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  1. Article ; Online: The antibiotic resistance reservoir of the lung microbiome expands with age in a population of critically ill patients.

    Chu, Victoria T / Tsitsiklis, Alexandra / Mick, Eran / Ambroggio, Lilliam / Kalantar, Katrina L / Glascock, Abigail / Osborne, Christina M / Wagner, Brandie D / Matthay, Michael A / DeRisi, Joseph L / Calfee, Carolyn S / Mourani, Peter M / Langelier, Charles R

    Nature communications

    2024  Volume 15, Issue 1, Page(s) 92

    Abstract: Antimicrobial resistant lower respiratory tract infections are an increasing public health threat and an important cause of global mortality. The lung microbiome can influence susceptibility of respiratory tract infections and represents an important ... ...

    Abstract Antimicrobial resistant lower respiratory tract infections are an increasing public health threat and an important cause of global mortality. The lung microbiome can influence susceptibility of respiratory tract infections and represents an important reservoir for exchange of antimicrobial resistance genes. Studies of the gut microbiome have found an association between age and increasing antimicrobial resistance gene burden, however, corollary studies in the lung microbiome remain absent. We performed an observational study of children and adults with acute respiratory failure admitted to the intensive care unit. From tracheal aspirate RNA sequencing data, we evaluated age-related differences in detectable antimicrobial resistance gene expression in the lung microbiome. Using a multivariable logistic regression model, we find that detection of antimicrobial resistance gene expression was significantly higher in adults compared with children after adjusting for demographic and clinical characteristics. This association remained significant after additionally adjusting for lung bacterial microbiome characteristics, and when modeling age as a continuous variable. The proportion of adults expressing beta-lactam, aminoglycoside, and tetracycline antimicrobial resistance genes was higher compared to children. Together, these findings shape our understanding of the lung resistome in critically ill patients across the lifespan, which may have implications for clinical management and global public health.
    MeSH term(s) Adult ; Child ; Humans ; Critical Illness ; Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/therapeutic use ; Microbiota/genetics ; Lung ; Drug Resistance, Microbial/genetics ; Respiratory Tract Infections/drug therapy
    Chemical Substances Anti-Bacterial Agents
    Language English
    Publishing date 2024-01-02
    Publishing country England
    Document type Observational Study ; Journal Article
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-44353-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Molecular Phenotypes of Acute Respiratory Distress Syndrome in the ROSE Trial Have Differential Outcomes and Gene Expression Patterns That Differ at Baseline and Longitudinally over Time.

    Sinha, Pratik / Neyton, Lucile / Sarma, Aartik / Wu, Nelson / Jones, Chayse / Zhuo, Hanjing / Liu, Kathleen D / Sanchez Guerrero, Estella / Ghale, Rajani / Love, Christina / Mick, Eran / Delucchi, Kevin L / Langelier, Charles R / Thompson, B Taylor / Matthay, Michael A / Calfee, Carolyn S

    American journal of respiratory and critical care medicine

    2024  Volume 209, Issue 7, Page(s) 816–828

    Abstract: Rationale: ...

    Abstract Rationale:
    MeSH term(s) Humans ; Phenotype ; Biomarkers ; Respiratory Distress Syndrome ; Blood Proteins/genetics ; Gene Expression
    Chemical Substances Biomarkers ; Blood Proteins
    Language English
    Publishing date 2024-01-26
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1180953-x
    ISSN 1535-4970 ; 0003-0805 ; 1073-449X
    ISSN (online) 1535-4970
    ISSN 0003-0805 ; 1073-449X
    DOI 10.1164/rccm.202308-1490OC
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The antibiotic resistance reservoir of the lung microbiome expands with age in a population of critically ill patients

    Victoria T. Chu / Alexandra Tsitsiklis / Eran Mick / Lilliam Ambroggio / Katrina L. Kalantar / Abigail Glascock / Christina M. Osborne / Brandie D. Wagner / Michael A. Matthay / Joseph L. DeRisi / Carolyn S. Calfee / Peter M. Mourani / Charles R. Langelier

    Nature Communications, Vol 15, Iss 1, Pp 1-

    2024  Volume 10

    Abstract: Abstract Antimicrobial resistant lower respiratory tract infections are an increasing public health threat and an important cause of global mortality. The lung microbiome can influence susceptibility of respiratory tract infections and represents an ... ...

