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951.
Anthony B. Pinkerton Eduard Sergienko Yalda Bravo Russell Dahl Chen-Ting Ma Qing Sun Michael R. Jackson Nicholas D.P. Cosford José Luis Millán 《Bioorganic & medicinal chemistry letters》2018,28(1):31-34
Tissue-nonspecific alkaline phosphatase (TNAP) is an ectoenzyme crucial for bone matrix mineralization via its ability to hydrolyze extracellular inorganic pyrophosphate (ePPi), a potent mineralization inhibitor, to phosphate (Pi). By the controlled hydrolysis of ePPi, TNAP maintains the correct ratio of Pi to ePPi and therefore enables normal skeletal and dental calcification. In other areas of the body low ePPi levels lead to the development of pathological soft-tissue calcification, which can progress to a number of disorders. TNAP inhibitors have been shown to prevent these processes via an increase of ePPi. Herein we describe the use of a whole blood assay to optimize a previously described series of TNAP inhibitors resulting in 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425), a potent, selective and oral bioavailable compound that robustly inhibits TNAP in vivo. 相似文献
952.
Neuronal loss characterizes many of the most intractable nervous system diseases that deprive our ageing population of their quality of life. Neuroprotective pharmacological modalities are urgently needed to address this burgeoning population. Small ubiquitin-like modifier (SUMO) conjugation has been established as an endogenous neuroprotective response, and we have discovered several classes of small molecules that enhance SUMO conjugation. Herein we describe the hit to lead campaign that enabled the discovery of 3 diverse classes of drug-like SUMOylation activators. Optimized compounds were ultimately validated in cell-based models of neuronal loss and provide a foundation for establishing systemically active SUMO activators to treat degenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and stroke. 相似文献
953.
954.
A portfolio is presented documenting economic, high-resolution correlative focused ion beam scanning electron microscopy (FIB/SEM) in routine, comprising: (i) the use of custom-labeled slides and coverslips, (ii) embedding of cells in thin, or ultra-thin resin layers for correlative light and electron microscopy (CLEM) and (iii) the claim to reach the highest resolution possible with FIB/SEM in xyz. Regions of interest (ROIs) defined in light microscope (LM), can be relocated quickly and precisely in SEM. As proof of principle, HeLa cells were investigated in 3D context at all stages of the cell cycle, documenting ultrastructural changes during mitosis: nuclear envelope breakdown and reassembly, Golgi degradation and reconstitution and the formation of the midzone and midbody. 相似文献
955.
The giant mycoheterotrophic orchid Erythrorchis altissima is associated mainly with a divergent set of wood‐decaying fungi
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Yuki Ogura‐Tsujita Gerhard Gebauer Hui Xu Yu Fukasawa Hidetaka Umata Kenshi Tetsuka Miho Kubota Julienne M.‐I. Schweiger Satoshi Yamashita Nitaro Maekawa Masayuki Maki Shiro Isshiki Tomohisa Yukawa 《Molecular ecology》2018,27(5):1324-1337
The climbing orchid Erythrorchis altissima is the largest mycoheterotroph in the world. Although previous in vitro work suggests that E. altissima has a unique symbiosis with wood‐decaying fungi, little is known about how this giant orchid meets its carbon and nutrient demands exclusively via mycorrhizal fungi. In this study, the mycorrhizal fungi of E. altissima were molecularly identified using root samples from 26 individuals. Furthermore, in vitro symbiotic germination with five fungi and stable isotope compositions in five E. altissima at one site were examined. In total, 37 fungal operational taxonomic units (OTUs) belonging to nine orders in Basidiomycota were identified from the orchid roots. Most of the fungal OTUs were wood‐decaying fungi, but underground roots had ectomycorrhizal Russula. Two fungal isolates from mycorrhizal roots induced seed germination and subsequent seedling development in vitro. Measurement of carbon and nitrogen stable isotope abundances revealed that E. altissima is a full mycoheterotroph whose carbon originates mainly from wood‐decaying fungi. All of the results show that E. altissima is associated with a wide range of wood‐ and soil‐inhabiting fungi, the majority of which are wood‐decaying taxa. This generalist association enables E. altissima to access a large carbon pool in woody debris and has been key to the evolution of such a large mycoheterotroph. 相似文献
956.
