replication stage
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2022 ◽  
Vol 12 ◽  
Author(s):  
Fuxin Zhao ◽  
Wei Chen ◽  
Hui Zhou ◽  
Peter S. Reinach ◽  
Yuhan Wang ◽  
...  

Myopia is the most common cause of refractive error worldwide. High myopia is a severe type of myopia, which usually accompanies pathological changes in the fundus. To identify high myopia susceptibility genes, DNA-pooling based genome-wide association analysis was used to search for a correlation between single nucleotide polymorphisms and high myopia in a Han Chinese cohort (cases vs. controls in discovery stage: 507 vs. 294; replication stage 1: 991 vs. 1,025; replication stage 2: 1,021 vs. 52,708). Three variants (rs10889602T/G, rs2193015T/C, rs9676191A/C) were identified as being significantly associated with high myopia in the discovery, and replication stage. rs10889602T/G is located at the third intron of phosphodiesterase 4B (PDE4B), whose functional assays were performed by comparing the effects of rs10889602T/T deletion of this risk allele on PDE4B and COL1A1 gene and protein expression levels in the rs10889602T/Tdel/del, rs10889602T/Tdel/wt, and normal control A549 cell lines. The declines in the PDE4B and COL1A1 gene expression levels were larger in the rs10889602T/T deleted A549 cells than in the normal control A549 cells (one-way ANOVA, p < 0.001). The knockdown of PDE4B by siRNA in human scleral fibroblasts led to downregulation of COL1A1. This correspondence between the declines in rs10889602 of the PDE4B gene, PDE4B knockdown, and COL1A1 protein expression levels suggest that PDE4B may be a novel high myopia susceptibility gene, which regulates myopia progression through controlling scleral collagen I expression levels. More studies are needed to determine if there is a correlation between PDE4B and high myopia in other larger sample sized cohorts.


Author(s):  
Sari Mattila ◽  
Pirjo Merilahti ◽  
Sarah Wazir ◽  
Tania Quirin ◽  
Mirko M. Maksimainen ◽  
...  

Alphaviruses are positive-strand RNA viruses causing febrile disease. Macrodomain-containing proteins, involved in ADP-ribose mediated signaling, are encoded by both host cells and several virus groups, including alphaviruses. In this study, compound MRS 2578 that targets the human MacroD1 protein inhibited Semliki Forest virus production as well as viral RNA replication and replicase protein expression. The inhibitor was similarly active in alphavirus trans -replication systems, indicating that it targets the viral RNA replication stage.


2021 ◽  
Vol 22 (13) ◽  
pp. 7071
Author(s):  
Satyavani Kaliamurthi ◽  
Gurudeeban Selvaraj ◽  
Chandrabose Selvaraj ◽  
Sanjeev Kumar Singh ◽  
Dong-Qing Wei ◽  
...  

Coronavirus disease (COVID)-19 is the leading global health threat to date caused by a severe acute respiratory syndrome coronavirus (SARS-CoV-2). Recent clinical trials reported that the use of Bruton’s tyrosine kinase (BTK) inhibitors to treat COVID-19 patients could reduce dyspnea and hypoxia, thromboinflammation, hypercoagulability and improve oxygenation. However, the mechanism of action remains unclear. Thus, this study employs structure-based virtual screening (SBVS) to repurpose BTK inhibitors acalabrutinib, dasatinib, evobrutinib, fostamatinib, ibrutinib, inositol 1,3,4,5-tetrakisphosphate, spebrutinib, XL418 and zanubrutinib against SARS-CoV-2. Molecular docking is conducted with BTK inhibitors against structural and nonstructural proteins of SARS-CoV-2 and host targets (ACE2, TMPRSS2 and BTK). Molecular mechanics-generalized Born surface area (MM/GBSA) calculations and molecular dynamics (MD) simulations are then carried out on the selected complexes with high binding energy. Ibrutinib and zanubrutinib are found to be the most potent of the drugs screened based on the results of computational studies. Results further show that ibrutinib and zanubrutinib could exploit different mechanisms at the viral entry and replication stage and could be repurposed as potential inhibitors of SARS-CoV-2 pathogenesis.


PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0251032
Author(s):  
Y-h. Taguchi ◽  
Turki Turki

The histone group added to a gene sequence must be removed during mitosis to halt transcription during the DNA replication stage of the cell cycle. However, the detailed mechanism of this transcription regulation remains unclear. In particular, it is not realistic to reconstruct all appropriate histone modifications throughout the genome from scratch after mitosis. Thus, it is reasonable to assume that there might be a type of “bookmark” that retains the positions of histone modifications, which can be readily restored after mitosis. We developed a novel computational approach comprising tensor decomposition (TD)-based unsupervised feature extraction (FE) to identify transcription factors (TFs) that bind to genes associated with reactivated histone modifications as candidate histone bookmarks. To the best of our knowledge, this is the first application of TD-based unsupervised FE to the cell division context and phases pertaining to the cell cycle in general. The candidate TFs identified with this approach were functionally related to cell division, suggesting the suitability of this method and the potential of the identified TFs as bookmarks for histone modification during mitosis.


2020 ◽  
Author(s):  
Y-H. Taguchi ◽  
Turki Turki

ABSTRACTThe histone group added to a gene sequence must be released during mitosis to halt transcription during the DNA replication stage of the cell cycle. However, the detailed mechanism of this transcription regulation remains unclear. In particular, it is not realistic to reconstruct all appropriate histone modifications throughout the genome from scratch after mitosis. Thus, it is reasonable to assume that there might be a type of “bookmark” that retains the positions of histone modifications, which can be readily restored after mitosis. We developed a novel computational approach comprising tensor decomposition (TD)-based unsupervised feature extraction (FE) to identify transcription factors (TFs) that bind to genes associated with reactivated histone modifications as candidate histone bookmarks. To the best of our knowledge, this is the first application of TD-based unsupervised FE to the cell division context and phases pertaining to the cell cycle in general. The candidate TFs identified with this approach were functionally related to cell division, suggesting the suitability of this method and the potential of the identified TFs as bookmarks for histone modification during mitosis.


2020 ◽  
Vol 16 (8) ◽  
pp. e1008760
Author(s):  
Elizabeth J. Fay ◽  
Stephanie L. Aron ◽  
Marissa G. Macchietto ◽  
Matthew W. Markman ◽  
Katharina Esser-Nobis ◽  
...  

2020 ◽  
Vol 94 (8) ◽  
Author(s):  
Ken-ichi Nakajima ◽  
Sara Guevara-Plunkett ◽  
Frank Chuang ◽  
Kang-Hsin Wang ◽  
Yuanzhi Lyu ◽  
...  

ABSTRACT Molecular mechanisms of Kaposi’s sarcoma-associated herpesvirus (KSHV) reactivation have been studied primarily by measuring the total or average activity of an infected cell population, which often consists of a mixture of both nonresponding and reactivating cells that in turn contain KSHVs at various stages of replication. Studies on KSHV gene regulation at the individual cell level would allow us to better understand the basis for this heterogeneity, and new preventive measures could be developed based on findings from nonresponding cells exposed to reactivation stimuli. Here, we generated a recombinant reporter virus, which we named “Rainbow-KSHV,” that encodes three fluorescence-tagged KSHV proteins (mBFP2-ORF6, mCardinal-ORF52, and mCherry-LANA). Rainbow-KSHV replicated similarly to a prototype reporter-KSHV, KSHVr.219, and wild-type BAC16 virus. Live imaging revealed unsynchronized initiation of reactivation and KSHV replication with diverse kinetics between individual cells. Cell fractionation revealed temporal gene regulation, in which early lytic gene expression was terminated in late protein-expressing cells. Finally, isolation of fluorescence-positive cells from nonresponders increased dynamic ranges of downstream experiments 10-fold. Thus, this study demonstrates a tool to examine heterogenic responses of KSHV reactivation for a deeper understanding of KSHV replication. IMPORTANCE Sensitivity and resolution of molecular analysis are often compromised by the use of techniques that measure the ensemble average of large cell populations. Having a research tool to nondestructively identify the KSHV replication stage in an infected cell would not only allow us to effectively isolate cells of interest from cell populations but also enable more precise sample selection for advanced single-cell analysis. We prepared a recombinant KSHV that can report on its replication stage in host cells by differential fluorescence emission. Consistent with previous host gene expression studies, our experiments reveal the highly heterogenic nature of KSHV replication/gene expression at individual cell levels. The utilization of a newly developed reporter-KSHV and initial characterization of KSHV replication in single cells are presented.


