1,332 results on '"Wallace, Douglas C."'
Search Results
2. Space radiation damage rescued by inhibition of key spaceflight associated miRNAs
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McDonald, J. Tyson, Kim, JangKeun, Farmerie, Lily, Johnson, Meghan L., Trovao, Nidia S., Arif, Shehbeel, Siew, Keith, Tsoy, Sergey, Bram, Yaron, Park, Jiwoon, Overbey, Eliah, Ryon, Krista, Haltom, Jeffrey, Singh, Urminder, Enguita, Francisco J., Zaksas, Victoria, Guarnieri, Joseph W., Topper, Michael, Wallace, Douglas C., Meydan, Cem, Baylin, Stephen, Meller, Robert, Muratani, Masafumi, Porterfield, D. Marshall, Kaufman, Brett, Mori, Marcelo A., Walsh, Stephen B., Sigaudo-Roussel, Dominique, Mebarek, Saida, Bottini, Massimo, Marquette, Christophe A., Wurtele, Eve Syrkin, Schwartz, Robert E., Galeano, Diego, Mason, Christopher E., Grabham, Peter, and Beheshti, Afshin
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- 2024
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3. Visualizing subcellular changes in the NAD(H) pool size versus redox state using fluorescence lifetime imaging microscopy of NADH
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Song, Angela, Zhao, Nicole, Hilpert, Diana C., Perry, Caroline, Baur, Joseph A., Wallace, Douglas C., and Schaefer, Patrick M.
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- 2024
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4. American Indian Prehistory as Written in the Mitochondrial DNA: A Review
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Wallace, Douglas C. and Torroni, Antonio
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- 2010
5. OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases
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Sturm, Gabriel, Karan, Kalpita R, Monzel, Anna S, Santhanam, Balaji, Taivassalo, Tanja, Bris, Céline, Ware, Sarah A, Cross, Marissa, Towheed, Atif, Higgins-Chen, Albert, McManus, Meagan J, Cardenas, Andres, Lin, Jue, Epel, Elissa S, Rahman, Shamima, Vissing, John, Grassi, Bruno, Levine, Morgan, Horvath, Steve, Haller, Ronald G, Lenaers, Guy, Wallace, Douglas C, St-Onge, Marie-Pierre, Tavazoie, Saeed, Procaccio, Vincent, Kaufman, Brett A, Seifert, Erin L, Hirano, Michio, and Picard, Martin
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Genetics ,Biological Sciences ,Aging ,Clinical Research ,Human Genome ,Underpinning research ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Aetiology ,Generic health relevance ,Humans ,Oxidative Phosphorylation ,Longevity ,Mitochondrial Diseases ,Mitochondria ,DNA ,Mitochondrial ,Biological sciences ,Biomedical and clinical sciences - Abstract
Patients with primary mitochondrial oxidative phosphorylation (OxPhos) defects present with fatigue and multi-system disorders, are often lean, and die prematurely, but the mechanistic basis for this clinical picture remains unclear. By integrating data from 17 cohorts of patients with mitochondrial diseases (n = 690) we find evidence that these disorders increase resting energy expenditure, a state termed hypermetabolism. We examine this phenomenon longitudinally in patient-derived fibroblasts from multiple donors. Genetically or pharmacologically disrupting OxPhos approximately doubles cellular energy expenditure. This cell-autonomous state of hypermetabolism occurs despite near-normal OxPhos coupling efficiency, excluding uncoupling as a general mechanism. Instead, hypermetabolism is associated with mitochondrial DNA instability, activation of the integrated stress response (ISR), and increased extracellular secretion of age-related cytokines and metabokines including GDF15. In parallel, OxPhos defects accelerate telomere erosion and epigenetic aging per cell division, consistent with evidence that excess energy expenditure accelerates biological aging. To explore potential mechanisms for these effects, we generate a longitudinal RNASeq and DNA methylation resource dataset, which reveals conserved, energetically demanding, genome-wide recalibrations. Taken together, these findings highlight the need to understand how OxPhos defects influence the energetic cost of living, and the link between hypermetabolism and aging in cells and patients with mitochondrial diseases.
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- 2023
6. A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies
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Liu, Xiaolei, Devadiga, Sudhish A., Stanley, Robert F., Morrow, Ryan M., Janssen, Kevin A., Quesnel-Vallieres, Mathieu, Pomp, Oz, Moverley, Adam A., Li, Chenchen, Skuli, Nicolas, Carroll, Martin, Huang, Jian, Wallace, Douglas C., Lynch, Kristen W., Abdel-Wahab, Omar, and Klein, Peter S.
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Oncology, Experimental ,Gene mutations -- Research ,Gene expression -- Research ,Myelodysplastic syndromes -- Development and progression -- Genetic aspects ,Mitochondria -- Genetic aspects -- Health aspects ,Cancer -- Research ,Health care industry - Abstract
Splicing factor mutations are common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how they alter cellular functions is unclear. We show that the pathogenic [SRSF2.sup.P95H/+] mutation disrupts the splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. We also identified a mitochondrial surveillance mechanism by which mitochondrial dysfunction modifies splicing of the mitophagy activator PINK1 to remove a poison intron, increasing the stability and abundance of PINK1 mRNA and protein. [SRSF2.sup.P95H]-induced mitochondrial dysfunction increased PINK1 expression through this mechanism, which is essential for survival of [SRSF2.sup.P95H/+] cells. Inhibition of splicing with a glycogen synthase kinase 3 inhibitor promoted retention of the poison intron, impairing mitophagy and activating apoptosis in [SRSF2.sup.P95H/+] cells. These data reveal a homeostatic mechanism for sensing mitochondrial stress through PINK1 splicing and identify increased mitophagy as a disease marker and a therapeutic vulnerability in [SRSF2.sup.P95H] mutant MDS and AML., Introduction Myelodysplastic syndrome (MDS) is a clonal hematopoietic disorder characterized by hyperproliferative bone marrow, dysplastic hematopoietic cells, peripheral cytopenias, and high risk of progression to acute myeloid leukemia (AML). Recurrent [...]
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- 2024
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7. Promoting validation and cross-phylogenetic integration in model organism research
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Cheng, Keith C, Burdine, Rebecca D, Dickinson, Mary E, Ekker, Stephen C, Lin, Alex Y, Lloyd, KC Kent, Lutz, Cathleen M, MacRae, Calum A, Morrison, John H, O'Connor, David H, Postlethwait, John H, Rogers, Crystal D, Sanchez, Susan, Simpson, Julie H, Talbot, William S, Wallace, Douglas C, Weimer, Jill M, and Bellen, Hugo J
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Biological Sciences ,Bioinformatics and Computational Biology ,Underpinning research ,1.1 Normal biological development and functioning ,Generic health relevance ,Life Below Water ,Animals ,Biological Evolution ,Humans ,Phylogeny ,Reproducibility of Results ,Model organisms ,Technology ,Human diseases ,Omics ,Integration ,Phenomics ,Research resources ,Validation ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Model organism (MO) research provides a basic understanding of biology and disease due to the evolutionary conservation of the molecular and cellular language of life. MOs have been used to identify and understand the function of orthologous genes, proteins, cells and tissues involved in biological processes, to develop and evaluate techniques and methods, and to perform whole-organism-based chemical screens to test drug efficacy and toxicity. However, a growing richness of datasets and the rising power of computation raise an important question: How do we maximize the value of MOs? In-depth discussions in over 50 virtual presentations organized by the National Institutes of Health across more than 10 weeks yielded important suggestions for improving the rigor, validation, reproducibility and translatability of MO research. The effort clarified challenges and opportunities for developing and integrating tools and resources. Maintenance of critical existing infrastructure and the implementation of suggested improvements will play important roles in maintaining productivity and facilitating the validation of animal models of human biology and disease.
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- 2022
8. SARS-CoV-2 mitochondrial metabolic and epigenomic reprogramming in COVID-19
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Guarnieri, Joseph W., Haltom, Jeffrey A., Albrecht, Yentli E. Soto, Lie, Timothy, Olali, Arnold Z., Widjaja, Gabrielle A., Ranshing, Sujata S., Angelin, Alessia, Murdock, Deborah, and Wallace, Douglas C.
