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  1. Article: Systemic Transplantation of Adult Multipotent Stem Cells Functionally Rejuvenates Aged Articular Cartilage.

    Thompson, Seth D / Pichika, Rajeswari / Lieber, Richard L / Budinger, G R Scott / Lavasani, Mitra

    Aging and disease

    2021  Volume 12, Issue 3, Page(s) 726–731

    Abstract: Osteoarthritis (OA) is the most common and debilitating joint disease of advanced age and has no universally effective therapy. Here, we demonstrate that systemic transplantation of adult multipotent muscle-derived stem/progenitor cells (MDSPCs)-isolated ...

    Abstract Osteoarthritis (OA) is the most common and debilitating joint disease of advanced age and has no universally effective therapy. Here, we demonstrate that systemic transplantation of adult multipotent muscle-derived stem/progenitor cells (MDSPCs)-isolated from young mice-rejuvenates the knee articular cartilage (AC) of naturally aged mice. This intervention reduced expression of pro-inflammatory cytokines (
    Language English
    Publishing date 2021-06-01
    Publishing country United States
    Document type Journal Article
    ISSN 2152-5250
    ISSN 2152-5250
    DOI 10.14336/AD.2020.1118
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Neurodevelopmental and synaptic defects in DNAJC6 parkinsonism, amenable to gene therapy.

    Abela, Lucia / Gianfrancesco, Lorita / Tagliatti, Erica / Rossignoli, Giada / Barwick, Katy / Zourray, Clara / Reid, Kimberley M / Budinger, Dimitri / Ng, Joanne / Counsell, John / Simpson, Arlo / Pearson, Toni S / Edvardson, Simon / Elpeleg, Orly / Brodsky, Frances M / Lignani, Gabriele / Barral, Serena / Kurian, Manju A

    Brain : a journal of neurology

    2024  

    Abstract: DNAJC6 encodes auxilin, a co-chaperone protein involved in clathrin-mediated endocytosis (CME) at the presynaptic terminal. Biallelic mutations in DNAJC6 cause a complex, early-onset neurodegenerative disorder characterized by rapidly progressive ... ...

    Abstract DNAJC6 encodes auxilin, a co-chaperone protein involved in clathrin-mediated endocytosis (CME) at the presynaptic terminal. Biallelic mutations in DNAJC6 cause a complex, early-onset neurodegenerative disorder characterized by rapidly progressive parkinsonism-dystonia in childhood. The disease is commonly associated with additional neurodevelopmental, neurological and neuropsychiatric features. Currently, there are no disease-modifying treatments for this condition, resulting in significant morbidity and risk of premature mortality. To investigate the underlying disease mechanisms in childhood-onset DNAJC6 parkinsonism, we generated induced pluripotent stem cells (iPSC) from three patients harboring pathogenic loss-of-function DNAJC6 mutations and subsequently developed a midbrain dopaminergic (mDA) neuronal model of disease. When compared to age-matched and CRISPR-corrected isogenic controls, the neuronal cell model revealed disease-specific auxilin deficiency as well as disturbance of synaptic vesicle (SV) recycling and homeostasis. We also observed neurodevelopmental dysregulation affecting ventral midbrain patterning and neuronal maturation. In order to explore the feasibility of a viral vector-mediated gene therapy approach, iPSC-derived neuronal cultures were treated with lentiviral DNAJC6 gene transfer, which restored auxilin expression and rescued CME. Our patient-derived neuronal model provides deeper insights into the molecular mechanisms of auxilin deficiency as well as a robust platform for the development of targeted precision therapy approaches.
    Language English
    Publishing date 2024-01-18
    Publishing country England
    Document type Journal Article
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awae020
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The Third Annual Symposium of the Midwest Aging Consortium.

    Keller, Andrea / Bai, Hua / Budinger, Scott / Eliazer, Susan / Hansen, Malene / Konopka, Adam R / Morales-Nebreda, Luisa / Najt, Charles P / Prahlad, Veena / Victorelli, Stella / Vorland, Colby J / Yuan, Rong / Rhoads, Timothy W / Mihaylova, Maria M

    The journals of gerontology. Series A, Biological sciences and medical sciences

    2023  Volume 79, Issue 2

    Abstract: The geroscience hypothesis suggests that addressing the fundamental mechanisms driving aging biology will prevent or mitigate the onset of multiple chronic diseases, for which the largest risk factor is advanced age. Research that investigates the root ... ...

