Network analysis of Dengue NS1 interacting core human proteins driving dengue pathogenesis

Current Chemical Biology ◽

10.2174/2212796816666211216115753 ◽

2021 ◽

Vol 16 ◽

Author(s):

Elakkiya Elumalai ◽

Suresh Kumar Muthuvel

Keyword(s):

Network Analysis ◽

Cathepsin L ◽

Dengue Infection ◽

Protein Translation ◽

Ras Signaling ◽

Protein Drug ◽

Core Proteins ◽

Interaction Partners ◽

Human Proteins ◽

The Common

Aim: We aimed to identify critical human proteins involved in cathepsin L regulation Background: It has been shown that Dengue Virus (DENV) NS1 activates cathepsin L (CTSL). The CTSL activates heparanase, which cleaves heparan sulfate proteoglycans and causes dengue pathogenesis. NS1 directly interacts with PTBP1 and Gab proteins. Gab protein activates the Ras signaling pathway. Still, no known direct interaction partners are linking GAB1 to cathepsin L. Objective: Our objective includes three main points.1-Network analysis of NS1 interacting human proteins 2- Identification of protein-drug and protein-disease interactions 3- Identification of core proteins involved in cathepsin L regulation. Method: We collected NS1 interacting Human proteins from DenHunt, Int-Act Molecular Interaction Database, Virus Mentha, Virus Pathogen Database and Analysis Resource (ViPR), and Virus MINT. We employed Pesca, cytohubba, and centiscape as the significant plug-ins in Cytoscape for network analysis. To study protein-diseases and protein-drugs interaction, we used NetworkAnalyst. Result: Based on the prior knowledge on the interaction of NS1 with GAB1 and PTBP1 human proteins, we found several core proteins that drive dengue pathogenesis. The proteins EED, NXF1, and MOV10, are the mediators between PTBP1 and CTSL. Similarly, DNM2, GRB2, PXN, PTPRC, and NTRK1 mediate GAB1 and PTBP1. The common first neighbors of MOV10, NXF1, and EED were identified, and the common primary pathways in all three subnetworks were mRNA processing and protein translation. The common interaction partners were considered for drug and disease network analysis. These proteins were; PARP1, NFKB2, HDAC2, SLC25A4, ATP5A1, EPN1, CTSL, UBR4, CLK3, and ARPC4. PARP1 was the highly connected node in the protein-drug network. The highest degree protein, LMNA, was associated with many diseases. The NXF1 is connected with LMNA. Here, we reported one essential protein, namely, NXF1 protein, which links PTBP1 with CTSL. The NXF1 is also connected with TPM3, which is connected to CTSL. Conclusion: We listed functionally important proteins which are involved in cathepsin L activation. Based on network properties, we proposed, NXF1 and TPM3 are the important high centrality proteins in dengue infection.

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Prediction of Protein-Protein Interactions Between Human Host and Two Mycobacterial Organisms

Computational Knowledge Discovery for Bioinformatics Research ◽

10.4018/978-1-4666-1785-8.ch010 ◽

2013 ◽

pp. 175-187

Author(s):

Oruganty Krishnadev ◽

Shveta Bisht ◽

Narayanaswamy Srinivasan

Keyword(s):

Protein Interactions ◽

Serine Proteases ◽

Cellular Membrane ◽

Human Pathogens ◽

Protein Protein Interactions ◽

Human Host ◽

Interaction Partners ◽

Human Proteins ◽

Mycobacterial Antigens ◽

Ras Signalling

The genomes of many human pathogens have been sequenced but the protein-protein interactions across a pathogen and human are still poorly understood. The authors apply a simple homology-based method to predict protein-protein interactions between human host and two mycobacterial organisms viz., M.tuberculosis and M.leprae. They focused on secreted proteins of pathogens and cellular membrane proteins to restrict to uncovering biologically significant and feasible interactions. Predicted interactions include five mycobacterial proteins of yet unknown function, thus suggesting a role for these proteins in pathogenesis. The authors predict interaction partners for secreted mycobacterial antigens such as MPT70, serine proteases and other proteins interacting with human proteins, such as toll-like receptors, ras signalling proteins and immune maintenance proteins, that are implicated in pathogenesis. These results suggest that the list of predicted interactions is suitable for further analysis and forms a useful step in the understanding of pathogenesis of these mycobacterial organisms.

