QRB Discovery最新文献_第5页

Amyloid-like Hfq interaction with single-stranded DNA: involvement in recombination and replication in Escherichia coli. 淀粉样蛋白Hfq与单链DNA的相互作用:参与大肠杆菌的重组和复制。

QRB Discovery Pub Date : 2022-01-01 DOI: 10.1017/qrd.2022.15

Krzysztof Kubiak, Frank Wien, Indresh Yadav, Nykola C Jones, Søren Vrønning Hoffmann, Eric Le Cam, Antoine Cossa, Frederic Geinguenaud, Johan R C van der Maarel, Grzegorz Węgrzyn, Véronique Arluison

{"title":"Amyloid-like Hfq interaction with single-stranded DNA: involvement in recombination and replication in Escherichia coli.","authors":"Krzysztof Kubiak, Frank Wien, Indresh Yadav, Nykola C Jones, Søren Vrønning Hoffmann, Eric Le Cam, Antoine Cossa, Frederic Geinguenaud, Johan R C van der Maarel, Grzegorz Węgrzyn, Véronique Arluison","doi":"10.1017/qrd.2022.15","DOIUrl":"https://doi.org/10.1017/qrd.2022.15","url":null,"abstract":"Interactions between proteins and single-stranded DNA (ssDNA) are crucial for many fundamental biological processes, including DNA replication and genetic recombination. Thus, understanding detailed mechanisms of these interactions is necessary to uncover regulatory rules occurring in all living cells. The RNA-binding Hfq is a pleiotropic bacterial regulator that mediates many aspects of nucleic acid metabolism. The protein notably mediates mRNA stability and translation efficiency by using stress-related small regulatory RNA as cofactors. In addition, Hfq helps to compact double-stranded DNA. In this paper, we focused on the action of Hfq on ssDNA. A combination of experimental methodologies, including spectroscopy and molecular imaging, has been used to probe the interactions of Hfq and its amyloid C-terminal region with ssDNA. Our analysis revealed that Hfq binds to ssDNA. Moreover, we demonstrate for the first time that Hfq drastically changes the structure and helical parameters of ssDNA, mainly due to its C-terminal amyloid-like domain. The formation of the nucleoprotein complexes between Hfq and ssDNA unveils important implications for DNA replication and recombination.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"3 ","pages":"e15"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10392684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10283214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

A novel statistical method predicts mutability of the genomic segments of the SARS-CoV-2 virus. 一种新的统计方法预测了SARS-CoV-2病毒基因组片段的易变性。

QRB Discovery Pub Date : 2022-01-01 DOI: 10.1017/qrd.2021.13

Amir Hossein Darooneh, Michelle Przedborski, Mohammad Kohandel

{"title":"A novel statistical method predicts mutability of the genomic segments of the SARS-CoV-2 virus.","authors":"Amir Hossein Darooneh, Michelle Przedborski, Mohammad Kohandel","doi":"10.1017/qrd.2021.13","DOIUrl":"https://doi.org/10.1017/qrd.2021.13","url":null,"abstract":"The SARS-CoV-2 virus has made the largest pandemic of the 21st century, with hundreds of millions of cases and tens of millions of fatalities. Scientists all around the world are racing to develop vaccines and new pharmaceuticals to overcome the pandemic and offer effective treatments for COVID-19 disease. Consequently, there is an essential need to better understand how the pathogenesis of SARS-CoV-2 is affected by viral mutations and to determine the conserved segments in the viral genome that can serve as stable targets for novel therapeutics. Here, we introduce a text-mining method to estimate the mutability of genomic segments directly from a reference (ancestral) whole genome sequence. The method relies on calculating the importance of genomic segments based on their spatial distribution and frequency over the whole genome. To validate our approach, we perform a large-scale analysis of the viral mutations in nearly 80,000 publicly available SARS-CoV-2 predecessor whole genome sequences and show that these results are highly correlated with the segments predicted by the statistical method used for keyword detection. Importantly, these correlations are found to hold at the codon and gene levels, as well as for gene coding regions. Using the text-mining method, we further identify codon sequences that are potential candidates for siRNA-based antiviral drugs. Significantly, one of the candidates identified in this work corresponds to the first seven codons of an epitope of the spike glycoprotein, which is the only SARS-CoV-2 immunogenic peptide without a match to a human protein.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"3 ","pages":"e1"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8795775/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9912917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Computational drug discovery under RNA times. RNA时代的计算药物发现。

