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  1. Article ; Online: SARS-CoV-2 viral spike G614 mutation exhibits higher case fatality rate.

    Becerra-Flores, Manuel / Cardozo, Timothy

    International journal of clinical practice

    2020  Volume 74, Issue 8, Page(s) e13525

    Abstract: Aim: The COVID-19 pandemic is caused by infection with the SARS-CoV-2 virus. The major mutation detected to date in the SARS-CoV-2 viral envelope spike protein, which is responsible for virus attachment to the host and is also the main target for host ... ...

    Abstract Aim: The COVID-19 pandemic is caused by infection with the SARS-CoV-2 virus. The major mutation detected to date in the SARS-CoV-2 viral envelope spike protein, which is responsible for virus attachment to the host and is also the main target for host antibodies, is a mutation of an aspartate (D) at position 614 found frequently in Chinese strains to a glycine (G). We sought to infer health impact of this mutation.
    Result: Increased case fatality rate correlated strongly with the proportion of viruses bearing G614 on a country by country basis. The amino acid at position 614 occurs at an internal protein interface of the viral spike, and the presence of G at this position was calculated to destabilise a specific conformation of the viral spike, within which the key host receptor binding site is more accessible.
    Conclusion: These results imply that G614 is a more pathogenic strain of SARS-CoV-2, which may influence vaccine design. The prevalence of this form of the virus should also be included in epidemiologic models predicting the COVID-19 health burden and fatality over time in specific regions. Physicians should be aware of this characteristic of the virus to anticipate the clinical course of infection.
    MeSH term(s) Aspartic Acid ; Betacoronavirus/genetics ; Betacoronavirus/pathogenicity ; Binding Sites ; COVID-19 ; Coronavirus Infections/mortality ; Glycine ; Humans ; Mutation ; Pandemics ; Pneumonia, Viral/mortality ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/genetics
    Chemical Substances Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Aspartic Acid (30KYC7MIAI) ; Glycine (TE7660XO1C)
    Keywords covid19
    Language English
    Publishing date 2020-06-03
    Publishing country India
    Document type Journal Article
    ZDB-ID 1386246-7
    ISSN 1742-1241 ; 1368-5031
    ISSN (online) 1742-1241
    ISSN 1368-5031
    DOI 10.1111/ijcp.13525
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  2. Article ; Online: SARS‐CoV‐2 viral spike G614 mutation exhibits higher case fatality rate

    Becerra‐Flores, Manuel / Cardozo, Timothy

    International Journal of Clinical Practice

    2020  Volume 74, Issue 8

    Keywords General Medicine ; covid19
    Language English
    Publisher Wiley
    Publishing country us
    Document type Article ; Online
    ZDB-ID 1386246-7
    ISSN 1742-1241 ; 1368-5031
    ISSN (online) 1742-1241
    ISSN 1368-5031
    DOI 10.1111/ijcp.13525
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article: SARS-CoV-2 viral spike G614 mutation exhibits higher case fatality rate

    Becerra-Flores, Manuel / Cardozo, Timothy

    Int J Clin Pract

    Abstract: AIM: The COVID-19 pandemic is caused by infection with the SARS-CoV-2 virus. The major mutation detected to date in the SARS-CoV-2 viral envelope spike protein, which is responsible for virus attachment to the host and is also the main target for host ... ...

    Abstract AIM: The COVID-19 pandemic is caused by infection with the SARS-CoV-2 virus. The major mutation detected to date in the SARS-CoV-2 viral envelope spike protein, which is responsible for virus attachment to the host and is also the main target for host antibodies, is a mutation of an aspartate (D) at position 614 found frequently in Chinese strains to a glycine (G). We sought to infer health impact of this mutation. RESULT: Increased case fatality rate correlated strongly with the proportion of viruses bearing G614 on a country by country basis. The amino acid at position 614 occurs at an internal protein interface of the viral spike, and the presence of G at this position was calculated to destabilise a specific conformation of the viral spike, within which the key host receptor binding site is more accessible. CONCLUSION: These results imply that G614 is a more pathogenic strain of SARS-CoV-2, which may influence vaccine design. The prevalence of this form of the virus should also be included in epidemiologic models predicting the COVID-19 health burden and fatality over time in specific regions. Physicians should be aware of this characteristic of the virus to anticipate the clinical course of infection.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #197772
    Database COVID19

