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1.
Common and rare susceptibility genetic variants predisposing to Brugada syndrome in Thailand.
Makarawate, P, Glinge, C, Khongphatthanayothin, A, Walsh, R, Mauleekoonphairoj, J, Amnueypol, M, Prechawat, S, Wongcharoen, W, Krittayaphong, R, Anannab, A, et al
Heart rhythm. 2020;(12):2145-2153
Abstract
BACKGROUND Mutations in SCN5A are rarely found in Thai patients with Brugada syndrome (BrS). Recent evidence suggested that common genetic variations may underlie BrS in a complex inheritance model. OBJECTIVE The purpose of this study was to find common and rare/low-frequency genetic variants predisposing to BrS in persons in Thailand. METHODS We conducted a genome-wide association study (GWAS) to explore the association of common variants in 154 Thai BrS cases and 432 controls. We sequenced SCN5A in 131 cases and 205 controls. Variants were classified according to current guidelines, and case-control association testing was performed for rare and low-frequency variants. RESULTS Two loci were significantly associated with BrS. The first was near SCN5A/SCN10A (lead marker rs10428132; odds ratio [OR] 2.4; P = 3 × 10-10). Conditional analysis identified a novel independent signal in the same locus (rs6767797; OR 2.3; P = 2.7 × 10-10). The second locus was near HEY2 (lead marker rs3734634; OR 2.5; P = 7 × 10-9). Rare (minor allele frequency [MAF] <0.0001) coding variants in SCN5A were found in 8 of the 131 cases (6.1% in cases vs 2.0% in controls; P = .046; OR 3.3; 95% confident interval [CI] 1.0-11.1), but an enrichment of low-frequency (MAF<0.001 and >0.0001) variants also was observed in cases, with 1 variant (SCN5A: p.Arg965Cys) detected in 4.6% of Thai BrS patients vs 0.5% in controls (P = 0.015; OR 9.8; 95% CI 1.2-82.3). CONCLUSION The genetic basis of BrS in Thailand includes a wide spectrum of variant frequencies and effect sizes. As previously shown in European and Japanese populations, common variants near SCN5A and HEY2 are associated with BrS in the Thai population, confirming the transethnic transferability of these 2 major BrS loci.
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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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Intercalation of a flavonoid, silibinin into DNA base pairs: Experimental and theoretical approach.
Pawar, SK, Jaldappagari, S
Journal of molecular recognition : JMR. 2020;(1):e2812
Abstract
Polyphenols are secondary plant metabolites, which have received much attention because of their potential health benefits. Silibinin (SIL) is a well-known naturally occurring flavonolignan, which is extensively used in treating a wide variety of diseases as a dietary supplement as well as a prescribed drug. The mechanism of binding of SIL to calf thymus DNA (ctDNA) was investigated by employing multispectroscopic techniques, viz., absorption, fluorescence, and circular dichroism besides viscosity measurements and docking studies. Analysis of fluorescence results indicated that SIL has interacted with ctDNA and quenched its intensity through static quenching mechanism. The binding constant at room temperature was found to be 2.48×104 mol-1 , suggesting moderate binding affinity between SIL and ctDNA. The hypochromicity observed in the absorption spectra of ctDNA in the presence of SIL revealed the intercalation of SIL into ctDNA base pairs. Further, the intercalative mode of binding between SIL and ctDNA was confirmed by viscosity measurements and molecular docking studies. The outcome of present study helps to decipher the interaction mechanism between SIL and DNA at physiological pH, which further assists in the design of a new analogue for better therapeutic effects.
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Synthesis, physicochemical characterization and biological properties of two novel Cu(II) complexes based on natural products curcumin and quercetin.
Halevas, E, Pekou, A, Papi, R, Mavroidi, B, Hatzidimitriou, AG, Zahariou, G, Litsardakis, G, Sagnou, M, Pelecanou, M, Pantazaki, AA
Journal of inorganic biochemistry. 2020;:111083
Abstract
Curcumin and quercetin are two of the most prominent natural polyphenols with a diverse spectrum of beneficial properties, including antioxidant, anti-inflammatory, chemopreventive and chemotherapeutic activity. The complexation of these natural products with bioactive transition metal ions can lead to the generation of novel metallodrugs with enhanced biochemical and pharmacological activities. Within this framework, the synthesis and detailed structural and physicochemical characterization of two novel complex assemblies of Cu(II) with curcumin and quercetin and the ancillary aromatic chelator 2,2'-bipyridine is presented. The two complexes represent the only crystallographically characterized structures with Cu(II) as the central metal ion and curcumin or quercetin as the ligands. The new complexes were biologically evaluated in vitro for their antioxidant potential, both exhibiting strong scavenging activity in the 2,2-diphenyl-1-picrylhydrazyl assay, and their plasmid DNA binding/cleavage properties. Both complexes appear to be non-toxic in the eukaryotic experimental model Saccharomyces cerevisiae and merit further investigation of their pharmacological profile.