QRB Discovery Pub Date : 2022-01-01 DOI: 10.1017/qrd.2022.20

Mattia Bernetti, Riccardo Aguti, Stefano Bosio, Maurizio Recanatini, Matteo Masetti, Andrea Cavalli

引用次数: 2

Resolving the fine structure in the energy landscapes of repeat proteins. 解析重复蛋白能量格局中的精细结构。

QRB Discovery Pub Date : 2022-01-01 DOI: 10.1017/qrd.2022.4

Murilo N Sanches, R Gonzalo Parra, Rafael G Viegas, Antonio B Oliveira, Peter G Wolynes, Diego U Ferreiro, Vitor B P Leite

{"title":"Resolving the fine structure in the energy landscapes of repeat proteins.","authors":"Murilo N Sanches, R Gonzalo Parra, Rafael G Viegas, Antonio B Oliveira, Peter G Wolynes, Diego U Ferreiro, Vitor B P Leite","doi":"10.1017/qrd.2022.4","DOIUrl":"https://doi.org/10.1017/qrd.2022.4","url":null,"abstract":"Ankyrin (ANK) repeat proteins are coded by tandem occurrences of patterns with around 33 amino acids. They often mediate protein-protein interactions in a diversity of biological systems. These proteins have an elongated non-globular shape and often display complex folding mechanisms. This work investigates the energy landscape of representative proteins of this class made up of 3, 4 and 6 ANK repeats using the energy-landscape visualisation method (ELViM). By combining biased and unbiased coarse-grained molecular dynamics AWSEM simulations that sample conformations along the folding trajectories with the ELViM structure-based phase space, one finds a three-dimensional representation of the globally funnelled energy surface. In this representation, it is possible to delineate distinct folding pathways. We show that ELViMs can project, in a natural way, the intricacies of the highly dimensional energy landscapes encoded by the highly symmetric ankyrin repeat proteins into useful low-dimensional representations. These projections can discriminate between multiplicities of specific parallel folding mechanisms that otherwise can be hidden in oversimplified depictions.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"3 ","pages":"e7"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10392621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9980662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Abnormal methylation in the NDUFA13 gene promoter of breast cancer cells breaks the cooperative DNA recognition by transcription factors. 乳腺癌细胞NDUFA13基因启动子甲基化异常破坏了转录因子对DNA的协同识别。

QRB Discovery Pub Date : 2022-01-01 DOI: 10.1017/qrd.2022.21

Johanna Hörberg, Björn Hallbäck, Kevin Moreau, Anna Reymer

{"title":"Abnormal methylation in the NDUFA13 gene promoter of breast cancer cells breaks the cooperative DNA recognition by transcription factors.","authors":"Johanna Hörberg, Björn Hallbäck, Kevin Moreau, Anna Reymer","doi":"10.1017/qrd.2022.21","DOIUrl":"https://doi.org/10.1017/qrd.2022.21","url":null,"abstract":"Selective DNA binding by transcription factors (TFs) is crucial for the correct regulation of DNA transcription. In healthy cells, promoters of active genes are hypomethylated. A single CpG methylation within a TF response element (RE) may change the binding preferences of the protein, thus causing the dysregulation of transcription programs. Here, we investigate a molecular mechanism driving the downregulation of the NDUFA13 gene, due to hypermethylation, which is associated with multiple cancers. Using bioinformatic analyses of breast cancer cell line MCF7, we identify a hypermethylated region containing the binding sites of two TFs dimers, CEBPB and E2F1-DP1, located 130 b.p. from the gene transcription start site. All-atom extended MD simulations of wild type and methylated DNA alone and in complex with either one or both TFs dimers provide mechanistic insights into the cooperative asymmetric binding order of the two dimers; the CEBPB binding should occur first to facilitate the E2F1-DP1-DNA association. The CpG methylation within the E2F1-DP1 RE and the linker decrease the cooperativity effects and renders the E2F1-DP1 binding site less recognizable by the TF dimer. Taken together, the identified CpG methylation site may contribute to the downregulation of the NDUFA13 gene.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"3 ","pages":"e23"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10392677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9980663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Erratum: Effect of Relative Humidity on Hydrogen Peroxide Production in Water Droplets - CORRIGENDUM. 更正：相对湿度对水滴中过氧化氢生成的影响 - 更正。

QRB Discovery Pub Date : 2021-11-04 eCollection Date: 2021-01-01 DOI: 10.1017/qrd.2021.11