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Evaluation of the Common Molecular Basis in Alzheimer’s and Parkinson’s Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms20153730 ◽

2019 ◽

Vol 20 (15) ◽

pp. 3730 ◽

Cited By ~ 3

Author(s):

Pratip Rana ◽

Edian F. Franco ◽

Yug Rao ◽

Khajamoinuddin Syed ◽

Debmalya Barh ◽

...

Keyword(s):

Network Analysis ◽

Literature Mining ◽

Extensive Literature ◽

Genome Wide ◽

Parkinson’S Diseases ◽

Epigenetic Regulator ◽

Major Genome ◽

The Common ◽

Exact Relationship ◽

Subsequent Literature

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative disorders related to aging. Though several risk factors are shared between these two diseases, the exact relationship between them is still unknown. In this paper, we analyzed how these two diseases relate to each other from the genomic, epigenomic, and transcriptomic viewpoints. Using an extensive literature mining, we first accumulated the list of genes from major genome-wide association (GWAS) studies. Based on these GWAS studies, we observed that only one gene (HLA-DRB5) was shared between AD and PD. A subsequent literature search identified a few other genes involved in these two diseases, among which SIRT1 seemed to be the most prominent one. While we listed all the miRNAs that have been previously reported for AD and PD separately, we found only 15 different miRNAs that were reported in both diseases. In order to get better insights, we predicted the gene co-expression network for both AD and PD using network analysis algorithms applied to two GEO datasets. The network analysis revealed six clusters of genes related to AD and four clusters of genes related to PD; however, there was very low functional similarity between these clusters, pointing to insignificant similarity between AD and PD even at the level of affected biological processes. Finally, we postulated the putative epigenetic regulator modules that are common to AD and PD.

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Nuclear exchange of the U1 and U2 snRNP-specific proteins.

The Journal of Cell Biology ◽

10.1083/jcb.110.4.871 ◽

1990 ◽

Vol 110 (4) ◽

pp. 871-881 ◽

Cited By ~ 14

Author(s):

R J Feeney ◽

G W Zieve

Keyword(s):

Common Core ◽

Kinetic Studies ◽

Isotopic Labeling ◽

Cell Fractionation ◽

Isolated Nuclei ◽

Core Proteins ◽

U2 Snrnp ◽

Specific Proteins ◽

The Common ◽

Nuclear Exchange

The snRNP particles include a set of common core snRNP proteins and snRNP specific proteins. In rodent cells the common core proteins are the B, D, D', E, F and G proteins in a suggested stoichiometry of B2D'2D2EFG. The additional U1- and U2-specific proteins are the 70-kD, A and C proteins and the A' and B" proteins, respectively. Previous cell fractionation and kinetic analysis demonstrated the snRNP core proteins are stored in the cytoplasm in large partially assembled snRNA-free intermediates that assemble with newly synthesized snRNAs during their transient appearance in the cytoplasm (Sauterer, R. A., R. J. Feeney, and G. W. Zieve. 1988. Exp. Cell Res. 176:344-359). This report investigates the assembly and intracellular distribution of the U1 and U2 snRNP-specific proteins. Cell enucleation and aqueous cell fractionation are used to prepare nuclear and cytoplasmic fractions and the U1- and U2-specific proteins are identified by isotopic labeling and immunoprecipitation or by immunoblotting with specific autoimmune antisera. The A, C, and A' proteins are found both assembled into mature nuclear snRNP particles and in unassembled pools in the nucleus that exchange with the assembled snRNP particles. The unassembled proteins leak from isolated nuclei prepared by detergent extraction. The unassembled A' protein sediments at 4S-6S in structures that may be multimers. The 70-kD and B" proteins are fully assembled with snRNP particles which do not leak from isolated nuclei. The kinetic studies suggest that the B" protein assembles with the U2 particle in the cytoplasm before it enters the nucleus.

