Multi-Omics and Integrated Network Approach to Unveil Evolutionary Patterns, Mutational Hotspots, Functional Crosstalk and Regulatory Interactions in SARS-CoV-2

AbstractSARS-CoV-2 responsible for the pandemic of the Severe Acute Respiratory Syndrome resulting in infections and death of millions worldwide with maximum cases and mortality in USA. The current study focuses on understanding the population specific variations attributing its high rate of infections in specific geographical regions which may help in developing appropriate treatment strategies for COVID-19 pandemic. Rigorous phylogenetic network analysis of 245 complete SARS-CoV-2 genomes inferred five central clades named a (ancestral), b, c, d and e (subtype e1 & e2) showing both divergent and linear evolution types. The clade d & e2 were found exclusively comprising of USA strains with highest known mutations. Clades were distinguished by ten co-mutational combinations in proteins; Nsp3, ORF8, Nsp13, S, Nsp12, Nsp2 and Nsp6 generated by Amino Acid Variations (AAV). Our analysis revealed that only 67.46 % of SNP mutations were carried by amino acid at phenotypic level. T1103P mutation in Nsp3 was predicted to increase the protein stability in 238 strains except six strains which were marked as ancestral type; whereas com (P5731L & Y5768C) in Nsp13 were found in 64 genomes of USA highlighting its 100% co-occurrence. Docking study highlighted mutation (D7611G) caused reduction in binding of Spike proteins with ACE2, but it also showed better interaction with TMPRSS2 receptor which may contribute to its high transmissibility in USA strains. In addition, we found host proteins, MYO5A, MYO5B & MYO5C had maximum interaction with viral hub proteins (Nucleocapsid, Spike & Membrane). Thus, blocking the internalization pathway by inhibiting MYO-5 proteins which could be an effective target for COVID-19 treatment. The functional annotations of the Host-Pathogen Interaction (HPI) network were found to be highly associated with hypoxia and thrombotic conditions confirming the vulnerability and severity of infection in the patients. We also considered the presence of CpG islands in Nsp1 and N proteins which may confers the ability of SARS-CoV-2 to enter and trigger methyltransferase activity inside host cell.

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Comparative Genomics and Integrated Network Approach Unveiled Undirected Phylogeny Patterns, Co-mutational Hot Spots, Functional Cross Talk, and Regulatory Interactions in SARS-CoV-2

mSystems ◽

10.1128/msystems.00030-21 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Vipin Gupta ◽

Shazia Haider ◽

Mansi Verma ◽

Nirjara Singhvi ◽

Kalaisaran Ponnusamy ◽

...

Keyword(s):

