Zobrazení zdroje stránky Reillyfield3469

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.In 1913, eccentric French composer Erik Satie wrote a fragmentary, diary-like essay where he depicted a strikingly rigid diet consisting solely of white foods eggs, sugar, coconuts, rice, cream cheese, fuchsia juice and so on. Satie's brief essay has later been used as one of many puzzle pieces in attempts to retrospectively diagnose him with autism spectrum disorder. With Satie's white meal as a starting point, this paper explores colour-based food preferences and selective eating in clinical and non-clinical populations, with a special focus on autism spectrum disorder and avoidant/restrictive food intake disorder (ARFID). [https://www.selleckchem.com/products/isrib.html ISRIB] General colour preferences and their causes as well as the impact of colour on taste and food identification are also explored. Selective eating during childhood is immensely common and does not generally lead to disordered eating in the long run, although subgroups may experience rigidity around food of a more enduring nature. Problems related to eating were repeatedly described in Kannessions. Published by BMJ.Within the pancreatic β-cells, insulin secretory granules (SG) exist in functionally distinct pools, displaying variations in motility, as well as docking and fusion capability. Current therapies that increase insulin secretion do not consider the existence of these distinct SG pools. Accordingly, these approaches are effective only for a short period, with a worsening of glycaemia associated with continued decline in β-cell function. Insulin granule age is underappreciated as a determinant for why an insulin granule is selected for secretion and may explain why newly synthesised insulin is preferentially secreted from β-cells. Here, using a novel fluorescent timer protein, we aimed to investigate the preferential secretion model of insulin secretion and identify how granule aging is affected by variation in the β-cell environment, such as hyperglycemia. We demonstrate the use of a fluorescent timer construct, syncollin-dsRedE5TIMER, which changes its fluorescence from green to red over 18 h, in both microscopy and fluorescence-assisted organelle sorting techniques. We confirm that the SG-targeting construct localises to insulin granules in β-cells and does not interfere with normal insulin SG behavior. We visualise insulin SG aging behavior in MIN6 and INS1 beta-cell lines, and in primary C57BL/6J mouse and non-diabetic human islet cells. Finally, we separated young and old insulin SGs, revealing that preferential secretion of younger granules occurs in glucose-stimulated insulin secretion. We also show that SG population age is modulated by the β-cell environment in vivo in the db/db mouse islets and ex vivo in C57BL/6J islets exposed to different glucose environments. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are major regulators of synaptic plasticity, and rhythmic activity in the heart and brain. Opening of HCN channels requires membrane hyperpolarization and is further facilitated by intracellular cyclic nucleotides (cNMPs).&nbsp; In HCN channels, membrane hyperpolarization is sensed by the membrane-spanning voltage sensor domain (VSD) and the cNMP-dependent gating is mediated by the intracellular cyclic nucleotide-binding domain (CNBD) connected to the pore-forming S6 transmembrane segment via the C-linker.&nbsp;&nbsp; Previous functional analysis of HCN channels has suggested a direct or allosteric coupling between the voltage- and cNMP-dependent activation mechanisms.&nbsp; However, the specifics of this coupling remain unclear.&nbsp; The first cryo-EM structure of an HCN1 channel revealed that a novel structural element, dubbed the HCN domain (HCND), forms a direct structural link between the VSD and C-linker/CNBD.&nbsp; In this study, we investigated the functional significance of the HCND.&nbsp; Deletion of the HCND prevented surface expression of HCN2 channels.&nbsp; Based on the HCN1 structure analysis, we identified R237 and G239 residues on the S2 of the VSD that form direct interactions with I135 on the HCND.&nbsp; Disrupting these interactions abolished HCN2 currents.&nbsp; We also identified three residues on the C-linker/CNBD (E478, Q382 and H559) that form direct interactions with residues R154 and S158 on the HCND.&nbsp; Disrupting these interactions affected both voltage- and cAMP-dependent gating of HCN2 channels.&nbsp; These findings indicate that the HCND is necessary for the cell-surface expression of HCN channels, and provides a functional link between voltage- and cAMP-dependent mechanisms of HCN channel gating. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.Aspergillus fumigatus is a human opportunistic fungal pathogen whose cell wall protects it from the extracellular environment, including host defense responses. Chitin, an essential component of the fungal cell wall, is synthesized from UDP-GlcNAc produced in the hexosamine biosynthetic pathway. Because this pathway is critical for fungal cell wall integrity, the hexosamine biosynthesis enzymes represent potential targets of antifungal drugs. Here, we provide genetic and chemical evidence that glucosamine 6-phosphate N-acetyltransferase (Gna1), a key enzyme in this pathway, is an exploitable antifungal drug target. GNA1 deletion resulted in loss of fungal viability and disruption of the cell wall, phenotypes that could be rescued by exogenous GlcNAc, the product of the Gna1 enzyme. In a murine model of aspergillosis, the Δgna1 mutant strain exhibited attenuated virulence. Using a fragment-based approach, we discovered a small heterocyclic scaffold that binds proximal to the Gna1 active site and can be optimized to a selective sub-micromolar binder. Taken together, we have provided genetic, structural, and chemical evidence that Gna1 is an antifungal target in A. fumigatus. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.The microtubule-associated protein Tau is implicated in the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease. Increasing evidence suggests that post-translational modifications play critical roles in regulating Tau's normal functions and its pathogenic properties in tauopathies. Very little is known about how phosphorylation of tyrosine residues influences the structure, aggregation, and microtubule- and lipid-binding properties of Tau. Here, we sought to determine the relative contributions of phosphorylation of one or several of the five tyrosine residues in Tau (Tyr-18, -29, -197, -310, and -394) to the regulation of its biophysical, aggregation, and functional properties. We used a combination of site-specific mutagenesis and in vitro phosphorylation by c-Abl kinase to generate Tau species phosphorylated at all five tyrosine residues, all tyrosine residues except Tyr-310 or Tyr-394 (pTau-Y310F and pTau-Y394F, respectively) and Tau phosphorylated only at Tyr-310 or Tyr-394 (4F\pY310 or 4F\pY394).