scholarly journals Missense variants in the TNFA epitopes and their effects on interaction with therapeutic antibodies—in silico analysis

2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Tamim Ahsan ◽  
Abu Ashfaqur Sajib
Keyword(s):  
Autoimmune Diseases ◽  
In Silico ◽  
Certolizumab Pegol ◽  
Individual Variability ◽  
High Rate ◽  
Therapeutic Antibodies ◽  
Necrosis Factor Alpha ◽  
Inflammatory Reactions ◽  
Missense Variants ◽  
Therapeutic Benefits

Abstract Background Tumor necrosis factor alpha (TNFA) is an important cytokine that influences multiple biological processes. It is one of the key mediators of acute and chronic systemic inflammatory reactions and plays a central role in several autoimmune diseases. A number of approved monoclonal antibodies (mAbs) are widely used to subside these autoimmune diseases. However, there is a high rate of non-responsiveness to treatments with these mAbs. Therefore, it is important to be able to predict responses of the patients in an individualistic manner to these therapeutic antibodies before administration. In the present study, we used in silico tools to explore the effects of missense variants in the respective epitopes of four therapeutic anti-TNFA mAbs—adalimumab (ADA), certolizumab pegol (CZP), golimumab (GLM), and infliximab (IFX)—on their interactions with TNFA. Results The binding affinities of CZP and ADA to corresponding epitopes appear to be reduced by four (TNFAR131Q, TNFAE135G, TNFAR138Q, and TNFAR138W) and two (TNFAG66C and TNFAG66S) variants, respectively. The binding of GLM and IFX appears to be affected by TNFAR141S and TNFAR138W, respectively. TNFAG66C and TNFAG66S may be associated with autoimmune diseases, whereas TNFAE135G, TNFAR138W, and TNFAR141S may be pathogenic per se. Conclusion These variants may contribute to the observed inter-individual variability in response to anti-TNFA mAbs treatments and be used as markers to predict responses, and thus optimize therapeutic benefits to the patients.

scholarly journals In silico screening of TMPRSS2 SNPs that affect its binding with SARS-CoV2 spike protein and directly involved in the interaction affinity changes

2021 ◽  
Author(s):  
Fatma Nouira ◽  
Manel Hamdi ◽  
Alaeddine Redissi ◽  
Soumaya Kouidhi ◽  
Cherine Charfeddine ◽  
...  
Keyword(s):  
In Silico ◽  
Function Analysis ◽  
In Silico Analysis ◽  
Md Simulations ◽  
European Population ◽  
Individual Variability ◽  
Nucleotide Polymorphisms ◽  
S Protein ◽  
Missense Variants ◽  
Important Interaction

In this paper, we used in silico analysis to shed light on the possible interaction between TMPRSS2 and SARS-CoV2 spike (S) protein by examining the role of TMPRSS2 single nucleotide polymorphisms (SNPs) in relation with susceptibility and inter-individual variability of SARS-CoV2 infection. First, we used molecular docking of human TMPRSS2 protein to predict the binding site of TMPRSS2, especially the TMPRSS2 link loops, in order to assess the effect TMPRSS2 SNPs. The latter lead to missense variants on the interaction between TMPRSS2 and SARS-CoV2 S protein. In a second step, we further refine our analysis by performing a structure-function analysis of the complexes using PyMol software, and finally by MD simulations to validate the as-obtained results. Our findings show that 17 SNPs among the 692 natural TMPRSS2 coding variants are in positions to influence the binding of TMPRSS2 with the viral S protein. All of them give more important interaction energy as assessed by docking. Among the 17 SNPs, four missense variants E389A, K392Q, T393S and Q438E lead to "directly increasing" the interaction affinity and 2 missense variants R470I and Y416C cause it "directly decreasing". The R470I and Y416C present in African and American population, respectively. While the other 4 SNP variants (E389A; K392Q; T393S and Q438E) are present only in the European population, which could link the viral infection susceptibility to demographic, geographic and genetic factors.

