Despite an ageing population we live in a culture full of fear about becoming older. Old age is seen as an almost entirely negative phenomenon with decline on all fronts. In a brilliant speech at a recent conference, Rosalie Hudson (2002) joined those pushing back the boundaries of the way we think about ageing. After all, the way we think about ageing is just that, thoughts, and thoughts have no power of their own except that which we choose to give them.
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| http://dx.doi.org/10.7748/ns.17.13.22.s37 | DOI Listing |
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Sanger validation of WGS variants.
Sci Rep
January 2025
Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies, Moscow, Russia, 125315.
With the development of next-generation sequencing (NGS) technologies it became possible to simultaneously analyze millions of variants. Despite the quality improvement, it is generally still required to confirm the variants before reporting. However, in recent years the dominant idea is that one could define the quality thresholds for "high quality" variants which do not require orthogonal validation.
View Article and Find Full Text PDFCopper-dependent halogenase catalyses unactivated C-H bond functionalization.
Nature
January 2025
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA, USA.
Carbon-hydrogen (C-H) bonds are the foundation of essentially every organic molecule, making them an ideal place to do chemical synthesis. The key challenge is achieving selectivity for one particular C(sp)-H bond. In recent years, metalloenzymes have been found to perform C(sp)-H bond functionalization.
View Article and Find Full Text PDFStructural insights into 2-oxindole-forming monooxygenase MarE: Divergent architecture and substrate positioning versus tryptophan dioxygenases.
J Biol Chem
January 2025
Department of Chemistry, The University of Texas at San Antonio, Texas 78249, United States. Electronic address:
MarE, a heme-dependent enzyme, catalyzes a unique 2-oxindole-forming monooxygenation reaction from tryptophan metabolites. To elucidate its enzyme-substrate interaction mode, we present the first X-ray crystal structures of MarE in complex with its prime substrate, (2S,3S)-β-methyl-L-tryptophan and cyanide at 1.89 Å resolution as well as a truncated yet catalytically active version in complex with the substrate at 2.
View Article and Find Full Text PDFA conserved chaperone protein is required for the formation of a non-canonical type VI secretion system spike tip complex.
J Biol Chem
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Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4K1; Michael DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada L8S 4K1. Electronic address:
Type VI secretion systems (T6SS) are dynamic protein nanomachines found in Gram-negative bacteria that deliver toxic effector proteins into target cells in a contact-dependent manner. Prior to secretion, many T6SS effector proteins require chaperones and/or accessory proteins for proper loading onto the structural components of the T6SS apparatus. However, despite their established importance, the precise molecular function of several T6SS accessory protein families remains unclear.
View Article and Find Full Text PDFDesign, synthesis and evaluation of (E)-1-(4-(2-(1H-pyrazol-5-yl)vinyl)phenyl) derivatives as next generation selective RET inhibitors overcoming RET solvent front mutations (G810C/R).
Eur J Med Chem
January 2025
College of Chemistry and Materials Science, Zhejiang Normal University, No. 688 Yingbin Road, Jinhua, Zhejiang Province, 321004, China. Electronic address:
RET is a well-recognized drug target for cancer treatment. Despite the promising efficacy of selective second-generation RET inhibitors Selpercatinib and Pralsetinib, the clinical benefits have been compromised due to the quickly developed resistance to these drugs. RET G810 mutations at the solvent front site have been identified as the major on-target mutations contributing to resistance against Selpercatinib and Pralsetinib.
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