Brodersenhorn5047

Growing efforts to measure fitness landscapes in molecular and microbial systems are motivated by a longstanding goal to predict future evolutionary trajectories. Sometimes under-appreciated, however, is that the fitness landscape and its topography do not by themselves determine the direction of evolution under sufficiently high mutation rates, populations can climb the closest fitness peak (survival of the fittest), settle in lower regions with higher mutational robustness (survival of the flattest), or even fail to adapt altogether (error catastrophes). I show that another measure of reproductive success, Fisher's reproductive value, resolves the trade-off between fitness and robustness in the quasi-species regime of evolution to forecast the motion of a population in genotype space, one should look for peaks in the (mutation-rate dependent) landscape of genotypic reproductive values-whether or not these peaks correspond to local fitness maxima or flat fitness plateaus. This new landscape picture turns quasi-species dynamics into an instance of non-equilibrium dynamics, in the physical sense of Markovian processes, potential landscapes, entropy production, etc.Tumors have developed multitude of ways to evade immune response and suppress cytotoxic T cells. Programed cell death protein 1 (PD-1) and programed cell death ligand 1 (PD-L1) are immune checkpoints that when activated, rapidly inactivate the cytolytic activity of T cells. CCT245737 Expression heterogeneity of PD-L1 and the surface receptor dynamics of both PD-1 and PD-L1 may be important parameters in modulating the immune response. PD-L1 is expressed on both tumor and non-tumor immune cells and this differential expression reflects different aspects of anti-tumor immunity. Here, we developed a mechanistic computational model to investigate the role of PD-1 and PD-L1 dynamics in modulating the efficacy of PD-1 and PD-L1 blocking antibodies. Our model incorporates immunological synapse restricted interaction of PD-1 and PD-L1, basal parameters for receptor dynamics, and T cell interaction with tumor and non-tumor immune cells. Simulations predict the existence of a threshold in PD-1 expression above which there is no efficacy for both anti-PD-1 and anti-PD-L1. Model also predicts that anti-tumor response is more sensitive to PD-L1 expression on non-tumor immune cells than tumor cells. New combination strategies are suggested that may enhance efficacy in resistant cases such as combining anti-PD-1 with a low dose of anti-PD-L1 or with inhibitors of PD-L1 recycling and synthesis. Another combination strategy suggested by the model is the combination of anti-PD-1 and anti-PD-L1 with enhancers of PD-L1 degradation rate. Virtual patients are then generated to test specific biomarkers of response. Intriguing predictions that emerge from the virtual patient simulations are that PD-1 blocking antibody results in higher response rate than PD-L1 blockade and that PD-L1 expression density on non-tumor immune cells rather than tumor cells is a predictor of response.Hepatocyte insulin resistance is one of the early factors of developing type II diabetes. If insulin resistance is treated early, type II diabetes could be prevented. In recent years, scientists have been conducting extensive research on the underlying issues on a cellular and molecular level. It was found that the modulation of IP3-receptors, the mitochondrial ability to form the mitochondria-associated membranes (MAMs) and the endoplasmic reticulum stress during Ca2+ signaling play a key role in hepatocyte being able to maintain euglycemia and provide metabolic flexibility. However, researchers cannot agree on what factor is the key one in resulting in insulin resistance. In this work, we propose a mathematical model of Ca2+ signaling. We included in the model all the major contributors of a proper Ca2+ signaling during both the fasting and the postprandial state. Our modeling results are in good agreement with available experimental data. The analysis of modeling results suggests that MAMs dysfunction alone cannot result in abnormal Ca2+ signaling and the wrong modulation of IP3-receptors is a more definite reason. However, both the MAMs dysfunction and the IP3 signaling dysregulation combined can lead to a robust Ca2+ signal and improper glucose release. In addition, our model results suggest a strong dependence of Ca2+ oscillations pattern on morphological characteristics of the ER and the mitochondria.A non-smooth SIR Filippov system is proposed to investigate the impacts of three control strategies (media coverage, vaccination and treatment) on the spread of an infectious disease. We synthetically consider both the number of infected population and its changing rate as the switching condition to implement the curing measures. By using the properties of the Lambert W function, we convert the proposed switching condition to a threshold value related to the susceptible population. The classical epidemic model involving media coverage, linear functions describing injecting vaccine and treatment strategies is examined when the susceptible population exceeds the threshold value. In addition, we consider another SIR model accompanied with the vaccination and treatment strategies represented by saturation functions when the susceptible population is smaller than the threshold value. The dynamics of these two subsystems and the sliding domain are discussed in detail. Four types of local sliding bifurcation are investigated, including boundary focus, boundary node, boundary saddle and boundary saddle-node bifurcations. In the meantime, the global bifurcation involving the appearance of limit cycles is examined, including touching bifurcation, homoclinic bifurcation to the pseudo-saddle and crossing bifurcation. Furthermore, the influence of some key parameters related to the three treatment strategies is explored. We also validate our model by the epidemic data sets of A/H1N1 and COVID-19, which can be employed to reveal the effects of media report and existing strategy related to the control of emerging infectious diseases on the variations of confirmed cases.