    Abstract The geroscience hypothesis suggests that addressing the fundamental mechanisms driving aging biology will prevent or mitigate the onset of multiple chronic diseases, for which the largest risk factor is advanced age. Research that investigates the root causes of aging is therefore of critical importance given the rising healthcare burden attributable to age-related diseases. The third annual Midwest Aging Consortium symposium was convened as a showcase of such research performed by investigators from institutions across the Midwestern United States. This report summarizes the work presented during a virtual conference across topics in aging biology, including immune function in the lung-particularly timely given the Corona Virus Immune Disease-2019 pandemic-along with the role of metabolism and nutrient-regulated pathways in cellular function with age, the influence of senescence on stem cell function and inflammation, and our evolving understanding of the mechanisms underlying observation of sex dimorphism in aging-related outcomes. The symposium focused on early-stage and emerging investigators, while including keynote presentations from leaders in the biology of aging field, highlighting the diversity and strength of aging research in the Midwest.
    MeSH term(s) Humans ; Aging/physiology ; Multiple Chronic Conditions ; Inflammation ; Lung ; Geroscience
    Language English
    Publishing date 2023-10-05
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1223643-3
    ISSN 1758-535X ; 1079-5006
    ISSN (online) 1758-535X
    ISSN 1079-5006
    DOI 10.1093/gerona/glad239
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Brain N-acetyl-L-aspartic acid in Alzheimer's disease: a proton magnetic resonance spectroscopy study.

    Kwo-On-Yuen, P F / Newmark, R D / Budinger, T F / Kaye, J A / Ball, M J / Jagust, W J

    Brain research

    1994  Volume 667, Issue 2, Page(s) 167–174

    Abstract: This study was performed in order to measure changes in brain N-acetyl-L-aspartic acid (NAA ...

    Abstract This study was performed in order to measure changes in brain N-acetyl-L-aspartic acid (NAA) in post-mortem brain tissue in Alzheimer's disease (AD) in comparison to normal control subjects using the technique of magnetic resonance spectroscopy. Brain tissue was obtained at autopsy and frozen until use, from seven patients diagnosed according to current research criteria for AD and 7 control subjects. Detailed clinical evaluations were available for all the dementia cases. Representative brain samples were obtained from three neocortical regions and a limbic region (parahippocampal gyrus) in white and grey matter. NAA was quantified on perchloric acid extracts using proton nuclear magnetic resonance (NMR) spectroscopy. Regional NAA did not vary significantly with age. In AD, reductions were present in the grey matter of the neocortex but not in the white matter. Within the parahippocampal gyrus there were reductions in both tissue types; only cortical levels correlated with clinical scales of dementia severity. A pattern of increasing correlation was observed between dementia severity as measured by the mini mental state examination during life and NAA levels from brain areas of increasing pathological predilection in AD. These post-mortem studies show reductions in brain NAA in AD which correlate with dementia severity during life and which support the use of future in vivo NAA spectroscopic images in the evaluation of AD patients.
    MeSH term(s) Aged ; Aged, 80 and over ; Alzheimer Disease/enzymology ; Alzheimer Disease/pathology ; Aspartic Acid/analogs & derivatives ; Aspartic Acid/metabolism ; Cerebral Cortex/enzymology ; Cerebral Cortex/pathology ; Female ; Hippocampus/enzymology ; Hippocampus/pathology ; Humans ; Magnetic Resonance Spectroscopy ; Male ; Middle Aged
    Chemical Substances Aspartic Acid (30KYC7MIAI) ; N-acetylaspartate (997-55-7)
    Language English
    Publishing date 1994-12-26
    Publishing country Netherlands
    Document type Journal Article ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 1200-2
    ISSN 1872-6240 ; 0006-8993
    ISSN (online) 1872-6240
    ISSN 0006-8993
    DOI 10.1016/0006-8993(94)91494-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Book ; Thesis: In vitro-Charakterisierung peripherer und kutaner T-Lymphozyten bei zellvermittelten und humoralen Immunantworten (am Beispiel des bullösen Pemphigoids und der Nickel-Allergie)

    Büdinger, Lioba

    2000  

    Author's details vorgelegt von Lioba Büdinger
    Language German
    Size 86 S, graph. Darst
    Document type Book ; Thesis
    Thesis / German Habilitation thesis Techn. Hochsch., Diss.--Aachen, 2000
    Database Former special subject collection: coastal and deep sea fishing

