Origins of robustness in translational control via eukaryotic translation initiation factor (eIF) 2.

Phosphorylation of eukaryotic translation initiation factor 2 (eIF2) is one of the best studied and most widely used means for regulating protein synthesis activity in eukaryotic cells. This pathway regulates protein synthesis in response to stresses, viral infections, and nutrient depletion, among others. We present analyses of an ordinary differential equation-based model of this pathway, which aim to identify its principal robustness-conferring features. Our analyses indicate that robustness is a distributed property, rather than arising from the properties of any one individual pathway species. However, robustness-conferring properties are unevenly distributed between the different species, and we identify a guanine nucleotide dissociation inhibitor (GDI) complex as a species that likely contributes strongly to the robustness of the pathway. Our analyses make further predictions on the dynamic response to different types of kinases that impinge on eIF2.

Hypertension: Constraining the Expression of ACE-II by Adopting Optimal Macronutrients Diet Predicted via Support Vector Machine.

The recent elevation of cases infected from novel COVID-19 has placed the human life in trepidation mode, especially for those suffering from comorbidities. Most of the studies in the last few months have undeniably raised concerns for hypertensive patients that face greater risk of fatality from COVID-19. Furthermore, one of the recent WHO reports has estimated a total of 1.13 billion people are at a risk of hypertension of which two-thirds live in low and middle income countries. The gradual escalation of the hypertension problem andthe sudden rise of COVID-19 cases have placed an increasingly higher number of human lives at risk in low and middle income countries. To lower the risk of hypertension, most physicians recommend drugs that have angiotensin-converting enzyme (ACE) inhibitors. However, prolonged use of such drugs is not recommended due to metabolic risks and the increase in the expression of ACE-II which could facilitate COVID-19 infection. In contrast, the intake of optimal macronutrients is one of the possible alternatives to naturally control hypertension. In the present study, a nontrivial feature selection and machine learning algorithm is adopted to intelligently predict the food-derived antihypertensive peptide. The proposed idea of the paper lies in reducing the computational power while retaining the performance of the support vector machine (SVM) by estimating the dominant pattern in the features space through feature filtering. The proposed feature filtering algorithm has reported a trade-off performance by reducing the chances of Type I error, which is desirable when recommending a dietary food to patients suffering from hypertension. The maximum achievable accuracy of the best performing SVM models through feature selection are 86.17% and 85.61%, respectively.

Inbuilt Tendency of the eIF2 Regulatory System to Counteract Uncertainties.

Eukaryotic initiation factor 2 (eIF2) plays a fundamental role in the regulation of protein synthesis. Investigations have revealed that the regulation of eIF2 is robust against intrinsic uncertainties and is able to efficiently counteract them. The robustness properties of the eIF2 pathway against intrinsic disturbances is also well known. However the reasons for this ability to counteract stresses is less well understood. In this article, the robustness conferring properties of the eIF2 dependent regulatory system is explored with the help of a mathematical model. The novelty of the work presented in this article lies in articulating the possible reason behind the inbuilt robustness of the highly engineered eIF2 system against intrinsic perturbations. Our investigations reveal that the robust nature of the eIF2 pathway may originate from the existence of an attractive natural sliding surface within the system satisfying reaching and sliding conditions that are well established in the domain of control engineering.

Anti-hypertensive Peptide Predictor: A Machine Learning-Empowered Web Server for Prediction of Food-Derived Peptides with Potential Angiotensin-Converting Enzyme-I Inhibitory Activity.

Angiotensin converting enzyme-I (ACE-I) is a key therapeutic target of the renin-angiotensin-aldosterone system (RAAS), the central pathway of blood pressure regulation. Food-derived peptides with ACE-I inhibitory activities are receiving significant research attention. However, identification of ACE-I inhibitory peptides from different food proteins is a labor-intensive, lengthy, and expensive process. For successful identification of potential ACE-I inhibitory peptides from food sources, a machine learning and structural bioinformatics-based web server has been developed and reported in this study. The web server can take input in the FASTA format or through UniProt ID to perform the in silico gastrointestinal digestion and then screen the resulting peptides for ACE-I inhibitory activity. This unique platform provides elaborated structural and functional features of the active peptides and their interaction with ACE-I. Thus, it can potentially enhance the efficacy and reduce the time and cost in identifying and characterizing novel ACE-I inhibitory peptides from food proteins. URL: http://hazralab.iitr.ac.in/ahpp/index.php.

Modeling and Dynamic Behavior of eIF2 Dependent Regulatory System With Disturbances.

Eukaryotic initiation factor 2 (eIF2) is a central controller of the eukaryotic translational machinery. To sustain the on-going translation activity, eIF2 cycles between its GTP and GDP bound states. However, in response to cellular stresses, the phosphorylation of eIF2 takes place, which acts as an inhibitor of the guanine nucleotide exchange factor eIF2B and switches the translation activity on physiological timescales. The main objective of this paper is to investigate the stability of the regulatory system under nominal conditions, parametric fluctuations, and structural damages. In this paper, a mathematical model of eIF2-dependent regulatory system is used to identify the stability-conferring features within the system with the help of direct and indirect methods of Lyapunov stability theory. To investigate the impact of intrinsic fluctuations and structural damages on the stability of regulatory system, the mathematical model has been linearized around feasible equilibrium point and the variation of system poles has been observed. The investigations have revealed that the regulatory model is stable and able to tolerate the intrinsic stressors but becomes unstable when particular complex is targeted to override the undesirable interaction. Our analyses indicate that, the stability is a collective property and damage in the structure of the system changes the stability of the system.