Hagai Levine Hideo Mohri Anders Ekbom Liliana Ramos Geoff Parker Eduardo Roldan Luca Jovine Sabine Koelle Anna Lindstrand Simone Immler Sharon Mortimer David Mortimer Gerhard van der Horst Sumio Ishijima Natalie Aneck-Hahn Elisabetta Baldi Roelof Menkveld Susan A Rothmann Aleksander Giwercman Yvonne Giwercman Mats Holmberg Ulrik Kvist Lars Björndahl Rebecka Holmberg Stefan Arver John Flanagan Joël R Drevet 《Andrologie》2018,28(1):13
On the occasion of the XIIIth International Symposium on Spermatology held from 9 to 13 May 2018 in Stockholm (Sweden), participants (guest speakers and audience) collectively felt the need to make a public statement on the general issue of male reproductive health. Our intention is to raise awareness of what we believe is a neglected area of research despite alarming situations around the world. The disclosure strategy desired by the co-authors is to bring it to the attention of the greatest number partly by considering co-publication in the various periodicals dealing with Reproductive Biology and Andrology. BaCA’s editorial office accepted this mission and found it natural that our periodical, the official journal of the French Andrology Society (SALF), should carry this message. 相似文献
957.
The dynamic recruitment of TRBP to neuronal membranes mediates dendritogenesis during development
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Anna Antoniou Sharof Khudayberdiev Agata Idziak Silvia Bicker Ralf Jacob Gerhard Schratt 《EMBO reports》2018,19(3)
MicroRNAs are important regulators of local protein synthesis during neuronal development. We investigated the dynamic regulation of microRNA production and found that the majority of the microRNA‐generating complex, consisting of Dicer, TRBP, and PACT, specifically associates with intracellular membranes in developing neurons. Stimulation with brain‐derived neurotrophic factor (BDNF), which promotes dendritogenesis, caused the redistribution of TRBP from the endoplasmic reticulum into the cytoplasm, and its dissociation from Dicer, in a Ca2+‐dependent manner. As a result, the processing of a subset of neuronal precursor microRNAs, among them the dendritically localized pre‐miR16, was impaired. Decreased production of miR‐16‐5p, which targeted the BDNF mRNA itself, was rescued by expression of a membrane‐targeted TRBP. Moreover, miR‐16‐5p or membrane‐targeted TRBP expression blocked BDNF‐induced dendritogenesis, demonstrating the importance of neuronal TRBP dynamics for activity‐dependent neuronal development. We propose that neurons employ specialized mechanisms to modulate local gene expression in dendrites, via the dynamic regulation of microRNA biogenesis factors at intracellular membranes of the endoplasmic reticulum, which in turn is crucial for neuronal dendrite complexity and therefore neuronal circuit formation and function. 相似文献
958.