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  6. Book ; Thesis: In vitro-Charakterisierung peripherer und kutaner T-Lymphozyten bei zellvermittelten und humoralen Immunantworten (am Beispiel des bullösen Pemphigoids und der Nickel-Allergie)

    Büdinger, Lioba

    2000  

    Author's details vorgelegt von Lioba Büdinger
    Language German
    Size 86 S, graph. Darst
    Document type Book ; Thesis
    Thesis / German Habilitation thesis Techn. Hochsch., Diss.--Aachen, 2000
    Database Library catalogue of the German National Library of Science and Technology (TIB), Hannover

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  7. Article ; Online: Prolonged exposure to lung-derived cytokines is associated with activation of microglia in patients with COVID-19.

    Grant, Rogan A / Poor, Taylor A / Sichizya, Lango / Diaz, Estefani / Bailey, Joseph I / Soni, Sahil / Senkow, Karolina J / Pérez-Leonor, Xóchitl G / Abdala-Valencia, Hiam / Lu, Ziyan / Donnelly, Helen K / Simons, Lacy M / Ozer, Egon A / Tighe, Robert M / Lomasney, Jon W / Wunderink, Richard G / Singer, Benjamin D / Misharin, Alexander V / Budinger, G R Scott

    JCI insight

    2024  Volume 9, Issue 8

    Abstract: BACKGROUNDSurvivors of pneumonia, including SARS-CoV-2 pneumonia, are at increased risk for cognitive dysfunction and dementia. In rodent models, cognitive dysfunction following pneumonia has been linked to the systemic release of lung-derived pro- ... ...

    Abstract BACKGROUNDSurvivors of pneumonia, including SARS-CoV-2 pneumonia, are at increased risk for cognitive dysfunction and dementia. In rodent models, cognitive dysfunction following pneumonia has been linked to the systemic release of lung-derived pro-inflammatory cytokines. Microglia are poised to respond to inflammatory signals from the circulation, and their dysfunction has been linked to cognitive impairment in murine models of dementia and in humans.METHODSWe measured levels of 55 cytokines and chemokines in bronchoalveolar lavage fluid and plasma from 341 patients with respiratory failure and 13 healthy controls, including 93 unvaccinated patients with COVID-19 and 203 patients with other causes of pneumonia. We used flow cytometry to sort neuroimmune cells from postmortem brain tissue from 5 patients who died from COVID-19 and 3 patients who died from other causes for single-cell RNA-sequencing.RESULTSMicroglia from patients with COVID-19 exhibited a transcriptomic signature suggestive of their activation by circulating pro-inflammatory cytokines. Peak levels of pro-inflammatory cytokines were similar in patients with pneumonia irrespective of etiology, but cumulative cytokine exposure was higher in patients with COVID-19. Treatment with corticosteroids reduced expression of COVID-19-specific cytokines.CONCLUSIONProlonged lung inflammation results in sustained elevations in circulating cytokines in patients with SARS-CoV-2 pneumonia compared with those with pneumonia secondary to other pathogens. Microglia from patients with COVID-19 exhibit transcriptional responses to inflammatory cytokines. These findings support data from rodent models causally linking systemic inflammation with cognitive dysfunction in pneumonia and support further investigation into the role of microglia in pneumonia-related cognitive dysfunction.FUNDINGSCRIPT U19AI135964, UL1TR001422, P01AG049665, P01HL154998, R01HL149883, R01LM013337, R01HL153122, R01HL147290, R01HL147575, R01HL158139, R01ES034350, R01ES027574, I01CX001777, U01TR003528, R21AG075423, T32AG020506, F31AG071225, T32HL076139.
    MeSH term(s) Humans ; COVID-19/immunology ; COVID-19/complications ; Microglia/metabolism ; Microglia/immunology ; Cytokines/metabolism ; Cytokines/blood ; Male ; Female ; Middle Aged ; SARS-CoV-2 ; Aged ; Lung/immunology ; Lung/pathology ; Lung/virology ; Lung/metabolism ; Bronchoalveolar Lavage Fluid/immunology ; Bronchoalveolar Lavage Fluid/cytology ; Cognitive Dysfunction/immunology ; Cognitive Dysfunction/metabolism ; Adult ; Brain/metabolism ; Brain/immunology ; Brain/pathology
    Chemical Substances Cytokines
    Language English
    Publishing date 2024-03-19
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.178859
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Cardiac glycosides restore autophagy flux in an iPSC-derived neuronal model of WDR45 deficiency.