    Abstract Abstract Antimicrobial resistant lower respiratory tract infections are an increasing public health threat and an important cause of global mortality. The lung microbiome can influence susceptibility of respiratory tract infections and represents an important reservoir for exchange of antimicrobial resistance genes. Studies of the gut microbiome have found an association between age and increasing antimicrobial resistance gene burden, however, corollary studies in the lung microbiome remain absent. We performed an observational study of children and adults with acute respiratory failure admitted to the intensive care unit. From tracheal aspirate RNA sequencing data, we evaluated age-related differences in detectable antimicrobial resistance gene expression in the lung microbiome. Using a multivariable logistic regression model, we find that detection of antimicrobial resistance gene expression was significantly higher in adults compared with children after adjusting for demographic and clinical characteristics. This association remained significant after additionally adjusting for lung bacterial microbiome characteristics, and when modeling age as a continuous variable. The proportion of adults expressing beta-lactam, aminoglycoside, and tetracycline antimicrobial resistance genes was higher compared to children. Together, these findings shape our understanding of the lung resistome in critically ill patients across the lifespan, which may have implications for clinical management and global public health.
    Keywords Science ; Q
    Subject code 610
    Language English
    Publishing date 2024-01-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Distinct mitochondrial defects trigger the integrated stress response depending on the metabolic state of the cell.

    Mick, Eran / Titov, Denis V / Skinner, Owen S / Sharma, Rohit / Jourdain, Alexis A / Mootha, Vamsi K

    eLife

    2020  Volume 9

    Abstract: Mitochondrial dysfunction is associated with activation of the integrated stress response (ISR) but the underlying triggers remain unclear. We systematically combined acute mitochondrial inhibitors with genetic tools for compartment-specific NADH ... ...

    Abstract Mitochondrial dysfunction is associated with activation of the integrated stress response (ISR) but the underlying triggers remain unclear. We systematically combined acute mitochondrial inhibitors with genetic tools for compartment-specific NADH oxidation to trace mechanisms linking different forms of mitochondrial dysfunction to the ISR in proliferating mouse myoblasts and in differentiated myotubes. In myoblasts, we find that impaired NADH oxidation upon electron transport chain (ETC) inhibition depletes asparagine, activating the ISR via the eIF2α kinase GCN2. In myotubes, however, impaired NADH oxidation following ETC inhibition neither depletes asparagine nor activates the ISR, reflecting an altered metabolic state. ATP synthase inhibition in myotubes triggers the ISR via a distinct mechanism related to mitochondrial inner-membrane hyperpolarization. Our work dispels the notion of a universal path linking mitochondrial dysfunction to the ISR, instead revealing multiple paths that depend both on the nature of the mitochondrial defect and on the metabolic state of the cell.
    MeSH term(s) Animals ; Asparagine/metabolism ; Cell Line ; Humans ; Metabolome/genetics ; Metabolome/physiology ; Mice ; Mitochondria/metabolism ; Mitochondria/pathology ; Muscle Fibers, Skeletal/metabolism ; Myoblasts/metabolism ; NAD/metabolism ; Oxidation-Reduction ; Stress, Physiological/genetics ; Stress, Physiological/physiology ; Transcriptome/genetics ; Transcriptome/physiology
    Chemical Substances NAD (0U46U6E8UK) ; Asparagine (7006-34-0)
    Language English
    Publishing date 2020-05-28
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.49178
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: The antibiotic resistance reservoir of the lung microbiome expands with age.

    Chu, Victoria T / Tsitsiklis, Alexandra / Mick, Eran / Ambroggio, Lilliam / Kalantar, Katrina L / Glascock, Abigail / Osborne, Christina M / Wagner, Brandie D / Matthay, Michael A / DeRisi, Joseph L / Calfee, Carolyn S / Mourani, Peter M / Langelier, Charles R

    Research square

    2023  

    Abstract: Antimicrobial resistant lower respiratory tract infections (LRTI) are an increasing public health threat, and an important cause of global mortality. The lung microbiome influences LRTI susceptibility and represents an important reservoir for exchange of ...

