Sequence-Based Structural B-cell Epitope Prediction by Using Two Layer SVM Model and Association Rule Features

(E-pub Ahead of Print)

Author(s): Jehn-Hwa Kuo, Chi-Chang Chang*, Chi-Wei Chen, Heng-Hao Liang, Chih-Yen Chang, Yen-Wei Chu*.

Journal Name: Current Bioinformatics

Abstract:

Background: Immune reaction is the most important defense mechanism for destroying invading pathogens in our body, and the epitope is the position of the antigen–antibody interaction on pathogenic proteins.

Objective: The majority of epitopes are structural; however, the existing sequence-based predicting websites still have several methods to improve the predicting performance. Therefore, in this study, we used SVM as a machine learning tool to predict the epitope based on protein sequences.

Method: First, we built five SVM models in the first layer according to five features, including binary composition, position-specific scoring matrix, secondary structure, accessible surface area, and association rule, and then chose the patterns that exhibited the best performance in each model. Second, using the confidence score of the first-layer models as the input value for the SVM model in the second layer, that SVM model was integrated into the first-layer SVM models for improving the predicting accuracy.

Results: The final prediction model was able to achieve up to 63% accuracy in predicting epitope results, and the predicting performance was better than that achieved by the existing predicting websites.

Conclusion: Finally, a case study using a two-subunit cytochrome c oxidase of Paracoccus denitrificans was tested, achieving an accuracy of up to 66%.

Keywords: structural epitope, support vector machines, association rule, position-specific scoring matristructural epitope, position-specific scoring matrix

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DOI: 10.2174/1574893614666181123155831
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Systematic Scrutinisation of Vital Factors for Fabrication and Evaluation of PGS-MCC Based Drug Loaded Pellets by Extrusion Spheronization Technique

Author(s): Hardik Rana, Vaishali Thakkar*, Kalpana Mudgal, Mukesh Gohel, Lalji Baldania, Mansi Dholakia, Tejal Gandhi.

Journal Name: Current Drug Therapy

Volume 14 , Issue 2 , 2019

Graphical Abstract:


Abstract:

Objective: The prime objective was to formulate pellet formulation incorporating a newer extrusion- pelletisation aid, Pregelatinised Starch (PGS) and to scrutinise the factors that can affect the quality of the pellets and to overcome the slower disintegration of Microcrystaline Cellulose (MCC).

Methods: Pellets were prepared initially using PGS, MCC, water, ethanol, HPMC K 4 M and Febuxostat was employed as model drug. Optimisation of formulation was done by employing Quality by design (QbD) and Design of experiment (DoE) approach. Ratio of PGS and MCC, ratio of binder and spheronisation speed were selected as independent variables and disintegration time and % cumulative drug release as dependent variables. In vitro in vivo correlation of the optimised batch was carried out using Wagner nelson method. Incompatibility studies have indicated compatibility of drug and excipients.

Results: From the experiments, it was proved that the batch comprising 3:1 ratio of PGS and MCC, 1:1 binder solution and 1500 speed yielded good pellets with decreased disintegration time and improved dissolution rate as compared to pure Febuxostat. IVIVC studies indicated one to one correlation between in vitro and in vivo parameters.

Conclusion: Pellets with good quality, minimum disintegration time and improved dissolution of model drug were successfully prepared with maximum amount of PGS. Optimisation using QbD approach was worth fruitful that affected the quality of pellets.

Keywords: Pellets, pregelatinised starch, MCC, immediate release, convolution, IVIVC.

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VOLUME: 14
ISSUE: 2
Year: 2019
Page: [168 - 182]
Pages: 15
DOI: 10.2174/1574885514666181123152641
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ERK/MAP Kinase Activation is Evident in Activated Microglia of the Striatum and Substantia Nigra in an Acute and Chronically-Induced Mouse Model of Parkinson’s Disease

Author(s): Sumit Sarkar*, Edward Lu, James Raymick, Joseph Hanig, Qiang Gu.