United States ◽

Comparative Genomics ◽

Cpg Islands ◽

Amino Acid Level ◽

The United States ◽

High Rate ◽

Antiviral Protein ◽

Integrated Network ◽

Geographical Regions ◽

Custom Made

ABSTRACT The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has resulted in 92 million cases in a span of 1 year. The study focuses on understanding population-specific variations attributing its high rate of infections in specific geographical regions particularly in the United States. Rigorous phylogenomic network analysis of complete SARS-CoV-2 genomes (245) inferred five central clades named a (ancestral), b, c, d, and e (subtypes e1 and e2). Clade d and subclade e2 were found exclusively comprised of U.S. strains. Clades were distinguished by 10 co-mutational combinations in Nsp3, ORF8, Nsp13, S, Nsp12, Nsp2, and Nsp6. Our analysis revealed that only 67.46% of single nucleotide polymorphism (SNP) mutations were at the amino acid level. T1103P mutation in Nsp3 was predicted to increase protein stability in 238 strains except for 6 strains which were marked as ancestral type, whereas co-mutation (P409L and Y446C) in Nsp13 were found in 64 genomes from the United States highlighting its 100% co-occurrence. Docking highlighted mutation (D614G) caused reduction in binding of spike proteins with angiotensin-converting enzyme 2 (ACE2), but it also showed better interaction with the TMPRSS2 receptor contributing to high transmissibility among U.S. strains. We also found host proteins, MYO5A, MYO5B, and MYO5C, that had maximum interaction with viral proteins (nucleocapsid [N], spike [S], and membrane [M] proteins). Thus, blocking the internalization pathway by inhibiting MYO5 proteins which could be an effective target for coronavirus disease 2019 (COVID-19) treatment. The functional annotations of the host-pathogen interaction (HPI) network were found to be closely associated with hypoxia and thrombotic conditions, confirming the vulnerability and severity of infection. We also screened CpG islands in Nsp1 and N conferring the ability of SARS-CoV-2 to enter and trigger zinc antiviral protein (ZAP) activity inside the host cell. IMPORTANCE In the current study, we presented a global view of mutational pattern observed in SARS-CoV-2 virus transmission. This provided a who-infect-whom geographical model since the early pandemic. This is hitherto the most comprehensive comparative genomics analysis of full-length genomes for co-mutations at different geographical regions especially in U.S. strains. Compositional structural biology results suggested that mutations have a balance of opposing forces affecting pathogenicity suggesting that only a few mutations are effective at the translation level. Novel HPI analysis and CpG predictions elucidate the proof of concept of hypoxia and thrombotic conditions in several patients. Thus, the current study focuses the understanding of population-specific variations attributing a high rate of SARS-CoV-2 infections in specific geographical regions which may eventually be vital for the most severely affected countries and regions for sharp development of custom-made vindication strategies.

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Comparative Genomic Analysis of Rapidly Evolving SARS-CoV-2 Viruses Reveal Mosaic Pattern of Phylogeographical Distribution

10.1101/2020.03.25.006213 ◽

2020 ◽

Cited By ~ 3

Author(s):

Roshan Kumar ◽

Helianthous Verma ◽

Nirjara Singhvi ◽

Utkarsh Sood ◽

Vipin Gupta ◽

...

Keyword(s):

Amino Acid ◽

Treatment Strategies ◽

Genomic Analysis ◽

Viral Proteins ◽

Comparative Genomic ◽

The Novel ◽

Nucleotide Polymorphisms ◽

Human Interactome ◽

Geographical Regions ◽

The Usa

AbstractThe Coronavirus Disease-2019 (COVID-19) that started in Wuhan, China in December 2019 has spread worldwide emerging as a global pandemic. The severe respiratory pneumonia caused by the novel SARS-CoV-2 has so far claimed more than 60,000 lives and has impacted human lives worldwide. However, as the novel SARS-CoV-2 displays high transmission rates, their underlying genomic severity is required to be fully understood. We studied the complete genomes of 95 SARS-CoV-2 strains from different geographical regions worldwide to uncover the pattern of the spread of the virus. We show that there is no direct transmission pattern of the virus among neighboring countries suggesting that the outbreak is a result of travel of infected humans to different countries. We revealed unique single nucleotide polymorphisms (SNPs) in nsp13-16 (ORF1b polyprotein) and S-Protein within 10 viral isolates from the USA. These viral proteins are involved in RNA replication, indicating highly evolved viral strains circulating in the population of USA than other countries. Furthermore, we found an amino acid addition in nsp16 (mRNA cap-1 methyltransferase) of the USA isolate (MT188341) leading to shift in amino acid frame from position 2540 onwards. Through the construction of SARS-CoV-2-human interactome, we further revealed that multiple host proteins (PHB, PPP1CA, TGF-β, SOCS3, STAT3, JAK1/2, SMAD3, BCL2, CAV1 & SPECC1) are manipulated by the viral proteins (nsp2, PL-PRO, N-protein, ORF7a, M-S-ORF3a complex, nsp7-nsp8-nsp9-RdRp complex) for mediating host immune evasion. Thus, the replicative machinery of SARS-CoV-2 is fast evolving to evade host challenges which need to be considered for developing effective treatment strategies.

