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  1. Article ; Online: Using big sequencing data to identify chronic SARS-Coronavirus-2 infections.

    Harari, Sheri / Miller, Danielle / Fleishon, Shay / Burstein, David / Stern, Adi

    Nature communications

    2024  Volume 15, Issue 1, Page(s) 648

    Abstract: The evolution of SARS-Coronavirus-2 (SARS-CoV-2) has been characterized by the periodic emergence of highly divergent variants. One leading hypothesis suggests these variants may have emerged during chronic infections of immunocompromised individuals, ... ...

    Abstract The evolution of SARS-Coronavirus-2 (SARS-CoV-2) has been characterized by the periodic emergence of highly divergent variants. One leading hypothesis suggests these variants may have emerged during chronic infections of immunocompromised individuals, but limited data from these cases hinders comprehensive analyses. Here, we harnessed millions of SARS-CoV-2 genomes to identify potential chronic infections and used language models (LM) to infer chronic-associated mutations. First, we mined the SARS-CoV-2 phylogeny and identified chronic-like clades with identical metadata (location, age, and sex) spanning over 21 days, suggesting a prolonged infection. We inferred 271 chronic-like clades, which exhibited characteristics similar to confirmed chronic infections. Chronic-associated mutations were often high-fitness immune-evasive mutations located in the spike receptor-binding domain (RBD), yet a minority were unique to chronic infections and absent in global settings. The probability of observing high-fitness RBD mutations was 10-20 times higher in chronic infections than in global transmission chains. The majority of RBD mutations in BA.1/BA.2 chronic-like clades bore predictive value, i.e., went on to display global success. Finally, we used our LM to infer hundreds of additional chronic-like clades in the absence of metadata. Our approach allows mining extensive sequencing data and providing insights into future evolutionary patterns of SARS-CoV-2.
    MeSH term(s) Humans ; COVID-19/genetics ; SARS-CoV-2/genetics ; Persistent Infection ; Mutation ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/chemistry
    Chemical Substances Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
    Language English
    Publishing date 2024-01-20
    Publishing country England
    Document type Journal Article
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-024-44803-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Using big sequencing data to identify chronic SARS-Coronavirus-2 infections

    Harari, Sheri / Miller, Danielle / Fleishon, Shay / Burstein, David / Stern, Adi

    bioRxiv

    Abstract: The evolution of SARS-Coronavirus-2 (SARS-CoV-2) has been characterized by the periodic emergence of highly divergent variants, many of which may have arisen during chronic infections of immunocompromised individuals. Here, we harness a global phylogeny ... ...

    Abstract The evolution of SARS-Coronavirus-2 (SARS-CoV-2) has been characterized by the periodic emergence of highly divergent variants, many of which may have arisen during chronic infections of immunocompromised individuals. Here, we harness a global phylogeny of ~11.7 million SARS-CoV-2 genomes and search for clades composed of sequences with identical metadata (location, age, and sex) spanning more than 21 days. We postulate that such clades represent repeated sampling from the same chronically infected individual. A set of 271 such chronic-like clades was inferred, and displayed signatures of an elevated rate of adaptive evolution, in line with validated chronic infections. More than 70% of adaptive mutations present in currently circulating variants are found in BA.1 chronic-like clades that predate the circulating variants by months, demonstrating the predictive nature of such clades. We find that in chronic-like clades the probability of observing adaptive mutations is approximately 10-20 higher than that in global transmission chains. We next employ language models to find mutations most predictive of chronic infections and use them to infer hundreds of additional chronic-like clades in the absence of metadata and phylogenetic information. Our proposed approach presents an innovative method for mining extensive sequencing data and providing valuable insights into future evolutionary patterns.
    Keywords covid19
    Language English
    Publishing date 2023-07-17
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2023.07.16.549184
    Database COVID19

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  3. Article ; Online: Saccharomyces cerevisiae

    Harshuk-Shabso, Dana / Castel, Noam / Israeli, Ran / Harari, Sheri / Pick, Elah

    Biomolecules

    2021  Volume 11, Issue 4

    Abstract: The COP9 signalosome (CSN) is a highly conserved eukaryotic multi-subunit enzyme, regulating cullin RING ligase activities and accordingly, substrate ubiquitination and degradation. We showed that the CSN complex ... ...

