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ADMET & DMPK ◽  
2022 ◽  
Author(s):  
Svetlana A. Berns ◽  
Julia A. Isakova ◽  
Polina Pekhtereva

Tuberculosis is one of the critical health problems worldwide. The search for ways to improve the results of tuberculosis treatment and overcome drug resistance lies in understanding the pathogenesis of the development of the infectious process. The interferon system, particularly the role of interferon-gamma, has been identified as the main link in the immune response in tuberculosis. The clinical efficacy of interferon-gamma has been studied and evaluated in clinical trials since the end of the last century. There was obtained evidence of the clinical efficacy of interferon-gamma as part of complex therapy. Recent experimental data make it possible to consider interferon-gamma as a promising therapeutic option for the treatment of multidrug-resistant tuberculosis as part of complex therapy worthy of further studies.  


2022 ◽  
Vol 18 (1) ◽  
pp. e1009634
Author(s):  
Georgy Antonov ◽  
Christopher Gagne ◽  
Eran Eldar ◽  
Peter Dayan

The replay of task-relevant trajectories is known to contribute to memory consolidation and improved task performance. A wide variety of experimental data show that the content of replayed sequences is highly specific and can be modulated by reward as well as other prominent task variables. However, the rules governing the choice of sequences to be replayed still remain poorly understood. One recent theoretical suggestion is that the prioritization of replay experiences in decision-making problems is based on their effect on the choice of action. We show that this implies that subjects should replay sub-optimal actions that they dysfunctionally choose rather than optimal ones, when, by being forgetful, they experience large amounts of uncertainty in their internal models of the world. We use this to account for recent experimental data demonstrating exactly pessimal replay, fitting model parameters to the individual subjects’ choices.


Vaccines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 70
Author(s):  
Takumi Kumai ◽  
Hidekiyo Yamaki ◽  
Michihisa Kono ◽  
Ryusuke Hayashi ◽  
Risa Wakisaka ◽  
...  

The success of the immune checkpoint blockade has provided a proof of concept that immune cells are capable of attacking tumors in the clinic. However, clinical benefit is only observed in less than 20% of the patients due to the non-specific activation of immune cells by the immune checkpoint blockade. Developing tumor-specific immune responses is a challenging task that can be achieved by targeting tumor antigens to generate tumor-specific T-cell responses. The recent advancements in peptide-based immunotherapy have encouraged clinicians and patients who are struggling with cancer that is otherwise non-treatable with current therapeutics. By selecting appropriate epitopes from tumor antigens with suitable adjuvants, peptides can elicit robust antitumor responses in both mice and humans. Although recent experimental data and clinical trials suggest the potency of tumor reduction by peptide-based vaccines, earlier clinical trials based on the inadequate hypothesis have misled that peptide vaccines are not efficient in eliminating tumor cells. In this review, we highlighted the recent evidence that supports the rationale of peptide-based antitumor vaccines. We also discussed the strategies to select the optimal epitope for vaccines and the mechanism of how adjuvants increase the efficacy of this promising approach to treat cancer.


Fluids ◽  
2021 ◽  
Vol 6 (12) ◽  
pp. 445
Author(s):  
Tommaso Missoni ◽  
Hiroki Yamaguchi ◽  
Irina Graur ◽  
Silvia Lorenzani

In the present paper, we provide an analytical expression for the first- and second-order thermal slip coefficients, σ1,T and σ2,T, by means of a variational technique that applies to the integrodifferential form of the Boltzmann equation based on the true linearized collision operator for hard-sphere molecules. The Cercignani-Lampis scattering kernel of the gas-surface interaction has been considered in order to take into account the influence of the accommodation coefficients (αt, αn) on the slip parameters. Comparing our theoretical results with recent experimental data on the mass flow rate and the slip coefficient for five noble gases (helium, neon, argon, krypton, and xenon), we found out that there is a continuous set of values for the pair (αt, αn) which leads to the same thermal slip parameters. To uniquely determine the accommodation coefficients, we took into account a further series of measurements carried out with the same experimental apparatus, where the thermal molecular pressure exponent γ has been also evaluated. Therefore, the new method proposed in the present work for extracting the accommodation coefficients relies on two steps. First of all, since γ mainly depends on αt, we fix the tangential momentum accommodation coefficient in such a way as to obtain a fair agreement between theoretical and experimental results. Then, among the multiple pairs of variational solutions for (αt, αn), giving the same thermal slip coefficients (chosen to closely approximate the measurements), we select the unique pair with the previously determined value of αt. The analysis carried out in the present work confirms that both accommodation coefficients increase by increasing the molecular weight of the considered gases, as already highlighted in the literature.