    Papandreou, Apostolos / Singh, Nivedita / Gianfrancesco, Lorita / Budinger, Dimitri / Barwick, Katy / Agrotis, Alexander / Luft, Christin / Shao, Ying / Lenaerts, An-Sofie / Gregory, Allison / Jeong, Suh Young / Hogarth, Penelope / Hayflick, Susan / Barral, Serena / Kriston-Vizi, Janos / Gissen, Paul / Kurian, Manju A / Ketteler, Robin

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Beta-Propeller Protein-Associated Neurodegeneration (BPAN) is one of the commonest forms of Neurodegeneration with Brain Iron Accumulation, caused by mutations in the gene encoding the autophagy-related protein, WDR45. The mechanisms linking autophagy, ... ...

    Abstract Beta-Propeller Protein-Associated Neurodegeneration (BPAN) is one of the commonest forms of Neurodegeneration with Brain Iron Accumulation, caused by mutations in the gene encoding the autophagy-related protein, WDR45. The mechanisms linking autophagy, iron overload and neurodegeneration in BPAN are poorly understood and, as a result, there are currently no disease-modifying treatments for this progressive disorder. We have developed a patient-derived, induced pluripotent stem cell (iPSC)-based midbrain dopaminergic neuronal cell model of BPAN (3 patient, 2 age-matched controls and 2 isogenic control lines) which shows defective autophagy and aberrant gene expression in key neurodegenerative, neurodevelopmental and collagen pathways. A high content imaging-based medium-throughput blinded drug screen using the FDA-approved Prestwick library identified 5 cardiac glycosides that both corrected disease-related defective autophagosome formation and restored BPAN-specific gene expression profiles. Our findings have clear translational potential and emphasise the utility of iPSC-based modelling in elucidating disease pathophysiology and identifying targeted therapeutics for early-onset monogenic disorders.
    Language English
    Publishing date 2023-09-13
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.09.13.556416
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Mitochondrial integrated stress response controls lung epithelial cell fate.

    Han, SeungHye / Lee, Minho / Shin, Youngjin / Giovanni, Regina / Chakrabarty, Ram P / Herrerias, Mariana M / Dada, Laura A / Flozak, Annette S / Reyfman, Paul A / Khuder, Basil / Reczek, Colleen R / Gao, Lin / Lopéz-Barneo, José / Gottardi, Cara J / Budinger, G R Scott / Chandel, Navdeep S

    Nature

    2023  Volume 620, Issue 7975, Page(s) 890–897

    Abstract: Alveolar epithelial type 1 (AT1) cells are necessary to transfer oxygen and carbon dioxide between the blood and air. Alveolar epithelial type 2 (AT2) cells serve as a partially committed stem cell population, producing AT1 cells during postnatal ... ...

    Abstract Alveolar epithelial type 1 (AT1) cells are necessary to transfer oxygen and carbon dioxide between the blood and air. Alveolar epithelial type 2 (AT2) cells serve as a partially committed stem cell population, producing AT1 cells during postnatal alveolar development and repair after influenza A and SARS-CoV-2 pneumonia
    MeSH term(s) Animals ; Mice ; Alveolar Epithelial Cells/cytology ; Alveolar Epithelial Cells/metabolism ; Alveolar Epithelial Cells/pathology ; Cell Differentiation ; Cell Lineage ; Lung/cytology ; Lung/metabolism ; Lung/pathology ; Mitochondria/enzymology ; Mitochondria/metabolism ; NAD/metabolism ; NADH Dehydrogenase/metabolism ; Protons ; RNA-Seq ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Single-Cell Gene Expression Analysis ; Stress, Physiological
    Chemical Substances NAD (0U46U6E8UK) ; NADH Dehydrogenase (EC 1.6.99.3) ; Ndi1 protein, S cerevisiae ; Ndufs2 protein, mouse (EC 7.1.1.2) ; Protons ; SDHD protein, mouse (EC 1.3.99.1)
    Language English
    Publishing date 2023-08-09
    Publishing country England
    Document type Journal Article
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-023-06423-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Clinical Characteristics and Outcomes of Patients With COVID-19-Associated Acute Respiratory Distress Syndrome Who Underwent Lung Transplant.