2019 ◽  
Vol 20 (4) ◽  
pp. 246-251 ◽  
Author(s):  
Leilei Xu ◽  
Zhichong Wu ◽  
Chao Xia ◽  
Nelson Tang ◽  
Jack C.Y. Cheng ◽  
...  

Background: Previous GWASs have revealed several susceptible variants associated with adolescent idiopathic scoliosis (AIS). Risk prediction based on these variants can potentially improve disease prognosis. We aimed to evaluate the combined effects of genetic factors on the development of AIS and to further develop a genetic predictive model. Methods: A total of 914 AIS patients and 1441 normal controls were included in the discovery stage, which was followed by the replication stage composed of 871 patients and 1239 controls. Genotyping assay was performed to analyze 10 previously reported susceptible variants, including rs678741 of LBX1, rs241215 of AJAP1, rs13398147 of PAX3, rs16934784 of BNC2, rs2050157 of GPR126, rs2180439 of PAX1, rs4940576 of BCL2, rs7593846 of MEIS1, rs7633294 of MAGI1 and rs9810566 of TNIK. Logistic regression analysis was performed to generate a risk predictive model. The predicted risk score was calculated for each participant in the replication stage. Results: The association of the 10 variants with AIS was successfully validated. The established model could explain approximately 7.9% of the overall variance. In the replication stage, patients were found to have a remarkably higher risk score as compared to the controls (44.2 ± 14.4 vs. 33.9 ± 12.5, p <0.001). There was a remarkably higher proportion of the risk score i.e. >40 in the patients than in the controls (59% vs. 28.9%, p <0.001). Conclusion: Risk predictive model based on the previously reported genetic variants has a remarkable discriminative power. More clinical and genetic factors need to be studied, to further improve the probability to predict the onset of AIS.


2019 ◽  
Author(s):  
Angélique Igel-Egalon ◽  
Florent Laferrière ◽  
Mohammed Moudjou ◽  
Mathieu Merzach ◽  
Tina Knäpple ◽  
...  

AbstractAggregation of misfolded forms from host-encoded proteins is key to the pathogenesis of a number of neurodegenerative disorders, including prion diseases, Alzheimer’s disease and Parkinson’s disease. In prion diseases, the cellular prion protein PrPCcan misfold into PrPScand auto-organize into conformationally distinct assemblies or strains. A plethora of observations reports the existence of PrPScstructural heterogeneity within prion strains, suggesting the emergence and coevolution of structurally distinct PrPScassemblies during prion replication in controlled environment. Such PrPScdiversification processes remain poorly understood. Although central to prion host-adaptation, structural diversification of PrPScassemblies is also a key issue for the formation of PrP conformers involved in neuronal injury. Here, we characterized the evolution of the PrPScquaternary structure during prion replicationin vivoand inbona fidecell-free amplification assays. Regardless of the strain studied, the early replication stage conduced to the preferential formation of small PrPScoligomers, thus highlighting a quaternary structural convergence phenomenon. Their evolutionary kinetics revealed the existence of a PrPC-dependent secondary templating pathway in concert with a structural rearrangement. This secondary templating pathway provides, for the first time, a mechanistic explanation for prion structural diversification during replication, a key determinant for prion adaptation on further transmission, including to other host species. The uncovered processes are also key for a better understanding of the accumulation mechanisms of other misfolded assemblies believed to propagate by a prion-like process.


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