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Clinical Features of Dengue Infection in Hospital for Tropical Diseases, Thailand

Asian Journal of Research in Infectious Diseases ◽

10.9734/ajrid/2018/v1i229767 ◽

2018 ◽

pp. 1-9

Author(s):

Kaung Zaw

Keyword(s):

Infectious Disease ◽

Clinical Features ◽

Dengue Infection ◽

Tropical Diseases ◽

Spontaneous Bleeding ◽

Patient Medical Record ◽

Common Infectious Disease ◽

Orbital Pain ◽

The Common ◽

The Difference

Background: Dengue infection is the common infectious disease in tropical countries caused by dengue virus, which has four serotypes (DEN 1, 2, 3 and 4). More data showed that dengue has caught worldwide attention due to its severe and fatal clinical outcome. This study aimed to describe the difference of clinical features of dengue infection between children and adults and among each dengue serotypes in Hospital for Tropical Diseases, Mahidol University, Bangkok, Thailand during 2011- 2013. Study Design: This study was a hospital-based retrospective. In- patient medical record of 50 children and 148 adults with clinical and laboratory confirmed dengue infection and admitted to Hospital for Tropical Diseases, Mahidol University, Bangkok, Thailand during July 2011- June 2013 were reviewed. Results: We found that headache and myalgia/arthalgia were found in most of the cases (182/198, 91.9%; 178/198, 89.9%, respectively). Epistaxis and hypermenorrhea were more common in children. Retro-orbital pain was more common in adult. The spontaneous bleeding tended to be more common in children than adults. DEN2 (48.9%) was the most common serotype followed by DEN3 (23.7%), DEN1 (22.2%) and DEN4 (5.2%). Regarding dengue serotypes, subjects infected with DEN1 had more shock, hypermenorrhea and epistaxis than others. Lymphadenopathy and rash during febrile stage were found in subjects infected with DEN2 only. Subjects infected with DEN4 infection had more retro-orbital pain and petechiae than others. Conclusion: The results show secondary dengue infection was most common and the most prevalent dengue serotype was serotype 2. Typical symptoms in adult involved retro orbital pain, nausea and arthralgia while children might suffer epistaxis and hypermenorrhea. We also found that DEN 1 tended to have more mucosa bleeding and shock. In DEN 4 infection, subjects had more retro-orbital pain and skin bleeding.

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Brothers in arms: proBDNF/BDNF and sAPPα/Aβ-signaling and their common interplay with ADAM10, TrkB, p75NTR, sortilin, and sorLA in the progression of Alzheimer’s disease

Biological Chemistry ◽

10.1515/hsz-2021-0330 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Simone Eggert ◽

Stefan Kins ◽

Kristina Endres ◽

Tanja Brigadski

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neuronal Death ◽

Common Features ◽

Interaction Partners ◽

The Central Nervous System ◽

Bdnf Signaling ◽

The Common ◽

The Brain

Abstract Brain-derived neurotrophic factor (BDNF) is an important modulator for a variety of functions in the central nervous system (CNS). A wealth of evidence, such as reduced mRNA and protein level in the brain, cerebrospinal fluid (CSF), and blood samples of Alzheimer’s disease (AD) patients implicates a crucial role of BDNF in the progression of this disease. Especially, processing and subcellular localization of BDNF and its receptors TrkB and p75 are critical determinants for survival and death in neuronal cells. Similarly, the amyloid precursor protein (APP), a key player in Alzheimer’s disease, and its cleavage fragments sAPPα and Aβ are known for their respective roles in neuroprotection and neuronal death. Common features of APP- and BDNF-signaling indicate a causal relationship in their mode of action. However, the interconnections of APP- and BDNF-signaling are not well understood. Therefore, we here discuss dimerization properties, localization, processing by α- and γ-secretase, relevance of the common interaction partners TrkB, p75, sorLA, and sortilin as well as shared signaling pathways of BDNF and sAPPα.

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PTPN11 and RAS Gene Mutation Pattern Identifies an Unique Feature of Upregulated RAS Function in Infant ALL.

Blood ◽

10.1182/blood.v104.11.996.996 ◽

2004 ◽

Vol 104 (11) ◽

pp. 996-996

Author(s):

Giovanni Cazzaniga ◽

Simone Martinelli ◽

Monique L. den Boer ◽

Lilia Corral ◽

Monica Spinelli ◽

...

