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281.
Diego Cantoni Matthew J Murray Mphatso D Kalemera Samuel J Dicken Lenka Stejskal Georgina Brown Spyros Lytras Jonathon D Coey James McKenna Stephen Bridgett David Simpson Derek Fairley Lucy G Thorne AnnKathrin Reuschl Calum Forrest Maaroothen Ganeshalingham Luke Muir Machaela Palor Lisa Jarvis Brian Willett Ultan F Power Laura E McCoy Clare Jolly Greg J Towers Katie J Doores David L Robertson Adrian J Shepherd Matthew B Reeves Connor G G Bamford Joe Grove 《EMBO reports》2022,23(10)
The emergence of SARS‐CoV‐2 variants has exacerbated the COVID‐19 global health crisis. Thus far, all variants carry mutations in the spike glycoprotein, which is a critical determinant of viral transmission being responsible for attachment, receptor engagement and membrane fusion, and an important target of immunity. Variants frequently bear truncations of flexible loops in the N‐terminal domain (NTD) of spike; the functional importance of these modifications has remained poorly characterised. We demonstrate that NTD deletions are important for efficient entry by the Alpha and Omicron variants and that this correlates with spike stability. Phylogenetic analysis reveals extensive NTD loop length polymorphisms across the sarbecoviruses, setting an evolutionary precedent for loop remodelling. Guided by these analyses, we demonstrate that variations in NTD loop length, alone, are sufficient to modulate virus entry. We propose that variations in NTD loop length act to fine‐tune spike; this may provide a mechanism for SARS‐CoV‐2 to navigate a complex selection landscape encompassing optimisation of essential functionality, immune‐driven antigenic variation and ongoing adaptation to a new host. 相似文献
282.
De Savi C Pape A Cumming JG Ting A Smith PD Burrows JN Mills M Davies C Lamont S Milne D Cook C Moore P Sawyer Y Gerhardt S 《Bioorganic & medicinal chemistry letters》2011,21(5):1376-1381
Two series of N-hydroxyformamide inhibitors of ADAM-TS4 were identified from screening compounds previously synthesised as inhibitors of matrix metalloproteinase-13 (collagenase-3). Understanding of the binding mode of this class of compound using ADAM-TS1 as a structural surrogate has led to the discovery of potent and very selective inhibitors with favourable DMPK properties. Synthesis, structure-activity relationships, and strategies to improve selectivity and lower in vivo metabolic clearance are described. 相似文献
283.
MCH receptor peptide agonists and antagonists 总被引:1,自引:1,他引:0
Melanin-concentrating hormone (MCH) is an important neuropeptide hormone involved in multiple physiological processes. Peptide derivatives of MCH have been developed as tools to aid research including potent radioligands, receptor selective agonists, and potent antagonists. These tools have been used to further understand the role of MCH in physiology, primarily in rodents. However, the tools could also help elucidate the role for MCHR1 and MCHR2 in mediating MCH signaling in higher species. 相似文献
284.
Toshihiro Sakamoto Minoru Moriya Yuji Haga Toshiyuki Takahashi Takunobu Shibata Osamu Okamoto Katsumasa Nonoshita Hidefumi Kitazawa Masayasu Hidaka Akira Gomori Hisashi Iwaasa Akane Ishihara Akio Kanatani Takehiro Fukami Ying-Duo Gao Douglas J. MacNeil Lihu Yang 《Bioorganic & medicinal chemistry letters》2009,19(6):1564-1568
A series of spiroindoline-3,4′-piperidine derivatives were synthesized and evaluated for their binding affinities and antagonistic activities at Y5 receptors. Potent Y5 antagonists were tested for their oral bioavailabilities and brain penetration in rats. Some of the antagonists showed good oral bioavailability and/or good brain penetration. In particular, compound 6e was orally bioavailable and brain penetrant, and oral administration of 6e inhibited bPP-induced food intake in rats with a minimum effective dose of 10 mg/kg. 相似文献
285.
Animal introductions can often have unexpected and complex consequences for both native and invader species. Freshwater crustaceans such as Gammarus spp. (amphipods) and Mysis relicta (an ‘opossum shrimp’) have frequently come into contact because of deliberate and accidental introductions. However, there remains poor understanding of mechanisms leading to the co-existence and/or exclusion among amphipods and mysids. Here, we examined predatory and interference interactions between native (Gammarus duebeni celticus) and invasive (Gammarus tigrinus and Crangonyx pseudogracilis) amphipods and the native M. relicta in Britain’s largest expanse of freshwater, Lough Neagh. Laboratory mesocosm experiments simulating near-shore/mid-lough benthic habitats showed that both Gammarus species, but not C. pseudogracilis, preyed on M. relicta, which itself preyed on C. pseudogracilis. Further, M. relicta micro-distribution and habitat use changed because of interference from G. d. celticus and to a lesser extent G. tigrinus, with C. pseudogracilis having no such impact. In smaller microcosms, predation of M. relicta adults and juveniles by Gammarus spp. was significant. Although predation of Gammarus spp. by M. relicta was low, adult C. pseudogracilis were killed by M. relicta and its predation of juvenile C. pseudogracilis was high. We discuss the concurrence of these laboratory interactions with known field patterns of co-existence amongst these species. 相似文献
286.