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An Unbiased Predictive Model to Detect DNA Methylation Propensity of CpG Islands in the Human Genome

Current Bioinformatics ◽

10.2174/1574893615999200724145835 ◽

2020 ◽

Vol 15 ◽

Author(s):

Dicle Yalcin ◽

Hasan H. Otu

Keyword(s):

Model Building ◽

De Novo ◽

Cpg Islands ◽

Treatment Strategies ◽

Area Under The Curve ◽

Global Methylation ◽

Sequence Features ◽

A Genome ◽

Combined Features ◽

Epigenetic Repression

Background: Epigenetic repression mechanisms play an important role in gene regulation, specifically in cancer development. In many cases, a CpG island’s (CGI) susceptibility or resistance to methylation are shown to be contributed by local DNA sequence features. Objective: To develop unbiased machine learning models–individually and combined for different biological features–that predict the methylation propensity of a CGI. Methods: We developed our model consisting of CGI sequence features on a dataset of 75 sequences (28 prone, 47 resistant) representing a genome-wide methylation structure. We tested our model on two independent datasets that are chromosome (132 sequences) and disease (70 sequences) specific. Results: We provided improvements in prediction accuracy over previous models. Our results indicate that combined features better predict the methylation propensity of a CGI (area under the curve (AUC) ~0.81). Our global methylation classifier performs well on independent datasets reaching an AUC of ~0.82 for the complete model and an AUC of ~0.88 for the model using select sequences that better represent their classes in the training set. We report certain de novo motifs and transcription factor binding site (TFBS) motifs that are consistently better in separating prone and resistant CGIs. Conclusion: Predictive models for the methylation propensity of CGIs lead to a better understanding of disease mechanisms and can be used to classify genes based on their tendency to contain methylation prone CGIs, which may lead to preventative treatment strategies. MATLAB and Python™ scripts used for model building, prediction, and downstream analyses are available at https://github.com/dicleyalcin/methylProp_predictor.

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Perspectives on the Therapeutic Benefits of Arginine Supplementation in Cancer Treatment

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530319666190116121451 ◽

2019 ◽

Vol 19 (7) ◽

pp. 913-920

Author(s):

Fabiani L. R. Beal ◽

Pedro R. Beal ◽

Juliana R. Beal ◽

Natan Carvalho-Neves ◽

Octávio L. Franco ◽

...

Keyword(s):

Amino Acid ◽

Side Effects ◽

Cancer Treatment ◽

Treatment Strategies ◽

Endothelial Permeability ◽

The Elderly ◽

Therapeutic Benefits ◽

Cell Growth And Differentiation ◽

The Cost ◽

Arginine Supplementation

Background: Arginine is considered a semi-essential amino acid in healthy adults and the elderly. This amino acid seems to improve the immune system, stimulate cell growth and differentiation, and increase endothelial permeability, among other effects. For those reasons, it has been theorized that arginine supplementation may be used as an adjuvant to conventional cancer therapy treatments. Objective: This review aims to evaluate the existing knowledge of the scientific community on arginine supplementation in order to improve the efficacy of current cancer treatment. Results: Despite the continued efforts of science to improve treatment strategies, cancer remains one of the greatest causes of death on the planet in adults and elderly people. Chemo and radiotherapy are still the most effective treatments but at the cost of significant side effects. Conclusion: Thus, new therapeutic perspectives have been studied in recent years, to be used in addition to traditional treatments or not, seeking to treat or even cure the various types of cancer with fewer side effects.

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Molecular Imaging of Brain Tumor-Associated Epilepsy

Diagnostics ◽

10.3390/diagnostics10121049 ◽

2020 ◽

Vol 10 (12) ◽

pp. 1049

Author(s):

Csaba Juhász ◽

Sandeep Mittal

Keyword(s):