Keyword(s):

Cell Population ◽

Gene Mutations ◽

Genetic Alterations ◽

Ras Signaling ◽

Ras Gene ◽

Ras Pathway ◽

Exon 1 ◽

Pediatric All ◽

The Common ◽

Genetic Events

Abstract Point mutations affecting RAS GTPase activity promote upregulation of RAS signaling, and are among the most common genetic alterations in human cancers. Oncogenic mutations in NRAS and KRAS2 genes are found with variable prevalence in hematological malignancies, including ALL. Upregulation of RAS signaling can also results from molecular lesions in genes coding transducers controlling RAS function. We recently provided evidence that PTPN11 is mutated in approximately one-third of pediatric ALL cases. Significantly, while PTPN11 mutations appeared to be preferentially associated with the common immunophenotype, mutations in NRAS or KRAS2 were uniformly distributed among the B-cell precursor ALL subtypes. Very few are the data on RAS pathway status in pediatric ALL patients aged <1 year (Infant). Infant ALL is a rare subgroup of leukemia peculiar for several characteristics, mainly related to a possible origin from a not-fully committed stem cell. In order to explore whether alterations of RAS signaling may identify specific subgroups within this heterogeneous patient population, we analyzed 87 Infant cases prospectively enrolled in the Interfant-99 International ALL protocol. This is the largest series of Infant ALL analyzed for alteration of the RAS pathway. PTPN11 (exon 3 and 13), NRAS (exon 1 and 2), and KRAS2 (exon 1 and 2) mutation analysis was performed by DHPLC analysis and direct sequencing. None of the 87 Infant cases carried a PTPN11 somatic mutation. By contrast, a high prevalence of mutations affecting NRAS and KRAS2 was observed (approximately 30%). Thirteen cases (14.9%) were positive for a mutation in exon 1 (codons 12 and 13, 10 cases, 11.5%) or exon 2 (codon 61, 3 cases, 3.4%) of the NRAS gene. Seventeen cases (19.5%) carried a variety of exon 1 KRAS2 mutations: codons 12 and 13, n=13 (14.9% of total); insAGC(30–32), n=1; G(40)C, n=1; C(53)A, n=1; G(57)C, n=1. Interestingly, in 9/27 cases (33.3% of RAS mutated cases, 10.3% of total) DHPLC and sequencing consistently showed the presence of the RAS mutation only in a fraction (10 to 40%) of the blast cells population. In one additional case a KRAS2 mutation was observed in a subset of cells along with a full NRAS mutation. In two more cases mutations affecting NRAS and KRAS2 coexisted on the same patient; in both cases the mutations were representative of a subgroup of the total cell population. In conclusion: differently from older children, PTPN11 gene mutations are a rare event in infant ALL. This could be related to the low incidence of the “common” immunophenotype in Infants. By contrast, the overall incidence of RAS gene mutations is high, accounting for about 30% of cases. Interestingly, in 10% of cases a mutation (or even more than one) was found in a fraction of the blast cell population. This could reflect the fact that RAS mutations were secondary to other genetic events, and in any case related to the oligoclonal characteristic of this age-specific ALL subgroup. The prognostic effect of these genetic events must be evaluated in a longer follow up time of prospective series of patient, as in the Interfant Consortium.

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Functional Constraints on Replacing an Essential Gene with Its Ancient and Modern Homologs

mBio ◽

10.1128/mbio.01276-17 ◽

2017 ◽

Vol 8 (4) ◽

Cited By ~ 19

Author(s):

Betül Kacar ◽

Eva Garmendia ◽

Nurcan Tuncbag ◽

Dan I. Andersson ◽

Diarmaid Hughes

Keyword(s):

