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  • 1
    Publication Date: 2016-03-31
    Description: Brown and beige adipose tissues can dissipate chemical energy as heat through thermogenic respiration, which requires uncoupling protein 1 (UCP1). Thermogenesis from these adipocytes can combat obesity and diabetes, encouraging investigation of factors that control UCP1-dependent respiration in vivo. Here we show that acutely activated thermogenesis in brown adipose tissue is defined by a substantial increase in levels of mitochondrial reactive oxygen species (ROS). Remarkably, this process supports in vivo thermogenesis, as pharmacological depletion of mitochondrial ROS results in hypothermia upon cold exposure, and inhibits UCP1-dependent increases in whole-body energy expenditure. We further establish that thermogenic ROS alter the redox status of cysteine thiols in brown adipose tissue to drive increased respiration, and that Cys253 of UCP1 is a key target. UCP1 Cys253 is sulfenylated during thermogenesis, while mutation of this site desensitizes the purine-nucleotide-inhibited state of the carrier to adrenergic activation and uncoupling. These studies identify mitochondrial ROS induction in brown adipose tissue as a mechanism that supports UCP1-dependent thermogenesis and whole-body energy expenditure, which opens the way to improved therapeutic strategies for combating metabolic disorders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chouchani, Edward T -- Kazak, Lawrence -- Jedrychowski, Mark P -- Lu, Gina Z -- Erickson, Brian K -- Szpyt, John -- Pierce, Kerry A -- Laznik-Bogoslavski, Dina -- Vetrivelan, Ramalingam -- Clish, Clary B -- Robinson, Alan J -- Gygi, Steve P -- Spiegelman, Bruce M -- DK31405/DK/NIDDK NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2016 Apr 7;532(7597):112-6. doi: 10.1038/nature17399. Epub 2016 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA. ; Department of Neurology, Harvard Medical School, Boston, Massachusetts 02215, USA. ; MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue, Brown/chemistry/cytology/metabolism ; Animals ; Cell Respiration ; Cysteine/*chemistry/genetics/metabolism ; *Energy Metabolism/drug effects ; Female ; Humans ; Ion Channels/*chemistry/deficiency/genetics/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/drug effects/*metabolism ; Mitochondrial Proteins/*chemistry/deficiency/genetics/*metabolism ; Mutant Proteins/chemistry/genetics/metabolism ; Oxidation-Reduction ; Reactive Oxygen Species/*metabolism ; Sulfhydryl Compounds/metabolism ; *Thermogenesis/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2011-06-15
    Description: Understanding the molecular mechanisms of osmolyte protection in protein stability has proved to be challenging. In particular, little is known about the role of osmolytes in the structure of the unfolding transition state of a protein, the main determinant of its dynamics. We have developed an experimental protocol to directly probe the transition state of a protein in a range of osmolyte environments. We use an atomic force microscope in force-clamp mode to apply mechanical forces to the protein I27 and obtain force-dependent rate constants of protein unfolding. We measure the distance to the unfolding transition state, Δxu, along a 1D reaction coordinate imposed by mechanical force. We find that for the small osmolytes, ethylene glycol, propylene glycol, and glycerol, Δxu scales with the size of the molecule, whereas for larger osmolytes, sorbitol and sucrose, Δxu remains the same as that measured in water. These results are in agreement with steered molecular dynamics simulations that show that small osmolytes act as solvent bridges in the unfolding transition state structure, whereas only water molecules act as solvent bridges in large osmolyte environments. These results demonstrate that novel force protocols combined with solvent substitution can directly probe angstrom changes in unfolding transition state structure. This approach creates new opportunities to gain molecular level understanding of the action of osmolytes in biomolecular processes.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 3
    Publication Date: 2018-09-21
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2017-10-02
    Description: In advanced robot control problems, on-line computation of inverse Jacobian solution is frequently required. Parallel processing architecture is an effective way to reduce computation time. A parallel processing architecture is developed for the inverse Jacobian (inverse differential kinematic equation) of the PUMA arm. The proposed pipeline/parallel algorithm can be inplemented on an IC chip using systolic linear arrays. This implementation requires 27 processing cells and 25 time units. Computation time is thus significantly reduced.