Maria T Dulay, Carlos Alberto Huerta-Aguilar, Christian F Chamberlayne, Richard N Zare, Adriaan Davidse, Sinisa Vukovic

引用次数: 0

Effect of relative humidity on hydrogen peroxide production in water droplets. 相对湿度对水滴中过氧化氢生成的影响。

QRB Discovery Pub Date : 2021-07-27 eCollection Date: 2021-01-01 DOI: 10.1017/qrd.2021.6

Maria T Dulay, Carlos Alberto Huerta-Aguilar, Christian F Chamberlayne, Richard N Zare, Adriaan Davidse, Sinisa Vukovic

{"title":"Effect of relative humidity on hydrogen peroxide production in water droplets.","authors":"Maria T Dulay, Carlos Alberto Huerta-Aguilar, Christian F Chamberlayne, Richard N Zare, Adriaan Davidse, Sinisa Vukovic","doi":"10.1017/qrd.2021.6","DOIUrl":"10.1017/qrd.2021.6","url":null,"abstract":"Mist is generated by ultrasonic cavitation of water (Fisher Biograde, pH 5.5-6.5) at room temperature (20-25 °C) in open air with nearly constant temperature (22-25 °C) but varying relative humidity (RH; 24-52%) over the course of many months. Water droplets in the mist are initially about 7 μm in diameter at about 50% RH. They are collected, and the concentration of hydrogen peroxide (H2O2) is measured using commercial peroxide test strips and by bromothymol blue oxidation. The quantification method is based on the Fenton chemistry of dye degradation to determine the oxidation capacity of water samples that have been treated by ultrasonication. It is found that the hydrogen peroxide concentration varies nearly linearly with RH over the range studied, reaching a low of 2 parts per million (ppm) at 24% RH and a high of 6 ppm at 52% RH. Some possible public health implications concerning the transmission of respiratory viral infections are suggested for this threefold change in H2O2 concentration with RH.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"2 ","pages":"e8"},"PeriodicalIF":0.0,"publicationDate":"2021-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/69/ae/S2633289221000065a.PMC10392617.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10301863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ultrafast enzymatic digestion of deoxyribonucleic acid in aqueous microdroplets for sequence discrimination and identification. 水微滴中脱氧核糖核酸的超快酶切，用于序列识别和鉴定。

QRB Discovery Pub Date : 2021-05-20 eCollection Date: 2021-01-01 DOI: 10.1017/qrd.2021.2

Xiaoqin Zhong, Hao Chen, Richard N Zare

{"title":"Ultrafast enzymatic digestion of deoxyribonucleic acid in aqueous microdroplets for sequence discrimination and identification.","authors":"Xiaoqin Zhong, Hao Chen, Richard N Zare","doi":"10.1017/qrd.2021.2","DOIUrl":"https://doi.org/10.1017/qrd.2021.2","url":null,"abstract":"We report the use of aqueous microdroplets to accelerate deoxyribonucleic acid (DNA) fragmentation by deoxyribonuclease I (DNase I), and we present a simple, ultrafast approach named DNA fragment mass fingerprinting to discriminate different DNA sequences by comparing their fragment mass patterns. DNA fragmentation in tiny microdroplets, which was produced by electrosonically spraying (+3 kV) a room temperature aqueous solution containing 10 μM DNA and 10 μg ml-1 DNase I from a homemade setup, takes less than 1 ms. High differentiation/identification fidelity could be obtained by applying a cosine correlation measure for similarity assessment between two fragment mass patterns, which compares both mass-to-charge ratios (m/z) with an error tolerance of 5 ppm and the peaks' relative intensities. A single-nucleotide mutation in the sequence of bases, as exemplified by the sickle cell anemia mutation, is differentiated by setting a cutoff value of similarity at 90%. The order change of two adjacent bases in the sequence could still be well discriminated with a similarity of only 62% between the fragment mass patterns of the two similar sequences, which have the same molecular weights and thus cannot be differentiated by gel electrophoresis or direct mass detection by mass spectrometry. Compared to traditional genotyping methods, such as quantitative real-time polymerase chain reaction, the identification process with our approach could be completed within several minutes without any other expensive and complicated reagents or experimental steps. The potential of our approach for convenient and fast microbe genetic discrimination or identification is further demonstrated by differentiating the Orf1ab gene fragments of two similar coronaviruses with a very high sequence homologous rate of 96%, SARS-CoV-2 and bat-SL-CoVZC45, with a similarity of 0% between their fragment mass patterns.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":" ","pages":"e4"},"PeriodicalIF":0.0,"publicationDate":"2021-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1017/qrd.2021.2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39125273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4