Brain Tumor ◽

Amino Acid ◽

Brain Tumors ◽

Treatment Strategies ◽

Amino Acid Uptake ◽

Seizure Outcome ◽

Acid Uptake ◽

Positron Emission ◽

Oncology Practice ◽

Glioneuronal Tumors

Epilepsy is a common clinical manifestation and a source of significant morbidity in patients with brain tumors. Neuroimaging has a pivotal role in neuro-oncology practice, including tumor detection, differentiation, grading, treatment guidance, and posttreatment monitoring. In this review, we highlight studies demonstrating that imaging can also provide information about brain tumor-associated epileptogenicity and assist delineation of the peritumoral epileptic cortex to optimize postsurgical seizure outcome. Most studies focused on gliomas and glioneuronal tumors where positron emission tomography (PET) and advanced magnetic resonance imaging (MRI) techniques can detect metabolic and biochemical changes associated with altered amino acid transport and metabolism, neuroinflammation, and neurotransmitter abnormalities in and around epileptogenic tumors. PET imaging of amino acid uptake and metabolism as well as activated microglia can detect interictal or peri-ictal cortical increased uptake (as compared to non-epileptic cortex) associated with tumor-associated epilepsy. Metabolic tumor volumes may predict seizure outcome based on objective treatment response during glioma chemotherapy. Advanced MRI, especially glutamate imaging, can detect neurotransmitter changes around epileptogenic brain tumors. Recently, developed PET radiotracers targeting specific glutamate receptor types may also identify therapeutic targets for pharmacologic seizure control. Further studies with advanced multimodal imaging approaches may facilitate development of precision treatment strategies to control brain tumor-associated epilepsy.

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Diversity of 3′ variable region of cagA gene in Helicobacter pylori strains isolated from Chinese population

Gut Pathogens ◽

10.1186/s13099-021-00419-3 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Zhijing Xue ◽

Yuanhai You ◽

Lihua He ◽

Yanan Gong ◽

Lu Sun ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Amino Acid ◽

Chinese Population ◽

Statistical Difference ◽

Variable Region ◽

Repeat Region ◽

Geographical Regions ◽

H Pylori ◽

Epiya Motifs

Abstract Background The cytotoxin-associated gene A (cagA) is one of the most important virulence factors of Helicobacter pylori (H. pylori). There is a highly polymorphic Glu-Pro-Ile-Tyr-Ala (EPIYA) repeat region in the C-terminal of CagA protein. This repeat region is thought to play an important role in the pathogenesis of gastrointestinal diseases. The aim of this study was to investigate the diversity of cagA 3′ variable region and the amino acid polymorphisms in the EPIYA segments of the CagA C-terminal region of H. pylori, and their association with gastroduodenal diseases. Methods A total of 515 H. pylori strains from patients in 14 different geographical regions of China were collected. The genomic DNA from each strain was extracted and the cagA 3′ variable region was amplified by polymerase chain reaction (PCR). The PCR products were sequenced and analyzed using MEGA 7.0 software. Results A total of 503 (97.7%) H. pylori strains were cagA-positive and 1,587 EPIYA motifs were identified, including 12 types of EPIYA or EPIYA-like sequences. In addition to the four reported major segments, several rare segments (e.g., B′, B″ and D′) were defined and 20 different sequence types (e.g., ABD, ABC) were found in our study. A total of 481 (95.6%) strains carried the East Asian type CagA, and the ABD subtypes were most prevalent (82.1%). Only 22 strains carried the Western type CagA, which included AC, ABC, ABCC and ABCCCC subtypes. The CagA-ABD subtype had statistical difference in different geographical regions (P = 0.006). There were seven amino acid polymorphisms in the sequences surrounding the EPIYA motifs, among which amino acids 893 and 894 had a statistical difference with gastric cancer (P = 0.004). Conclusions In this study, 503 CagA sequences were studied and analyzed in depth. In Chinese population, most H. pylori strains were of the CagA-ABD subtype and its presence was associated with gastroduodenal diseases. Amino acid polymorphisms at residues 893 and 894 flanking the EPIYA motifs had a statistically significant association with gastric cancer.

