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Aminoacyl-tRNA synthetases as therapeutic targets
Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for protein synthesis with evolutionarily conserved enzymatic mechanisms. Despite their similarity across organisms, scientists have been able to generate effective anti-infective agents based on the structural differences in the catalytic clefts of ARSs from pathogens and humans. However, recent genomic, proteomic and functionomic advances have unveiled unexpected disease-associated mutations and altered expression, secretion and interactions in human ARSs, revealing hidden biological functions beyond their catalytic roles in protein synthesis. These studies have also brought to light their potential as a rich and unexplored source for new therapeutic targets and agents through multiple avenues, including direct targeting of the catalytic sites, controlling disease-associated protein–protein interactions and developing novel biologics from the secreted ARS proteins or their parts. This Review addresses the emerging biology and therapeutic applications of human ARSs in diseases including autoimmune and rare diseases, and cancer.Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for protein synthesis with evolutionarily conserved enzymatic mechanisms. Research advances have unveiled unexpected disease-associated alterations in human ARSs that have highlighted their potential as therapeutic targets. This Review addresses the emerging biology and therapeutic applications of human ARSs.
Journal Article
Technology Ecosystem Governance
Technology platform strategies offer a novel way to orchestrate a rich portfolio of contributions made by the many independent actors who form an ecosystem of heterogeneous complementors around a stable platform core. This form of organising has been successfully used in smartphone, gaming, commercial software, and industrial sectors. Technology ecosystems require stability and homogeneity to leverage common investments in standard components, but they also need variability and heterogeneity to meet evolving market demand. Although the required balance between stability and evolvability in the ecosystem has been addressed conceptually in the literature, we have less understanding of its underlying mechanics or appropriate governance. Through an extensive case study of a business software ecosystem consisting of a major multinational manufacturer of enterprise resource planning software at the core and a heterogeneous system of independent implementation partners and solution developers on the periphery, our research identifies three salient tensions that characterize the ecosystem: standard–variety, control–autonomy, and collective–individual. We then highlight the specific ecosystem governance mechanisms designed to simultaneously manage desirable and undesirable variance across each tension. Paradoxical tensions may manifest as dualities, where tensions are framed as complementary and mutually enabling. Alternatively, they may manifest as dualisms, where actors are faced with contradictory and disabling “either…or” decisions. We identify conditions where latent, complementary tensions become manifest as salient, contradictory tensions. By identifying conditions in which complementary logics are overshadowed by contradictory logics, our study further contributes to the understanding of the dynamics of technology ecosystems, as well as the effective design of technology ecosystem governance that can explicitly embrace paradoxical tensions toward generative outcomes.
Journal Article
Antoni in the kitchen
The food guru and member of the Netflix show \"Queer Eye\" unveils the stylishly accessible, healthy recipes fans have been waiting for.
Book
Aminoacyl‐tRNA synthetases in medicine and disease
Aminoacyl‐tRNA synthetases (ARSs) are essential and ubiquitous ‘house‐keeping’ enzymes responsible for charging amino acids to their cognate tRNAs and providing the substrates for global protein synthesis. Recent studies have revealed a role of multiple ARSs in pathology, and their potential use as pharmacological targets and therapeutic reagents. The ongoing discovery of genetic mutations in human ARSs is increasing exponentially and can be considered an important determinant of disease etiology. Several chemical compounds target bacterial, fungal and human ARSs as antibiotics or disease‐targeting medicines. Remarkably, ongoing exploration of noncanonical functions of ARSs has shown important contributions to control of angiogenesis, inflammation, tumourigenesis and other important physiopathological processes. Here, we summarize the roles of ARSs in human diseases and medicine, focusing on the most recent and exciting discoveries.
Graphical Abstract
Aminoacyl‐tRNA synthetases have been implicated in multiple pathologies and have potential as pharmacological targets and therapeutic reagents. This review discusses recent findings on the roles of ARSs in human disease and therapeutic approaches.
Journal Article
Analysis of Germline Stem Cell Differentiation Following Loss of GLP-1 Notch Activity in Caenorhabditis elegans
Stem cells generate the differentiated progeny cells of adult tissues. Stem cells in the Caenorhabditis elegans hermaphrodite germline are maintained within a proliferative zone of ∼230 cells, ∼20 cell diameters in length, through GLP-1 Notch signaling. The distal tip cell caps the germline and supplies GLP-1-activating ligand, and the distal-most germ cells that occupy this niche are likely self-renewing stem cells with active GLP-1 signaling. As germ cells are displaced from the niche, GLP-1 activity likely decreases, yet mitotically cycling germ cells are found throughout the proliferative zone prior to overt meiotic differentiation. Following loss of GLP-1 activity, it remains unclear whether stem cells undergo transit-amplifying (TA) divisions or more directly enter meiosis. To distinguish between these possibilities we employed a temperature-sensitive (ts) glp-1 mutant to manipulate GLP-1 activity. We characterized proliferative zone dynamics in glp-1(ts) mutants at permissive temperature and then analyzed the kinetics of meiotic entry of proliferative zone cells after loss of GLP-1. We found that entry of proliferative zone cells into meiosis following loss of GLP-1 activity is largely synchronous and independent of their distal-proximal position. Furthermore, the majority of cells complete only a single mitotic division before entering meiosis, independent of their distal-proximal position. We conclude that germ cells do not undergo TA divisions following loss of GLP-1 activity. We present a model for the dynamics of the proliferative zone that utilizes cell cycle rate and proliferative zone size and output and incorporates the more direct meiotic differentiation of germ cells following loss of GLP-1 activity.
Journal Article
Fame
Passions will be tested and young hearts will be broken. Ultimately, talent, dedication and hard work will triumph. Centers around a group of dancers, singers, musicians and actors at the New York City High School of Performing Arts, and their spirited drive to live out their dreams of stardom. In an incredibly competitive atmosphere, each student must shine amidst the tumult of school work, deep friendships, budding romance and self-discovery.
DVD
Inflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis
Copper levels are known to be elevated in inflamed and malignant tissues. But the mechanism underlying this selective enrichment has been elusive. In this study, we report a axis by which inflammatory cytokines, such as IL-17, drive cellular copper uptake via the induction of a metalloreductase, STEAP4. IL-17-induced elevated intracellular copper level leads to the activation of an E3-ligase, XIAP, which potentiates IL-17-induced NFκB activation and suppresses the caspase 3 activity. Importantly, this IL-17-induced STEAP4-dependent cellular copper uptake is critical for colon tumor formation in a murine model of colitis-associated tumorigenesis and STEAP4 expression correlates with IL-17 level and XIAP activation in human colon cancer. In summary, this study reveals a IL-17-STEAP4-XIAP axis through which the inflammatory response induces copper uptake, promoting colon tumorigenesis.
STEAP4 promotes the uptake of copper, and copper is known to be enhanced in cancer tissues. Here, the authors show that STEAP4 is induced by IL17, which is increased in inflamed tissues, consequently the increased copper levels activate NFκB signalling and suppression of apoptosis.
Journal Article