Combined electrochemistry and mass spectrometry imaging to interrogate the mechanism of action of modafinil, a cognition-enhancing drug, at the cellular and sub-cellular level. 结合电化学和质谱成像在细胞和亚细胞水平上探讨认知增强药物莫达非尼的作用机制。

QRB Discovery Pub Date : 2021-01-01 DOI: 10.1017/qrd.2021.4

Elias Ranjbari, Mai H Philipsen, Zhaoying Wang, Andrew G Ewing

{"title":"Combined electrochemistry and mass spectrometry imaging to interrogate the mechanism of action of modafinil, a cognition-enhancing drug, at the cellular and sub-cellular level.","authors":"Elias Ranjbari, Mai H Philipsen, Zhaoying Wang, Andrew G Ewing","doi":"10.1017/qrd.2021.4","DOIUrl":"https://doi.org/10.1017/qrd.2021.4","url":null,"abstract":"Modafinil is a mild psychostimulant-like drug enhancing wakefulness, improving attention and developing performance in various cognitive tasks, but its mechanism of action is not completely understood. This is the first combination of amperometry, electrochemical cytometry and mass spectrometry to interrogate the mechanism of action of a drug, here modafinil, at cellular and sub-cellular level. We employed single-cell amperometry (SCA) and intracellular vesicle impact electrochemical cytometry (IVIEC) to investigate the alterations in exocytotic release and vesicular catecholamine storage following modafinil treatment. The SCA results reveal that modafinil slows down the exocytosis process so that, the number of catecholamines released per exocytotic event is enhanced in the modafinil-treated cells. Also, IVIEC results offer an upregulation effect of modafinil on the vesicular catecholamine storage. Mass spectrometry imaging by time-of-flight secondary ion mass spectrometry (ToF-SIMS) illustrates that treatment with modafinil reduces the cylindrical-shaped phosphatidylcholine at the cellular membrane, while the high curvature lipids with conical structures such as phosphatidylethanolamine and phosphatidylinositol are elevated after modafinil treatment. Combining the results obtained by SCA, IVIEC and ToF-SIMS suggests that modafinil-treated cells release a larger portion of their vesicular content at least in part by changing the lipid composition of the cell membrane, suggesting regulation of cognition.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"2 ","pages":"e6"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1017/qrd.2021.4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10283663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Structural basis of anti-SARS-CoV-2 activity of HCQ: specific binding to N protein to disrupt its interaction with nucleic acids and LLPS. HCQ抗sars - cov -2活性的结构基础:特异性结合N蛋白破坏其与核酸和LLPS的相互作用。

QRB Discovery Pub Date : 2021-01-01 DOI: 10.1017/qrd.2021.12

Mei Dang, Jianxing Song

{"title":"Structural basis of anti-SARS-CoV-2 activity of HCQ: specific binding to N protein to disrupt its interaction with nucleic acids and LLPS.","authors":"Mei Dang, Jianxing Song","doi":"10.1017/qrd.2021.12","DOIUrl":"https://doi.org/10.1017/qrd.2021.12","url":null,"abstract":"SARS-CoV-2 nucleocapsid (N) protein plays the essential roles in key steps of the viral life cycle, thus representing a top drug target. Functionality of N protein including liquid-liquid phase separation (LLPS) depends on its interaction with nucleic acids. Only the variants with N proteins functional in binding nucleic acids might survive and spread in evolution and indeed, the residues critical for binding nucleic acids are highly conserved. Hydroxychloroquine (HCQ) was shown to prevent the transmission in a large-scale clinical study in Singapore but so far, no specific SARS-CoV-2 protein was experimentally identified to be targeted by HCQ. Here by NMR, we unambiguously decode that HCQ specifically binds NTD and CTD of N protein with Kd of 112.1 and 57.1 μM, respectively to inhibit their interaction with nucleic acid, as well as to disrupt LLPS. Most importantly, HCQ-binding residues are identical in SARS-CoV-2 variants and therefore HCQ is likely effective to different variants. The results not only provide a structural basis for the anti-SARS-CoV-2 activity of HCQ, but also renders HCQ to be the first known drug capable of targeting LLPS. Furthermore, the unique structure of the HCQ-CTD complex suggests a promising strategy for design of better anti-SARS-CoV-2 drugs from HCQ.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"2 ","pages":"e13"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10392676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9917606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3