    Abstract The COP9 signalosome (CSN) is a highly conserved eukaryotic multi-subunit enzyme, regulating cullin RING ligase activities and accordingly, substrate ubiquitination and degradation. We showed that the CSN complex of
    MeSH term(s) COP9 Signalosome Complex/chemistry ; COP9 Signalosome Complex/genetics ; COP9 Signalosome Complex/metabolism ; Cullin Proteins/metabolism ; Humans ; Protein Subunits/chemistry ; Protein Subunits/genetics ; Protein Subunits/metabolism ; Reactive Oxygen Species/metabolism ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/chemistry ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Substrate Specificity ; Ubiquitination ; Ubiquitins/chemistry ; Ubiquitins/genetics ; Ubiquitins/metabolism
    Chemical Substances Cullin Proteins ; Protein Subunits ; RUB1 protein, S cerevisiae ; Reactive Oxygen Species ; Saccharomyces cerevisiae Proteins ; Ubiquitins ; COP9 Signalosome Complex (EC 3.4.19.12)
    Language English
    Publishing date 2021-03-25
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2701262-1
    ISSN 2218-273X ; 2218-273X
    ISSN (online) 2218-273X
    ISSN 2218-273X
    DOI 10.3390/biom11040497
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Drivers of adaptive evolution during chronic SARS-CoV-2 infections.

    Harari, Sheri / Tahor, Maayan / Rutsinsky, Natalie / Meijer, Suzy / Miller, Danielle / Henig, Oryan / Halutz, Ora / Levytskyi, Katia / Ben-Ami, Ronen / Adler, Amos / Paran, Yael / Stern, Adi

    Nature medicine

    2022  Volume 28, Issue 7, Page(s) 1501–1508

    Abstract: In some immunocompromised patients with chronic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, considerable adaptive evolution occurs. Some substitutions found in chronic infections are lineage-defining mutations in variants of ... ...

    Abstract In some immunocompromised patients with chronic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, considerable adaptive evolution occurs. Some substitutions found in chronic infections are lineage-defining mutations in variants of concern (VOCs), which has led to the hypothesis that VOCs emerged from chronic infections. In this study, we searched for drivers of VOC-like emergence by consolidating sequencing results from a set of 27 chronic infections. Most substitutions in this set reflected lineage-defining VOC mutations; however, a subset of mutations associated with successful global transmission was absent from chronic infections. We further tested the ability to associate antibody evasion mutations with patient-specific and virus-specific features and found that viral rebound is strongly correlated with the emergence of antibody evasion. We found evidence for dynamic polymorphic viral populations in most patients, suggesting that a compromised immune system selects for antibody evasion in particular niches in a patient's body. We suggest that a tradeoff exists between antibody evasion and transmissibility and that extensive monitoring of chronic infections is necessary to further understanding of VOC emergence.
    MeSH term(s) COVID-19 ; Graft vs Host Disease ; Humans ; Mutation/genetics ; SARS-CoV-2/genetics
    Language English
    Publishing date 2022-06-20
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/s41591-022-01882-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Drivers of within-host genetic diversity in acute infections of viruses.

    Gelbart, Maoz / Harari, Sheri / Ben-Ari, Ya'ara / Kustin, Talia / Wolf, Dana / Mandelboim, Michal / Mor, Orna / Pennings, Pleuni S / Stern, Adi

    PLoS pathogens

    2020  Volume 16, Issue 11, Page(s) e1009029

    Abstract: Genetic diversity is the fuel of evolution and facilitates adaptation to novel environments. However, our understanding of what drives differences in the genetic diversity during the early stages of viral infection is somewhat limited. Here, we use ultra- ...