Essential Gene ◽

Elongation Factor ◽

Network Connectivity ◽

Protein Translation ◽

Protein Activity ◽

E Coli ◽

Functional Conservation ◽

Interaction Partners ◽

Multiple Interaction ◽

Successful Transfer

ABSTRACTGenes encoding proteins that carry out essential informational tasks in the cell, in particular where multiple interaction partners are involved, are less likely to be transferable to a foreign organism. Here, we investigated the constraints on transfer of a gene encoding a highly conserved informational protein, translation elongation factor Tu (EF-Tu), by systematically replacing the endogenoustufAgene in theEscherichia coligenome with its extant and ancestral homologs. The extant homologs representedtufvariants from both near and distant homologous organisms. The ancestral homologs represented phylogenetically resurrectedtufsequences dating from 0.7 to 3.6 billion years ago (bya). Our results demonstrate that all of the foreigntufgenes are transferable to theE. coligenome, provided that an additional copy of the EF-Tu gene,tufB, remains present in theE. coligenome. However, when thetufBgene was removed, only the variants obtained from the gammaproteobacterial family (extant and ancestral) supported growth which demonstrates the limited functional interchangeability ofE. coli tufwith its homologs. Relative bacterial fitness correlated with the evolutionary distance of the extanttufhomologs inserted into theE. coligenome. This reduced fitness was associated with reduced levels of EF-Tu and reduced rates of protein synthesis. Increasing the expression oftufpartially ameliorated these fitness costs. In summary, our analysis suggests that the functional conservation of protein activity, the amount of protein expressed, and its network connectivity act to constrain the successful transfer of this essential gene into foreign bacteria.IMPORTANCEHorizontal gene transfer (HGT) is a fundamental driving force in bacterial evolution. However, whether essential genes can be acquired by HGT and whether they can be acquired from distant organisms are very poorly understood. By systematically replacingtufwith ancestral homologs and homologs from distantly related organisms, we investigated the constraints on HGT of a highly conserved gene with multiple interaction partners. The ancestral homologs represented phylogenetically resurrectedtufsequences dating from 0.7 to 3.6 bya. Only variants obtained from the gammaproteobacterial family (extant and ancestral) supported growth, demonstrating the limited functional interchangeability ofE. coli tufwith its homologs. Our analysis suggests that the functional conservation of protein activity, the amount of protein expressed, and its network connectivity act to constrain the successful transfer of this essential gene into foreign bacteria.

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A catalogue of putative HIV-1 protease host cell substrates

Biological Chemistry ◽

10.1515/hsz-2012-0168 ◽

2012 ◽

Vol 393 (9) ◽

pp. 915-931 ◽

Cited By ~ 16

Author(s):

Francis Impens ◽

Evy Timmerman ◽

An Staes ◽

Kathleen Moens ◽

Kevin K. Ariën ◽

...

Keyword(s):

Large Scale ◽

Viral Protease ◽

Peptide Substrates ◽

Immunodeficiency Virus ◽

Interaction Partners ◽

Unbiased Manner ◽

Human Proteins ◽

Wide Scale ◽

Hiv 1

Abstract Processing of human immunodeficiency virus (HIV) proteins by the HIV-1 protease is essential for HIV infectivity. In addition, several studies have revealed cleavage of human proteins by this viral protease during infection; however, no large-scale HIV-1 protease degradomics study has yet been performed. To identify putative host substrates in an unbiased manner and on a proteome-wide scale, we used positional proteomics to identify peptides reporting protein processing by the HIV-1 protease, and a catalogue of over 120 cellular HIV-1 protease substrates processed in vitro was generated. This catalogue includes previously reported substrates as well as recently described interaction partners of HIV-1 proteins. Cleavage site alignments revealed a specificity profile in good correlation with previous studies, even though the ELLE consensus motif was not cleaved efficiently when incorporated into peptide substrates due to subsite cooperativity. Our results are further discussed in the context of HIV-1 infection and the complex substrate recognition by the viral protease.

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Common Ownership in the U.S. Pharmaceutical Industry: A Network Analysis

The Antitrust Bulletin ◽

10.1177/0003603x20985796 ◽

2021 ◽

Vol 66 (1) ◽

pp. 68-99

Author(s):

Albert Banal-Estañol ◽

Melissa Newham ◽

Jo Seldeslachts

Keyword(s):

Network Analysis ◽

Pharmaceutical Industry ◽

Generic Drugs ◽

The Other ◽

New Drugs ◽

Common Ownership ◽

The Common ◽

The One ◽

The U.S ◽

Over Time

We investigate patterns in common ownership networks between firms that are active in the U.S. pharmaceutical industry for the period 2004–2014. Our main findings are that “brand firms”—that is, firms that have research and development capabilities and launch new drugs—exhibit relatively dense common ownership networks with each other that further increase significantly in density over time, whereas the network of “generic firms”—that is, firms that primarily specialize in developing and launching generic drugs—is much sparser and stays that way over the span of our sample. Finally, when considering the common ownership links between brands firms, on the one hand, and generic firms, on the other, we find that brand firms have become more connected to generic firms over time. We discuss the potential antitrust implications of these findings.

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