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  • 1
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    Signaling {alpha}-helix in the insulin receptor [Biochemistry] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-07-11
    Description: The primary hormone-binding surface of the insulin receptor spans one face of the N-terminal β-helix of the α-subunit (the L1 domain) and an α-helix in its C-terminal segment (αCT). Crystallographic analysis of the free ectodomain has defined a contiguous dimer-related motif in which the αCT α-helix packs against L1 β-strands 2 and 3. To relate structure to function, we exploited expanded genetic-code technology to insert photo-activatable probes at key sites in L1 and αCT. The pattern of αCT-mediated photo–cross-linking within the free and bound receptor is in accord with the crystal structure and prior mutagenesis. Surprisingly, L1 photo-probes in β-strands 2 and 3, predicted to be shielded by αCT, efficiently cross-link to insulin. Furthermore, anomalous mutations were identified on neighboring surfaces of αCT and insulin that impair hormone-dependent activation of the intracellular receptor tyrosine kinase (contained within the transmembrane β-subunit) disproportionately to their effects on insulin binding. Taken together, these results suggest that αCT, in addition to its hormone-recognition role, provides a signaling element in the mechanism of receptor activation.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 2
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    A PPARgamma-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-04-24
    Description: Although feast and famine cycles illustrate that remodelling of adipose tissue in response to fluctuations in nutrient availability is essential for maintaining metabolic homeostasis, the underlying mechanisms remain poorly understood. Here we identify fibroblast growth factor 1 (FGF1) as a critical transducer in this process in mice, and link its regulation to the nuclear receptor PPARgamma (peroxisome proliferator activated receptor gamma), which is the adipocyte master regulator and the target of the thiazolidinedione class of insulin sensitizing drugs. FGF1 is the prototype of the 22-member FGF family of proteins and has been implicated in a range of physiological processes, including development, wound healing and cardiovascular changes. Surprisingly, FGF1 knockout mice display no significant phenotype under standard laboratory conditions. We show that FGF1 is highly induced in adipose tissue in response to a high-fat diet and that mice lacking FGF1 develop an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with a high-fat diet. Further analysis of adipose depots in FGF1-deficient mice revealed multiple histopathologies in the vasculature network, an accentuated inflammatory response, aberrant adipocyte size distribution and ectopic expression of pancreatic lipases. On withdrawal of the high-fat diet, this inflamed adipose tissue fails to properly resolve, resulting in extensive fat necrosis. In terms of mechanisms, we show that adipose induction of FGF1 in the fed state is regulated by PPARgamma acting through an evolutionarily conserved promoter proximal PPAR response element within the FGF1 gene. The discovery of a phenotype for the FGF1 knockout mouse establishes the PPARgamma-FGF1 axis as critical for maintaining metabolic homeostasis and insulin sensitization.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3358516/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3358516/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jonker, Johan W -- Suh, Jae Myoung -- Atkins, Annette R -- Ahmadian, Maryam -- Li, Pingping -- Whyte, Jamie -- He, Mingxiao -- Juguilon, Henry -- Yin, Yun-Qiang -- Phillips, Colin T -- Yu, Ruth T -- Olefsky, Jerrold M -- Henry, Robert R -- Downes, Michael -- Evans, Ronald M -- DK057978/DK/NIDDK NIH HHS/ -- DK062434/DK/NIDDK NIH HHS/ -- DK063491/DK/NIDDK NIH HHS/ -- DK090962/DK/NIDDK NIH HHS/ -- HL105278/HL/NHLBI NIH HHS/ -- P30 CA014195/CA/NCI NIH HHS/ -- P30 DK063491/DK/NIDDK NIH HHS/ -- R01 DK033651/DK/NIDDK NIH HHS/ -- R01 HL105278/HL/NHLBI NIH HHS/ -- R01 HL105278-21/HL/NHLBI NIH HHS/ -- R24 DK090962/DK/NIDDK NIH HHS/ -- R24 DK090962-02/DK/NIDDK NIH HHS/ -- R37 DK033651/DK/NIDDK NIH HHS/ -- R37 DK057978/DK/NIDDK NIH HHS/ -- R37 DK057978-34/DK/NIDDK NIH HHS/ -- U19 DK062434/DK/NIDDK NIH HHS/ -- U19 DK062434-10/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 May 17;485(7398):391-4. doi: 10.1038/nature10998.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22522926" target="_blank"〉PubMed〈/a〉
    Keywords: Adipocytes/drug effects/metabolism/pathology ; Animals ; Base Sequence ; Cell Size/drug effects ; Diabetes Mellitus, Experimental/chemically induced/genetics/pathology ; Diet, High-Fat/adverse effects ; Fibroblast Growth Factor 1/deficiency/*genetics/*metabolism ; *Homeostasis/drug effects ; Humans ; Inflammation/genetics ; Insulin/metabolism ; Insulin Resistance ; Intra-Abdominal Fat/drug effects/*metabolism/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Necrosis/enzymology ; PPAR gamma/*metabolism ; Promoter Regions, Genetic/genetics ; Response Elements/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Structural basis of Lewisb antigen binding by the Helicobacter pylori adhesin BabA (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-08-16
