involved stakeholders. Depending on the purpose of the novel concept, each approach can be beneficial and result in practice-related and operational products, such as guidance documents or planning strategies. However, the cases also show that in any new context an exchange about fuzzy concepts is not only needed but also a chance to stimulate cooperation and joint understanding about urban challenges and how to address them.

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