    Type: Jet Propulsion Lab., California Inst. of Tech., Proceedings of the Workshop on Space Telerobotics, Volume 3; p 317-324
    Format: application/pdf
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  • 5
    Publication Date: 2016-12-08
    Description: The Cancer Genome Atlas project has generated multi-dimensional and highly integrated genomic data from a large number of patient samples with detailed clinical records across many cancer types, but it remains unclear how to best integrate the massive amount of genomic data into clinical practice. We report here our methodology to build a multi-dimensional subnetwork atlas for cancer prognosis to better investigate the potential impact of multiple genetic and epigenetic (gene expression, copy number variation, microRNA expression and DNA methylation) changes on the molecular states of networks that in turn affects complex cancer survivorship. We uncover an average of 38 novel subnetworks in the protein–protein interaction network that correlate with prognosis across four prominent cancer types. The clinical utility of these subnetwork biomarkers was further evaluated by prognostic impact evaluation, functional enrichment analysis, drug target annotation, tumor stratification and independent validation. Some pathways including the dynactin, cohesion and pyruvate dehydrogenase-related subnetworks are identified as promising new targets for therapy in specific cancer types. In conclusion, this integrative analysis of existing protein interactome and cancer genomics data allows us to systematically dissect the molecular mechanisms that underlie unexpected outcomes for cancer, which could be used to better understand and predict clinical outcomes, optimize treatment and to provide new opportunities for developing therapeutics related to the subnetworks identified.
    Print ISSN: 1467-5463
    Electronic ISSN: 1477-4054
    Topics: Biology , Computer Science
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  • 6
    Publication Date: 2014-06-14
    Description: Features of fishbone-like trapped energetic electrons driven modes (TEEMs), which are a particular manifestation of the fishbone gap modes, are investigated taking into account model radial profile and the pitch angle distribution of the energetic electrons (EEs). The TEEMs are found unstable only when the beta values of EEs β h (=pressure of the energetic electrons/pressure of magnetic field) are higher than certain critical values which are proportional to perturbed energy δ W ̂ c of background plasma and much lower than that for traditional fishbone modes. In addition, TEEMs become stable again and enter a second stable regime when β h values are higher than second critical values. Furthermore, the modes can only be excited in plasmas which are stable for MHD instabilities. The real frequency and growth rate of the modes are approximately linear and parabolic functions of β h , respectively. The real frequency is very low but not zero in the vicinity of lower beta region, whereas it is comparable to the toroidal precession frequency of the EEs in higher critical beta region. The numerical results show that the second stable regime is easy to form when q  = 1 flux surface is close to the magnetic axis. Suitable density gradient of EEs and magnetic shear are other two necessary conditions for excitation of the TEEMs.
    Print ISSN: 1070-664X
    Electronic ISSN: 1089-7674
    Topics: Physics
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  • 7
    Publication Date: 2018-05-03
    Description: Gas-evolving vertical electrode system is a typical electrochemical industrial reactor. Gas bubbles are released from the surfaces of the anode and affect the electrolyte flow pattern and even the cell performance. In the current work, the hydrodynamics induced by the air bubbles in a cold model was experimentally and numerically investigated. Particle image velocimetry and volumetric three-component velocimetry techniques were applied to experimentally visualize the hydrodynamics characteristics and flow fields in a two-dimensional (2D) plane and a three-dimensional (3D) space, respectively. Measurements were performed at different gas rates. Furthermore, the corresponding mathematical model was developed under identical conditions for the qualitative and quantitative analyses. The experimental measurements were compared with the numerical results based on the mathematical model. The study of the time-averaged flow field, three velocity components, instantaneous velocity and turbulent intensity indicate that the numerical model qualitatively reproduces liquid motion. The 3D model predictions capture the flow behaviour more accurately than the 2D model in this study.
    Keywords: chemical physics, fluid mechanics
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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