    Description: Helicobacter pylori is a leading cause of peptic ulceration and gastric cancer worldwide. To achieve colonization of the stomach, this Gram-negative bacterium adheres to Lewis b (Le b ) antigens in the gastric mucosa using its outer membrane protein BabA. Structural information for BabA has been elusive, and thus, its molecular mechanism for recognizing Le b antigens remains unknown. We present the crystal structure of the extracellular domain of BabA, from H. pylori strain J99, in the absence and presence of Le b at 2.0- and 2.1-Å resolutions, respectively. BabA is a predominantly α-helical molecule with a markedly kinked tertiary structure containing a single, shallow Le b binding site at its tip within a β-strand motif. No conformational change occurs in BabA upon binding of Le b , which is characterized by low affinity under acidic [ K D (dissociation constant) of ~227 μM] and neutral ( K D of ~252 μM) conditions. Binding is mediated by a network of hydrogen bonds between Le b Fuc1, GlcNAc3, Fuc4, and Gal5 residues and a total of eight BabA amino acids (C189, G191, N194, N206, D233, S234, S244, and T246) through both carbonyl backbone and side-chain interactions. The structural model was validated through the generation of two BabA variants containing N206A and combined D233A/S244A substitutions, which result in a reduction and complete loss of binding affinity to Le b , respectively. Knowledge of the molecular basis of Le b recognition by BabA provides a platform for the development of therapeutics targeted at inhibiting H. pylori adherence to the gastric mucosa.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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  • 4
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    A single fast radio burst localized to a massive galaxy at cosmological distance (2019)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2019
    Description: 〈p〉Fast Radio Bursts (FRBs) are brief radio emissions from distant astronomical sources. Some are known to repeat, but most are single bursts. Non-repeating FRB observations have had insufficient positional accuracy to localize them to an individual host galaxy. We report the interferometric localization of the single pulse FRB 180924 to a position 4 kpc from the center of a luminous galaxy at redshift 0.3214. The burst has not been observed to repeat. The properties of the burst and its host are markedly different from the only other accurately localized FRB source. The integrated electron column density along the line of sight closely matches models of the intergalactic medium, indicating that some FRBs are clean probes of the baryonic component of the cosmic web.〈/p〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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  • 5
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    A single fast radio burst localized to a massive galaxy at cosmological distance (2019)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2019
    Description: 〈p〉Fast radio bursts (FRBs) are brief radio emissions from distant astronomical sources. Some are known to repeat, but most are single bursts. Nonrepeating FRB observations have had insufficient positional accuracy to localize them to an individual host galaxy. We report the interferometric localization of the single-pulse FRB 180924 to a position 4 kiloparsecs from the center of a luminous galaxy at redshift 0.3214. The burst has not been observed to repeat. The properties of the burst and its host are markedly different from those of the only other accurately localized FRB source. The integrated electron column density along the line of sight closely matches models of the intergalactic medium, indicating that some FRBs are clean probes of the baryonic component of the cosmic web.〈/p〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 6
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    Changes in European wind energy generation potential within a 1.5 °C warmer world (2018)
    Institute of Physics (IOP)
    Details
    Publication Date: 2018-05-17
    Description: Global climate model simulations from the ‘ Half a degree Additional warming, Prognosis and Projected Impacts’ (HAPPI) project were used to assess how wind power generation over Europe would change in a future world where global temperatures reach 1.5 °C above pre-industrial levels. Comparing recent historical (2006–2015) and future 1.5 °C forcing experiments highlights that the climate models demonstrate a northward shift in the Atlantic jet, leading to a significant ( p  
    Print ISSN: 1748-9318
    Electronic ISSN: 1748-9326
    Topics: Biology , Energy, Environment Protection, Nuclear Power Engineering
    Published by Institute of Physics (IOP)
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