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- 2024
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9. APOGEE 2: multi-layer machine-learning model for the interpretable prediction of mitochondrial missense variants
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Bianco, Salvatore Daniele, Parca, Luca, Petrizzelli, Francesco, Biagini, Tommaso, Giovannetti, Agnese, Liorni, Niccolò, Napoli, Alessandro, Carella, Massimo, Procaccio, Vincent, Lott, Marie T., Zhang, Shiping, Vescovi, Angelo Luigi, Wallace, Douglas C., Caputo, Viviana, and Mazza, Tommaso
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- 2023
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10. Optimization of differential filtration-based mitochondrial isolation for mitochondrial transplant to cerebral organoids
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Bodenstein, David F., Powlowski, Pavel, Zachos, Kassandra A., El Soufi El Sabbagh, Dana, Jeong, Hyunjin, Attisano, Liliana, Edgar, Landon, Wallace, Douglas C., and Andreazza, Ana Cristina
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- 2023
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11. Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling
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Walter, David M., Gladstein, Amy C., Doerig, Katherine R., Natesan, Ramakrishnan, Baskaran, Saravana G., Gudiel, A. Andrea, Adler, Keren M., Acosta, Jonuelle O., Wallace, Douglas C., Asangani, Irfan A., and Feldser, David M.
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- 2023
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12. Photobleaching and phototoxicity of mitochondria in live cell fluorescent super-resolution microscopy
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Lee, Chia-Hung, Wallace, Douglas C., and Burke, Peter J.
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- 2024
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13. An ultra-high bandwidth nano-electronic interface to the interior of living cells with integrated fluorescence readout of metabolic activity.
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Ren, Dandan, Nemati, Zahra, Lee, Chia-Hung, Li, Jinfeng, Haddadi, Kamel, Wallace, Douglas C, and Burke, Peter J
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We present the first ever broadband, calibrated electrical connection to the inside of a cell. The interior of a vital, living cell contains multiple dynamic and electrically active organelles such as mitochondria, chloroplasts, lysosomes, and the endoplasmic reticulum. However, little is known about the detailed electrical activity inside the cell. Here we show an ultra-high bandwidth nano-electronic interface to the interior of living cells with integrated fluorescence readout of metabolic activity. On-chip/on-petri dish nanoscale capacitance calibration standards are used to quantify the electronic coupling from bench to cell from DC to 26 GHz (with cell images at 22 GHz). The interaction of static to high frequency electromagnetic fields with the cell constituents induce currents of free charges and local reorganization of linked charges. As such, this enables a direct, calibrated, quantitative, nanoscale electronic interface to the interior of living cells. The interface could have a variety of applications in interfacing life sciences to nano-electronics, including electronic assays of membrane potential dynamics, nano-electronic actuation of cellular activity, and tomographic, nano-radar imaging of the morphology of vital organelles in the cytoplasm, during all phases of the cell life cycle (from development to senescence), under a variety of physiological environments, and under a broad suite of pharmacological manipulations.
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- 2020
14. Scanning Microwave Microscopy of Vital Mitochondria in Respiration Buffer
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Li, Jinfeng, Nemati, Zahra, Haddadi, Kamel, Wallace, Douglas C., and Burke, Peter J.
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Physics - Biological Physics ,Condensed Matter - Mesoscale and Nanoscale Physics - Abstract
We demonstrate imaging using scanning microwave microscopy (SMM) of vital mitochondria in respiration buffer. The mitochondria are isolated from cultured HeLa cells and tethered to a solid graphene support. The mitochondria are kept vital (alive) using a respiration buffer, which provides nutrients to sustain the Krebs cycle. We verify that the mitochondria are "alive" by measuring the membrane potential using a voltage sensitive fluorescent dye (TMRE). The organelles are measured capacitively at 7 GHz. Several technical advances are demonstrated which enable this work: 1) The SMM operates in an electrophysiologically relevant liquid (hence conducting) environment; 2) The SMM operates in tapping mode, averaging the microwave reflection measurement over many tapping periods; 3) A tuned reflectometer enables increased sensitivity; 4) Variable frequencies up to 18 GHz are used; 5) In contrast with traditional matching/resonant methods that exhibit high quality factor that fail in the presence of liquids, interferometric/tuned reflectometer gives the possibility to adjust the quality factor or sensitivity even in the presence of the liquid., Comment: Accepted for publication in IMS 2018
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- 2018
15. H+ transport is an integral function of the mitochondrial ADP/ATP carrier.
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Bertholet, Ambre M, Chouchani, Edward T, Kazak, Lawrence, Angelin, Alessia, Fedorenko, Andriy, Long, Jonathan Z, Vidoni, Sara, Garrity, Ryan, Cho, Joonseok, Terada, Naohiro, Wallace, Douglas C, Spiegelman, Bruce M, and Kirichok, Yuriy
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Mitochondria ,Animals ,Mice ,Protons ,Coenzymes ,Fatty Acids ,Mitochondrial ADP ,ATP Translocases ,Adenosine Diphosphate ,Adenosine Triphosphate ,Ion Transport ,Oxygen Consumption ,Male ,Mitochondrial ADP ,ATP Translocases ,General Science & Technology - Abstract
The mitochondrial ADP/ATP carrier (AAC) is a major transport protein of the inner mitochondrial membrane. It exchanges mitochondrial ATP for cytosolic ADP and controls cellular production of ATP. In addition, it has been proposed that AAC mediates mitochondrial uncoupling, but it has proven difficult to demonstrate this function or to elucidate its mechanisms. Here we record AAC currents directly from inner mitochondrial membranes from various mouse tissues and identify two distinct transport modes: ADP/ATP exchange and H+ transport. The AAC-mediated H+ current requires free fatty acids and resembles the H+ leak via the thermogenic uncoupling protein 1 found in brown fat. The ADP/ATP exchange via AAC negatively regulates the H+ leak, but does not completely inhibit it. This suggests that the H+ leak and mitochondrial uncoupling could be dynamically controlled by cellular ATP demand and the rate of ADP/ATP exchange. By mediating two distinct transport modes, ADP/ATP exchange and H+ leak, AAC connects coupled (ATP production) and uncoupled (thermogenesis) energy conversion in mitochondria.
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- 2019
16. An mtDNA mutant mouse demonstrates that mitochondrial deficiency can result in autism endophenotypes
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Yardeni, Tal, Cristancho, Ana G., McCoy, Almedia J., Schaefer, Patrick M., McManus, Meagan J., Marsh, Eric D., and Wallace, Douglas C.
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- 2021
17. Mitochondrial antioxidants abate SARS-COV-2 pathology in mice.
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Guarnieri, Joseph W., Lie, Timothy, Soto Albrecht, Yentli E., Hewin, Peter, Jurado, Kellie A., Widjaja, Gabrielle A., Yi Zhu, McManus, Meagan J., Kilbaugh, Todd J., Keith, Kelsey, Potluri, Prasanth, Taylor, Deanne, Angelin, Alessia, Murdock, Deborah G., and Wallace, Douglas C.
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SARS-CoV-2 ,ANGIOTENSIN converting enzyme ,MITOCHONDRIAL DNA ,VIRAL proteins ,GENE expression - Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection inhibits mito-chondrial oxidative phosphorylation (OXPHOS) and elevates mitochondrial reactive oxygen species (ROS, mROS) which activates hypoxia-inducible factor-1alpha (HIF-1a), shifting metabolism toward glycolysis to drive viral biogenesis but also causing the release of mitochondrial DNA (mtDNA) and activation of innate immunity. To determine whether mitochondrially targeted antioxidants could mitigate these viral effects, we challenged mice expressing human angiotensin-converting enzyme 2 (ACE2) with SARS-CoV-2 and intervened using transgenic and pharmacological mitochondrially targeted catalytic antioxidants. Transgenic expression of mitochondrially targeted catalase (mCAT) or systemic treatment with EUK8 decreased weight loss, clinical severity, and circulating levels of mtDNA; as well as reduced lung levels of HIF-1α, viral proteins, and inflammatory cytokines. RNA-sequencing of infected lungs revealed that mCAT and Eukarion 8 (EUK8) up-regulated OXPHOS gene expression and down-regulated HIF-1α and its target genes as well as innate immune gene expression. These data demonstrate that SARS-CoV-2 pathology can be mitigated by catalytically reducing mROS, potentially providing a unique host-directed pharmacological therapy for COVID-19 which is not subject to viral mutational resistance. [ABSTRACT FROM AUTHOR]
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- 2024
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18. Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1) rescues the cellular phenotype of MELAS by inducing homeostatic mechanisms
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Aras, Siddhesh, Purandare, Neeraja, Gladyck, Stephanie, Somayajulu-Nitu, Mallika, Zhang, Kezhong, Wallace, Douglas C., and Grossman, Lawrence I.