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  4. Article ; Online: Effect of Passive Administration of Monoclonal Antibodies Recognizing Simian Immunodeficiency Virus (SIV) V2 in CH59-Like Coil/Helical or β-Sheet Conformations on Time of SIV

    Stamos, James D / Rahman, Mohammad Arif / Gorini, Giacomo / Silva de Castro, Isabela / Becerra-Flores, Manuel / Van Wazer, David J / N'Guessan, Kombo F / Clark, Natasha M / Bissa, Massimiliano / Gutowska, Anna / Mason, Rosemarie D / Kim, Jiae / Rao, Mangala / Roederer, Mario / Paquin-Proulx, Dominic / Evans, David T / Cicala, Claudia / Arthos, James / Kwong, Peter D /
    Zhou, Tongqing / Cardozo, Timothy / Franchini, Genoveffa

    Journal of virology

    2023  Volume 97, Issue 4, Page(s) e0186422

    Abstract: The monoclonal antibodies (MAbs) NCI05 and NCI09, isolated from a vaccinated macaque that was protected from multiple simian immunodeficiency virus (SIV) challenges, both target an overlapping, conformationally dynamic epitope in SIV envelope variable ... ...

    Abstract The monoclonal antibodies (MAbs) NCI05 and NCI09, isolated from a vaccinated macaque that was protected from multiple simian immunodeficiency virus (SIV) challenges, both target an overlapping, conformationally dynamic epitope in SIV envelope variable region 2 (V2). Here, we show that NCI05 recognizes a CH59-like coil/helical epitope, whereas NCI09 recognizes a β-hairpin linear epitope.
    MeSH term(s) Simian Immunodeficiency Virus/immunology ; Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/isolation & purification ; Antibodies, Monoclonal/metabolism ; Viral Proteins/chemistry ; Viral Proteins/immunology ; Epitopes/immunology ; Simian Acquired Immunodeficiency Syndrome/immunology ; Simian Acquired Immunodeficiency Syndrome/prevention & control ; Protein Structure, Tertiary ; Models, Molecular ; CHO Cells ; Cricetulus ; Animals ; Macaca/immunology ; Macaca/virology ; Antibodies, Viral/blood
    Chemical Substances Antibodies, Monoclonal ; Viral Proteins ; Epitopes ; Antibodies, Viral
    Language English
    Publishing date 2023-03-28
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/jvi.01864-22
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  5. Article ; Online: Cholera toxin B scaffolded, focused SIV V2 epitope elicits antibodies that influence the risk of SIV

    Rahman, Mohammad Arif / Becerra-Flores, Manuel / Patskovsky, Yury / Silva de Castro, Isabela / Bissa, Massimiliano / Basu, Shraddha / Shen, Xiaoying / Williams, LaTonya D / Sarkis, Sarkis / N'guessan, Kombo F / LaBranche, Celia / Tomaras, Georgia D / Aye, Pyone Pyone / Veazey, Ronald / Paquin-Proulx, Dominic / Rao, Mangala / Franchini, Genoveffa / Cardozo, Timothy

    Frontiers in immunology

    2023  Volume 14, Page(s) 1139402

    Abstract: Introduction: An efficacious HIV vaccine will need to elicit a complex package of innate, humoral, and cellular immune responses. This complex package of responses to vaccine candidates has been studied and yielded important results, yet it has been a ... ...