    Abstract Antimicrobial resistant lower respiratory tract infections (LRTI) are an increasing public health threat, and an important cause of global mortality. The lung microbiome influences LRTI susceptibility and represents an important reservoir for exchange of antimicrobial resistance genes (ARGs). Studies of the gut microbiome have found an association between age and increasing antimicrobial resistance gene (ARG) burden, however corollary studies in the lung microbiome remain absent, despite the respiratory tract representing one of the most clinically significant sites for drug resistant infections. We performed a prospective, multicenter observational study of 261 children and 88 adults with acute respiratory failure, ranging in age from 31 days to ≥ 89 years, admitted to intensive care units in the United States. We performed RNA sequencing on tracheal aspirates collected within 72 hours of intubation, and evaluated age-related differences in detectable ARG expression in the lung microbiome as a primary outcome. Secondary outcomes included number and classes of ARGs detected, proportion of patients with an ARG class, and composition of the lung microbiome. Multivariable logistic regression models (adults vs children) or continuous age (years) were adjusted for sex, race/ethnicity, LRTI status, and days from intubation to specimen collection. Detection of ARGs was significantly higher in adults compared with children after adjusting for sex, race/ethnicity, LRTI diagnosis, and days from intubation to specimen collection (adjusted odds ratio (aOR): 2.16, 95% confidence interval (CI): 1.10-4.22). A greater proportion of adults compared with children had beta-lactam ARGs (31% (CI: 21-41%) vs 13% (CI: 10-18%)), aminoglycoside ARGs (20% (CI: 13-30%) vs 2% (CI: 0.6-4%)), and tetracycline ARGs (14% (CI: 7-23%) vs 3% (CI: 1-5%)). Adults ≥70 years old had the highest proportion of these three ARG classes. The total bacterial abundance of the lung microbiome increased with age, and microbiome alpha diversity varied with age. Taxonomic composition of the lung microbiome, measured by Bray Curtis dissimilarity index, differed between adults and children (p = 0.003). The association between age and increased ARG detection remained significant after additionally including lung microbiome total bacterial abundance and alpha diversity in the multivariable logistic regression model (aOR: 2.38, (CI: 1.25-4.54)). Furthermore, this association remained robust when modeling age as a continuous variable (aOR: 1.02, (CI: 1.01-1.03) per year of age). Taken together, our results demonstrate that age is an independent risk factor for ARG detection in the lower respiratory tract microbiome. These data shape our understanding of the lung resistome in critically ill patients across the lifespan, which may have implications for clinical management and global public health.
    Language English
    Publishing date 2023-09-18
    Publishing country United States
    Document type Preprint
    DOI 10.21203/rs.3.rs-3283415/v1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: High-resolution metagenomics.

    Mick, Eran / Sorek, Rotem

    Nature biotechnology

    2014  Volume 32, Issue 8, Page(s) 750–751

    MeSH term(s) Metagenomics ; Microbiota
    Language English
    Publishing date 2014-08-07
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1311932-1
    ISSN 1546-1696 ; 1087-0156
    ISSN (online) 1546-1696
    ISSN 1087-0156
    DOI 10.1038/nbt.2962
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  7. Article ; Online: Exploring the In Vivo Role of the Mitochondrial Calcium Uniporter in Brown Fat Bioenergetics.

    Flicker, Daniel / Sancak, Yasemin / Mick, Eran / Goldberger, Olga / Mootha, Vamsi K

    Cell reports

    2019  Volume 27, Issue 5, Page(s) 1364–1375.e5

    Abstract: The mitochondrial calcium uniporter has been proposed to coordinate the organelle's energetics with calcium signaling. Uniporter current has previously been reported to be extremely high in brown adipose tissue (BAT), yet it remains unknown how the ... ...

