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Evolutionary Theories of Aging: A Systemic and Mechanistic Perspective
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Robustness is defined as the ability to function against changes in the parameters of a given system. In the case of the system considered here, one needs to consider changes of genetic and epigenetic origin. The former concerns structural robustness of the phenotype, that is, rigidity of the phenotype against the genetic changes produced by mutations which are represented by changes in the network topology. The latter concerns the robustness against the stochasticity that can appear as a result of fluctuations in initial states and stochasticity occurring during developmental dynamics or in the environment. In terms of dynamical systems, these two types of robustness are the stability of a state, also called attractor, to external noise and the structural stability of the state against changes in the underlying equations.
Applications of the CRISPR-Cas system for infectious disease diagnostics
Published in Expert Review of Molecular Diagnostics, 2021
Peipei Li, Li Wang, Junning Yang, Li-Jun Di, Jingjing Li
Nevertheless, some major drawbacks should be considered. The sequences recognized by CRISPR-Cas effector proteins are limited, which is a general problem in most CRISPR-Cas systems. A specific PAM sequence is essential for Cas9/dCas9 and Cas12a/b to bind with target dsDNA, while a PFS is required for the Cas13 effector. The ‘off‐target’ effect is another disadvantage of CRISPR-Cas systems, particularly Cas9, which leads to false negative or positive results, but online software can reduce the probability of off‐target effects. Cas proteins have the characteristic of nucleotide mismatch tolerance, and it causes nonspecific binding of templates by Cas proteins, which reduces the signal and the reliability of the test. On the other hand, mismatch tolerance may increase robustness to identify mutation-prone pathogens. Cas protein detection alone has lower sensitivity, and the combination of target nucleic acid amplification and CRISPR-Cas systems solves this issue. Similar to PCR-based assays, CRISPR-Cas systems rely on known DNA sequences, so they are less robust for unknown outbreaks and limit their application. Meanwhile, due to PCR-based assays are easier to set up and are familiar to us, major efforts should be done by companies and researchers who want to invest in this field to promote CRISPR-Cas systems.
Genetic functional algorithm model, docking studies and in silico design of novel proposed compounds against Mycobacterium tuberculosis
Published in Egyptian Journal of Basic and Applied Sciences, 2020
Proposed QSAR model capable of predicting the activities triazole analogues against M. tuberculosis was successfully achieved via Genetic Functional Approbation (GFA) approach. This model served as a prominent tool for structural insight to design new hypothetical anti-tubercular compounds against multiple strain M. tuberculosis. The fitness, robustness reliability and significant of the model has been fully established via internal and external assessment. Analysis of the applicability domain shows that the proposed model has a high predictability rate to predict all the anti-tubercular compounds that fall within its leverage boundry. In addition, evaluation of the binding interaction via molecular docking studies showed that compound 20 has noticeable bind affinities from (−17.79 kcal/mol). Hence, it served as structure template and insight to design fourteen novel hypothetical agents with more competent activities. Meanwhile, compound 20 j was observed with high activity among the designed compounds with more prominent binding affinities of −24.3 kcal/mol. Therefore, the pharmacokinetic properties via in-vivo, in-vitro screening should be carried out in order to determine the toxicity of the designed compounds and also establish it potency against Mycobacterium tuberculosis.
The therapeutic potential of a calorie-restricted ketogenic diet for the management of Leber hereditary optic neuropathy
Published in Nutritional Neuroscience, 2019
Mithu Storoni, Matthieu P. Robert, Gordon T. Plant
LHON carriers are known to have increased susceptibility to optic nerve damage occurring as a result of raised intraocular pressures and an elevated intraocular pressure can add to the disease burden in LHON.76 There is evidence that mitochondrial robustness confers protection from pressure-related damage even in the absence of the LHON mutation. Recent observations suggest that there may be mild impairment in complex I function in the setting of primary open angle glaucoma (POAG). Complex-I enzyme-specific activity was seen to be reduced by 18% in lymphoblasts from POAG patients and by 29% in lymphoblasts from LHON patients, prompting the evaluation of POAG as a mitochondrial disorder.77,78 Improving mitochondrial performance through enhanced biogenesis and reduced ROS production has the potential of reducing visual loss in LHON carriers exposed to raised intraocular pressures.