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- 2020
19. Mitochondrial DNA associations with East Asian metabolic syndrome
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Chalkia, Dimitra, Chang, Yi-Cheng, Derbeneva, Olga, Lvova, Maria, Wang, Ping, Mishmar, Dan, Liu, Xiaogang, Singh, Larry N, Chuang, Lee-Ming, and Wallace, Douglas C
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Biological Sciences ,Genetics ,Nutrition ,2.1 Biological and endogenous factors ,Aetiology ,Metabolic and endocrine ,Adult ,Asian People ,Case-Control Studies ,DNA ,Mitochondrial ,Diabetes Mellitus ,Type 2 ,Asia ,Eastern ,Female ,Haplotypes ,Humans ,Male ,Metabolic Syndrome ,Middle Aged ,Mitochondria ,Pedigree ,Phenotype ,Polymorphism ,Single Nucleotide ,mtDNA ,Haplogroup ,Diabetes ,Obesity ,Cybrids ,Physical Chemistry (incl. Structural) ,Biochemistry and Cell Biology ,Biophysics ,Biochemistry and cell biology - Abstract
Mitochondrial dysfunction has repeatedly been reported associated with type 2 diabetes mellitus (T2DM) and metabolic syndrome (MS), as have mitochondrial DNA (mtDNA) tRNA and duplication mutations and mtDNA haplogroup lineages. We identified 19 Taiwanese T2DM and MS pedigrees from Taiwan, with putative matrilineal transmission, one of which harbored the pathogenic mtDNA tRNALeu(UUR) nucleotide (nt) 3243A>G mutation on the N9a3 haplogroup background. We then recruited three independent Taiwanese cohorts, two from Taipei (N = 498, mean age 52 and N = 1002, mean age 44) and one from a non-urban environment (N = 501, mean age 57). All three cohorts were assessed for an array of metabolic parameters, their mtDNA haplogroups determined, and the haplogroups correlated with T2DM/MS phenotypes. Logistic regression analysis revealed that mtDNA haplogroups D5, F4, and N9a conferred T2DM protection, while haplogroups F4 and N9a were risk factors for hypertension (HTN), and F4 was a risk factor for obesity (OB). Additionally, the 5263C>T (ND2 A165V) variant commonly associated with F4 was associated with hypertension (HTN). Cybrids were prepared with macro-haplogroup N (defined by variants m.ND3 10398A (114T) and m.ATP6 8701A (59T)) haplogroups B4 and F1 mtDNAs and from macro-haplogroup M (variants m.ND3 10398G (114A) and m.ATP6 8701G (59A)) haplogroup M9 mtDNAs. Additionally, haplogroup B4 and F1 cybrids were prepared with and without the mtDNA variant in ND1 3394T>C (Y30H) reported to be associated with T2DM. Assay of mitochondria complex I in these cybrids revealed that macro-haplogroup N cybrids had lower activity than M cybrids, that haplogroup F cybrids had lower activity than B4 cybrids, and that the ND1 3394T>C (Y30H) variant reduced complex I on both the B4 and F1 background but with very different cumulative effects. These data support the hypothesis that functional mtDNA variants may contribute to the risk of developing T2DM and MS.
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- 2018
20. Resistive flow sensing of vital mitochondria with nanoelectrodes
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Zand, Katayoun, Pham, Ted DA, Li, Jinfeng, Zhou, Weiwei, Wallace, Douglas C, and Burke, Peter J
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Nanotechnology ,Bioengineering ,Electrodes ,Energy Metabolism ,HeLa Cells ,Humans ,Membrane Potential ,Mitochondrial ,Microfluidics ,Mitochondria ,Nanotubes ,Resistive sensing ,Carbon nanotube ,Bioenergetics ,Label-free ,Hela Cells ,Genetics ,Biochemistry & Molecular Biology - Abstract
We report label-free detection of single mitochondria with high sensitivity using nanoelectrodes. Measurements of the conductance of carbon nanotube transistors show discrete changes of conductance as individual mitochondria flow over the nanoelectrodes in a microfluidic channel. Altering the bioenergetic state of the mitochondria by adding metabolites to the flow buffer induces changes in the mitochondrial membrane potential detected by the nanoelectrodes. During the time when mitochondria are transiently passing over the nanoelectrodes, this (nano) technology is sensitive to fluctuations of the mitochondrial membrane potential with a resolution of 10mV with temporal resolution of order milliseconds. Fluorescence based assays (in ideal, photon shot noise limited setups) are shown to be an order of magnitude less sensitive than this nano-electronic measurement technology. This opens a new window into the dynamics of an organelle critical to cellular function and fate.
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- 2017
21. Single-cell NAD(H) levels predict clonal lymphocyte expansion dynamics
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Turner, Lucien, primary, Van Le, Tran Ngoc, additional, Cross, Eric, additional, Queriault, Clemence, additional, Knight, Montana, additional, Trihemasava, Krittin, additional, Davis, James, additional, Schaefer, Patrick, additional, Nguyen, Janet, additional, Xu, Jimmy, additional, Goldspiel, Brian, additional, Hall, Elise, additional, Rome, Kelly, additional, Scaglione, Michael, additional, Eggert, Joel, additional, Au-Yeung, Byron, additional, Wallace, Douglas C., additional, Mesaros, Clementina, additional, Baur, Joseph A., additional, and Bailis, Will, additional
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- 2024
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22. Mitochondrial DNA variation and cancer
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Kopinski, Piotr K., Singh, Larry N., Zhang, Shiping, Lott, Marie T., and Wallace, Douglas C.
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- 2021
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23. Precancer Atlas to Drive Precision Prevention Trials
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Spira, Avrum, Yurgelun, Matthew B, Alexandrov, Ludmil, Rao, Anjana, Bejar, Rafael, Polyak, Kornelia, Giannakis, Marios, Shilatifard, Ali, Finn, Olivera J, Dhodapkar, Madhav, Kay, Neil E, Braggio, Esteban, Vilar, Eduardo, Mazzilli, Sarah A, Rebbeck, Timothy R, Garber, Judy E, Velculescu, Victor E, Disis, Mary L, Wallace, Douglas C, and Lippman, Scott M
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Immunization ,Cancer ,Digestive Diseases ,Rare Diseases ,Genetics ,Prevention ,Genetic Testing ,Aging ,Clinical Research ,Good Health and Well Being ,Animals ,Cancer Vaccines ,Cellular Microenvironment ,DNA ,Mitochondrial ,Epigenesis ,Genetic ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Germ-Line Mutation ,High-Throughput Nucleotide Sequencing ,Humans ,Mitochondria ,Neoplasms ,Precancerous Conditions ,Precision Medicine ,Single-Cell Analysis ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Cancer development is a complex process driven by inherited and acquired molecular and cellular alterations. Prevention is the holy grail of cancer elimination, but making this a reality will take a fundamental rethinking and deep understanding of premalignant biology. In this Perspective, we propose a national concerted effort to create a Precancer Atlas (PCA), integrating multi-omics and immunity - basic tenets of the neoplastic process. The biology of neoplasia caused by germline mutations has led to paradigm-changing precision prevention efforts, including: tumor testing for mismatch repair (MMR) deficiency in Lynch syndrome establishing a new paradigm, combinatorial chemoprevention efficacy in familial adenomatous polyposis (FAP), signal of benefit from imaging-based early detection research in high-germline risk for pancreatic neoplasia, elucidating early ontogeny in BRCA1-mutation carriers leading to an international breast cancer prevention trial, and insights into the intricate germline-somatic-immunity interaction landscape. Emerging genetic and pharmacologic (metformin) disruption of mitochondrial (mt) respiration increased autophagy to prevent cancer in a Li-Fraumeni mouse model (biology reproduced in clinical pilot) and revealed profound influences of subtle changes in mt DNA background variation on obesity, aging, and cancer risk. The elaborate communication between the immune system and neoplasia includes an increasingly complex cellular microenvironment and dynamic interactions between host genetics, environmental factors, and microbes in shaping the immune response. Cancer vaccines are in early murine and clinical precancer studies, building on the recent successes of immunotherapy and HPV vaccine immune prevention. Molecular monitoring in Barrett's esophagus to avoid overdiagnosis/treatment highlights an important PCA theme. Next generation sequencing (NGS) discovered age-related clonal hematopoiesis of indeterminate potential (CHIP). Ultra-deep NGS reports over the past year have redefined the premalignant landscape remarkably identifying tiny clones in the blood of up to 95% of women in their 50s, suggesting that potentially premalignant clones are ubiquitous. Similar data from eyelid skin and peritoneal and uterine lavage fluid provide unprecedented opportunities to dissect the earliest phases of stem/progenitor clonal (and microenvironment) evolution/diversity with new single-cell and liquid biopsy technologies. Cancer mutational signatures reflect exogenous or endogenous processes imprinted over time in precursors. Accelerating the prevention of cancer will require a large-scale, longitudinal effort, leveraging diverse disciplines (from genetics, biochemistry, and immunology to mathematics, computational biology, and engineering), initiatives, technologies, and models in developing an integrated multi-omics and immunity PCA - an immense national resource to interrogate, target, and intercept events that drive oncogenesis. Cancer Res; 77(7); 1510-41. ©2017 AACR.