p53, an anti-tumour protein, is significantly inactivated in most tumours. A small molecule of nutlin-3a is used to activate its function by repressing (Mouse double minute 2 homolog) Mdm2 protein which inhibits its activity. In cancer patients, a high risk of drug-drug interactions (DDIs) is observed owing to their multi-dosing prescriptions, which may lead them to harmful effects. In the presented work, we have aimed to investigate the effect of pharmacodynamical interaction between two anti-cancer drugs, nutlin-3a and aspirin in the activation of p53 protein.

We have adapted control system techniques and designed a Proportional-Integral-Derivative (PID) controller. This controller is used to activate p53 protein. A drug interaction parameter is used to incorporate the effect of both drugs. Extensive simulation is performed using two different doses of aspirin, i.e. a low and a high dose of aspirin.

The result shows no harmful effects of pharmacodynamical interaction when a low dose is administered along with nutlin-3a. When a high dose of aspirin is administered it acts as input disturbance and leads to undesirable over-expression of p53 protein. This can further harm other growth cells, thus inducing harmful effects. A comparative analysis is also tabulated with different dosing regimens which shows that a combination of nutlin-3a and a low dose of aspirin provides better results than a high dose of aspirin.

Overall, the work provides an insight to the activation of p53 protein in cancer patients under the presence of pharmacodynamical interaction and might contribute to the effective management of cancer patients.

Overall, the work provides an insight to the activation of p53 protein in cancer patients under the presence of pharmacodynamical interaction and might contribute to the effective management of cancer patients.Endomorphin analogs containing unnatural amino acids have demonstrated potent analgesic effects in our previous studies. In the present study, the differences in antinociception and the mechanisms thereof for analogs 1-3 administered intracerebroventricularly and intrathecally were explored. All analogs at different routes of administration produced potent analgesia compared to the parent peptide endomorphin-1. Multiple antagonists and antibodies were used to explore the mechanisms of action of these analogs, and it was inferred that analogs 1-3 stimulated the μ opioid receptor to induce antinociception. Moreover, the antibody data suggested that analog 2 may induce the release of immunoreactive [Leu5]-enkephaline and [Met5]-enkephaline to produce a secondary component of antinociception at the spinal level and analog 3 may stimulate the the release of immunoreactive [Met5]-enkephaline at the spinal level. Finally, analogs 2 and 3 produced no acute tolerance in the spinal cord. We hypothesize that the unique characteristics of the endomorphin analogs result from their capacities to stimulate the release of endogenous antinociceptive substances.A new class of peptides, cyclic cell-penetrating peptides (CPPs), has great potential for delivering a vast variety of therapeutics intracellularly for treating diverse ailments. CPPs have been used previously; however, their further use is limited due to instability, toxicity, endosomal degradation, and insufficient cellular penetration. Cyclic CPPs are being investigated in delivering therapeutics to treat various ailments, including multi-drug resistant microbial infections, HIV, and cancer. They can act as a carrier for a variety of cargos and target intracellularly. Approximately 40 cyclic peptides-based therapeutics are available in the market, and annually one cyclic peptide-based drug enters the market. Numerous research and review articles have been published in the last decade about linear and cyclic peptides separately. This review is the first to provide a comprehensive deliberation about cationic and amphipathic cyclic CPPs. Herein, we highlights their structures, significant advantages, translocation mechanisms, and delivery application in the area of biomedical sciences.Metabolic stress resulting from either lack or excess of nutrients often causes infertility in both sexes. Kisspeptin-neurokinin B-dynorphin A (KNDy) neurons in the arcuate nucleus (ARC) has been suggested to be a key players in reproduction via direct stimulation of the pulsatile gonadotropin-releasing hormone (GnRH) and subsequent gonadotropin release in mammalian species. In this study, we investigated the effect of high-fat diet (HFD) on hypothalamic KNDy gene expression to examine the pathogenic mechanism underlying obesity-induced infertility in male and female rats. Male and female rats at 7 weeks of age were fed with either a standard or HFD for 4 months. In the male rats, the HFD caused a significant suppression of ARC Kiss1 and Pdyn gene expressions, but did not affect the plasma luteinizing hormone (LH) levels and sizes of the morphology of the testis and epididymis. In the female rats, 58% of the HFD-fed female rats exhibited irregular estrous cycles, whereas the remaining rats showed regular cycles.