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Utilization of the genome aggregation database, in silico tools, and heterologous expression patch-clamp studies to identify and demote previously published type 2 long QT syndrome: Causative variants from pathogenic to likely benign.
Mattivi, CL, Ye, D, Tester, DJ, Clemens, DJ, Zhou, W, Giudicessi, JR, Ackerman, MJ
Heart rhythm. 2020;(2):315-323
Abstract
BACKGROUND Loss-of-function variants in the KCNH2-encoded Kv11.1 potassium channel cause long QT syndrome (LQTS) type 2 (LQT2). Presently, hundreds of KCNH2 missense variants (MVs) have been published as "disease-causative." However, an estimated 10% of rare published LQTS MVs may be "false positives." OBJECTIVE The purpose of this study was to determine which published KCNH2 MVs are likely false positives and warrant demotion to "likely benign" status. METHODS A list of 337 LQT2-associated MVs from 6 large compendia was compiled. MV frequency within the Genome Aggregation Database (gnomAD) (n = 141,352 individuals) was assessed, and MVs were analyzed with 8 in silico tools. Variants with minor allele frequency (MAF) >7*10E-6, the calculated maximum credible frequency of LQT2, and predicted "benign" by all tools were demoted to "likely benign." Ultra-rare variants (n = 8) absent in gnomAD but predicted "benign" by all tools were considered as potential false positives and were characterized functionally using whole-cell patch clamp. RESULTS Overall, 14 of 337 published KCNH2 MVs (4%) were observed at MAF >7*10E-6, whereas 252 of 337 (75%) were absent in gnomAD. Among the latter, 8 variants (I96V, G187S, A203T, P241L, H254Q, G314S, P935S, P963T) were predicted benign by 8 tools and lacked characterization. Patch clamp showed no functional perturbation for these 8 MVs. CONCLUSION This study offers compelling evidence for the demotion of 22 of 337 KCNH2 variants (6.5%) in the literature. Meticulous "pruning" of compendia using exome/genome databases, in silico tools, and in vitro functional studies must be conducted not only for putatively pathogenic LQTS MVs but for the entire field of genetic heart disease.
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Binding patterns and dynamics of double-stranded DNA on the phosphorene surface.
Li, B, Xie, X, Duan, G, Chen, SH, Meng, XY, Zhou, R
Nanoscale. 2020;(17):9430-9439
Abstract
Phosphorene, a monolayer of black phosphorus, has emerged as one of the most promising two-dimensional (2D) nanomaterials for various applications in the post-graphene-discovery period due to its highly anisotropic structure and novel properties. In order to apply phosphorene in biomedical fields, it is crucial to understand how it interacts with biomolecules. Herein, we use both molecular dynamics (MD) simulations and experimental techniques to investigate the interactions of phosphorene with a dsDNA segment. Our results reveal that dsDNA can form a stable binding on the phosphorene surface through the terminal base pairs and adopt an upright orientation regardless of its initial configurations. Moreover, the binding strength of dsDNA with phosphorene is found to be mild and does not cause significant distortion in the internal structure of dsDNA. This phenomenon is attributed to the weaker dispersion interaction between dsDNA and phosphorene. Further analysis of the free energy profile calculated by the umbrella sampling technique suggests that the puckered surface morphology significantly reduces the adsorption free energy of DNA bases to phosphorene. Compared to graphene, phosphorene is found to show a milder attraction to DNA, which is confirmed by our electrophoresis experiments. We believe that these findings provide valuable insight into the molecular interactions between phosphorene and dsDNA which may prompt further investigation of phosphorene for future biomedical applications.
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Association between Aldose Reductase Gene C(-106)T Polymorphism and Diabetic Retinopathy: A Systematic Review and Meta-Analysis.
