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  1. Article ; Online: Cell cycle specific, differentially tagged ribosomal proteins to measure phase specific transcriptomes from asynchronously cycling cells.

    Cochran, Jesse D / Leathers, Tess A / Maldosevic, Emir / Siejda, Klara W / Vitello, Julian / Lee, Haesol / Bradley, Leigh A / Young, Alex / Jomaa, Ahmad / Wolf, Matthew J

    Scientific reports

    2024  Volume 14, Issue 1, Page(s) 1623

    Abstract: Asynchronously cycling cells pose a challenge to the accurate characterization of phase-specific gene expression. Current strategies, including RNAseq, survey the steady state gene expression across the cell cycle and are inherently limited by their ... ...

    Abstract Asynchronously cycling cells pose a challenge to the accurate characterization of phase-specific gene expression. Current strategies, including RNAseq, survey the steady state gene expression across the cell cycle and are inherently limited by their inability to resolve dynamic gene regulatory networks. Single cell RNAseq (scRNAseq) can identify different cell cycle transcriptomes if enough cycling cells are present, however some cells are not amenable to scRNAseq. Therefore, we merged two powerful strategies, the CDT1 and GMNN degrons used in Fluorescent Ubiquitination-based Cell Cycle Indicator (FUCCI) cell cycle sensors and the ribosomal protein epitope tagging used in RiboTrap/Tag technologies to isolate cell cycle phase-specific mRNA for sequencing. The resulting cell cycle dependent, tagged ribosomal proteins (ccTaggedRP) were differentially expressed during the cell cycle, had similar subcellular locations as endogenous ribosomal proteins, incorporated into ribosomes and polysomes, and facilitated the recovery of cell cycle phase-specific RNA for sequencing. ccTaggedRP has broad applications to investigate phase-specific gene expression in complex cell populations.
    MeSH term(s) Cell Cycle Proteins/genetics ; Transcriptome ; Cell Cycle/genetics ; Ribosomal Proteins/genetics ; Ribosomes/genetics
    Chemical Substances Cell Cycle Proteins ; Ribosomal Proteins
    Language English
    Publishing date 2024-01-18
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-024-52085-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Progressive Sub-MIC Exposure of

    Anderson, Jasmine R / Lam, Nghi B / Jackson, Jazmyne L / Dorenkott, Sean M / Ticer, Taylor / Maldosevic, Emir / Velez, Amanda / Camden, Megan R / Ellis, Terri N

    Antibiotics (Basel, Switzerland)

    2023  Volume 12, Issue 5

    Abstract: Bacterial exposure to antibiotic concentrations below the minimum inhibitory concentration (MIC) may result in a selection window allowing for the rapid evolution of resistance. These sub-MIC concentrations are commonly found in soils and water supplies ... ...

    Abstract Bacterial exposure to antibiotic concentrations below the minimum inhibitory concentration (MIC) may result in a selection window allowing for the rapid evolution of resistance. These sub-MIC concentrations are commonly found in soils and water supplies in the greater environment. This study aimed to evaluate the adaptive genetic changes in
    Language English
    Publishing date 2023-05-10
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2681345-2
    ISSN 2079-6382
    ISSN 2079-6382
    DOI 10.3390/antibiotics12050887
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Porin loss in Klebsiella pneumoniae clinical isolates impacts production of virulence factors and survival within macrophages.

    Brunson, Debra N / Maldosevic, Emir / Velez, Amanda / Figgins, Erika / Ellis, Terri N

    International journal of medical microbiology : IJMM

    2019  Volume 309, Issue 3-4, Page(s) 213–224

    Abstract: Clinical isolates of Klebsiella pneumoniae are often resistant to beta-lactam antibiotics via the acquisition of extended spectrum beta lactamase (ESBL) enzymes paired with loss of one or both major outer membrane porins. It has been well established ... ...

