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Bioengineering Aids to Reproductive Medicine
Published in Sujoy K. Guba, Bioengineering in Reproductive Medicine, 2020
When the total dose falls below 5 rads none of the above mentioned harm is encountered with a frequency significantly greater than the natural occurrence of the abnormalities. Other consequences such as mutagenesis of, failure of implantation and oncogenesis then merit consideration. Although the incidence mutagenic variations and implantation failure may not be statistically significantly different from controls, it cannot be ruled out that radiation in an individual case may induce these effects. The data regarding oncogenicity is more definitive. The quantitative figures reported by investigators differ but there is almost constant pattern of findings that the incidence of leukemia in children who were exposed to maternal radiation dose of 1 to 2 rads while in utero is greater than the nonexposed population. Practical significance of this observation in terms of counselling exposed mothers is far from clear. Equally strong correlation between increased incidence of leukemia and other conditions such as maternal allergy have also been noted. Therefore there is no justification in advising abortion in cases of such low level exposure. Cn the other hand it is evidently a sound advice to avoid radiation exposure during pregnancy.
Three-Dimensional Structures of the Chemokine Family
Published in Richard Horuk, Chemoattractant Ligands and Their Receptors, 2020
Wayne J. Fairbrother, Nicholas J. Skelton
In this chapter we describe and compare the chemokine structures that have been determined to date and discuss the structural differences in terms of observed functional differences between the chemokine proteins. The results of mutagenesis studies reported in the literature are rationalized in structural terms. The structures presented here also provide a starting point for the rational (structure-based) design of further functional studies.
Rodent Autosomal Dominant Polycystic Kidney Disease Models
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Sara J. Holditch, Raphael A. Nemenoff, Katharina Hopp
Genetically engineered rodent models (GERMs) are widely recognized as a vital tool to study human disease. This holds true for ADPKD, where GERMs have proven critical to delineate the natural disease history and elucidate molecular/cellular mechanisms of pathogenesis. Moreover, GERMs have built the foundation for preclinical testing of therapeutic compounds with the promise of alleviating clinically relevant disease pathologies. In recent years, the use of engineered nucleases (ZNFs, TALENs, CRISPER/Cas9)38 have replaced classical methodologies to produce GERMs. However, none of the current PKD models were generated through these novel approaches, and therefore, the technical aspects of using engineered nucleases will not be reviewed here. It is important to note that not all PKD models are founded on the basis of genetic engineering. Instead, some models arose through spontaneous mutations, chemical induction, or insertional mutagenesis. This is particularly the case for PKD rat models and various models mimicking syndromic forms of human PKD, classified as ciliopathies.9,21 These will be briefly discussed in Section 10.7 of this chapter.
Non-canonical roles of apoptotic and DNA double-strand break repair factors in mediating cellular response to ionizing radiation
Published in International Journal of Radiation Biology, 2023
Despite numerous studies that validated the initial observations of radiation-induced delayed genetic instability in mammalian cells, the molecular mechanisms involved were not understood well. Theoretically, radiation-induced mutagenesis of key DNA repair genes is one plausible mechanism for the widespread and transgenerational upregulation of mutation rates in the progeny of irradiated cells. However, such a scenario is highly unlikely given the high prevalence of the delayed genetic instability phenotype (10-30% of survivor cells) that would require radiation-induced mutation rates to be in the range of 10−2–10−1 per gene per cell division for the putative DNA repair genes. However, under most circumstances, mutation rates in most mammalian genes are usually in the range of 10−5–10−7 per gene per cell division, including the so-called “mutator” cell lines with mismatch repair deficiencies (DeMars and Held 1972; Kat et al. 1993; Bhattacharyya et al. 1994). Therefore, the delayed genetic instability observed in irradiated cells is more likely caused by non-genetic processes or factors induced by radiation that can be transmitted into the progeny of irradiated cells at relatively high frequencies (e.g, 10-30% of irradiated cells).
In silico high throughput mutagenesis and screening of signal peptides to mitigate N-terminal heterogeneity of recombinant monoclonal antibodies
Published in mAbs, 2022
Xin Yu, Merlinda Conyne, Marc R. Lake, Karl A. Walter, Jing Min
Two strategies are commonly used in mutagenesis. The first strategy involves conducting mutagenesis step by step. For example, wildtype SPs are screened first, then only the best wildtype SPs are moved forward as templates for creating single aa mutants. Subsequently, only the best single aa mutants are moved forward for the next round of mutagenesis. In the second strategy, all wildtype SPs and their theoretically possible single and double aa mutants are generated and screened. Here, we demonstrated that the second approach is preferred for in silico SP screening. In Supp. Figure 6, four wildtype SPs were selected: sp_10, sp_15, VL3_3 l, and VL10_10a. CS scores from the wildtype SP, as well as its highest-scoring single aa mutant and its highest-scoring double aa mutant were plotted. SP sp_15 had the highest score among the selected wildtype SPs. As for sp_10, it had a lower score to start with, but its best double aa mutant was on par with that from sp_15. In addition, VL3_3I and VL10_10a had extremely low scores (< 0.06) as wildtypes. However, their best double aa mutants were able to reach scores between 0.71–0.98, a significant improvement compared to their wildtypes. The results suggest that it is possible to convert a low-scoring SP to a high-scoring one with one to two mutations. As a result, even though covering all theoretically possible mutants demands more computational time, it is still desirable as it avoids missing potentially high-scoring mutants.
Gamma irradiation to induce beneficial mutants in proso millet (Panicum miliaceum L.): an underutilized food crop
Published in International Journal of Radiation Biology, 2022
Neethu Francis, Ravikesavan Rajasekaran, Iyanar Krishnamoorthy, Raveendran Muthurajan, Chitdeshwari Thiyagarajan, Senthil Alagarswamy
Mutation breeding offers a viable option for broadening the genetic base and creation of new variation. Among field crops, mutation as a pre-breeding method has been widely used in rice, maize, wheat, barley, soybean, etc. Though mutant varieties have been released in foxtail and finger millet, mutation breeding attempts in proso millet is limited. Varieties like Kharkovskoye, Lipetskoe and Cheget have been documented as developed through mutation breeding, using chemical mutagens, during 1980s and 1990s (Maluszynski et al. 2000). Physical mutagens like gamma, X-rays, thermal neutrons, ion beams, protons, beta and alpha particles are also being utilized in many crops (Suprasanna et al. 2015). Gamma rays are one of the most widely used electro-magnetic radiation due to its high and uniform penetrating capacity (Piri et al. 2011; Oladosu et al. 2016). They cause double strand breaks in the target organism which leads to deletions, insertions, translocation, and duplications in the chromosomes (Mba et al. 2010; Oladosu et al. 2016) and result in increased recombinational frequency. The present study focuses on creation of variation through physical mutagenesis.