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Host Defense and Parasite Evasion
Published in Eric S. Loker, Bruce V. Hofkin, Parasitology, 2023
Eric S. Loker, Bruce V. Hofkin
One noteworthy defense strategy is the restriction-modification system in bacteria. A typical system couples an endonuclease with a modification enzyme. The endonuclease recognizes specific sequences in phage DNA and cleaves (or restricts) the DNA at these sites, thus disabling the phage. The modification enzyme, often a methyltransferase, adds a methyl group to the host bacterium’s DNA, thereby protecting it from endonuclease attack. This is a system of self–non-self recognition that can selectively disable non-self entities such as viruses. In response, phages have been selected to avoid using nucleotide sequences targeted by restriction enzymes. They may also incorporate unusual or modified nucleotides at target sites, or they may protect the sites by cloaking them in proteins. Alternatively, they may hijack host methyltransferases to methylate and thus protect their target sequences. Clearly, the classic elements of an arms race exist within this system.
Hypoxia, Free Radicals, and Reperfusion Injury Following Cold Storage and Reperfusion of Livers for Transplantation
Published in John J. Lemasters, Constance Oliver, Cell Biology of Trauma, 2020
Ronald G. Thurman, Wenshi Gao, Henry D. Connor, Sigrid Bachmann, Robert T. Currin, Ronald P. Mason, John J. Lemasters
Acute cellular necrosis from hypoxia/ischemia should be distinguished from apoptosis, also called programmed cell death or shrinkage necrosis.36,37 In apoptosis, specific stimuli result in the expression of a genetic program leading to orderly dissolution and resorption of cells. Specifically, activated endonucleases cause internucleosomal DNA degradation and nuclear fragmentation, proteins are cross-linked, and new receptors appear on the surface of the cell. Large bleb-like evaginations are formed, shed, and then taken up by macrophages. In contrast to blebs formed during acute hypoxic injury, the blebs in apoptosis contain different nuclear fragments and well-preserved large organelles such as mitochondria and lysosomes. Shrunken, apoptotic hepatocytes give rise to the Councilman bodies of hepatic pathology.
Science of biotechnology – Recombinant DNA technology
Published in Ronald P. Evens, Biotechnology, 2020
The circular plasmid DNA must be cut open to accept the human DNA (gene) using unique bacterial enzymes (restriction endonucleases). Each endonuclease enzyme is highly specific to a certain nucleic acid sequence, creating a very specific cut, that is, an opening in the DNA plasmid structure appropriate for a specific gene’s incorporation and permitting efficient recombination. DNA materials will recombine naturally with the human gene sequence inserted into the circular plasmid sequence. A DNA ligase enzyme is employed to enhance the DNA recombination process. Figure 2.9 displays such restriction endonuclease enzymes found in nature in specific bacteria as noted. The very high specificity to an individual DNA sequence of nucleotides for endonucleases is shown in Figure 2.9.
A systematic review comparing allogeneic hematopoietic stem cell transplant to gene therapy in sickle cell disease
Published in Hematology, 2023
Lianne E. Rotin, Auro Viswabandya, Rajat Kumar, Christopher J. Patriquin, Kevin H.M. Kuo
GT is a newer strategy utilizing autologous HSCs. With this approach, ex vivo gene addition or editing techniques are used to reverse the SCD phenotype by inducing expression of anti-sickling β-globin or γ-globin (fetal globin) via silencing or disruption of the fetal globin repressor, BCL11A [5,6]. Current gene addition approaches use lentiviral vectors for ex vivo transduction of patient-derived HSCs with anti-sickling globin genes [5]. Gene editing techniques use endonucleases to induce DNA double-stranded breaks at targeted sites and take advantage of endogenous non-homologous end joining to create insertions or deletions that disrupt the function of the targeted gene (e.g. BCL11A) [5]. Following a myeloablative conditioning regimen similar to that used for HSCT, successful engraftment of modified patient-derived HSCs results in the expression of anti-sickling or fetal globin genes. While gene therapy still carries the risk of conditioning regimen-associated toxicity, the use of autologous over allogeneic HSCs eliminates GVHD risk and the need for HSC donors [3].
Small interfering RNA-based nanotherapeutics for treating skin-related diseases
Published in Expert Opinion on Drug Delivery, 2023
Yen-Tzu Chang, Tse-Hung Huang, Ahmed Alalaiwe, Erica Hwang, Jia-You Fang
siRNA is a double-stranded RNA (dsRNA) consisting of 20‒30 nucleotides in length. The investigation of siRNA originated with the exploration of RNA interference (RNAi). It is a novel class of RNA inhibitors acting by the RNA-induced silencing complex (RISC) to specifically degrade target RNAs [26]. RNAi mediated by dsRNA was first determined by Fire et al. in 1998 [27]. siRNA-mediated gene silencing is then demonstrated to be act as the posttranscriptional sequence-specific procedure [28]. The functional RISC has four subunits: helicase, endonuclease exonuclease, and homology-searching domains. As siRNA binds to RISC, the duplex siRNA can be unwound by helicase, leading to the formation of two single strands. This effect produces the binding of the antisense strand to the target RNA molecules [29]. The endonuclease can hydrolyze mRNA homologous at the area that the antisense strand is bound. RNAi shows an antisense mechanism as a single-stranded RNA binds to the target RNA by Watson – Crick base pairing and recruits a ribonuclease degrading the target RNA (Figure 2). Basically, siRNA can target any gene of interest as long as the coding sequence for the target gene is known. This results in a shorter duration for research and development.
Strategies for targeting RNA with small molecule drugs
Published in Expert Opinion on Drug Discovery, 2023
Christopher L. Haga, Donald G. Phinney
Several methods have been developed to experimentally determine the secondary structure folding of RNA. These methods largely focus on determining regions of RNA susceptible to attack or modification by nucleases, chemical reagents, or electrophiles, thereby identifying the solvent-exposed regions of the RNA structure (Figure 2) [18]. Early experimentation in determining RNA structures was carried out via enzymatic mapping via specific endonucleases that cleave single-stranded RNA regions without sequence preference [19]. These experiments relied on hydrolysis of radioactively labeled RNA generating a specific cleavage pattern which was then directly analyzed by gel electrophoresis or by detecting reverse transcription stops of cleaved products by Sanger sequencing [20]. However, due to local steric hindrance effects and the possibility that nucleotides may be obscured by RNA tertiary structures, enzymatic reactions are infeasible for practical and accurate probing of RNA secondary structures at the level of the transcriptome.