An Update of In Silico Tools for the Prediction of Pathogenesis in Missense Variants

2011 ◽  
Vol 6 (2) ◽  
pp. 185-198
Author(s):  
Alejandro j. Brea-Fernandez ◽  
Marta Ferro ◽  
Ceres Fernandez-Rozadilla ◽  
Ana Blanco ◽  
Laura Fachal ◽  
...  
Keyword(s):  
In Silico ◽  
Missense Variants ◽  
In Silico Tools

scholarly journals Gene engineered mesenchymal stem cells: greater transgene expression and efficacy with minicircle vs. plasmid DNA vectors in a mouse model of acute lung injury

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Maria Florian ◽  
Jia-Pey Wang ◽  
Yupu Deng ◽  
Luciana Souza-Moreira ◽  
Duncan J. Stewart ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Transgene Expression ◽  
Vascular Inflammation ◽  
Pulmonary Inflammation ◽  
Necrosis Factor Alpha ◽  
Monocyte Chemoattractant Protein 1 ◽  
Therapeutic Benefits

Abstract Background Acute lung injury (ALI) and in its severe form, acute respiratory distress syndrome (ARDS), results in increased pulmonary vascular inflammation and permeability and is a major cause of mortality in many critically ill patients. Although cell-based therapies have shown promise in experimental ALI, strategies are needed to enhance the potency of mesenchymal stem cells (MSCs) to develop more effective treatments. Genetic modification of MSCs has been demonstrated to significantly improve the therapeutic benefits of these cells; however, the optimal vector for gene transfer is not clear. Given the acute nature of ARDS, transient transfection is desirable to avoid off-target effects of long-term transgene expression, as well as the potential adverse consequences of genomic integration. Methods Here, we explored whether a minicircle DNA (MC) vector containing human angiopoietin 1 (MC-ANGPT1) can provide a more effective platform for gene-enhanced MSC therapy of ALI/ARDS. Results At 24 h after transfection, nuclear-targeted electroporation using an MC-ANGPT1 vector resulted in a 3.7-fold greater increase in human ANGPT1 protein in MSC conditioned media compared to the use of a plasmid ANGPT1 (pANGPT1) vector (2048 ± 567 pg/mL vs. 552.1 ± 33.5 pg/mL). In the lipopolysaccharide (LPS)-induced ALI model, administration of pANGPT1 transfected MSCs significantly reduced bronchoalveolar lavage (BAL) neutrophil counts by 57%, while MC-ANGPT1 transfected MSCs reduced it by 71% (p < 0.001) by Holm-Sidak’s multiple comparison test. Moreover, compared to pANGPT1, the MC-ANGPT1 transfected MSCs significantly reduced pulmonary inflammation, as observed in decreased levels of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2). pANGPT1-transfected MSCs significantly reduced BAL albumin levels by 71%, while MC-ANGPT1-transfected MSCs reduced it by 85%. Conclusions Overall, using a minicircle vector, we demonstrated an efficient and sustained expression of the ANGPT1 transgene in MSCs and enhanced the therapeutic effect on the ALI model compared to plasmid. These results support the potential benefits of MC-ANGPT1 gene enhancement of MSC therapy to treat ARDS.

scholarly journals Truncated Non-Nuclear Transposable Elements in Grapevine: A Mini Review

2019 ◽  
Vol 50 (4) ◽  
pp. 219-227
Author(s):  
A.V. Milovanov ◽  
J. Tello ◽  
U.C.M. Anhalt ◽  
A. Forneck
Keyword(s):  
Gene Transfer ◽  
Mitochondrial Genome ◽  
Transposable Elements ◽  
Vitis Vinifera ◽  
In Silico ◽  
Gene Evolution ◽  
High Rate ◽  
Miniature Inverted Transposable Elements ◽  
High Level ◽  
Inner Region

Abstract In this mini-review we present insight to the non-nuclear transposable elements and in silico analysis of miniature inverted transposable elements (MITEs) in the grapevine mitochondrial genome. Here we report the identification of 17 truncated sequences in grapevine (Vitis vinifera L.) mitochondrial genome which expectedly belongs to the four ancient transposon families (hAT, Tc1Mariner, Mutator and PIF/Harbinger). Some sequences with a high rate of homology in chloroplast and nuclear genomes were also identified. Thus, it suggests the intercellular gene transfer between these three organelles. These partial sequences showed a high level of similitude with full MITE sequences, and they were found in their inner region, supporting their MITE origin. Further analysis revealed these sequences in other life kingdoms (including eubacteria and archaea), which indicates their ancient origin. Further research showed that 13 out of the 17 sequences are conserved domains of the genes where they are located, suggesting their contribution to gene evolution. Therefore, we suppose that more studies of nature, origin and functional meaning of these sequences and their fusion with genes are necessary. In the light of our observations it will be useful for further studies of V. vinifera genome organizing and systematics, as well as for other species.

scholarly journals A combined in silico, in vitro and clinical approach to characterise novel pathogenic missense variants in PRPF31 in retinitis pigmentosa

