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Mycobacterium tuberculosis
Published in Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies, Clinical Tuberculosis, 2020
Before the development of gene transfer we did not know: (1) acid-fastness is regulated by a signal transduction pathway; (2) the primary attenuation of BCG is a loss of a Type VII secretion system; (3) M. tuberculosis lives an autarkic lifestyle; (4) the targets of isoniazid, its mechanisms of action, and its mechanism of resistance; (5) the targets for other TB-specific drugs; and (6) persistence is mediated by a unique expression profile and can be reversed by stimulating respiration. These unknown facts seemed surprising for the pathogen that Koch demonstrated to be the cause of an infectious disease. A brief summary follows of how genetics provides the critical mutants for elucidating the facts.
Familial Aggregation of Chronic Obstructive Pulmonary Disease
Published in Stephen D. Litwin, Genetic Determinants of Pulmonary Disease, 2020
Bernice H. Cohen, Gary A. Chase
In summary, in rare recessive conditions, familial aggregation would be discernible primarily in sibs, and although observed collaterally in a single generation, it would not be apparent in successive generations. However, with a dominant condition—even a rare dominant—familial aggregation shows a vertical pattern, being readily observed in parents and offspring as well as in sibs, and thus appears in consecutive generations. In fact, with dominant inheritance, except for new mutants, all affected individuals would be expected to have at least one affected parent, provided parents survived to age of onset of the condition in question.
The Human Cancer Situation
Published in Samuel C. Morris, Cancer Risk Assessment, 2020
In the course of millions of years of evolution, many possible alternatives have been tried before and found wanting. It should not be surprising, therefore, that most mutations are harmful. In population genetics, a mutant offspring represents a varient to the species. In the rare circumstance that the mutation gives an advantage to the offspring, a new species may develop. More frequently, the mutation is either fatal to the offspring or poses some disadvantage to the offspring and, although it may propagate through some future generations, is sooner or later eliminated through evolutionary pressure in the population. The single change in a nucleic-acid base responsible for the disease sickle-cell anemia, for example, in addition to causing a debilitating disease, apparently also conferred a resistance to malaria. The latter may have been the predominant effect when the genetic trait was confined to Africa, but its desirability is now outweighed by the sickle-cell disease.
Repurposing of rabeprazole as an anti-Trypanosoma cruzi drug that targets cellular triosephosphate isomerase
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Itzhel García-Torres, Ignacio De la Mora-De la Mora, Gabriel López-Velázquez, Nallely Cabrera, Luis Antonio Flores-López, Ingeborg Becker, Juliana Herrera-López, Roberto Hernández, Ruy Pérez-Montfort, Sergio Enríquez-Flores
The preceding results show that Rbz can derivatize several Cys and can differentially contribute to inactivating TcTIM. Therefore, we performed tests on single Cys mutants of TcTIM, substituting each Cys for alanine (Ala), a relatively silent mutation, to evaluate the contribution of each Cys to the inactivation of the glycolytic enzyme. After overexpressing and purifying the enzymes, we exposed them to increasing concentrations of Rbz, incubating for 2 h at 37 °C. At the end of the assays, we took an aliquot and determined the enzymatic activity (Figure 7). The results showed that all the single mutants experienced an inactivation effect. The C127A and C118A mutants showed the highest sensitivity to the effect of Rbz, followed by the WT, the C40A, and C15A mutants (Figure 7). However, almost total inactivation was promoted in all enzymes. Therefore, our results show that the inactivating effect of Rbz on TcTIM involves the combination of several Cys residues, which contribute to the high sensitivity of the enzyme towards the drug.
Acrylonitrile’s genotoxicity profile: mutagenicity in search of an underlying molecular mechanism
Published in Critical Reviews in Toxicology, 2023
Richard J. Albertini, Christopher R. Kirman, Dale E. Strother
Testing for ACN’s capacity for inducing mutations due to DNA damage in male germ cells can now be accomplished by studies in transgenic rodents. Strict protocols have been developed to focus analyses to specific germ cell stages (Marchetti et al. 2018; OECD Guideline 488, 2019). Studies of mutations in transgenic animals allow for sequencing of mutations to discover specific mutational spectra for identifying causative mutagens. A negative study of lacZ mutations in the transgenic Muta-Mouse system was described above. More informative would be a study of germ cell mutations in ACN-treated mice using the gpt delta transgenic system for reasons outlined above. Much has been gleaned from studies in both ENU and acrylamide-treated C57BL/6 gpt delta transgenic mice demonstrating that these agents increased mutant frequencies in spermatozoa obtained from the cauda epididymis (Masumura et al. 2016, 2021; Hagio et al. 2021). Sequencing of mutants indicated that causation was due to the treatments in both cases.
A polypeptide inhibitor of calcineurin blocks the calcineurin-NFAT signalling pathway in vivo and in vitro
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Ping Wang, Wenying Li, Yumeng Yang, Na Cheng, Yuchen Zhang, Nan Zhang, Yanxia Yin, Li Tong, Zhimei Li, Jing Luo
Pep4 is composed of pep1s (PVIVIT), linker and pep2 (NFATc1-LxVP). We compared the CN binding ability of pep4 with that of two single binding motifs. The GST pull-down results showed that the binding ability of pep4 with CN was stronger than that of a single binding motif (Figure 1(A,B)). We performed site-directed mutations of the main CN binding sites in pep4 (Figure 1(C)). The first mutation (Mutant 1) changed pep4-PVIVIT (pep1s) to pep4-PAIAIT, and the second mutation (Mutant 2) changed pep4-YLAVP (pep2) to pep4-YAAAA. The third mutation (Mutant 3) is the combination of the first two mutations. Using GST pull-down assay, we compared the CN binding ability of pep4 with three mutants. The results showed that the mutations in PVIVIT, YLAVP or both affected the binding of pep4 to CN (Figure 1(D,E)). It is obvious that the key amino acids in the two binding motifs are mutated, which has a significant impact on the binding force between pep4 and CN. This finding indicated that the binding sites in pep4 were consistent with our expected design and that the corresponding binding regions on CN could be identified.