scholarly journals Erythrocytes: Oxygen Sensors and Modulators of Vascular Tone

Physiology ◽  
2009 ◽  
Vol 24 (2) ◽  
pp. 107-116 ◽  
Author(s):  
Mary L. Ellsworth ◽  
Christopher G. Ellis ◽  
Daniel Goldman ◽  
Alan H. Stephenson ◽  
Hans H. Dietrich ◽  
...  

Through oxygen-dependent release of the vasodilator ATP, the mobile erythrocyte plays a fundamental role in matching microvascular oxygen supply with local tissue oxygen demand. Signal transduction within the erythrocyte and microvessels as well as feedback mechanisms controlling ATP release have been described. Our understanding of the impact of this novel control mechanism will rely on the integration of in vivo experiments and computational models.

2018 ◽  
Vol 2 (1) ◽  
pp. e000002 ◽  
Author(s):  
Nathalie Percie du Sert ◽  
Viki Hurst ◽  
Amrita Ahluwalia ◽  
Sabina Alam ◽  
Douglas G Altman ◽  
...  

In 2010, the NC3Rs published the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines to improve the reporting of animal research. Despite considerable levels of support from the scientific community, the impact on the quality of reporting in animal research publications has been limited. This position paper highlights the strategy of an expert working group established to revise the guidelines and facilitate their uptake. The group’s initial work will focus on three main areas: prioritisation of the ARRIVE items into a tiered system, development of an explanation and elaboration document, and revision of specific items.


2021 ◽  
Author(s):  
Raphaelle Delattre ◽  
Jeremy Seurat ◽  
Feyrouz Haddad ◽  
Thu-Thuy Nguyen ◽  
Baptiste Gaborieau ◽  
...  

The clinical (re)development of phage therapy to treat antibiotic resistant infections requires grasping specific biological properties of bacteriophages (phages) as antibacterial. However, identification of optimal dosing regimens is hampered by the poor understanding of phage-bacteria interactions in vivo. Here we developed a general strategy coupling in vitro and in vivo experiments with a mathematical model to characterize the interplay between phage and bacterial dynamics during pneumonia induced by a pathogenic strain of Escherichia coli. The model estimates some key parameters for phage therapeutic efficacy, in particular the impact of dose and route of administration on phage dynamics and the synergism of phage and the innate immune response on the bacterial clearance rate. Simulations predict a low impact of the intrinsic phage characteristics in agreement with the current semi-empirical choices of phages for compassionate treatments. Model-based approaches will foster the deployment of future phage therapy clinical trials.


2008 ◽  
Vol 100 (4) ◽  
pp. 1770-1799 ◽  
Author(s):  
I. A. Rybak ◽  
R. O'Connor ◽  
A. Ross ◽  
N. A. Shevtsova ◽  
S. C. Nuding ◽  
...  

A large body of data suggests that the pontine respiratory group (PRG) is involved in respiratory phase-switching and the reconfiguration of the brain stem respiratory network. However, connectivity between the PRG and ventral respiratory column (VRC) in computational models has been largely ad hoc. We developed a network model with PRG-VRC connectivity inferred from coordinated in vivo experiments. Neurons were modeled in the “integrate-and-fire” style; some neurons had pacemaker properties derived from the model of Breen et al. We recapitulated earlier modeling results, including reproduction of activity profiles of different respiratory neurons and motor outputs, and their changes under different conditions (vagotomy, pontine lesions, etc.). The model also reproduced characteristic changes in neuronal and motor patterns observed in vivo during fictive cough and during hypoxia in non-rapid eye movement sleep. Our simulations suggested possible mechanisms for respiratory pattern reorganization during these behaviors. The model predicted that network- and pacemaker-generated rhythms could be co-expressed during the transition from gasping to eupnea, producing a combined “burst-ramp” pattern of phrenic discharges. To test this prediction, phrenic activity and multiple single neuron spike trains were monitored in vagotomized, decerebrate, immobilized, thoracotomized, and artificially ventilated cats during hypoxia and recovery. In most experiments, phrenic discharge patterns during recovery from hypoxia were similar to those predicted by the model. We conclude that under certain conditions, e.g., during recovery from severe brain hypoxia, components of a distributed network activity present during eupnea can be co-expressed with gasp patterns generated by a distinct, functionally “simplified” mechanism.


2018 ◽  
Vol 7 (4) ◽  
pp. 1-19
Author(s):  
Luciandra Macedo de Toledo ◽  
Thayná Barcelos Fernandes ◽  
Mateus José Rodrigues Paranhos da Costa ◽  
Luis Alberto Ambrósio

The dynamics of the first suckling is critical for the formation of the complex cow-calf dyad system, where interactions occur among animals and natural and anthropic environments. In this study, the system dynamics method was applied to build conceptual and computational models to better understand the dynamics of dyadic behavior and its interactions with the environment. The model showed that dyadic behavior is manifested by reinforcing feedback loops in which the calf stimulates the cow's maternal functions, which in turn results in caring stimuli towards the calf. Moreover, ecological factors affect the performance of the animals' behavioral system by influencing the rate of direct events for both, cow and calf. The cow-calf dyad model can be used in silico experiments involving animal behavior, which allows computational verification of dynamic ex-ante hypotheses in vivo experiments, thus reducing costs and honoring the ethical principle of minimizing the experimental use of animals.