Journal Name: Current Neurovascular Research

Volume 15 , Issue 4 , 2018

Abstract:

Introduction: Parkinson’s Disease (PD) is a debilitating, age-related disorder characterized by selective degeneration of dopaminergic neurons in the midbrain substantia nigra (SNc). Dopaminergic neurons originating in the midbrain project to the striatum (Caudate-putamen-CPU). Although studies have suggested that the extracellular signal-regulated kinase ½ (ERK ½) in the brain is activated after 1-Methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP) exposure, to our knowledge no study has yet been done to demonstrate whether such activation occurs in neurons or in glia.

Material and Methods: In the current study, we utilized both an acute and a repeat dose mouse model of PD using the neurotoxicant MPTP as the causative agent. Immunohistochemical studies using phospho ERK ½ antibody suggested that ERK ½ activation takes place in the striatum (CPU) and SNc of both animal models. Moreover, double immunolabeling studies using phospho ERK ½ and the microglial marker, CD11b or the astrocyte marker, Glial Fibrillary Acidic Protein (GFAP) suggested that the phospho ERK ½ was present exclusively in the microglia and not in the astrocytes.

Results: Western Blot results suggested that there were no alterations in ERK in either MPTPtreated animals or in control animals; however, phospho ERK ½ was found to be significantly increased in the striatum and SNc in both acute chronic mouse PD models. Tyrosine Hydroxylase (TH) immunolabeling revealed significant decreases in dopaminergic neurons in the SNc in both animal models’ concomitant with activation of microglia and ERK activation.

Conclusion: These observations suggest that ERK activation takes place following MPTP treatment and that activation of ERK occurs primarily in the microglia. The data provided also suggest that ERK activation may be involved in transcriptional activation of microglia following neurotoxicant insults.

Keywords: ERK, pERK, microglia, Parkinson's Disease, striatum, Alzheimer's Disease (AD).

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VOLUME: 15
ISSUE: 4
Year: 2018
Page: [336 - 344]
Pages: 9
DOI: 10.2174/1567202616666181123152601
Price: $58

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Bradykinin Receptors in Ischemic Injury

Author(s): Min Tang*, Fangping He, Li Ma, Ping Liu, Jianwen Wang, Xiongchao Zhu.

Journal Name: Current Neurovascular Research

Volume 15 , Issue 4 , 2018

Abstract:

Bradykinin (BK) is a major kinin substance in the Kallikrein-Kinin System (KKS) that acts in conjunction with target cell bradykinin receptors and is involved in a variety of systems and organs. Functional regulation and pathophysiological processes such as cardiovascular, renal, central nervous system regulation, glucose metabolism, cell proliferation, smooth muscle contraction, inflammation, pain, shock, and tissue damage processes, etc. The role and mechanism of receptors in the mediation of ischemic injury in tissues was reviewed.

Keywords: Kallikrein-Kinin System (KKS), Bradykinin (BK), B1 Receptor (B1R), B2 Receptor (B2R), myocardial ischemia, ischemia/reperfusion, hypoxia/reperfusion, angiogenesis, apoptosis.

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VOLUME: 15
ISSUE: 4
Year: 2018
Page: [359 - 366]
Pages: 8
DOI: 10.2174/1567202616666181123151629
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Elevated Serum Human Cytomegalovirus IgM Levels in the Acute Phase of Ischemic Stroke are Associated with Increased Risk of Death and Major Disability

Author(s): Chenhuan Zhang, Ping Huang, Peipei Zhang, Mo Zhou, Ya Gao, Yonghong Zhang, Yumei Guo, Liying Lv, Tan Xu*.

Journal Name: Current Neurovascular Research

Volume 15 , Issue 4 , 2018

Abstract:

Background: There was a lack of studies on the association between Human Cytomegalovirus (HCMV) infection and prognosis of ischemic stroke, although it was indicated that human cytomegalovirus DNA has played a role in several cardiovascular disorders.

Objective: To examine the association between HCMV IgM levels in the acute phase and death and major disability after 2 weeks of acute ischemic stroke.

Methods: Serum HCMV IgM levels were measured in 1150 participants in China. Study outcome data on major disability and combined outcome of death and major disability were collected at 2 weeks after stroke onset or hospital discharge.