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Cholangiocarcinoma therapeutics: an update

Current Cancer Drug Targets ◽

10.2174/1568009621666210204152028 ◽

2021 ◽

Vol 21 ◽

Author(s):

Mai Ly Thi Nguyen ◽

Nguyen Linh Toan ◽

Maria Bozko ◽

Khac Cuong Bui ◽

Przemyslaw Bozko

Keyword(s):

Treatment Outcome ◽

Targeted Therapies ◽

Treatment Strategies ◽

Favourable Outcome ◽

High Rate ◽

Postoperative Treatment ◽

Clinical Indication ◽

Tumour Resection ◽

First Line ◽

Treatment Methods

Background: Background: Cholangiocarcinoma (CCA) is the second most common hepatobiliary cancer and associated with poor prognosis. Only one-third of CCA cases are diagnosed at operable stages. However, a high rate of relapse has been observed post-operatively. Besides screening for operable individuals, efficacious therapeutic for recurrent and advanced CCA is urgently needed. Treatment outcome of available therapeutics is important to clarify clinical indication and facilitate development of treatment strategies. Objective: This review aims to compare the treatment outcome of different therapeutics based on both overall survival and progression-free survival. Methods: Over one hundred peer-reviewed articles were examined. We compared the treatment outcome between different treatment methods, including tumour resection with or without postoperative systematic therapy, chemotherapies including FOFLOX and targeted therapies, such as IDH1, K-RAS and FGFR inhibitors. Notably, the scientific basis and outcome of available treatment methods werecompared with the standard first-line therapy. Results: CCAs at early stages should firstly undergo tumour resection surgery, followed by postoperative treatment with Capecitabine. Chemotherapy can be considered as a preoperative option for unresectable CCAs. Inoperable CCAs with genetic aberrances like FGFR alterations, IDH1 and K-RAS mutations should be considered with targeted therapies. Fluoropyrimidine prodrug (S-1)/Gemcitabine/Cisplatin and nab-Paclitaxel/Gemcitabine/Cisplatin show favourable outcome which hints on the triplet regimen to be superior to Gemcitabine/Cisplatinon CCA. Thetriplet chemotherapeutic should be tested further compared toGemcitabine/Cisplatin among CCAs without genetic alterations.Gemcitabine plus S-1 was recently suggested as the convenient and equivalent standard first line for advanced/recurrent biliary tract cancer. Conclusions: Thisreview provides a comparative outcomebetween novel targeted therapies and currently available therapeutics.

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Caustic and Toxic Ingestions

10.2310/7ccsp.8137 ◽

2017 ◽

Author(s):

CDR Thomas Q Gallagher ◽

CDR Robert L Ricca

Keyword(s):

Surgical Management ◽

Management Strategies ◽

Treatment Strategies ◽

Tracheobronchial Tree ◽

High Rate ◽

Health Concern ◽

Endoscopic Management ◽

Caustic Ingestion ◽

Stricture Formation ◽

Accidental Ingestion

Ingestion of caustic substances remains a potentially fatal public health concern with extensive morbidity and the possibility of long-term sequelae. The management strategies of these complex injuries continue to be extensively studied in the literature. Areas of interest include the most efficacious treatment of caustic esophageal stricture to preserve the native esophagus, use of steroids, and use of esophageal stents. Prevention of accidental ingestion through strategies to limit the availability of caustic substances is a key factor in reducing the incidence of injury, but there continues to be a high rate of accidental ingestion in developing countries with less rigorous manufacturing standards. Initial evaluation includes endoscopic evaluation of the esophagus and tracheobronchial tree. Optimal treatment strategies, including the use of proton pump inhibitors to reduce gastroesophageal reflux, steroid use to prevent stricture formation, and use of stents for management of strictures, continue to be debated. Initial surgical management includes esophagectomy for full-thickness injury with abdominal exploration. Multiple surgical options exist for both restoration of gastrointestinal continuity after esophagectomy and the management of strictures refractory to medical management, including reverse gastric tube, colonic interposition, and gastric advancement. Numerous small studies have evaluated the efficacy of these interventions, but there continues to be a need for larger prospective studies to develop a worldwide consensus opinion on best practices. We provide a review of the recent literature and practice recommendations for the management of injuries due to caustic ingestion. Key words: caustic ingestion, endoscopic management, stricture, surgical management