    Abstract Introduction: An efficacious HIV vaccine will need to elicit a complex package of innate, humoral, and cellular immune responses. This complex package of responses to vaccine candidates has been studied and yielded important results, yet it has been a recurring challenge to determine the magnitude and protective effect of specific
    Method: We generated a novel vaccine by incorporating the V2 loop B-cell epitope in the cholera toxin B (CTB) scaffold and compared two new immunization regimens to a historically protective 'standard' vaccine regimen (SVR) consisting of 2xDNA prime boosted with 2xALVAC-SIV and 1xΔV1gp120. We immunized a cohort of macaques with 5xCTB-V2c vaccine+alum intramuscularly simultaneously with topical intrarectal vaccination of CTB-V2c vaccine without alum (5xCTB-V2/alum). In a second group, we tested a modified version of the SVR consisting of 2xDNA prime and boosted with 1xALVAC-SIV and 2xALVAC-SIV+CTB-V2/alum, (DA/CTB-V2c/alum).
    Results: In the absence of any other anti-viral antibodies, V2c epitope was highly immunogenic when incorporated in the CTB scaffold and generated highly functional anti-V2c antibodies in the vaccinated animals. 5xCTB-V2c/alum vaccination mediated non-neutralizing ADCC activity and efferocytosis, but produced low avidity, trogocytosis, and no neutralization of tier 1 virus. Furthermore, DA/CTB-V2c/alum vaccination also generated lower total ADCC activity, avidity, and neutralization compared to the SVR. These data suggest that the ΔV1gp120 boost in the SVR yielded more favorable immune responses than its CTB-V2c counterpart. Vaccination with the SVR generates CCR5
    Conclusion: Taken together, these data suggest that individual viral spike B-cell epitopes can be highly immunogenic and functional as isolated immunogens, although they might not be sufficient on their own to provide full protection against HIV/SIV infection.
    MeSH term(s) Animals ; Cholera Toxin ; Epitopes ; Macaca mulatta ; AIDS Vaccines ; HIV Infections/prevention & control
    Chemical Substances aluminum sulfate (34S289N54E) ; Cholera Toxin (9012-63-9) ; Epitopes ; AIDS Vaccines
    Language English
    Publishing date 2023-04-21
    Publishing country Switzerland
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Intramural
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2023.1139402
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  6. Article: Corrigendum to "Triazolo[4,5-

    Lough, Lea / Sherman, Dan / Becerra-Flores, Manuel / Vasudevan, Deepika / Lavinda, Olga / Ni, Eric / Wang, Hong / Ryoo, Hyung Don / Tibes, Raoul / Cardozo, Timothy

    Computational and structural biotechnology journal

    2020  Volume 18, Page(s) 1092

    Abstract: This corrects the article DOI: 10.1016/j.csbj.2018.09.003.]. ...

    Abstract [This corrects the article DOI: 10.1016/j.csbj.2018.09.003.].
    Language English
    Publishing date 2020-05-05
    Publishing country Netherlands
    Document type Published Erratum
    ISSN 2001-0370
    ISSN 2001-0370
    DOI 10.1016/j.csbj.2020.04.016
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  7. Article: CL-705G: a novel chemical Kir6.2-specific K

    Gando, Ivan / Becerra Flores, Manuel / Chen, I-Shan / Yang, Hua-Qian / Nakamura, Tomoe Y / Cardozo, Timothy J / Coetzee, William A

    Frontiers in pharmacology

    2023  Volume 14, Page(s) 1197257

    Abstract: Background: ...

    Abstract Background:
    Language English
    Publishing date 2023-06-20
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2587355-6
    ISSN 1663-9812
    ISSN 1663-9812
    DOI 10.3389/fphar.2023.1197257
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  8. Article: Triazolo[4,5-d]pyrimidines as Validated General Control Nonderepressible 2 (GCN2) Protein Kinase Inhibitors Reduce Growth of Leukemia Cells

    Lough, Lea / Sherman, Dan / Becerra-Flores, Manuel / Vasudevan, Deepika / Lavinda, Olga / Ni, Eric / Wang, Hong / Ryoo, Hyung Don / Tibes, Raoul / Cardozo, Timothy

    Computational and Structural Biotechnology Journal. 2018, v. 16

    2018  

    Abstract: Cellular stress signals activate adaptive signaling pathways of the mammalian integrated stress response (ISR), of which the unfolded protein response (UPR) is a subset. These pathways converge at the phosporylation of eIF2α. Drug-like, potent and ... ...