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- 2017
24. Influence of Immune Cell Subtypes on Mitochondrial Measurements in Peripheral Blood Mononuclear Cells From Children With Sepsis
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Weiss, Scott L., Henrickson, Sarah E., Lindell, Robert B., Sartori, Laura F., Zhang, Donglan, Bush, Jenny, Farooqi, Sumera, Starr, Jonathan, Deutschman, Clifford S., McGowan, Francis X., Jr, Becker, Lance, Tuluc, Florin, Wherry, E. John, Picard, Martin, and Wallace, Douglas C.
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- 2021
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25. Impaired Lymphocyte Responses in Pediatric Sepsis Vary by Pathogen Type and are Associated with Features of Immunometabolic Dysregulation
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Lindell, Robert B., Zhang, Donglan, Bush, Jenny, Wallace, Douglas C., Rabinowitz, Joshua D., Lu, Wenyun, Wherry, E. John, Weiss, Scott L., and Henrickson, Sarah E.
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- 2022
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26. High throughput gene complementation screening permits identification of a mammalian mitochondrial protein synthesis (ρ−) mutant
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Potluri, Prasanth, Procaccio, Vincent, Scheffler, Immo E, and Wallace, Douglas C
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Biochemistry and Cell Biology ,Bioinformatics and Computational Biology ,Biological Sciences ,Genetics ,Biotechnology ,Generic health relevance ,Amino Acid Sequence ,Animals ,CHO Cells ,Cricetulus ,Galactose ,Gene Library ,Genetic Complementation Test ,Genetic Vectors ,HEK293 Cells ,High-Throughput Screening Assays ,Humans ,Mice ,Mitochondria ,Mitochondrial Proteins ,Mitochondrial Ribosomes ,Molecular Sequence Data ,Mutation ,Oxidative Phosphorylation ,Peptides ,Protein Biosynthesis ,RNA ,Ribosomal ,Retroviridae ,Sequence Alignment ,Mitochondrial diseases ,Complementation cloning ,OXPHOS ,Mitochondrial ribosomes ,bS6m ,Physical Sciences ,Biological sciences ,Physical sciences - Abstract
To identify nuclear DNA (nDNA) oxidative phosphorylation (OXPHOS) gene mutations using cultured cells, we have developed a complementation system based on retroviral transduction with a full length cDNA expression library and selection for OXHOS function by growth in galactose. We have used this system to transduce the Chinese hamster V79-G7 OXPHOS mutant cell line with a defect in mitochondrial protein synthesis. The complemented cells were found to have acquired the cDNA for the bS6m polypeptide of the small subunit of the mitochondrial ribosome. bS6m is a 14 kDa polypeptide located on the outside of the mitochondrial 28S ribosomal subunit and interacts with the rRNA. The V79-G7 mutant protein was found to harbor a methionine to threonine missense mutation at codon 13. The hamster bS6m null mutant could also be complemented by its orthologs from either mouse or human. bS6m protein tagged at its C-terminus by HA, His or GFP localized to the mitochondrion and was fully functional. Through site-directed mutagenesis we identified the probable RNA interacting residues of the bS6m peptide and tested the functional significance of mammalian specific C-terminal region. The N-terminus of the bS6m polypeptide functionally corresponds to that of the prokaryotic small ribosomal subunit, but deletion of C-terminal residues along with the zinc ion coordinating cysteine had no functional effect. Since mitochondrial diseases can result from hundreds to thousands of different nDNA gene mutations, this one step viral complementation cloning may facilitate the molecular diagnosis of a range of nDNA mitochondrial disease mutations. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.
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- 2016
27. Deficiency in the mouse mitochondrial adenine nucleotide translocator isoform 2 gene is associated with cardiac noncompaction
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Kokoszka, Jason E, Waymire, Katrina G, Flierl, Adrian, Sweeney, Katelyn M, Angelin, Alessia, MacGregor, Grant R, and Wallace, Douglas C
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Biological Sciences ,Genetics ,Heart Disease ,Cardiovascular ,2.1 Biological and endogenous factors ,Aetiology ,Adenine ,Adenine Nucleotide Translocator 2 ,Animals ,Biological Transport ,Cell Proliferation ,Embryo ,Mammalian ,Female ,Gene Expression Regulation ,Developmental ,Genes ,Lethal ,Heart Defects ,Congenital ,Heart Failure ,Heart Ventricles ,Integrases ,Male ,Mice ,Mice ,Transgenic ,Mitochondria ,Mitochondrial Swelling ,Myocytes ,Cardiac ,Organogenesis ,Phenotype ,Heart ,Cardiomyopathy ,Adenine nucleotide translocator 2 ,Hypertrabeculation ,Noncompaction ,Physical Sciences ,Biological sciences ,Physical sciences - Abstract
The mouse fetal and adult hearts express two adenine nucleotide translocator (ANT) isoform genes. The predominant isoform is the heart-muscle-brain ANT-isoform gene 1 (Ant1) while the other is the systemic Ant2 gene. Genetic inactivation of the Ant1 gene does not impair fetal development but results in hypertrophic cardiomyopathy in postnatal mice. Using a knockin X-linked Ant2 allele in which exons 3 and 4 are flanked by loxP sites combined in males with a protamine 1 promoter driven Cre recombinase we created females heterozygous for a null Ant2 allele. Crossing the heterozygous females with the Ant2(fl), PrmCre(+) males resulted in male and female ANT2-null embryos. These fetuses proved to be embryonic lethal by day E14.5 in association with cardiac developmental failure, immature cardiomyocytes having swollen mitochondria, cardiomyocyte hyperproliferation, and cardiac failure due to hypertrabeculation/noncompaction. ANTs have two main functions, mitochondrial-cytosol ATP/ADP exchange and modulation of the mitochondrial permeability transition pore (mtPTP). Previous studies imply that ANT2 biases the mtPTP toward closed while ANT1 biases the mtPTP toward open. It has been reported that immature cardiomyocytes have a constitutively opened mtPTP, the closure of which signals the maturation of cardiomyocytes. Therefore, we hypothesize that the developmental toxicity of the Ant2 null mutation may be the result of biasing the cardiomyocyte mtPTP to remain open thus impairing cardiomyocyte maturation and resulting in cardiomyocyte hyperproliferation and failure of trabecular maturation. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.