    Abstract Genetic diversity is the fuel of evolution and facilitates adaptation to novel environments. However, our understanding of what drives differences in the genetic diversity during the early stages of viral infection is somewhat limited. Here, we use ultra-deep sequencing to interrogate 43 clinical samples taken from early infections of the human-infecting viruses HIV, RSV and CMV. Hundreds to thousands of virus templates were sequenced per sample, allowing us to reveal dramatic differences in within-host genetic diversity among virus populations. We found that increased diversity was mostly driven by presence of multiple divergent genotypes in HIV and CMV samples, which we suggest reflect multiple transmitted/founder viruses. Conversely, we detected an abundance of low frequency hyper-edited genomes in RSV samples, presumably reflecting defective virus genomes (DVGs). We suggest that RSV is characterized by higher levels of cellular co-infection, which allow for complementation and hence elevated levels of DVGs.
    MeSH term(s) Cytomegalovirus/genetics ; Cytomegalovirus Infections/virology ; Genetic Variation ; Genotype ; HIV Infections/virology ; HIV-1/genetics ; Humans ; Respiratory Syncytial Virus Infections/virology ; Respiratory Syncytial Viruses/genetics
    Language English
    Publishing date 2020-11-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7366
    ISSN (online) 1553-7374
    ISSN 1553-7366
    DOI 10.1371/journal.ppat.1009029
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Dual anti-viral treatment for persistent COVID-19 in immunocompromised hemato-oncological patients is associated with a favorable prognosis and minor side effects.

    Meijer, Suzy E / Halutz, Ora / Adler, Amos / Levytskyi, Katya / Tau, Luba / Dekel, Michal / Cohen-Poradosu, Ronit / Katchman, Evgene / Shasha, David / Ablin, Jacob / Choshen, Guy / Jacob, Giris / Wasserman, Asaf / Ingbir, Merav / Cohen, Yael C / Perry, Chava / Ram, Ron / Herishanu, Yair / Bar On, Yael /
    van Thijn, Elma / Rutsinsky, Natalie / Harari, Sheri / Stern, Adi / Ben-Ami, Ronen / Paran, Yael

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy

    2023  Volume 30, Issue 3, Page(s) 271–275

    Abstract: In hemato-oncological patients, COVID-19 can present as a persistent infection with ongoing symptoms and viral replication over a prolonged period of time. Data are scarce on the preferred treatment options for these patients. We describe our experience ... ...

    Abstract In hemato-oncological patients, COVID-19 can present as a persistent infection with ongoing symptoms and viral replication over a prolonged period of time. Data are scarce on the preferred treatment options for these patients. We describe our experience with a five-day course of dual anti-viral treatment with remdesivir and nirmatrelvir/ritonavir for hemato-oncological immunocompromised patients with persistent COVID-19. Fifteen patients with a history of lymphoma, CLL, and MM were included. Eight were male, median age was 74. All patients had an immediate clinical and virological response. In 73 % of patients, PCR for SARS-CoV-2 became negative at the end of treatment and the rest had an increase in PCR cycle threshold (CT) values, with a median increase of 6 cycles. After a follow-up of three months, 60 % of patients remained in full clinical and virological remission. None required invasive mechanical ventilation or died. The side effects we observed, neutropenia, lactatemia and elevated transaminases, were mild and almost all transient in nature. We conclude that dual anti-viral treatment appears to be a valid treatment option for persistent COVID-19.
    MeSH term(s) Humans ; Male ; Aged ; Female ; COVID-19/complications ; SARS-CoV-2 ; Prognosis ; Time Factors ; Antiviral Agents/adverse effects
    Chemical Substances Antiviral Agents
    Language English
    Publishing date 2023-11-07
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 1355399-9
    ISSN 1437-7780 ; 1341-321X
    ISSN (online) 1437-7780
    ISSN 1341-321X
    DOI 10.1016/j.jiac.2023.10.022
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Drivers of adaptive evolution during chronic SARS-CoV-2 infections

    Harari, Sheri / Tahor, Maayan / Rutsinsky, Natalie / Meijer, Suzy / Miller, Danielle / Henig, Oryan / Halutz, Ora / Levytskyi, Katia / Ben-Ami, Ronen / Adler, Amos / Paran, Yael / Stern, Adi

    medRxiv

    Abstract: In some immunocompromised patients with chronic SARS-CoV-2 infection, dramatic adaptive evolution occurs, with substitutions reminiscent of those in variants of concern (VOCs). Here, we searched for drivers of VOC-like emergence by consolidating ... ...