2021 ◽  
Author(s):  
Edward J Hancock ◽  
Scott D Zawieja ◽  
Charlie Macaskill ◽  
Michael J Davis ◽  
Christopher D Bertram

Lymphoedema develops due to chronic dysfunction of the lymphatic vascular system which results in fluid accumulation between cells. The condition is commonly acquired secondary to diseases such as cancer or the therapies associated with it. The primary driving force for fluid return through the lymphatic vasculature is provided by contractions of the muscularized lymphatic collecting vessels, driven by electrical oscillations. However, there is an incomplete understanding of the molecular and bioelectric mechanisms involved in lymphatic muscle cell excitation, hampering the development and use of pharmacological therapies. Modelling in silico has contributed greatly to understanding the contributions of specific ion channels to the cardiac action potential, but modelling of these processes in lymphatic muscle remains limited. Here, we propose a model of oscillations in the membrane voltage (M-clock) and intracellular calcium concentrations (C-clock) of lymphatic muscle cells. We modify a model by Imtiaz and colleagues to enable the M-clock to drive the C-clock oscillations. This approach differs from typical models of calcium oscillators in lymphatic and related cell types, but is required to fit recent experimental data. We include an additional voltage dependence in the gating variable control for the L type calcium channel, enabling the M-clock to oscillate independently of the C-clock. We use phase-plane analysis to show that these M-clock oscillations are qualitatively similar to those of a generalised FitzHugh-Nagumo model. We also provide phase plane analysis to understand the interaction of the M-clock and C-clock oscillations. The model and methods have the potential to help determine mechanisms and find targets for pharmacological treatment of lymphoedema.


2021 ◽  
Vol 3 ◽  
Author(s):  
Andre Zeumault ◽  
Shamiul Alam ◽  
Zack Wood ◽  
Ryan J. Weiss ◽  
Ahmedullah Aziz ◽  
...  

In neuromorphic computing, memristors (or “memory resistors”) have been primarily studied as key elements in artificial synapse implementations, where the memristor provides a variable weight with intrinsic long-term memory capabilities, based on its modifiable resistive-switching characteristics. Here, we demonstrate an efficient methodology for simulating resistive-switching of HfO2 memristors within Synopsys TCAD Sentaurus—a well established, versatile framework for electronic device simulation, visualization and modeling. Kinetic Monte Carlo is used to model the temporal dynamics of filament formation and rupture wherein additional band-to-trap electronic transitions are included to account for polaronic effects due to strong electron-lattice coupling in HfO2. The conductive filament is modeled as oxygen vacancies which behave as electron traps as opposed to ionized donors, consistent with recent experimental data showing p-type conductivity in HfOx films having high oxygen vacancy concentrations and ab-initio calculations showing the increased thermodynamic stability of neutral and charged oxygen vacancies under conditions of electron injection. Pulsed IV characteristics are obtained by inputting the dynamic state of the system—which consists of oxygen ions, unoccupied oxygen vacancies, and occupied oxygen vacancies at various positions—into Synopsis TCAD Sentaurus for quasi-static simulations. This allows direct visualization of filament electrostatics as well as the implementation of a nonlocal, trap-assisted-tunneling model to estimate current-voltage characteristics during switching. The model utilizes effective masses and work functions of the top and bottom electrodes as additional parameters influencing filament dynamics. Together, this approach can be used to provide valuable device- and circuit-level insight, such as forming voltage, resistance levels and success rates of programming operations, as we demonstrate.