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- 2016
28. Microchambers with Solid-State Phosphorescent Sensor for Measuring Single Mitochondrial Respiration.
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Pham, Ted D, Wallace, Douglas C, and Burke, Peter J
- Subjects
Mitochondria ,Humans ,Dimethylpolysiloxanes ,Adenosine Triphosphate ,Cell Respiration ,Oxygen Consumption ,PtTFPP ,mitochondria ,oxygen consumption rate ,phosphorescent probes ,respiration ,Analytical Chemistry ,Electrical and Electronic Engineering ,Environmental Science and Management ,Ecology - Abstract
It is now well established that, even within a single cell, multiple copies of the mitochondrial genome may be present (genetic heteroplasmy). It would be interesting to develop techniques to determine if and to what extent this genetic variation results in functional variation from one mitochondrion to the next (functional heteroplasmy). Measuring mitochondrial respiration can reveal the organelles' functional capacity for Adenosine triphosphate (ATP) production and determine mitochondrial damage that may arise from genetic or age related defects. However, available technologies require significant quantities of mitochondria. Here, we develop a technology to assay the respiration of a single mitochondrion. Our "micro-respirometer" consists of micron sized chambers etched out of borofloat glass substrates and coated with an oxygen sensitive phosphorescent dye Pt(II) meso-tetra(pentafluorophenyl)porphine (PtTFPP) mixed with polystyrene. The chambers are sealed with a polydimethylsiloxane layer coated with oxygen impermeable Viton rubber to prevent diffusion of oxygen from the environment. As the mitochondria consume oxygen in the chamber, the phosphorescence signal increases, allowing direct determination of the respiration rate. Experiments with coupled vs. uncoupled mitochondria showed a substantial difference in respiration, confirming the validity of the microchambers as single mitochondrial respirometers. This demonstration could enable future high-throughput assays of mitochondrial respiration and benefit the study of mitochondrial functional heterogeneity, and its role in health and disease.
- Published
- 2016
29. Post-Transcriptional Methylation of Mitochondrial-tRNA Differentially Contributes to Mitochondrial Pathology
- Author
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Maharjan, Sunita, primary, Gamper, Howard, additional, Yamaki, Yuka, additional, Henley, Robert Y., additional, Li, Nan-Sheng, additional, Suzuki, Takeo, additional, Suzuki, Tsutomu, additional, Piccirilli, Joseph A., additional, Wanunu, Meni, additional, Seifert, Erin, additional, Wallace, Douglas C., additional, and Hou, Ya-Ming, additional
- Published
- 2023
- Full Text
- View/download PDF
30. SARS-CoV-2 Orphan Gene ORF10 Contributes to More Severe COVID-19 Disease
- Author
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Haltom, Jeffrey A, primary, Trovao, Nidia S, additional, Guarnieri, Joseph, additional, Vincent, Pan,, additional, Singh, Urminder, additional, Tsoy, Sergey, additional, O'Leary, Collin A, additional, Bram, Yaron, additional, Widjaja, Gabrielle A, additional, Cen, Zimu, additional, Meller, Robert,, additional, Baylin, Stephen B, additional, Moss, Walter N, additional, Nikolau, Basil J, additional, Enguita, Francisco J, additional, Wallace, Douglas C, additional, Beheshti, Afshin, additional, Schwartz, Robert, additional, and Wurtele, Eve Syrkin, additional
- Published
- 2023
- Full Text
- View/download PDF
31. LETHAL COVID-19 ASSOCIATES WITH RAAS-INDUCED INFLAMMATION FOR MULTIPLE ORGAN DAMAGE INCLUDING MEDIASTINAL LYMPH NODES
- Author
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Guarnieri, Joseph W, primary, Topper, Michael, additional, Beigel, Katherine, additional, Haltoom, Jeff A, additional, Chadburn, Amy, additional, Frere, Justin, additional, An, Julia, additional, Cope, Henry, additional, Borczuk, Alain, additional, Sinha, Saloni, additional, Lim, Christine, additional, Kim, JangKeun, additional, Park, Jiwoon, additional, Meydan, Cem, additional, Foox, Jonathan, additional, Mozsary, Christopher, additional, Bram, Yaron, additional, Richard, Stephanie, additional, Epsi, Nusrat, additional, Agan, Brian, additional, Chenoweth, Josh, additional, Simons, Mark, additional, Tribble, David, additional, Burgess, Timothy, additional, Dalgard, Clifton L., additional, Heise, Mark T., additional, Moorman, Nathaniel, additional, Baxter, Victoria, additional, Madden, Emily A., additional, Taft-Benz, Sharon, additional, Anderson, Elizabeth, additional, Sanders, Wes A., additional, Dickmander, Rebekah J., additional, Widjaja, Gabrielle A., additional, Janssen, Kevin, additional, Lie, Timothy, additional, Murdock, Deborah G, additional, Angelin, Alessia, additional, Albrecht, Yentli E. S., additional, Olali, Arnold, additional, Dybas, Joseph M., additional, Priebe, Waldemar, additional, Emmett, Mark R., additional, Best, Sonja, additional, Johnson, Maya Kelsey, additional, Trovao, Nidia S., additional, Clark, Kevin B., additional, Zaksiene, Viktoria, additional, Miller, Rob, additional, Grabhamr, Peter, additional, Schisler, Jonathan C, additional, Moraes-vieira, Pedro, additional, Pollett, Simon, additional, Mason, Christopher E., additional, Wurtele, Eve Syrkin, additional, Taylor, Deanne, additional, Schwartz, Robert E., additional, Beheshti, Afshin, additional, Wallace, Douglas C., additional, and Baylin, Stephen B., additional
- Published
- 2023
- Full Text
- View/download PDF
32. Regulation of nuclear epigenome by mitochondrial DNA heteroplasmy
- Author
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Kopinski, Piotr K., Janssen, Kevin A., Schaefer, Patrick M., Trefely, Sophie, Perry, Caroline E., Potluri, Prasanth, Tintos-Hernandez, Jesus A., Singh, Larry N., Karch, Kelly R., Campbell, Sydney L., Doan, Mary T., Jiang, Helen, Nissim, Itzhak, Nakamaru-Ogiso, Eiko, Wellen, Kathryn E., Snyder, Nathaniel W., Garcia, Benjamin A., and Wallace, Douglas C.
- Published
- 2019
33. Mitochondrial DNA variants can mediate methylation status of inflammation, angiogenesis and signaling genes
- Author
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Atilano, Shari R, Malik, Deepika, Chwa, Marilyn, Cáceres-Del-Carpio, Javier, Nesburn, Anthony B, Boyer, David S, Kuppermann, Baruch D, Jazwinski, S. Michal, Miceli, Michael V, Wallace, Douglas C, Udar, Nitin, and Kenney, M. Cristina
- Published
- 2015
34. Mutations of human NARS2, encoding the mitochondrial asparaginyl-tRNA synthetase, cause nonsyndromic deafness and Leigh syndrome.