    Abstract The mitochondrial calcium uniporter has been proposed to coordinate the organelle's energetics with calcium signaling. Uniporter current has previously been reported to be extremely high in brown adipose tissue (BAT), yet it remains unknown how the uniporter contributes to BAT physiology. Here, we report the generation and characterization of a mouse model lacking Mcu, the pore forming subunit of the uniporter, specifically in BAT (BAT-Mcu-KO). BAT-Mcu-KO mice lack uniporter-based calcium uptake in BAT mitochondria but exhibit unaffected cold tolerance, diet-induced obesity, and transcriptional response to cold in BAT. Unexpectedly, we found in wild-type animals that cold powerfully activates the ATF4-dependent integrated stress response (ISR) in BAT and upregulates circulating FGF21 and GDF15, raising the hypothesis that the ISR partly underlies the pleiotropic effects of BAT on systemic metabolism. Our study demonstrates that the uniporter is largely dispensable for BAT thermogenesis and demonstrates activation of the ISR in BAT in response to cold.
    MeSH term(s) Activating Transcription Factor 4/metabolism ; Adipose Tissue, Brown/metabolism ; Animals ; Calcium/metabolism ; Calcium Channels/genetics ; Cell Line ; Cold-Shock Response ; Diet, High-Fat/adverse effects ; Energy Metabolism ; Female ; Fibroblast Growth Factors/genetics ; Fibroblast Growth Factors/metabolism ; Growth Differentiation Factor 15/genetics ; Growth Differentiation Factor 15/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/metabolism ; Mitochondrial Proteins/genetics ; Obesity/etiology ; Obesity/genetics ; Thermogenesis
    Chemical Substances Atf4 protein, mouse ; Calcium Channels ; Gdf15 protein, mouse ; Growth Differentiation Factor 15 ; Mcu protein, mouse ; Mitochondrial Proteins ; fibroblast growth factor 21 ; Activating Transcription Factor 4 (145891-90-3) ; Fibroblast Growth Factors (62031-54-3) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2019-05-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2019.04.013
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Exploring the In Vivo Role of the Mitochondrial Calcium Uniporter in Brown Fat Bioenergetics

    Daniel Flicker / Yasemin Sancak / Eran Mick / Olga Goldberger / Vamsi K. Mootha

    Cell Reports, Vol 27, Iss 5, Pp 1364-1375.e

    2019  Volume 5

    Abstract: Summary: The mitochondrial calcium uniporter has been proposed to coordinate the organelle’s energetics with calcium signaling. Uniporter current has previously been reported to be extremely high in brown adipose tissue (BAT), yet it remains unknown how ... ...

    Abstract Summary: The mitochondrial calcium uniporter has been proposed to coordinate the organelle’s energetics with calcium signaling. Uniporter current has previously been reported to be extremely high in brown adipose tissue (BAT), yet it remains unknown how the uniporter contributes to BAT physiology. Here, we report the generation and characterization of a mouse model lacking Mcu, the pore forming subunit of the uniporter, specifically in BAT (BAT-Mcu-KO). BAT-Mcu-KO mice lack uniporter-based calcium uptake in BAT mitochondria but exhibit unaffected cold tolerance, diet-induced obesity, and transcriptional response to cold in BAT. Unexpectedly, we found in wild-type animals that cold powerfully activates the ATF4-dependent integrated stress response (ISR) in BAT and upregulates circulating FGF21 and GDF15, raising the hypothesis that the ISR partly underlies the pleiotropic effects of BAT on systemic metabolism. Our study demonstrates that the uniporter is largely dispensable for BAT thermogenesis and demonstrates activation of the ISR in BAT in response to cold. : Flicker et al. generate a mouse lacking mitochondrial calcium uniporter activity in brown fat. They show that the uniporter is dispensable for brown fat bioenergetics. Unexpectedly, they find that in wild type animals, cold stress induces ATF4 signaling in normal brown fat, suggesting a mechanism for cold-induced GDF15 and FGF21 elevation. Keywords: mitochondria, calcium, uniporter, MCU, brown fat, thermogenesis, ATF4, integrated stress response, FGF21, GDF15
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2019-04-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Plasma metabolic profiling implicates dysregulated lipid metabolism and glycolytic shift in hyperinflammatory ARDS.