2018 ◽  
Author(s):  
Gabrielle Wheway ◽  
Liliya Nazlamova ◽  
Nervine Meshad ◽  
Samantha Hunt ◽  
Nicola Jackson ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
In Silico ◽  
Autosomal Dominant ◽  
Missense Variant ◽  
Incomplete Penetrance ◽  
Clinical Approach ◽  
Loss Of Function ◽  
Autosomal Dominant Retinitis Pigmentosa ◽  
Missense Variants

AbstractAt least six different proteins of the spliceosome, including PRPF3, PRPF4, PRPF6, PRPF8, PRPF31 and SNRNP200, are mutated in autosomal dominant retinitis pigmentosa (adRP). These proteins have recently been shown to localise to the base of the connecting cilium of the retinal photoreceptor cells, elucidating this form of RP as a retinal ciliopathy. In the case of loss-of-function variants in these genes, pathogenicity can easily be ascribed. In the case of missense variants, this is more challenging. Furthermore, the exact molecular mechanism of disease in this form of RP remains poorly understood.In this paper we take advantage of the recently published cryo EM-resolved structure of the entire human spliceosome, to predict the effect of a novel missense variant in one component of the spliceosome; PRPF31, found in a patient attending the genetics eye clinic at Bristol Eye Hospital. Monoallelic variants in PRPF31 are a common cause of autosomal dominant retinitis pigmentosa (adRP) with incomplete penetrance. We use in vitro studies to confirm pathogenicity of this novel variant PRPF31 c.341T>A, p.Ile114Asn.This work demonstrates how in silico modelling of structural effects of missense variants on cryo-EM resolved protein complexes can contribute to predicting pathogenicity of novel variants, in combination with in vitro and clinical studies. It is currently a considerable challenge to assign pathogenic status to missense variants in these proteins.

scholarly journals Comparison of Predictive In Silico Tools on Missense Variants in GJB2, GJB6, and GJB3 Genes Associated with Autosomal Recessive Deafness 1A (DFNB1A)

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Vera G. Pshennikova ◽  
Nikolay A. Barashkov ◽  
Georgii P. Romanov ◽  
Fedor M. Teryutin ◽  
Aisen V. Solov’ev ◽  
...  
Keyword(s):  
Clinical Significance ◽  
In Silico ◽  
Autosomal Recessive ◽  
Area Under The Curve ◽  
Roc Curves ◽  
Missense Variants ◽  
Functional Studies ◽  
Connexin Genes ◽  
Predictive Software ◽  
And Control

In silico predictive software allows assessing the effect of amino acid substitutions on the structure or function of a protein without conducting functional studies. The accuracy of in silico pathogenicity prediction tools has not been previously assessed for variants associated with autosomal recessive deafness 1A (DFNB1A). Here, we identify in silico tools with the most accurate clinical significance predictions for missense variants of the GJB2 (Cx26), GJB6 (Cx30), and GJB3 (Cx31) connexin genes associated with DFNB1A. To evaluate accuracy of selected in silico tools (SIFT, FATHMM, MutationAssessor, PolyPhen-2, CONDEL, MutationTaster, MutPred, Align GVGD, and PROVEAN), we tested nine missense variants with previously confirmed clinical significance in a large cohort of deaf patients and control groups from the Sakha Republic (Eastern Siberia, Russia): Сх26: p.Val27Ile, p.Met34Thr, p.Val37Ile, p.Leu90Pro, p.Glu114Gly, p.Thr123Asn, and p.Val153Ile; Cx30: p.Glu101Lys; Cx31: p.Ala194Thr. We compared the performance of the in silico tools (accuracy, sensitivity, and specificity) by using the missense variants in GJB2 (Cx26), GJB6 (Cx30), and GJB3 (Cx31) genes associated with DFNB1A. The correlation coefficient (r) and coefficient of the area under the Receiver Operating Characteristic (ROC) curve as alternative quality indicators of the tested programs were used. The resulting ROC curves demonstrated that the largest coefficient of the area under the curve was provided by three programs: SIFT (AUC = 0.833, p = 0.046), PROVEAN (AUC = 0.833, p = 0.046), and MutationAssessor (AUC = 0.833, p = 0.002). The most accurate predictions were given by two tested programs: SIFT and PROVEAN (Ac = 89%, Se = 67%, Sp = 100%, r = 0.75, AUC = 0.833). The results of this study may be applicable for analysis of novel missense variants of the GJB2 (Cx26), GJB6 (Cx30), and GJB3 (Cx31) connexin genes.

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