Results: After 2 weeks of follow-up, 351 participants (30.52%) suffered from a major disability or died. Serum HCMV IgM was correlated with the combined outcome of death and major disability significantly after adjustment confounding factors. For example, the highest quartile of HCMV IgM was related to an odds ratio (95% confidence interval) of 1.84 (1.12-3.11) for the combined outcome. Risk prediction of the combined outcome was improved by the addition of serum HCMV IgM to conventional risk factors (net reclassification index 25.41%, p=0.0002; integrated discrimination improvement 0.70%, p=0.04377).

Conclusions: Elevated serum HCMV IgM levels in the acute phase of ischemic stroke were correlated with increased risk of combined outcome of death and major disability, indicating that serum HCMV IgM could be an important predictive factor for poor prognosis of ischemic stroke.

Keywords: Ischemic stroke, China, human cytomegalovirus, infection, population-based study, prognosis.

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VOLUME: 15
ISSUE: 4
Year: 2018
Page: [305 - 311]
Pages: 7
DOI: 10.2174/1567202616666181123150917
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Insights into Ebola Virus VP35 and VP24 Interferon Inhibitory Functions and their Initial Exploitation as Drug Targets

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Author(s): Elisa Fanunza, Aldo Frau, Angela Corona, Enzo Tramontano*.

Journal Name: Infectious Disorders - Drug Targets
(Formerly Current Drug Targets - Infectious Disorders)

Abstract:

Upon viral infection, the interferon (IFN) system triggers potent antiviral mechanisms limiting viral growth and spread. Hence, to sustain their infection, viruses evolved efficient counteracting strategies to evade IFN control. Ebola virus (EBOV), member of the family Filoviridae, is one of the most virulent and deadly pathogen ever faced by humans. The etiological agent of the Ebola Virus Disease (EVD), EBOV can be undoubtedly considered the perfect example of a powerful inhibitor of the host organism immune response activation. Particularly, the efficacious suppression of the IFN cascade contributes to disease progression and severity. Among the EBOVencoded proteins, the Viral Proteins 35 (VP35) and 24 (VP24) are responsible for the EBOV extreme virulence, representing the core of such inhibitory function through which EBOV determines its very effective shield to the cellular immune defenses. VP35 inhibits the activation of the cascade leading to IFN production, while VP24 inhibits the activation of the IFN-stimulated genes. A number of studies demonstrated that both VP35 and VP24 is validated target for drug development. Insights into the structural characteristics of VP35 and VP24 domains revealed crucial pockets exploitable for drug development. Considered the lack of therapy for EVD, restoring the immune activation is a promising approach for drug development. In the present review, we summarize the importance of VP35 and VP24 proteins in counteracting the host IFN cellular response and discuss their potential as druggable viral targets as a promising approach toward attenuation of EBOV virulence.

Keywords: Ebola virus, Interferon, IFN production, IFN signaling, VP35, VP24, small molecules and FDA approved drugs.

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DOI: 10.2174/1871526519666181123145540
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Acknowledgements to Reviewers

Author(s): .

Journal Name: Current Green Chemistry

Volume 5 , Issue 3 , 2018

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VOLUME: 5
ISSUE: 3
Year: 2018
Page: [198 - 198]
Pages: 1
DOI: 10.2174/221334610503181123143549

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Meet Our Editorial Board Member

Author(s): Luigi Pasqua.

Journal Name: Current Green Chemistry

Volume 5 , Issue 3 , 2018

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VOLUME: 5
ISSUE: 3
Year: 2018
Page: [136 - 137]
Pages: 2
DOI: 10.2174/221334610503181123143506

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Microwave Irradiation as a Substitute for Catalysts; Case Studies from Organophosphorus Chemistry

Author(s): György Keglevich*.

Journal Name: Current Green Chemistry

Volume 5 , Issue 3 , 2018

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VOLUME: 5
ISSUE: 3
Year: 2018
Page: [131 - 135]
Pages: 5
DOI: 10.2174/221334610503181123143409

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Current Green Chemistry

Editor-in-Chief:

György Keglevich
Budapest University of Technology and Economics
Budapest
Hungary

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