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Functional Stratification of Cancer Drugs through Integrated Network Similarity

10.21203/rs.3.rs-646155/v1 ◽

2022 ◽

Author(s):

Nurcan Tuncbag ◽

Seyma Unsal Beyge

Keyword(s):

Cell Lines ◽

Drug Targets ◽

Hdac Inhibitors ◽

Treatment Strategies ◽

Network Models ◽

Drug Combinations ◽

Multiple Cancer ◽

Integrated Network ◽

Drug Molecules ◽

The Difference

Abstract Heterogeneity across tumors is the main obstacle in developing treatment strategies. Drug molecules not only perturb their immediate protein targets but also modulate multiple signaling pathways. In this study, we explored the networks modulated by several drug molecules across multiple cancer cell lines by integrating the drug targets with transcriptomic and phosphoproteomic data. As a result, we obtained 236 reconstructed networks covering five cell lines and 70 drugs. A rigorous topological and pathway analysis showed that chemically and functionally different drugs may modulate overlapping networks. Additionally, we revealed a set of tumor-specific hidden pathways with the help of drug network models that are not detectable from the initial data. The difference in the target selectivity of the drugs leads to disjoint networks despite sharing the exact mechanism of action, e.g., HDAC inhibitors. We also used the reconstructed network models to study potential drug combinations based on the topological separation, found literature evidence for a set of drug pairs. Overall, the network-level exploration of the drug perturbations may potentially help optimize treatment strategies and suggest new drug combinations.

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Diversity of 3’ variable region of cagA gene in Helicobacter pylori strains isolated from Chinese population

10.21203/rs.3.rs-127429/v2 ◽

2021 ◽

Author(s):

Zhijing Xue ◽

Yuanhai You ◽

Lihua He ◽

Yanan Gong ◽

Lu Sun ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Amino Acid ◽

Chinese Population ◽

Statistical Difference ◽

Variable Region ◽

Repeat Region ◽

Geographical Regions ◽

H Pylori ◽

Epiya Motifs

Abstract Background: The cytotoxin-associated gene A (cagA) is one of the most important virulence factors of Helicobacter pylori (H. pylori). There is a highly polymorphic Glu-Pro-Ile-Tyr-Ala (EPIYA) repeat region in the C-terminal of CagA protein. This repeat region is thought to play an important role in the pathogenesis of gastrointestinal diseases. The aim of this study was to investigate the diversity of cagA 3’ variable region and the amino acid polymorphisms in the EPIYA segments of the CagA C-terminal region of H. pylori, and their association with gastroduodenal diseases.Methods: A total of 515 H. pylori strains from patients in 14 different geographical regions of China were collected. The genomic DNA from each strain was extracted and the cagA 3’ variable region was amplified by polymerase chain reaction (PCR). The PCR products were sequenced and analyzed using MEGA 7.0 software.Results: A total of 503 (97.7%) H. pylori strains were cagA-positive and 1,587 EPIYA motifs were identified, including 12 types of EPIYA or EPIYA-like sequences. In addition to the four reported major segments, several rare segments (e.g., B’, B’’ and D’) were defined and 20 different sequence types (e.g., ABD, ABC) were found in our study. A total of 481 (95.6%) strains carried the East Asian type CagA, and the ABD subtypes were most prevalent (82.1%). Only 22 strains carried the Western type CagA, which include AC, ABC, ABCC and ABCCCC subtypes. The CagA-ABD subtype had statistical difference in different geographic regions (P = 0.006). There are seven amino acid polymorphisms in the sequences surrounding the EPIYA motifs, among which amino acid residue 893 and 894 had a statistical difference with gastric cancer (P = 0.004).Conclusions: In this study, 503 CagA sequences was studied and analyzed in depth. In Chinese population, most H. pylori strains are of the CagA-ABD subtype and its presence was associated with gastroduodenal diseases. Amino acid polymorphisms at residue 893 and 894 flanking the EPIYA motif had a statistically significant association with gastric cancer.

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