    Abstract Cellular stress signals activate adaptive signaling pathways of the mammalian integrated stress response (ISR), of which the unfolded protein response (UPR) is a subset. These pathways converge at the phosporylation of eIF2α. Drug-like, potent and selective chemical inhibitors (valid chemical probes) targeting major ISR kinases have been previously identified, with the exception of GCN2. We synthesized and evaluated a series of GCN2 inhibitors based on a triazolo[4,5-d]pyrimidine scaffold. Several compounds potently inhibited GCN2 in vitro and displayed good selectivity over the related kinases PERK, HRI, and IRE1. The compounds inhibited phosporylation of eIF2α in HEK293T cells with an IC50 < 150 nM, validating them as chemical probes for cellular studies. These probes were screened against the National Cancer Institute NCI-60 human cancer cell line panel. Uniform growth inhibition was observed in the leukemia group of cell lines. Growth inhibition in the most sensitive cell lines coincided with high GCN2 mRNA expression levels. Oncomine analysis revealed high GCN2 expression accompanied by lower asparagine synthetase (ASNS) expression in patient-derived acute lymphoblastic leukemias with B-Cell origins (B-ALL) as well. Notably, asparaginase, which depletes amino acids and triggers GCN2 activity, is a licensed, first-line B-ALL treatment. Thus, we hypothesize that leukemias exhibiting high GCN2 expression and low ASNS expression may be susceptible to pharmacologic GCN2 inhibition.
    Keywords B-lymphocytes ; amino acids ; asparaginase ; aspartate-ammonia ligase ; biotechnology ; enzyme inhibitors ; gene expression ; growth retardation ; human cell lines ; humans ; inhibitory concentration 50 ; leukemia ; messenger RNA ; neoplasm cells ; protein kinases ; pyrimidines ; signal transduction ; stress response ; unfolded protein response
    Language English
    Size p. 350-360.
    Publishing place Elsevier B.V.
    Document type Article
    ISSN 2001-0370
    DOI 10.1016/j.csbj.2018.09.003
    Database NAL-Catalogue (AGRICOLA)

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  9. Article: Conformational change of the

    Kim, David / Tracey, John / Becerra Flores, Manuel / Chaudhry, Kanita / Nasim, Rafae / Correa-Medina, Abraham / Knipling, Leslie / Chen, Qing / Stibitz, Scott / Jenkins, Lisa M M / Moon, Kyung / Cardozo, Tim / Hinton, Deborah M

    Computational and structural biotechnology journal

    2022  Volume 20, Page(s) 6431–6442

    Abstract: The BvgAS two-component system regulates virulence gene expression ... ...

    Abstract The BvgAS two-component system regulates virulence gene expression in
    Language English
    Publishing date 2022-11-06
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2694435-2
    ISSN 2001-0370
    ISSN 2001-0370
    DOI 10.1016/j.csbj.2022.10.042
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  10. Article ; Online: A Review of the Antimicrobial Activity of Selenium Nanoparticles.

    Martínez-Esquivias, Fernando / Guzmán-Flores, Juan Manuel / Pérez-Larios, Alejandro / González Silva, Napoleón / Becerra-Ruiz, Julieta Saraí

    Journal of nanoscience and nanotechnology

    2021  Volume 21, Issue 11, Page(s) 5383–5398

    Abstract: Antimicrobial resistance has become a severe problem for health systems worldwide, and counteractions are challenging because of the lack of interest of pharmaceutical companies in generating new and effective antimicrobial drugs. Selenium nanoparticles ... ...

    Abstract Antimicrobial resistance has become a severe problem for health systems worldwide, and counteractions are challenging because of the lack of interest of pharmaceutical companies in generating new and effective antimicrobial drugs. Selenium nanoparticles have attracted considerable interest in treating bacteria, fungi, parasites, and viruses of clinical importance due to their high therapeutic efficacy and almost zero generation of adverse effects. Some studies have revealed that the antimicrobial activity of these nanoparticles is due to the generation of reactive oxygen species, but more studies are needed to clarify their antimicrobial mechanisms. Other studies show that their antimicrobial activity is increased when the surface of the nanoparticles is functionalized with some biomolecules or when their surface carries a specific drug. This review addresses the existing background on the antimicrobial potential offered by selenium nanoparticles against viruses, bacteria, fungi, and parasites of clinical importance.
    MeSH term(s) Anti-Infective Agents/pharmacology ; Fungi ; Nanoparticles ; Pharmaceutical Preparations ; Selenium
    Chemical Substances Anti-Infective Agents ; Pharmaceutical Preparations ; Selenium (H6241UJ22B)
    Language English
    Publishing date 2021-05-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ISSN 1533-4899
    ISSN (online) 1533-4899
    DOI 10.1166/jnn.2021.19471
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