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1.
Harnessing the physicochemical properties of DNA as a multifunctional biomaterial for biomedical and other applications.
Chakraborty, A, Ravi, SP, Shamiya, Y, Cui, C, Paul, A
Chemical Society reviews. 2021;(13):7779-7819
Abstract
The biological purpose of DNA is to store, replicate, and convey genetic information in cells. Progress in molecular genetics have led to its widespread applications in gene editing, gene therapy, and forensic science. However, in addition to its role as a genetic material, DNA has also emerged as a nongenetic, generic material for diverse biomedical applications. DNA is essentially a natural biopolymer that can be precisely programed by simple chemical modifications to construct materials with desired mechanical, biological, and structural properties. This review critically deciphers the chemical tools and strategies that are currently being employed to harness the nongenetic functions of DNA. Here, the primary product of interest has been crosslinked, hydrated polymers, or hydrogels. State-of-the-art applications of macroscopic, DNA-based hydrogels in the fields of environment, electrochemistry, biologics delivery, and regenerative therapy have been extensively reviewed. Additionally, the review encompasses the status of DNA as a clinically and commercially viable material and provides insight into future possibilities.
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2.
Congenital stationary night blindness: an update and review of the disease spectrum in Saudi Arabia.
Almutairi, F, Almeshari, N, Ahmad, K, Magliyah, MS, Schatz, P
Acta ophthalmologica. 2021;(6):581-591
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Abstract
Congenital stationary night blindness (CSNB) is a group of rare, mainly stationary disorders of the retina, resulting from dysfunction of several specific and essential visual processing mechanisms. The inheritance is often recessive and as such, CSNB may be more common among populations with a high degree of consanguinity. Here, we present a topic update and a review of the clinical and molecular genetic spectrum of CSNB in Saudi Arabia. Since a major review article on CSNB in 2015, which described 17 genes underlying CSNB, an additional four genes have been incriminated in autosomal recessive CSNB RIMS2, GNB3, GUCY2D and ABCA4. These have been associated with syndromic cone-rod synaptic disease, ON bipolar cell dysfunction with reduced cone sensitivity, CSNB with dysfunction of the phototransduction (Riggs type) and CSNB with cone-rod dystrophy, respectively. In Saudi Arabia, a total of 24 patients with CSNB were identified, using a combination of literature search and retrospective study of previously unpublished cases. Recessive mutations in TRPM1 and CABP4 accounted for the majority of cases (5 and 13 for each gene, respectively). These genes were associated with complete (cCSNB) and incomplete (icCSNB), respectively, and were associated with high myopia in the former and hyperopia in the latter. Four novel mutations were identified. For the first time, we describe the fundus albipunctatus in two patients from Saudi Arabia, caused by recessive mutation in RDH5 and RPE65, where the former in addition featured findings compatible with cone dystrophy. No cases were identified with any dominantly inherited CSNB.
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DNA numerical encoding schemes for exon prediction: a recent history.
Das, L, Das, JK, Mohapatra, S, Nanda, S
Nucleosides, nucleotides & nucleic acids. 2021;(10):985-1017
Abstract
Bioinformatics in the present day has been firmly established as a regulator in genomics. In recent times, applications of Signal processing in exon prediction have gained a lot of attention. The exons carry protein information. Proteins are composed of connected constituents known as amino acids that characterize the specific function. Conversion of the nucleotide character string into a numerical sequence is the gateway before analyzing it through signal processing methods. This numeric encoding is the mathematical descriptor of nucleotides and is based on some statistical properties of the structure of nucleic acids. Since the type of encoding extremely affects the exon detection accuracy, this paper is devised for the review of existing encoding (mapping) schemes. The comparative analysis is formulated to emphasize the importance of the genetic code setting of amino acids considered for application related to computational elucidation for exon detection. This work covers much helpful information for future applications.
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Smart-RRBS for single-cell methylome and transcriptome analysis.
Gu, H, Raman, AT, Wang, X, Gaiti, F, Chaligne, R, Mohammad, AW, Arczewska, A, Smith, ZD, Landau, DA, Aryee, MJ, et al
Nature protocols. 2021;(8):4004-4030
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Abstract
The integration of DNA methylation and transcriptional state within single cells is of broad interest. Several single-cell dual- and multi-omics approaches have been reported that enable further investigation into cellular heterogeneity, including the discovery and in-depth study of rare cell populations. Such analyses will continue to provide important mechanistic insights into the regulatory consequences of epigenetic modifications. We recently reported a new method for profiling the DNA methylome and transcriptome from the same single cells in a cancer research study. Here, we present details of the protocol and provide guidance on its utility. Our Smart-RRBS (reduced representation bisulfite sequencing) protocol combines Smart-seq2 and RRBS and entails physically separating mRNA from the genomic DNA. It generates paired epigenetic promoter and RNA-expression measurements for ~24% of protein-coding genes in a typical single cell. It also works for micro-dissected tissue samples comprising hundreds of cells. The protocol, excluding flow sorting of cells and sequencing, takes ~3 d to process up to 192 samples manually. It requires basic molecular biology expertise and laboratory equipment, including a PCR workstation with UV sterilization, a DNA fluorometer and a microfluidic electrophoresis system.
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An Overview of Dps: Dual Acting Nanovehicles in Prokaryotes with DNA Binding and Ferroxidation Properties.
Williams, SM, Chatterji, D
Sub-cellular biochemistry. 2021;:177-216
Abstract
DNA binding proteins under starvation (Dps) are proteins belonging to the ferritin family with the capacity for DNA binding, in addition to iron storage and ferroxidation. Present only in the prokaryotes, these multifaceted proteins have been assigned with a number of roles, from pathogenesis to nucleoid condensation and protection. They have a significant role in protecting the cells from free radical assaults, indirectly by sequestration of iron and by directly binding to the DNA. Due to their symmetry, stability and biomineralization capacity, these proteins have ever increasing potential applications in biotechnology and drug delivery. This chapter tries to bring together all these aspects of Dps in the view of current understanding and older perspectives by studies of our group as well as other experts in the field.