2019 ◽  
Author(s):  
Zhongling Jiang ◽  
Bin Zhang

Nucleosome positioning controls the accessible regions of chromatin and plays essential roles in DNA-templated processes. ATP driven remodeling enzymes are known to be crucial for its establishment in vivo, but their non-equilibrium nature has hindered the development of a unified theoretical framework for nucleosome positioning. Using a perturbation theory, we show that the effect of these enzymes can be well approximated by effective equilibrium models with rescaled temperatures and interactions. Numerical simulations support the accuracy of the theory in predicting both kinetic and steady-state quantities, including the effective temperature and the radial distribution function, in biologically relevant regimes. The energy landscape view emerging from our study provides an intuitive understanding for the impact of remodeling enzymes in either reinforcing or overwriting intrinsic signals for nucleosome positioning, and may help improve the accuracy of computational models for its prediction in silico.


2021 ◽  
Author(s):  
Raphaël Conradin ◽  
Christophe Coreixas ◽  
Jonas Latt ◽  
Bastien Chopard

AbstractIn silico, cell based approaches for modeling biological morphogenesis are used to test and validate our understanding of the biological and mechanical process that are at work during the growth and the organization of multi-cell tissues. As compared to in vivo experiments, computer based frameworks dedicated to tissue modeling allow us to easily test different hypotheses, and to quantify the impact of various biophysically relevant parameters.Here, we propose a formalism based on a detailed, yet simple, description of cells that accounts for intra-, inter- and extra-cellular mechanisms. More precisely, the cell growth and division is described through the space and time evolution of the membrane vertices. These vertices follow a Newtonian dynamics, meaning that their evolution is controlled by different types of forces: a membrane force (spring and bending), an adherence force (inter-cellular spring), external and internal pressure forces. Different evolution laws can be applied on the internal pressure, depending on the intra-cellular mechanism of interest. In addition to the cells dynamics, our formalism further relies on a lattice Boltzmann method, using the Palabos library, to simulate the diffusion of chemical signals. The latter aims at driving the growth and migration of a tissue by simply changing the state of the cells.All of this leads to an accurate description of the growth and division of cells, with realistic cell shapes and where membranes can have different properties. While this work is mainly of methodological nature, we also propose to validate our framework through simple, yet biologically relevant benchmark tests at both single-cell and full tissue scales. This includes free and chemically controlled cell tissue growth in an unbounded domain. The ability of our framework to simulate cell migration, cell compression and morphogenesis under external constraints is also investigated in a qualitative manner.


Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Manuel Thieme ◽  
Sema Sivritas ◽  
Sebastian A Potthoff ◽  
Evanthia Mergia ◽  
Lars C Rump ◽  
...  

The kidney plays an outstanding role in the blood pressure (BP) regulation. The renal vasoconstrictor response to angiotensin (Ang) II is balanced by the NO/cGMP-signalling cascade. Ang II causes hypertension and vascular dysfunction by reducing cGMP sensitivity. Ang II is able to increase cGMP degradation by activating phosphodiesterase (PDE)1 and PDE5. The aim of the present study was to identify the predominant PDE subunit regulating renal blood flow (RBF) and vascular tone during hypertension. Therefore, we tested in vivo effects of acute PDE1 (vinpocetine) and PDE5 (sildenafil) inhibition at baseline and during acute Ang II infusion (200ng/kg/min). Furthermore, we examined the impact of PDE-inhibition on Ang II dependent hypertension (500ng/kg/min; 14 days) and on renal vascular function in the isolated perfused kidney. Acute vinpocetine administration (0.8-800μg/kg BW) showed almost no effect on systemic BP and RBF at baseline and during acute Ang II infusion. In contrast, sildenafil (0.8-800μg/kg BW) significantly decreased BP under baseline conditions. During acute Ang II infusion, BP reduction and RBF increase induced by sildenafil was even more pronounced suggesting a pivotal role of the PDE5 in the regulation of renal vascular tone. Based on these results, we tested whether inhibition of the PDE5 protects from hypertension and vascular dysfunction. Indeed, chronic sildenafil treatment significantly attenuated Ang II dependent hypertension in C57BL/6 (vehicle vs. sil: 156±4 vs. 139±7; p<0.05). Moreover, Sildenafil treatment significantly improved NO-dependent vasorelaxation in kidneys of Ang II- treated C57BL/6. To confirm that PDE5 is activated by an increased NO/cGMP signaling, we used eNOS-KO mice, a model known for decreased NO dependent cGMP generation. In eNOS-KO mice, sildenafil failed to reduce Ang II dependent hypertension (172,4 ± 4,3 mmHg vs. 166,1 ± 3,8 mmHg, p=0,2753) and did not improve vascular dysfunction in Ang II treated kidneys. In summary, the PDE5 is the predominant PDE regulating RBF. Inhibition of PDE5 by sildenafil ameliorates chronic Ang II dependent hypertension and improves vascular dysfunction. This study reveals new evidence for the pivotal role of PDE5 in the pathogenesis of AngII-induced hypertension.