    Abstract Clinical isolates of Klebsiella pneumoniae are often resistant to beta-lactam antibiotics via the acquisition of extended spectrum beta lactamase (ESBL) enzymes paired with loss of one or both major outer membrane porins. It has been well established that loss of OmpK35 and/or OmpK36 correlates with increased minimum inhibitory concentrations of antibiotics that target the peptidoglycan. However, little is known concerning the downstream effects porin loss might have on other major virulence factors such as the polysaccharide capsule or LPS. Furthermore, it is unknown whether these cumulative changes impact pathogenesis. Therefore, the focus of this study was to identify alterations in production of the major virulence factors due to porin loss; and to investigate the effect these changes have on host pathogen interactions. Our data demonstrates that loss of a single porin is paired with reductions in capsule, increased LPS content, and up-regulated transcription of compensatory porin genes. In contrast, loss of both porins resulted in a significant increase in capsule production. Loss of OmpK35 alone or dual porin loss was further associated with reduced oxidative burst by macrophages and increased ability of the bacteria to survive phagocytic killing. These data indicate that porin loss is accompanied by a suite of changes in other virulence-associated factors. These cumulative changes act to nullify any negative fitness effect due to lack of the nonspecific porin proteins, allowing the bacteria to grow and survive phagocytic immune responses.
    MeSH term(s) Animals ; Bacterial Capsules/metabolism ; Bacterial Outer Membrane Proteins/genetics ; Bacterial Outer Membrane Proteins/metabolism ; Host-Pathogen Interactions ; Humans ; Klebsiella Infections/microbiology ; Klebsiella pneumoniae/genetics ; Klebsiella pneumoniae/isolation & purification ; Klebsiella pneumoniae/pathogenicity ; Klebsiella pneumoniae/physiology ; Lipopolysaccharides/metabolism ; Macrophages/metabolism ; Macrophages/microbiology ; Mice ; Microbial Viability ; Porins/deficiency ; Porins/genetics ; RAW 264.7 Cells ; Transcription, Genetic ; Virulence Factors/genetics ; Virulence Factors/metabolism ; beta-Lactamases/genetics ; beta-Lactamases/metabolism
    Chemical Substances Bacterial Outer Membrane Proteins ; Lipopolysaccharides ; Porins ; Virulence Factors ; beta-Lactamases (EC 3.5.2.6)
    Language English
    Publishing date 2019-04-16
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 2006518-8
    ISSN 1618-0607 ; 1438-4221
    ISSN (online) 1618-0607
    ISSN 1438-4221
    DOI 10.1016/j.ijmm.2019.04.001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: AT-101 Enhances the Antitumor Activity of Lenalidomide in Patients with Multiple Myeloma.

    Ailawadhi, Sikander / Parrondo, Ricardo D / Dutta, Navnita / Han, Bing / Ciccio, Gina / Cherukuri, Yesesri / Alegria, Victoria R / LaPlant, Betsy R / Roy, Vivek / Sher, Taimur / Edwards, Brett / Lanier, Stephanie / Manna, Alak / Heslop, Keisha / Caulfield, Thomas / Maldosevic, Emir / Storz, Peter / Manochakian, Rami / Asmann, Yan /
    Chanan-Khan, Asher A / Paulus, Aneel

    Cancers

    2023  Volume 15, Issue 2

    Abstract: Bcl-2 and Mcl-1 proteins play a role in multiple myeloma (MM) cell survival, for which targeted inhibitors are being developed. AT-101 is an oral drug, which disrupts Bcl-2 and Mcl-1 function, impedes mitochondrial bioenergetic processes and induces ... ...

    Abstract Bcl-2 and Mcl-1 proteins play a role in multiple myeloma (MM) cell survival, for which targeted inhibitors are being developed. AT-101 is an oral drug, which disrupts Bcl-2 and Mcl-1 function, impedes mitochondrial bioenergetic processes and induces apoptosis in MM cells. When combined with lenalidomide and dexamethasone (Rd), AT-101 significantly reduced tumor burden in an in vivo xenograft model of MM. These data provided rationale for a phase I/II study to establish the effective dose of AT-101 in combination with Rd (ARd regimen) in relapsed/refractory MM. A total of 10 patients were enrolled, most with high-risk cytogenetics (80%) and prior stem cell transplant (70%). Three patients were lenalidomide-refractory, 2 were bortezomib-refractory and 3 were daratumumab-refractory. The ARd combination was well tolerated with most common grade 3/4 adverse events being cytopenia's. The overall response rate was 40% and clinical benefit rate was 90%. The median progression free survival was 14.9 months (95% CI 7.1-NE). Patients responsive to ARd showed a decrease in Bcl-2:Bim or Mcl-1:Noxa protein complexes, increased CD8+ T and NK cells and depletion of T and B-regulatory cells. The ARd regimen demonstrated an acceptable safety profile and promising efficacy in patients with relapsed/refractory MM prompting further investigation in additional patients.
    Language English
    Publishing date 2023-01-12
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers15020477
    Database MEDical Literature Analysis and Retrieval System OnLINE

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