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Hydroxyl radical is a significant player in oxidative DNA damage in vivo.
Halliwell, B, Adhikary, A, Dingfelder, M, Dizdaroglu, M
Chemical Society reviews. 2021;(15):8355-8360
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Abstract
Recent publications have suggested that oxidative DNA damage mediated by hydroxyl radical (˙OH) is unimportant in vivo, and that carbonate anion radical (CO3˙-) plays the key role. We examine these claims and summarize the evidence that ˙OH does play a key role as an important member of the reactive oxygen species (ROS) in vivo.
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The importance of the RET gene in thyroid cancer and therapeutic implications.
Salvatore, D, Santoro, M, Schlumberger, M
Nature reviews. Endocrinology. 2021;(5):296-306
Abstract
Since the discovery of the RET receptor tyrosine kinase in 1985, alterations of this protein have been found in diverse thyroid cancer subtypes. RET gene rearrangements are observed in papillary thyroid carcinoma, which result in RET fusion products. By contrast, single amino acid substitutions and small insertions and/or deletions are typical of hereditary and sporadic medullary thyroid carcinoma. RET rearrangements and mutations of extracellular cysteines facilitate dimerization and kinase activation, whereas mutations in the RET kinase coding domain drive dimerization-independent kinase activation. Thus, RET kinase inhibition is an attractive therapeutic target in patients with RET alterations. This approach was initially achieved using multikinase inhibitors, which affect multiple deregulated pathways that include RET kinase. In clinical practice, use of multikinase inhibitors in patients with advanced thyroid cancer resulted in therapeutic efficacy, which was associated with frequent and sometimes severe adverse effects. However, remarkable progress has been achieved with the identification of novel potent and selective RET kinase inhibitors for the treatment of advanced thyroid cancer. Although expanded clinical validation in future trials is needed, the sustained antitumoural activity and the improved safety profile of these novel compounds is opening a new exciting era in precision oncology for RET-driven cancers.
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DNA origami-based protein networks: from basic construction to emerging applications.
Kong, G, Xiong, M, Liu, L, Hu, L, Meng, HM, Ke, G, Zhang, XB, Tan, W
Chemical Society reviews. 2021;(3):1846-1873
Abstract
Natural living systems are driven by delicate protein networks whose functions are precisely controlled by many parameters, such as number, distance, orientation, and position. Focusing on regulation rather than just imitation, the construction of artificial protein networks is important in many research areas, including biomedicine, synthetic biology and chemical biology. DNA origami, sophisticated nanostructures with rational design, can offer predictable, programmable, and addressable scaffolds for protein assembly with nanometer precision. Recently, many interdisciplinary efforts have achieved the precise construction of DNA origami-based protein networks, and their emerging application in many areas. To inspire more fantastic research and applications, herein we highlight the applicability and potentiality of DNA origami-based protein networks. After a brief introduction to the development and features of DNA origami, some important factors for the precise construction of DNA origami-based protein networks are discussed, including protein-DNA conjugation methods, networks with different patterns and the controllable parameters in the networks. The discussion then focuses on the emerging application of DNA origami-based protein networks in several areas, including enzymatic reaction regulation, sensing, bionics, biophysics, and biomedicine. Finally, current challenges and opportunities in this research field are discussed.
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Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations.
Cremers, FPM, Lee, W, Collin, RWJ, Allikmets, R
Progress in retinal and eye research. 2020;:100861
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Abstract
The ABCA4 protein (then called a "rim protein") was first identified in 1978 in the rims and incisures of rod photoreceptors. The corresponding gene, ABCA4, was cloned in 1997, and variants were identified as the cause of autosomal recessive Stargardt disease (STGD1). Over the next two decades, variation in ABCA4 has been attributed to phenotypes other than the classically defined STGD1 or fundus flavimaculatus, ranging from early onset and fast progressing cone-rod dystrophy and retinitis pigmentosa-like phenotypes to very late onset cases of mostly mild disease sometimes resembling, and confused with, age-related macular degeneration. Similarly, analysis of the ABCA4 locus uncovered a trove of genetic information, including >1200 disease-causing mutations of varying severity, and of all types - missense, nonsense, small deletions/insertions, and splicing affecting variants, of which many are located deep-intronic. Altogether, this has greatly expanded our understanding of complexity not only of the diseases caused by ABCA4 mutations, but of all Mendelian diseases in general. This review provides an in depth assessment of the cumulative knowledge of ABCA4-associated retinopathy - clinical manifestations, genetic complexity, pathophysiology as well as current and proposed therapeutic approaches.
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10.
Reversal of nucleobase methylation by dioxygenases.
Xu, GL, Bochtler, M
Nature chemical biology. 2020;(11):1160-1169
Abstract
The repertoire of nucleobase methylation in DNA and RNA, introduced by chemical agents or enzymes, is large. Most methylation can be reversed either directly by restoration of the original nucleobase or indirectly by replacement of the methylated nucleobase with an unmodified nucleobase. In many direct and indirect demethylation reactions, ALKBH (AlkB homolog) and TET (ten eleven translocation) hydroxylases play a role. Here, we suggest a chemical classification of methylation types. We then discuss pathways for removal, emphasizing oxidation reactions. We highlight the recently expanded repertoire of ALKBH- and TET-catalyzed reactions and describe the discovery of a TET-like protein that resembles the hydroxylases but uses an alternative co-factor and catalyzes glyceryl transfer rather than hydroxylation.