- Author
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Simon, Mariella, Richard, Elodie M, Wang, Xinjian, Shahzad, Mohsin, Huang, Vincent H, Qaiser, Tanveer A, Potluri, Prasanth, Mahl, Sarah E, Davila, Antonio, Nazli, Sabiha, Hancock, Saege, Yu, Margret, Gargus, Jay, Chang, Richard, Al-Sheqaih, Nada, Newman, William G, Abdenur, Jose, Starr, Arnold, Hegde, Rashmi, Dorn, Thomas, Busch, Anke, Park, Eddie, Wu, Jie, Schwenzer, Hagen, Flierl, Adrian, Florentz, Catherine, Sissler, Marie, Khan, Shaheen N, Li, Ronghua, Guan, Min-Xin, Friedman, Thomas B, Wu, Doris K, Procaccio, Vincent, Riazuddin, Sheikh, Wallace, Douglas C, Ahmed, Zubair M, Huang, Taosheng, and Riazuddin, Saima
- Subjects
Mitochondria ,Fibroblasts ,Animals ,Humans ,Mice ,Deafness ,Leigh Disease ,Genetic Predisposition to Disease ,Aspartate-tRNA Ligase ,RNA ,Transfer ,Amino Acyl ,Pedigree ,Gene Expression ,Amino Acid Sequence ,Oxygen Consumption ,Mutation ,Missense ,Adult ,Middle Aged ,Female ,Ear ,Inner ,Male ,RNA ,Transfer ,Amino Acyl ,Mutation ,Missense ,Ear ,Inner ,Brain Disorders ,Genetics ,Neurodegenerative ,Rare Diseases ,Neurosciences ,2.1 Biological and endogenous factors ,Neurological ,Congenital Disorders ,Developmental Biology - Abstract
Here we demonstrate association of variants in the mitochondrial asparaginyl-tRNA synthetase NARS2 with human hearing loss and Leigh syndrome. A homozygous missense mutation ([c.637G>T; p.Val213Phe]) is the underlying cause of nonsyndromic hearing loss (DFNB94) and compound heterozygous mutations ([c.969T>A; p.Tyr323*] + [c.1142A>G; p.Asn381Ser]) result in mitochondrial respiratory chain deficiency and Leigh syndrome, which is a neurodegenerative disease characterized by symmetric, bilateral lesions in the basal ganglia, thalamus, and brain stem. The severity of the genetic lesions and their effects on NARS2 protein structure cosegregate with the phenotype. A hypothetical truncated NARS2 protein, secondary to the Leigh syndrome mutation p.Tyr323* is not detectable and p.Asn381Ser further decreases NARS2 protein levels in patient fibroblasts. p.Asn381Ser also disrupts dimerization of NARS2, while the hearing loss p.Val213Phe variant has no effect on NARS2 oligomerization. Additionally we demonstrate decreased steady-state levels of mt-tRNAAsn in fibroblasts from the Leigh syndrome patients. In these cells we show that a decrease in oxygen consumption rates (OCR) and electron transport chain (ETC) activity can be rescued by overexpression of wild type NARS2. However, overexpression of the hearing loss associated p.Val213Phe mutant protein in these fibroblasts cannot complement the OCR and ETC defects. Our findings establish lesions in NARS2 as a new cause for nonsyndromic hearing loss and Leigh syndrome.
- Published
- 2015
35. Mitochondrial DNA Variation Dictates Expressivity and Progression of Nuclear DNA Mutations Causing Cardiomyopathy
- Author
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McManus, Meagan J., Picard, Martin, Chen, Hsiao-Wen, De Haas, Hans J., Potluri, Prasanth, Leipzig, Jeremy, Towheed, Atif, Angelin, Alessia, Sengupta, Partho, Morrow, Ryan M., Kauffman, Brett A., Vermulst, Marc, Narula, Jagat, and Wallace, Douglas C.
- Published
- 2019
- Full Text
- View/download PDF
36. MITOMAP: a human mitochondrial genome database--2004 update
- Author
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Brandon, Marty C., Lott, Marie T., Nguyen, Kevin Cuong, Spolim, Syawal, Navathe, Shamkant B., Baldi, Pierre, and Wallace, Douglas C.
- Subjects
mtdna control-region ,replication ,mutations - Abstract
MITOMAP (http://www.MITOMAP.org), a database for the human mitochondrial genome, has grown rapidly in data content over the past several years as interest in the role of mitochondrial DNA (mtDNA) variation in human origins, forensics, degenerative diseases, cancer and aging has increased dramatically. To accommodate this information explosion, MITOMAP has implemented a new relational database and an improved search engine, and all programs have been rewritten. System administrative changes have been made to improve security and efficiency, and to make MITOMAP compatible with a new automatic mtDNA sequence analyzer known as Mitomaster.
- Published
- 2014
37. Assessing Bioenergetic Compromise in Autism Spectrum Disorder With 31P Magnetic Resonance Spectroscopy
- Author
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Golomb, Beatrice A, Erickson, Laura C, Zeeland, Ashley A Scott-Van, Koperski, Sabrina, Haas, Richard H, Wallace, Douglas C, Naviaux, Robert K, Lincoln, Alan J, Reiner, Gail E, and Hamilton, Gavin
- Subjects
Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Intellectual and Developmental Disabilities (IDD) ,Brain Disorders ,Pediatric ,Autism ,Mental Health ,Clinical Research ,2.1 Biological and endogenous factors ,Aetiology ,Mental health ,Adolescent ,Case-Control Studies ,Child ,Child Development Disorders ,Pervasive ,Energy Metabolism ,Exercise ,Female ,Frontal Lobe ,Humans ,Hydrogen-Ion Concentration ,Leg ,Magnetic Resonance Spectroscopy ,Male ,Muscle ,Skeletal ,Phosphocreatine ,Phosphorus Isotopes ,Pilot Projects ,Time Factors ,autism spectrum disorder ,P-31-MRS ,brain ,muscle ,bioenergetics ,31P-MRS ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Abstract
We sought to examine, via Phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) in a case-control design, whether bioenergetic deficits in autism spectrum disorders extend to the brain and muscle. Six cases with autism spectrum disorder with suspected mitochondrial dysfunction (age 6-18 years) and 6 age/sex-matched controls underwent (31)P magnetic resonance spectroscopy. The outcomes of focus were muscle resting phosphocreatine and intracellular pH as well as postexercise phosphocreatine recovery time constant and frontal brain phosphocreatine. Intracellular muscle pH was lower in each autism spectrum disorder case than their matched control (6/6, P = .03; P = .0048, paired t test). Muscle phosphocreatine (5/6), brain phosphocreatine (3/4), and muscle phosphocreatine recovery time constant (3/3) trends were in the predicted direction (not all participants completed each). This study introduces (31)P magnetic resonance spectroscopy as a noninvasive tool for assessment of mitochondrial function in autism spectrum disorder enabling bioenergetic assessment in brain and provides preliminary evidence suggesting that bioenergetic defects in cases with autism spectrum disorder are present in muscle and may extend to brain.
- Published
- 2014
38. Molecular and bioenergetic differences between cells with African versus European inherited mitochondrial DNA haplogroups: Implications for population susceptibility to diseases
- Author
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Kenney, M Cristina, Chwa, Marilyn, Atilano, Shari R, Falatoonzadeh, Payam, Ramirez, Claudio, Malik, Deepika, Tarek, Mohamed, Del Carpio, Javier Cáceres, Nesburn, Anthony B, Boyer, David S, Kuppermann, Baruch D, Vawter, Marquis P, Jazwinski, S Michal, Miceli, Michael V, Wallace, Douglas C, and Udar, Nitin
- Subjects
Genetics ,Aetiology ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Underpinning research ,Generic health relevance ,Adenosine Triphosphate ,Adult ,Blacks ,Cell Line ,Cell Proliferation ,DNA ,Mitochondrial ,Energy Metabolism ,Gene Dosage ,Gene Expression Profiling ,Genes ,Mitochondrial ,Genetic Predisposition to Disease ,Haplotypes ,Humans ,Hybrid Cells ,Lactates ,Middle Aged ,Oligonucleotide Array Sequence Analysis ,Polymorphism ,Single Nucleotide ,Reactive Oxygen Species ,Reverse Transcriptase Polymerase Chain Reaction ,Whites ,Mitochondrion ,Complement activation ,Innate immunity ,Haplogroup ,Cybrid ,Retina ,White People ,Black People ,ABI ,ARPE-19 ,ATP ,Adenosine triphosphate ,Applied Biosystems ,C1s ,C3 ,C4B ,CFH ,Carbonyl Cyanide 4-trifluoromethoxy-phenylhydrazone ,Complement component 1 ,s subcomponent ,Complement component 3 ,Complement component 4B ,Complement factor H ,DMEM ,DNA ,Deoxyribonucleic acid ,Dulbecco's modified Eagle's medium ,ECAR ,EDTA ,ETC ,Electron transport chain ,Ethylenediaminetetracetic acid ,Extracellular acidification rate ,FCCP ,MT-CO1 ,MT-CO2 ,MT-CO3 ,MT-CYB ,MT-ND1 ,MT-ND3 ,MT-ND5 ,Maximal oxygen uptake ,MicroMolar ,Mitochondria encoded NADH dehydrogenase 1 ,Mitochondria encoded NADH dehydrogenase 3 ,Mitochondria encoded NADH dehydrogenase 5 ,Mitochondria encoded cytochrome B ,Mitochondria encoded cytochrome oxidase 1 ,Mitochondria encoded cytochrome oxidase 2 ,Mitochondria encoded cytochrome oxidase 3 ,OCR ,OXPHOS ,Oxidative phosphorylation ,Oxygen consumption rate ,Q-PCR ,Quantitative polymerase chain reaction ,Retinal pigmented epithelium cell line ,SEM ,SNPs ,Single nucleotide polymorphisms ,Standard error mean ,UCLA ,University of California ,Los Angeles ,VO2(max) ,μM ,Physical Sciences ,Biological Sciences - Abstract
The geographic origins of populations can be identified by their maternally inherited mitochondrial DNA (mtDNA) haplogroups. This study compared human cybrids (cytoplasmic hybrids), which are cell lines with identical nuclei but mitochondria from different individuals with mtDNA from either the H haplogroup or L haplogroup backgrounds. The most common European haplogroup is H while individuals of maternal African origin are of the L haplogroup. Despite lower mtDNA copy numbers, L cybrids had higher expression levels for nine mtDNA-encoded respiratory complex genes, decreased ATP (adenosine triphosphate) turnover rates and lower levels of reactive oxygen species production, parameters which are consistent with more efficient oxidative phosphorylation. Surprisingly, GeneChip arrays showed that the L and H cybrids had major differences in expression of genes of the canonical complement system (5 genes), dermatan/chondroitin sulfate biosynthesis (5 genes) and CCR3 (chemokine, CC motif, receptor 3) signaling (9 genes). Quantitative nuclear gene expression studies confirmed that L cybrids had (a) lower expression levels of complement pathway and innate immunity genes and (b) increased levels of inflammation-related signaling genes, which are critical in human diseases. Our data support the hypothesis that mtDNA haplogroups representing populations from different geographic origins may play a role in differential susceptibilities to diseases.