GSK-3 phosphorylation of the Alzheimer epitope within collapsin response mediator proteins regulates axon elongation in primary neurons 总被引:1,自引:0,他引:1
Cole AR Knebel A Morrice NA Robertson LA Irving AJ Connolly CN Sutherland C 《The Journal of biological chemistry》2004,279(48):50176-50180
Elevated glycogen synthase kinase-3 (GSK-3) activity is associated with Alzheimer disease. We have found that collapsin response mediator proteins (CRMP) 2 and 4 are physiological substrates of GSK-3. The amino acids targeted by GSK-3 comprise a hyperphosphorylated epitope first identified in plaques isolated from Alzheimer brain. Expression of wild type CRMP2 in primary hippocampal neurons or SH-SY5Y neuroblastoma cells promotes axon elongation. However, a GSK-3-insensitive CRMP2 mutant has dramatically reduced ability to promote axon elongation, a similar effect to pharmacological inhibition of GSK-3. Hence, we propose that phosphorylation of CRMP proteins by GSK-3 regulates axon elongation. This work provides a direct connection between hyperphosphorylation of these residues and elevated GSK-3 activity, both of which are observed in Alzheimer brain. 相似文献
287.
Ye Z Guo L Barakat KJ Pollard PG Palucki BL Sebhat IK Bakshi RK Tang R Kalyani RN Vongs A Chen AS Chen HY Rosenblum CI MacNeil T Weinberg DH Peng Q Tamvakopoulos C Miller RR Stearns RA Cashen DE Martin WJ Metzger JM Strack AM MacIntyre DE Van der Ploeg LH Patchett AA Wyvratt MJ Nargund RP 《Bioorganic & medicinal chemistry letters》2005,15(15):3501-3505
A novel isoquinuclidine containing selective melanocortin subtype-4 receptor small molecule agonist, 3 (RY764), is reported. Its in vivo characterization revealed mechanism-based food intake reduction and erectile activity augmentation in rodents. 相似文献
288.
289.
Melanin-concentrating hormone receptor subtypes 1 and 2: species-specific gene expression 总被引:16,自引:0,他引:16
Tan CP Sano H Iwaasa H Pan J Sailer AW Hreniuk DL Feighner SD Palyha OC Pong SS Figueroa DJ Austin CP Jiang MM Yu H Ito J Ito M Ito M Guan XM MacNeil DJ Kanatani A Van der Ploeg LH Howard AD 《Genomics》2002,79(6):785-792
To assess the contribution of potential central nervous system pathways implicated in the control of appetite regulation and energy metabolism, it is essential to first identify appropriate animal models. Melanin-concentrating hormone (MCH), a conserved cyclic neuropeptide implicated in the modulation of food intake, has been shown to bind and activate two G-protein-coupled receptors, called GPR24 and MCHR2, expressed in human brain and other tissues. Here we show that several non-human species (rat, mouse, hamster, guinea pig, and rabbit) do not have functional MCHR2 receptors, or encode a nonfunctional MCHR2 pseudogene while retaining GPR24 expression. We identified three species for further evaluation that express both MCH receptor subtypes. We cloned and functionally characterized dog, ferret, and rhesus GPR24 and MCHR2 in mammalian cells and studied their brain distribution patterns by in situ hybridization. The homology, expression profile, and functional similarity of the receptors in the dog, ferret, and rhesus to that of human support the potential use of these species as preclinical animal models in the development of therapeutic agents for obesity or other MCH-mediated disorders. 相似文献
290.
D MacNeil G Krystal M Fairhurst J D Waterfield 《Journal of immunology (Baltimore, Md. : 1950)》1986,137(11):3464-3468
MRL-+ and MRL-lpr congenic mice differ by the presence and expression of the homozygous recessive lymphoproliferation (lpr) gene. One manifestation of this gene is a massive T cell proliferation that results in a generalized lymphadenopathy in older animals. Interleukin 3 (IL 3), a recently described lymphokine, has been shown to influence lymphocyte differentiation. It was possible that abberrant IL 3 production was the mechanism responsible for the lpr controlled lymphadenopathy. Consequently, in this paper we tested the MRL congenic mice for their ability to produce IL 3. We report that the T lymphocytes from MRL-+ and MRL-lpr could neither respond to pokeweed mitogen in the induction of proliferation nor produce IL 3. Moreover, IL 3 was not produced constitutively nor could be induced at any time period up to 5 days in vitro. This hyporesponsiveness was shown to be controlled at the accessory cell level. Addition of T cell-depleted peritoneal exudate cells from normal major histocompatibility complex (MHC) compatible mice was able to restore the ability to secrete IL 3 in response to pokeweed mitogen in MRL-+ and young MRL-lpr mice. The defect in the accessory cells could be overridden by two means: the incorporation of phorbol myristate acetate in the induction system and preincubation of the cells in tissue culture. 相似文献