Repositioned Drugs for COVID-19-the Impact on Multiple Organs.

This review summarizes published findings of the beneficial and harmful effects on the heart, lungs, immune system, kidney, liver, and central nervous system of 47 drugs that have been proposed to treat COVID-19. Many of the repurposed drugs were chosen for their benefits to the pulmonary system, as well as immunosuppressive and anti-inflammatory effects. However, these drugs have mixed effects on the heart, liver, kidney, and central nervous system. Drug treatments are critical in the fight against COVID-19, along with vaccines and public health protocols. Drug treatments are particularly needed as variants of the SARS-Cov-2 virus emerge with some mutations that could diminish the efficacy of the vaccines. Patients with comorbidities are more likely to require hospitalization and greater interventions. The combination of treating severe COVID-19 symptoms in the presence of comorbidities underscores the importance of understanding the effects of potential COVID-19 treatments on other organs. Supplementary Information: The online version contains supplementary material available at 10.1007/s42399-021-00874-8.

Mathematical Models of Cell Response Following Heating.

The cells of the cardiovascular system can experience temperature excesses of a few degrees during a diseased state or of tens of degrees during a thermal therapy treatment. These raised temperatures may be acute or of long duration. The multiple cell lines that compose each tissue then react, in approximate order of increasing thermal insult, by expressing heat shock proteins, undergoing apoptosis, or suffering necrosis. Mathematical models of the response of cells could aid in planning and designing thermal therapies. The multi-factor nature of the cell response makes it challenging to develop such models. The models most used clinically are mathematically simple and based on the response of representative tissues. The model that might provide the most fundamental understanding of the biochemical response of cells requires many parameters, some of which are difficult to measure. None of the semi-empirical models that provide improved prediction of cell fate have been widely accepted to plan therapies. There remain great opportunities for developing mathematical models cell response.

Comparison of models of post-hyperthermia cell survival.

Several existing mathematical models of the survival of mammalian cells in culture following heating are compared. These models describe the fraction of cells that survive in a normal culture environment following a relatively brief period of heating between approximately 43 °C and 60 °C. The models have been developed either from rate process or mechanistic arguments. Little quantitative comparison between such models has been made using the same sets of data. The models are compared using the Akaike Information Criterion (AICc) after the model parameters have been estimated for two sets of existing data: human prostate cancer cells and Chinese hamster ovary cells. Most of the models capture the cell survival response. Scaled sensitivity coefficients show that some of the models have parameters that are difficult to estimate reliably. Relatively small variations in the AICc suggest that more measurements are needed before ranking the models.

The role of fatty acid unsaturation in minimizing biophysical changes on the structure and local effects of bilayer membranes.

Studying the effects of saturated and unsaturated fatty acids on biological and model (liposomes) membranes could provide insight into the contribution of biophysical effects on the cytotoxicity observed with saturated fatty acids. In vitro experiments suggest that unsaturated fatty acids, such as oleate and linoleate, are less toxic, and have less impact on the membrane fluidity. To understand and assess the biophysical changes in the presence of the different fatty acids, we performed computational analyses of model liposomes with palmitate, oleate, and linoleate. The computational results indicate that the unsaturated fatty acid chain serves as a membrane stabilizer by preventing changes to the membrane fluidity. Based on a Voronoi tessellation analysis, unsaturated fatty acids have structural properties that can reduce the lipid ordering within the model membranes. In addition, hydrogen bond analysis indicates a more uniform level of membrane hydration in the presence of oleate and linoleate as compared to palmitate. Altogether, these observations from the computational studies provide a possible mechanism by which unsaturated fatty acids minimize biophysical changes and protect the cellular membrane and structure. To corroborate our findings, we also performed a liposomal leakage study to assess how the different fatty acids alter the membrane integrity of liposomes. This showed that palmitate, a saturated fatty acid, caused greater destabilization of liposomes (more "leaky") than oleate, an unsaturated fatty acid.

On the computation of stress in affine versus nonaffine fibril kinematics within planar collagen network models.

Some recent analyses modeled the response of collagenous tissues, such as epicardium, using a hypothetical network consisting of interconnected springlike fibers. The fibers in the network were organized such that internal nodes served as the connection point between three such collagen springs. The results for assumed affine and nonaffine deformations are contrasted after a homogeneous deformation at the boundary. Affine deformation provides a stiffer mechanical response than nonaffine deformation. In contrast to nonaffine deformation, affine deformation determines the displacement of internal nodes without imposing detailed force balance, thereby complicating the simplest intuitive notion of stress, one based on free body cuts, at the single node scale. The standard notion of stress may then be recovered via average field theory computations based on large micromesh realizations. An alternative and by all indications complementary viewpoint for the determination of stress in these collagen fiber networks is discussed here, one in which stress is defined using elastic energy storage, a notion which is intuitive at the single node scale. It replaces the average field theory computations by an averaging technique over randomly oriented isolated simple elements. The analytical operations do not require large micromesh realizations, but the tedious nature of the mathematical manipulation is clearly aided by symbolic algebra calculation. For the example case of linear elastic deformation, this results in material stiffnesses that relate the infinitesimal strain and stress. The result that the affine case is stiffer than the nonaffine case is recovered, as would be expected. The energy framework also lends itself to the natural inclusion of changes in mechanical response due to the chemical, electrical, or thermal environment.