- Published
- 2014
39. Human Retinal Transmitochondrial Cybrids with J or H mtDNA Haplogroups Respond Differently to Ultraviolet Radiation: Implications for Retinal Diseases
- Author
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Malik, Deepika, Hsu, Tiffany, Falatoonzadeh, Payam, Cáceres-del-Carpio, Javier, Tarek, Mohamed, Chwa, Marilyn, Atilano, Shari R, Ramirez, Claudio, Nesburn, Anthony B, Boyer, David S, Kuppermann, Baruch D, Jazwinski, S Michal, Miceli, Michael V, Wallace, Douglas C, Udar, Nitin, and Kenney, M Cristina
- Subjects
Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Cells ,Cultured ,DNA ,Mitochondrial ,Gene Expression Regulation ,Humans ,Macular Degeneration ,Mitochondria ,Polymorphism ,Single Nucleotide ,Retina ,Ultraviolet Rays ,General Science & Technology - Abstract
BackgroundIt has been recognized that cells do not respond equally to ultraviolet (UV) radiation but it is not clear whether this is due to genetic, biochemical or structural differences of the cells. We have a novel cybrid (cytoplasmic hybrids) model that allows us to analyze the contribution of mitochondrial DNA (mtDNA) to cellular response after exposure to sub-lethal dose of UV. mtDNA can be classified into haplogroups as defined by accumulations of specific single nucleotide polymorphisms (SNPs). Recent studies have shown that J haplogroup is high risk for age-related macular degeneration while the H haplogroup is protective. This study investigates gene expression responses in J cybrids versus H cybrids after exposure to sub-lethal doses of UV-radiation.Methodology/principal findingsCybrids were created by fusing platelets isolated from subjects with either H (n = 3) or J (n = 3) haplogroups with mitochondria-free (Rho0) ARPE-19 cells. The H and J cybrids were cultured for 24 hours, treated with 10 mJ of UV-radiation and cultured for an additional 120 hours. Untreated and treated cybrids were analyzed for growth rates and gene expression profiles. The UV-treated and untreated J cybrids had higher growth rates compared to H cybrids. Before treatment, J cybrids showed lower expression levels for CFH, CD55, IL-33, TGF-A, EFEMP-1, RARA, BCL2L13 and BBC3. At 120 hours after UV-treatment, the J cybrids had decreased CFH, RARA and BBC3 levels but increased CD55, IL-33 and EFEMP-1 compared to UV-treated H cybrids.Conclusion/significanceIn cells with identical nuclei, the cellular response to sub-lethal UV-radiation is mediated in part by the mtDNA haplogroup. This supports the hypothesis that differences in growth rates and expression levels of complement, inflammation and apoptosis genes may result from population-specific, hereditary SNP variations in mtDNA. Therefore, when analyzing UV-induced damage in tissues, the mtDNA haplogroup background may be important to consider.
- Published
- 2014
40. Super-Resolution Imaging of Voltages in the Interior of Individual, Vital Mitochondria.
- Author
-
Lee, ChiaHung, Wallace, Douglas C., and Burke, Peter J.
- Published
- 2024
- Full Text
- View/download PDF
41. Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts
- Author
-
Guarnieri, Joseph W., primary, Dybas, Joseph M., additional, Fazelinia, Hossein, additional, Kim, Man S., additional, Frere, Justin, additional, Zhang, Yuanchao, additional, Soto Albrecht, Yentli, additional, Murdock, Deborah G., additional, Angelin, Alessia, additional, Singh, Larry N., additional, Weiss, Scott L., additional, Best, Sonja M., additional, Lott, Marie T., additional, Zhang, Shiping, additional, Cope, Henry, additional, Zaksas, Victoria, additional, Saravia-Butler, Amanda, additional, Meydan, Cem, additional, Foox, Jonathan, additional, Mozsary, Christopher, additional, Bram, Yaron, additional, Kidane, Yared, additional, Priebe, Waldemar, additional, Emmett, Mark R., additional, Meller, Robert, additional, Demharter, Sam, additional, Stentoft-Hansen, Valdemar, additional, Salvatore, Marco, additional, Galeano, Diego, additional, Enguita, Francisco J., additional, Grabham, Peter, additional, Trovao, Nidia S., additional, Singh, Urminder, additional, Haltom, Jeffrey, additional, Heise, Mark T., additional, Moorman, Nathaniel J., additional, Baxter, Victoria K., additional, Madden, Emily A., additional, Taft-Benz, Sharon A., additional, Anderson, Elizabeth J., additional, Sanders, Wes A., additional, Dickmander, Rebekah J., additional, Baylin, Stephen B., additional, Wurtele, Eve Syrkin, additional, Moraes-Vieira, Pedro M., additional, Taylor, Deanne, additional, Mason, Christopher E., additional, Schisler, Jonathan C., additional, Schwartz, Robert E., additional, Beheshti, Afshin, additional, and Wallace, Douglas C., additional
- Published
- 2023
- Full Text
- View/download PDF
42. Summary of the mitochondrial findings in a series of 300 cases
- Author
-
Xu, Shiqin, Vu, Nhi Huong T, Chao, Elizabeth, Simon, Mariella, Zoleikhaeian, Mehrdad, Kimonis, Virginia, Huang, Taosheng, Mozaffar, Tahseen, and Wallace, Douglas C
- Subjects
Genetics ,Biochemistry & Molecular Biology - Published
- 2013
43. Differential Gene Expression Reveals Mitochondrial Dysfunction in an Imprinting Center Deletion Mouse Model of Prader–Willi Syndrome
- Author
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Yazdi, Puya G, Su, Hailing, Ghimbovschi, Svetlana, Fan, Weiwei, Coskun, Pinar E, Nalbandian, Angèle, Knoblach, Susan, Resnick, James L, Hoffman, Eric, Wallace, Douglas C, and Kimonis, Virginia E
- Subjects
Paediatrics ,Biomedical and Clinical Sciences ,Intellectual and Developmental Disabilities (IDD) ,Pediatric ,Obesity ,Rare Diseases ,Nutrition ,Genetics ,Congenital Structural Anomalies ,Brain Disorders ,2.1 Biological and endogenous factors ,Metabolic and endocrine ,Animals ,Brain ,Disease Models ,Animal ,Electron Transport Chain Complex Proteins ,Gene Expression Profiling ,Gene Expression Regulation ,Gene Regulatory Networks ,Genome ,Genomic Imprinting ,Mice ,Mitochondria ,Muscles ,Oligonucleotide Array Sequence Analysis ,Prader-Willi Syndrome ,RNA ,Messenger ,Reproducibility of Results ,Sequence Deletion ,Prader-Willi syndrome ,differential gene expression ,PWS-IC mouse model ,Cardiorespiratory Medicine and Haematology ,Oncology and Carcinogenesis ,Other Medical and Health Sciences ,General Clinical Medicine ,Cardiovascular medicine and haematology ,Pharmacology and pharmaceutical sciences - Abstract
Prader-Willi syndrome (PWS) is a genetic disorder caused by deficiency of imprinted gene expression from the paternal chromosome 15q11-15q13 and clinically characterized by neonatal hypotonia, short stature, cognitive impairment, hypogonadism, hyperphagia, morbid obesity, and diabetes. Previous clinical studies suggest that a defect in energy metabolism may be involved in the pathogenesis of PWS. We focused our attention on the genes associated with energy metabolism and found that there were 95 and 66 mitochondrial genes differentially expressed in PWS muscle and brain, respectively. Assessment of enzyme activities of mitochondrial oxidative phosphorylation complexes in the brain, heart, liver, and muscle were assessed. We found the enzyme activities of the cardiac mitochondrial complexes II+III were up-regulated in the PWS imprinting center deletion mice compared to the wild-type littermates. These studies suggest that differential gene expression, especially of the mitochondrial genes may contribute to the pathophysiology of PWS.