Stephanie Pohlmann Stefanie Scheu Verena Ziegler Nicole Schupp Christian Henninger Gerhard Fritz 《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2018,1865(9):1277-1292
Background
The Ras-homologous GTPase Rac1 plays a key role in the regulation of gene expression, cytoskeleton-associated processes and cell death as well as carcinogenesis and inflammation. Here, we investigated the impact of Rac1 signaling on liver-mediated immune homeostasis.Methods
We employed a constitutive Alb-Cre-driven rac1 knock-out and a poly I:C-inducible Mx1-Cre-based knock-out model and analyzed cytokine expression profiles in liver and other organs under basal situation and following LPS-induced endotoxemia by flow cytometry, qRT-PCR and immunocytochemistry.Results
Constitutive Alb-Cre-driven rac1 knockout in hepatocytes altered the basal distribution and activation of immune cells in the liver and likewise in kidney and lung. Early systemic alterations in cytokine serum levels following LPS treatment remained unaffected by Rac1. Furthermore, lack of Rac1 in hepatocytes of untreated animals shifted the liver to a chronic inflammatory state, as depicted by an enhanced mRNA expression of marker genes related to activated macrophages. Upon acute LPS-induced endotoxemia, increased IL-10 mRNA expression in the liver of Alb-Cre Rac1-deficient mice provided an anti-inflammatory response. Employing a poly I:C-inducible Mx1-Cre-based rac1 knock-out, which allows a more widespread rac1 deletion in both hepatocytes and non-hepatocytes, we observed substantial differences regarding both basal and LPS-stimulated cytokine expression profiles as compared to the Alb-Cre system.Conclusions
Rac1-dependent mechanisms in hepatocytes and non-hepatocytes contribute to the maintenance of liver immune homeostasis under basal situation and following LPS-induced endotoxemia. Disturbed Rac1-regulated hepatocyte functions may promote liver damage under pathophysiological situation involving inflammatory stress. 相似文献959.
The nucleotide sequence of a genomic fragment from Halobacterium salinarium containing an open reading frame encoding a protein with a calculated molecular mass of 71 kDa was determined. Database searches
revealed that this protein, Hp71, has similarities to eukaryotic cytoskeletal proteins. Heterologous production of Hp71 in
Escherichia coli allowed the isolation of anti-Hp71 antibodies. The antibodies were used (1) to verify the production of Hp71 in H. salinarium and (2) to determine its cytoplasmic localization by immune electron microscopy. Homologous overproduction of Hp71 in H. salinarium and heterologous production in Haloferax volcanii resulted in modifications of cell morphology from rods to extended rods, and from pleiomorphic cells to rods, respectively.
Structure prediction methods indicated that Hp71 has a head-rod-tail configuration, including an N-terminal domain with a
nucleotide binding motif (P-loop), and an extended discontinuous coiled-coil domain of 330 amino acids. To identify related
proteins, the complete genomes of Haemophilus influenzae, Mycoplasma genitalium, and Methanococcus jannaschii were searched for deduced proteins with extended coiled-coil domains. Only one or two proteins were found for each organism,
showing that Hp71 is one of only a few prokaryotic intracellular proteins with extended coiled-coil domains. The phenotype
upon overproduction and the similarity of Hp71 to the SMC superfamily of P-loop head-rod-tail proteins (named after SMC1,
which is involved in the “stability of minichromosomes” in yeast) indicate that Hp71 might be involved in cytoskeleton formation
and/or chromosome partitioning in H. salinarium.
Received: 25 March 1997 / Accepted: 11 August 1997 相似文献
960.
Rapid reactions comprising efflux of K+ and Cl−, phosphorylation of a 63-kDa protein (pp63), extracellular alkalinization and synthesis of H2O2 are equally induced in cells of Picea abies (L.) Karst. by chitotetraose, colloidal chitin and cell wall elicitors from the ectomycorrhizal fungus Hebeloma crustuliniforme (Bull. ex Fries.) Quél. an ectomycorrhizal partner of spruce. Cleavage of fungal cell wall elicitors and of artificial chitin
elicitors to monomeric and dimeric fragments by apoplasmic spruce chitinases (36-kDa class I chitinase, pI 8.0, and 28-kDa
chitinase, pI 8.7; EC 3.2.1.14) equally prevented induction of these rapid reactions. Also, N-acetylglucosamine oligomers
and elicitors from the fungal cell walls showed a similar dependence of their activity on the degree of polymerisation. From
these results it is suggested that, during ectomycorrhiza formation, only some of the chitin-derived elicitors reach their
receptors at the plant plasma membrane, initiating reactions of the hypersensitive response in the host cells. The remaining
fungal elicitors will be degraded to varying extents by wall-localized chitinases of the host root, reducing the defence reactions
of the plant and allowing symbiotic interactions of both organisms.
Received: 6 January 1997 / Accepted: 14 March 1997 相似文献