Energies ◽  
2021 ◽  
Vol 14 (19) ◽  
pp. 6233
Author(s):  
Alexey Kiverin ◽  
Ivan Yakovenko

Combustible aqueous foams and foamed emulsions represent prospective energy carriers. This paper is devoted to the overview of model assumptions required for numerical simulations of combustion and detonation processes in aqueous foams. The basic mathematical model is proposed and used for the analysis of the combustion development in the wet aqueous foam containing bubbles filled with reactive gas. The numerical results agree with the recent experimental data on combustion and detonation in aqueous foams containing premixed hydrogen–oxygen. The obtained results allowed for distinguishing the mechanisms of flame acceleration, transition to detonation, detonation propagation, and decay.


Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4940
Author(s):  
Wook-Geun Shin ◽  
Dousatsu Sakata ◽  
Nathanael Lampe ◽  
Oleg Belov ◽  
Ngoc Hoang Tran ◽  
...  

Accurately modeling the radiobiological mechanisms responsible for the induction of DNA damage remains a major scientific challenge, particularly for understanding the effects of low doses of ionizing radiation on living beings, such as the induction of carcinogenesis. A computational approach based on the Monte Carlo technique to simulate track structures in a biological medium is currently the most reliable method for calculating the early effects induced by ionizing radiation on DNA, the primary cellular target of such effects. The Geant4-DNA Monte Carlo toolkit can simulate not only the physical, but also the physico-chemical and chemical stages of water radiolysis. These stages can be combined with simplified geometric models of biological targets, such as DNA, to assess direct and indirect early DNA damage. In this study, DNA damage induced in a human fibroblast cell was evaluated using Geant4-DNA as a function of incident particle type (gammas, protons, and alphas) and energy. The resulting double-strand break yields as a function of linear energy transfer closely reproduced recent experimental data. Other quantities, such as fragment length distribution, scavengeable damage fraction, and time evolution of damage within an analytical repair model also supported the plausibility of predicting DNA damage using Geant4-DNA.The complete simulation chain application “molecularDNA”, an example for users of Geant4-DNA, will soon be distributed through Geant4.


Symmetry ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1777
Author(s):  
Hua Zheng ◽  
Aldo Bonasera

We analyzed recent experimental data on the disassembly of 28Si into 7α in terms of a hybrid α-cluster model. We calculated the probability of breaking into several α-like fragments for high l-spin values for identical and non-identical spin zero nuclei. Resonant energies were found for each l-value and compared to the data and other theoretical models. Toroidal-like structures were revealed in coordinate and momentum space when averaging over many events at high l. The transition from quantum to classical mechanics is highlighted.


2021 ◽  
Author(s):  
Chuqiao Huyan ◽  
Alexander Golden ◽  
Xinwen Zhu ◽  
Pankaj Mehta ◽  
Allyson E. Sgro

Complex multicellular behaviors are coordinated at the level of biochemical signaling networks, yet how this decentralized control mechanism enables robust coordination in variable environments and over many orders of magnitude of spatiotemporal scales remains an open question. A stunning example of these behaviors is found in the microbe Dictyostelium discoideum, which uses the small molecule cyclic AMP (cAMP) to drive the propagation of collective signaling oscillations and spatial waves leading to multicellular development. The critical design features of the Dictyostelium signaling network remain unclear despite decades of mathematical modeling and experimental research because the mathematical models make different assumptions about the network architecture. To resolve this discrepancy, we use recent experimental data to normalize the time and response scales of five major signal relay network models to one another and assess their ability to recapitulate experimentally-observed population and single-cell dynamics. We find that to successfully reproduce the full range of observed behaviors, single cells must be excitable and respond to the relative fold-change of environmental signals, suggesting that these features represent robust principles for controlling cellular populations and that single-cell excitable dynamics are a generalizable route for controlling population behaviors.


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