    Alipanah-Lechner, Narges / Neyton, Lucile / Mick, Eran / Willmore, Andrew / Leligdowicz, Aleksandra / Contrepois, Kévin / Jauregui, Alejandra / Zhuo, Hanjing / Hendrickson, Carolyn / Gomez, Antonio / Sinha, Pratik / Kangelaris, Kirsten N / Liu, Kathleen D / Matthay, Michael A / Rogers, Angela J / Calfee, Carolyn S

    American journal of physiology. Lung cellular and molecular physiology

    2023  Volume 324, Issue 3, Page(s) L297–L306

    Abstract: Using latent class analysis (LCA) of clinical and protein biomarkers, researchers have identified two phenotypes of the acute respiratory distress syndrome (ARDS) with divergent clinical trajectories and treatment responses. We investigated whether ... ...

    Abstract Using latent class analysis (LCA) of clinical and protein biomarkers, researchers have identified two phenotypes of the acute respiratory distress syndrome (ARDS) with divergent clinical trajectories and treatment responses. We investigated whether plasma metabolites differed among patients with LCA-derived hyperinflammatory and hypoinflammatory ARDS, and we tested the prognostic utility of adding metabolic clusters to LCA phenotypes. We analyzed data from 93 patients with ARDS and sepsis enrolled in a multicenter prospective cohort of critically ill patients, comparing 970 metabolites between the two LCA-derived phenotypes. In all, 188 metabolites were differentially abundant between the two LCA-derived phenotypes. After adjusting for age, sex, confounding medications, and comorbid liver and kidney disease, 82 metabolites remained significantly different. Patients with hyperinflammatory ARDS had reduced circulating lipids but high levels of pyruvate, lactate, and malate. Metabolic cluster and LCA-derived phenotypes were each significantly and independently associated with survival. Patients with hyperinflammatory ARDS may be experiencing a glycolytic shift leading to dysregulated lipid metabolism. Metabolic profiling offers prognostic information beyond what is captured by LCA phenotypes alone. Deeper biological profiling may identify key differences in pathogenesis among patients with ARDS and may lead to novel targeted therapies.
    MeSH term(s) Humans ; Prospective Studies ; Lipid Metabolism ; Biomarkers ; Phenotype ; Respiratory Distress Syndrome/therapy
    Chemical Substances Biomarkers
    Language English
    Publishing date 2023-01-17
    Publishing country United States
    Document type Multicenter Study ; Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1013184-x
    ISSN 1522-1504 ; 1040-0605
    ISSN (online) 1522-1504
    ISSN 1040-0605
    DOI 10.1152/ajplung.00278.2022
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Distinct mitochondrial defects trigger the integrated stress response depending on the metabolic state of the cell

    Eran Mick / Denis V Titov / Owen S Skinner / Rohit Sharma / Alexis A Jourdain / Vamsi K Mootha

    eLife, Vol

    2020  Volume 9

    Abstract: Mitochondrial dysfunction is associated with activation of the integrated stress response (ISR) but the underlying triggers remain unclear. We systematically combined acute mitochondrial inhibitors with genetic tools for compartment-specific NADH ... ...

    Abstract Mitochondrial dysfunction is associated with activation of the integrated stress response (ISR) but the underlying triggers remain unclear. We systematically combined acute mitochondrial inhibitors with genetic tools for compartment-specific NADH oxidation to trace mechanisms linking different forms of mitochondrial dysfunction to the ISR in proliferating mouse myoblasts and in differentiated myotubes. In myoblasts, we find that impaired NADH oxidation upon electron transport chain (ETC) inhibition depletes asparagine, activating the ISR via the eIF2α kinase GCN2. In myotubes, however, impaired NADH oxidation following ETC inhibition neither depletes asparagine nor activates the ISR, reflecting an altered metabolic state. ATP synthase inhibition in myotubes triggers the ISR via a distinct mechanism related to mitochondrial inner-membrane hyperpolarization. Our work dispels the notion of a universal path linking mitochondrial dysfunction to the ISR, instead revealing multiple paths that depend both on the nature of the mitochondrial defect and on the metabolic state of the cell.
    Keywords integrated stress response ; mitochondria ; metabolism ; ATF4 ; GCN2 ; p53 ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2020-05-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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