Author(s):  
A.J. Lawrence

An in vitro bioassay has been developed which shows that oogenesis in Harmothoe imbricata is controlled by a gonadotrophic hormone which promotes egg protein synthesis in developing oocytes. A similar endocrine control mechanism is found in Eulalia viridis and analysis of in vivo assays indicate that the hormone acts as a transducer between the environment and the gamete. The timing of gametogenesis is controlled by environmental cues in both species and may be affected by predicted global climate change. With the development of these sensitive hormone assays it is possible to test the impact of climate change on both species, providing a possible early warning system for global warming and potential bio-indicators of climate change. Harmothoe imbricata is likely to be the more sensitive indicator species.


2019 ◽  
pp. 96-104
Author(s):  
N. Hrynchuk ◽  
N. Vrynchanu

The emergence and spread of antibiotic-resistant strains of microorganisms reduces the effectiveness of antibiotic therapy and requires finding solutions to problems, one of which is the study of antimicrobial properties in drugs of various pharmacological groups. The purpose of the work was to summarize the data on the antibacterial activity of thioridazine and its derivatives to determine the feasibility and prospects of creating new antibacterial drugs on their basis. The paper presents literature data on the effects of thioridazine on the causative agent of tuberculosis, antistaphylococcal activity, susceptibility of plasmodium and trypanosoma. The antibacterial activity of the drug was established within in vitro studies with the determination of MIC towards gram-positive and gram-negative microorganisms, ex vivo using macrophage lines, as well as within in vivo experiments on mice. It is established that the neuroleptic thioridazine is characterized by pronounced anti-tuberculosis activity, the mechanism of action is associated with the impact on the cell membrane of M. tuberculosis, inactivation by calmodulin and inhibition of specific NADH-dehydrogenase type II. The literature data indicate that thioridazine is able to increase the activity of isoniazid against the strains of mycobacteria that are susceptible and resistant to its action. It has been established that resistance to thioridazine in antibiotic-resistant M. tuberculosis strains is not formed. The drug is characterized by its ability to inhibit the growth and reproduction of both methicylin-sensitive (MSSA) and methicilin-resistant (MRSA) strains of Staphylococcus aureus, which has been proven within in vitro experiments. The effectiveness of thioridazine has been proven within in vivo experiments in case of skin infection and sepsis caused by S. aureus. Antimicrobial effect of the drug is also observed towards to plasmodium (P. falciparum) and trypanosomes (Trypanosoma spp.). Currently, the synthesis of thioridazine derivatives is carried out to identify compounds with a pronounced antibacterial effect. Some of the first synthesized compounds are not inferior or superior to thioridazine by the inhibitory effect. Thus, these data suggest that drugs of different pharmacological groups, including drugs that affect the nervous system - thioridazine and its derivatives, can be a source of replenishment of the arsenal of antimicrobial drugs to control such threatening infections as tuberculosis and diseases caused by polyresistant strains of microorganisms.


2020 ◽  
Author(s):  
Christian Günzel ◽  
Felix Kühnl ◽  
Katharina Arnold ◽  
Sven Findeiß ◽  
Christina Weinberg ◽  
...  

AbstractGene regulation in prokaryotes often depends on RNA elements such as riboswitches or RNA thermometers located in the 5’ untranslated region of mRNA. Rearrangements of the RNA structure in response, e. g., to the binding of small molecules or ions control translational initiation or premature termination of transcription and thus mRNA expression. Such structural responses are amenable to computational modeling, making it possible to rationally design synthetic riboswitches for a given aptamer. Starting from an artificial aptamer, we construct the first synthetic transcriptional riboswitches that respond to the antibiotic neomycin. We show that the switching behavior in vivo critically depends not only on the sequence of the riboswitch itself, but also on its sequence context. We therefore developed in silico methods to predict the impact of the context, making it possible to adapt the design and to rescue non-functional riboswitches. We furthermore analyze the influence of 5’ hairpins with varying stability on neomycin riboswitch activity. Our data highlight the limitations of a simple plug-and-play approach in the design of complex genetic circuits and demonstrate that detailed computational models significantly simplify, improve, and automate the design of transcriptional circuits. Our design software is available under a free license on Github.1


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