- Published
- 2013
44. Bioinformatics resources, databases, and tools for human mtDNA
- Author
-
Attimonelli, Marcella, primary, Preste, Roberto, additional, Vitale, Ornella, additional, Lott, Marie T., additional, Procaccio, Vincent, additional, Shiping, Zhang, additional, and Wallace, Douglas C., additional
- Published
- 2020
- Full Text
- View/download PDF
45. List of Contributors
- Author
-
Achilli, Alessandro, primary, Attimonelli, Marcella, additional, Bacman, Sandra R., additional, Barrientos, Antoni, additional, Berridge, Michael V., additional, Burr, Stephen P., additional, Calabrese, Claudia, additional, Calabrese, Francesco Maria, additional, Chinnery, Patrick F., additional, De Luise, Monica, additional, Diaz, Francisca, additional, Doimo, Mara, additional, Fontanesi, Flavia, additional, Fu, Yi, additional, Gammage, Payam A., additional, Garone, Caterina, additional, Gasparre, Giuseppe, additional, Ghelli, Anna, additional, Girolimetti, Giulia, additional, Glasgow, Ruth I.C., additional, Gomez-Duran, Aurora, additional, Grasso, Carole, additional, Herst, Patries M., additional, Holt, Ian James, additional, Iommarini, Luisa, additional, Kang, Dongchon, additional, Kurelac, Ivana, additional, Lim, Albert Z., additional, Lott, Marie T., additional, Matsuda, Shigeru, additional, McFarland, Robert, additional, Minczuk, Michal, additional, Moraes, Carlos T., additional, Nicholls, Thomas J., additional, Oláhová, Monika, additional, Olivieri, Anna, additional, Pfeiffer, Annika, additional, Pinheiro, Pedro, additional, Pitceathly, Robert D.S., additional, Porcelli, Anna Maria, additional, Preste, Roberto, additional, Procaccio, Vincent, additional, Quadalti, Corinne, additional, Rahman, Shamima, additional, Reyes, Aurelio, additional, Semino, Ornella, additional, Sfeir, Agnel, additional, Shiping, Zhang, additional, Sia, Elaine Ayres, additional, Spinazzola, Antonella, additional, Stein, Alexis, additional, Szczepanowska, Karolina, additional, Tagliabracci, Adriano, additional, Taylor, Robert W., additional, Tigano, Marco, additional, Torroni, Antonio, additional, Trifunovic, Aleksandra, additional, Turchi, Chiara, additional, Vitale, Ornella, additional, Wallace, Douglas C., additional, Wanrooij, Paulina H., additional, Wanrooij, Sjoerd, additional, and Yasukawa, Takehiro, additional
- Published
- 2020
- Full Text
- View/download PDF
46. Leber Hereditary Optic Neuropathy: Exemplar of an mtDNA Disease
- Author
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Wallace, Douglas C., Lott, Marie T., Barrett, James E., Editor-in-chief, Flockerzi, Veit, Series editor, Frohman, Michael A., Series editor, Geppetti, Pierangelo, Series editor, Hofmann, Franz B., Series editor, Michel, Martin C., Series editor, Page, Clive P, Series editor, Rosenthal, Walter, Series editor, Wang, KeWei, Series editor, Singh, Harpreet, editor, and Sheu, Shey-Shing, editor
- Published
- 2017
- Full Text
- View/download PDF
47. Severity of cardiomyopathy associated with adenine nucleotide translocator-1 deficiency correlates with mtDNA haplogroup
- Author
-
Strauss, Kevin A., DuBiner, Lauren, Simon, Mariella, Zaragoza, Michael, Sengupta, Partho P., Li, Peng, Narula, Navneet, Dreike, Sandra, Platt, Julia, Procaccio, Vincent, Ortiz-Gonzalez, Xilma R., Puffenberger, Erik G., Kelley, Richard I., Morton, D. Holmes, Narula, Jagat, and Wallace, Douglas C.
- Abstract
Mutations of both nuclear and mitochondrial DNA (mtDNA)–encoded mitochondrial proteins can cause cardiomyopathy associated with mitochondrial dysfunction. Hence, the cardiac phenotype of nuclear DNA mitochondrial mutations might be modulated by mtDNA variation. We studied a 13-generation Mennonite pedigree with autosomal recessive myopathy and cardiomyopathy due to an SLC25A4 frameshift null mutation (c.523delC, p.Q175RfsX38), which codes for the heart-muscle isoform of the adenine nucleotide translocator–1. Ten homozygous null (adenine nucleotide translocator–1−/−) patients monitored over a median of 6 years had a phenotype of progressive myocardial thickening, hyperalaninemia, lactic acidosis, exercise intolerance, and persistent adrenergic activation. Electrocardiography and echocardiography with velocity vector imaging revealed abnormal contractile mechanics, myocardial repolarization abnormalities, and impaired left ventricular relaxation. End-stage heart disease was characterized by massive, symmetric, concentric cardiac hypertrophy; widespread cardiomyocyte degeneration; overabundant and structurally abnormal mitochondria; extensive subendocardial interstitial fibrosis; and marked hypertrophy of arteriolar smooth muscle. Substantial variability in the progression and severity of heart disease segregated with maternal lineage, and sequencing of mtDNA from five maternal lineages revealed two major European haplogroups, U and H. Patients with the haplogroup U mtDNAs had more rapid and severe cardiomyopathy than those with haplogroup H.
- Published
- 2013
48. Mitochondrial DNA Variants Mediate Energy Production and Expression Levels for CFH, C3 and EFEMP1 Genes: Implications for Age-Related Macular Degeneration
- Author
-
Kenney, M. Cristina, Chwa, Marilyn, Atilano, Shari R, Pavlis, Janelle M, Falatoonzadeh, Payam, Ramirez, Claudio, Malik, Deepika, Hsu, Tiffany, Woo, Grace, Soe, Kyaw, Nesburn, Anthony B, Boyer, David S, Kuppermann, Baruch D, Jazwinski, S. Michal, Miceli, Michael V, Wallace, Douglas C, Udar, Nitin, and Lukiw, Walter
- Subjects
Factor-H Polymorphism ,Myosin Viia ,Oxidative Stress ,Drusen Formation ,Saudi Patients ,Risk ,Haplogroups ,Population ,Mtdna ,Dysfunction - Published
- 2013
49. An Inherited Heteroplasmic Mutation in Mitochondrial Gene COI in a Patient with Prostate Cancer Alters Reactive Oxygen, Reactive Nitrogen and Proliferation
- Author
-
Arnold, Rebecca S, Sun, Qian, Sun, Carrie Q, Richards, Jendai C, O'Hearn, Sean, Osunkoya, Adeboye O, Wallace, Douglas C, and Petros, John A
- Subjects
Nitric-Oxide Synthase ,Expression ,Dna ,Cells ,Tumor ,Genome ,Identification ,Progression ,Survival ,Benign - Published
- 2013
50. Mitochondrial genetic medicine
- Author
-
Wallace, Douglas C.
- Published
- 2018
- Full Text
- View/download PDF
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