    Kurihara, Chitaru / Manerikar, Adwaiy / Querrey, Melissa / Felicelli, Christopher / Yeldandi, Anjana / Garza-Castillon, Rafael / Lung, Kalvin / Kim, Samuel / Ho, Bing / Tomic, Rade / Arunachalam, Ambalavanan / Budinger, G R Scott / Pesce, Lorenzo / Bharat, Ankit

    JAMA

    2022  Volume 327, Issue 7, Page(s) 652–661

    Abstract: Importance: Lung transplantation is a potentially lifesaving treatment for patients who are critically ill due to COVID-19-associated acute respiratory distress syndrome (ARDS), but there is limited information about the long-term outcome.: Objective!# ...

    Abstract Importance: Lung transplantation is a potentially lifesaving treatment for patients who are critically ill due to COVID-19-associated acute respiratory distress syndrome (ARDS), but there is limited information about the long-term outcome.
    Objective: To report the clinical characteristics and outcomes of patients who had COVID-19-associated ARDS and underwent a lung transplant at a single US hospital.
    Design, setting, and participants: Retrospective case series of 102 consecutive patients who underwent a lung transplant at Northwestern University Medical Center in Chicago, Illinois, between January 21, 2020, and September 30, 2021, including 30 patients who had COVID-19-associated ARDS. The date of final follow-up was November 15, 2021.
    Exposures: Lung transplant.
    Main outcomes and measures: Demographic, clinical, laboratory, and treatment data were collected and analyzed. Outcomes of lung transplant, including postoperative complications, intensive care unit and hospital length of stay, and survival, were recorded.
    Results: Among the 102 lung transplant recipients, 30 patients (median age, 53 years [range, 27 to 62]; 13 women [43%]) had COVID-19-associated ARDS and 72 patients (median age, 62 years [range, 22 to 74]; 32 women [44%]) had chronic end-stage lung disease without COVID-19. For lung transplant recipients with COVID-19 compared with those without COVID-19, the median lung allocation scores were 85.8 vs 46.7, the median time on the lung transplant waitlist was 11.5 vs 15 days, and preoperative venovenous extracorporeal membrane oxygenation (ECMO) was used in 56.7% vs 1.4%, respectively. During transplant, patients who had COVID-19-associated ARDS received transfusion of a median of 6.5 units of packed red blood cells vs 0 in those without COVID-19, 96.7% vs 62.5% underwent intraoperative venoarterial ECMO, and the median operative time was 8.5 vs 7.4 hours, respectively. Postoperatively, the rates of primary graft dysfunction (grades 1 to 3) within 72 hours were 70% in the COVID-19 cohort vs 20.8% in those without COVID-19, the median time receiving invasive mechanical ventilation was 6.5 vs 2.0 days, the median duration of intensive care unit stay was 18 vs 9 days, the median post-lung transplant hospitalization duration was 28.5 vs 16 days, and 13.3% vs 5.5% required permanent hemodialysis, respectively. None of the lung transplant recipients who had COVID-19-associated ARDS demonstrated antibody-mediated rejection compared with 12.5% in those without COVID-19. At follow-up, all 30 lung transplant recipients who had COVID-19-associated ARDS were alive (median follow-up, 351 days [IQR, 176-555] after transplant) vs 60 patients (83%) who were alive in the non-COVID-19 cohort (median follow-up, 488 days [IQR, 368-570] after lung transplant).
    Conclusions and relevance: In this single-center case series of 102 consecutive patients who underwent a lung transplant between January 21, 2020, and September 30, 2021, survival was 100% in the 30 patients who had COVID-19-associated ARDS as of November 15, 2021.
    MeSH term(s) Adult ; Aged ; COVID-19/complications ; Extracorporeal Membrane Oxygenation ; Female ; Humans ; Lung Transplantation/mortality ; Male ; Middle Aged ; Respiration, Artificial ; Respiratory Distress Syndrome/etiology ; Respiratory Distress Syndrome/surgery ; Retrospective Studies ; Treatment Outcome
    Language English
    Publishing date 2022-01-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2958-0
    ISSN 1538-3598 ; 0254-9077 ; 0002-9955 ; 0098-7484
    ISSN (online) 1538-3598
    ISSN 0254-9077 ; 0002-9955 ; 0098-7484
    DOI 10.1001/jama.2022.0204
    Database MEDical Literature Analysis and Retrieval System OnLINE

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