    Abstract In some immunocompromised patients with chronic SARS-CoV-2 infection, dramatic adaptive evolution occurs, with substitutions reminiscent of those in variants of concern (VOCs). Here, we searched for drivers of VOC-like emergence by consolidating sequencing results from a set of twenty-seven chronic infections. Most substitutions in this set reflected lineage-defining VOC mutations, yet a subset of mutations associated with successful global transmission was absent from chronic infections. The emergence of these mutations might dictate when variants from chronic infections can dramatically spread onwards. Next, we tested the ability to predict antibody-evasion mutations from patient- and viral-specific features, and found that viral rebound is strongly associated with the emergence of antibody-evasion. We found evidence for dynamic polymorphic viral populations in most patients, suggesting that a compromised immune system selects for antibody-evasion in particular niches in a patient9s body. We suggest that a trade-off exists between antibody-evasion and transmissibility that potentially constrains VOC emergence, and that monitoring chronic infections may be a means to predict future VOCs.
    Keywords covid19
    Language English
    Publishing date 2022-02-28
    Publisher Cold Spring Harbor Laboratory Press
    Document type Article ; Online
    DOI 10.1101/2022.02.17.22270829
    Database COVID19

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  8. Article ; Online: Drivers of within-host genetic diversity in acute infections of viruses.

    Maoz Gelbart / Sheri Harari / Ya'ara Ben-Ari / Talia Kustin / Dana Wolf / Michal Mandelboim / Orna Mor / Pleuni S Pennings / Adi Stern

    PLoS Pathogens, Vol 16, Iss 11, p e

    2020  Volume 1009029

    Abstract: Genetic diversity is the fuel of evolution and facilitates adaptation to novel environments. However, our understanding of what drives differences in the genetic diversity during the early stages of viral infection is somewhat limited. Here, we use ultra- ...

    Abstract Genetic diversity is the fuel of evolution and facilitates adaptation to novel environments. However, our understanding of what drives differences in the genetic diversity during the early stages of viral infection is somewhat limited. Here, we use ultra-deep sequencing to interrogate 43 clinical samples taken from early infections of the human-infecting viruses HIV, RSV and CMV. Hundreds to thousands of virus templates were sequenced per sample, allowing us to reveal dramatic differences in within-host genetic diversity among virus populations. We found that increased diversity was mostly driven by presence of multiple divergent genotypes in HIV and CMV samples, which we suggest reflect multiple transmitted/founder viruses. Conversely, we detected an abundance of low frequency hyper-edited genomes in RSV samples, presumably reflecting defective virus genomes (DVGs). We suggest that RSV is characterized by higher levels of cellular co-infection, which allow for complementation and hence elevated levels of DVGs.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2020-11-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Correction: Modeling suggests that microliter volumes of contaminated blood caused an outbreak of hepatitis C during computerized tomography.

    Shteyer, Eyal / Shekhtman, Louis / Zinger, Tal / Harari, Sheri / Gafanovich, Inna / Wolf, Dana / Ivgi, Hefziba / Barsuk, Rima / Dery, Ilana / Armoni, Daniela / Rivkin, Mila / Pipalia, Rahul / Eliav, Michal Cohen / Skorochod, Yizhak / Breuer, Gabriel S / Tur-Kaspa, Ran / Wiener, Yonit Weil / Stern, Adi / Cotler, Scott J /
    Dahari, Harel / Lurie, Yoav

    PloS one

    2019  Volume 14, Issue 2, Page(s) e0212252

    Abstract: This corrects the article DOI: 10.1371/journal.pone.0210173.]. ...

    Abstract [This corrects the article DOI: 10.1371/journal.pone.0210173.].
    Language English
    Publishing date 2019-02-07
    Publishing country United States
    Document type Published Erratum
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0212252
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Correction

    Eyal Shteyer / Louis Shekhtman / Tal Zinger / Sheri Harari / Inna Gafanovich / Dana Wolf / Hefziba Ivgi / Rima Barsuk / Ilana Dery / Daniela Armoni / Mila Rivkin / Rahul Pipalia / Michal Cohen Eliav / Yizhak Skorochod / Gabriel S Breuer / Ran Tur-Kaspa / Yonit Weil Wiener / Adi Stern / Scott J Cotler /
    Harel Dahari / Yoav Lurie

    PLoS ONE, Vol 14, Iss 2, p e

    Modeling suggests that microliter volumes of contaminated blood caused an outbreak of hepatitis C during computerized tomography.

    2019  Volume 0212252

    Abstract: This corrects the article DOI:10.1371/journal.pone.0210173.]. ...

    Abstract [This corrects the article DOI:10.1371/journal.pone.0210173.].
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2019-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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