Lin, S, Peng, Y, Cao, M, Chen, R, Hu, J, Pu, Z, Cai, Z, Mou, L
Ophthalmic research. 2020;(3):224-233
Abstract
Controversial results regarding the associations between aldose reductase (AR) genetic polymorphisms and diabetic retinopathy (DR) have been reported for many years. The present meta-analysis was performed to clarify the effects of the AR gene C(-106)T polymorphism on DR risk. The PubMed, Web of Sciences, Cochrane library, EMBASE, Chinese National Knowledge Infrastructure, and Wan Fang databases were extensively searched in Chinese to select relevant studies with an updated date of April 25, 2018. The Newcastle-Ottawa Scale (NOS) was applied to assess quality. The random-effects model was applied to calculate the pooled OR and 95% CI. This meta-analysis identified 23 studies with an average score of 7.52 for NOS analysis, including 4,313 DR cases and 5,128 diabetes mellitus (DM) control cases. In the overall analysis, a significant association between the AR gene C(-106)T polymorphism and DR susceptibility was found. In subgroups stratified by DM type and ethnicity, significantly increased risks for DR were found in DM type 1, East Asian populations, and Middle Eastern populations. Compared with DR control cases, the following associations were found: T vs. C: OR 0.91, 95% CI 0.85-0.97, I2 = 72.9%; CT + TT vs. CC: OR 0.75, 95% CI 0.68-0.81, I2 = 86.7%; and CT vs. CC: OR 0.86, 95% CI 0.78-0.94, I2 = 70.5%. The results of this meta-analysis showed a significant association between the AR gene C(-106)T polymorphism and susceptibility to DR in DM patients. DM patients with allele T and CT+TT genotype of the AR gene may have a lower risk of DR.
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Rare-Earth Metal Complexes of the Antibacterial Drug Oxolinic Acid: Synthesis, Characterization, DNA/Protein Binding and Cytotoxicity Studies.
Maciuca, AM, Munteanu, AC, Mihaila, M, Badea, M, Olar, R, Nitulescu, GM, Munteanu, CVA, Bostan, M, Uivarosi, V
Molecules (Basel, Switzerland). 2020;(22)
Abstract
"Drug repositioning" is a current trend which proved useful in the search for new applications for existing, failed, no longer in use or abandoned drugs, particularly when addressing issues such as bacterial or cancer cells resistance to current therapeutic approaches. In this context, six new complexes of the first-generation quinolone oxolinic acid with rare-earth metal cations (Y3+, La3+, Sm3+, Eu3+, Gd3+, Tb3+) have been synthesized and characterized. The experimental data suggest that the quinolone acts as a bidentate ligand, binding to the metal ion via the keto and carboxylate oxygen atoms; these findings are supported by DFT (density functional theory) calculations for the Sm3+ complex. The cytotoxic activity of the complexes, as well as the ligand, has been studied on MDA-MB 231 (human breast adenocarcinoma), LoVo (human colon adenocarcinoma) and HUVEC (normal human umbilical vein endothelial cells) cell lines. UV-Vis spectroscopy and competitive binding studies show that the complexes display binding affinities (Kb) towards double stranded DNA in the range of 9.33 × 104 - 10.72 × 105. Major and minor groove-binding most likely play a significant role in the interactions of the complexes with DNA. Moreover, the complexes bind human serum albumin more avidly than apo-transferrin.
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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.
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[Detection methods for results of a loop-mediated isothermal amplification of DNA.].
Petrusha, OA, Faizuloev, EB
Klinicheskaia laboratornaia diagnostika. 2020;(1):67-72
Abstract
The loop mediated isothermal amplification (LAMP) was developed by T. Notomi et al. in 2000. It has become one of the most promising methods for point-of-care diagnostics due to its accuracy, sensitivity and ease of execution. In this review, various methods for detecting the results of the LAMP reaction are considered; their advantages and disadvantages are revealed. Methods for detecting LAMP results can be divided into indirect and direct. Indirect methods aimed at detecting changes in the chemical composition of the reaction mixture include real-time turbidimetry, fluorescence detection with calcein, colorimetric detection with hydroxynaphthol blue, and detection using modified gold nanoparticles. Direct methods based on the detection of accumulation amplicons during the reaction include fluorimetric detection with intercalating dyes, resonance fluorescence energy transfer, enzyme immunoassay, immunochromatography, using cationic polymers and gold nanoparticles. The development in the field of point-of-care diagnostics is characterized by a pronounced tendency to miniaturization, the LAMP reaction on microchips and microfluidic devices with an electrochemical or optical detection method. The most promising for the diagnosis of infectious diseases are turbidimetry methods and the use of intercalating dyes. The development of portable domestic instruments for detecting of LAMP results based on real-time fluorescence detection or turbidimetry will contribute to the widespread introduction of the method into clinical laboratory diagnostic practice. A literature research was conducted in the Pubmed ncbi based on keywords.