SciCombinator

Discover the most talked about and latest scientific content & concepts.

Concept: Contract bridge

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The aerial view of the concept of data sharing is beautiful. What could be better than having high-quality information carefully reexamined for the possibility that new nuggets of useful data are lying there, previously unseen? The potential for leveraging existing results for even more benefit pays appropriate increased tribute to the patients who put themselves at risk to generate the data. The moral imperative to honor their collective sacrifice is the trump card that takes this trick. However, many of us who have actually conducted clinical research, managed clinical studies and data collection and analysis, and curated data sets have . . .

Concepts: Experimental design, Clinical trial, Medical statistics, Avicenna, Clinical research, Morality, Contract bridge, Donald Trump

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A small library of divalent fucosidase inhibitors containing pyrrolidine motifs and separated by polyamino and triazole-benzylated spacers was prepared and evaluated as α-fucosidase inhibitors. Although a weak multivalent effect was observed in polyamino derived dimers, useful structural information can be deduced about the length of the bridge, the number of nitrogen atoms present and the moieties close to the pyrrolidine. Within these investigations one of the best α-fucosidase inhibitors containing a pyrrolidine framework was obtained (, Ki = 3.7 nM).

Concepts: Nitrogen, .NET Framework, Bridge, Contract bridge

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Four new copper complexes, viz. [{Cu(2-aminopyridine)(N3)2(H2O)}2]n (1), [Cu3(3-aminopyridine)2(N3)6]n (2), [{Cu(3-aminopyridine)(N3)2}2]n (3), and [Cu(4-aminopyridine)2(N3)2]n (4), have been synthesized with isomeric aminopyridines, viz. 2-aminopyridine (2-ap), 3-aminopyridine (3-ap), and 4-aminopyridine (4-ap), to probe the role of ligand and reactant molar ratios in directing the polynuclear assemblage and the associated magnetic properties. Ligand geometry is quite influential as can be seen through the versatile structures formed, viz. a hydrogen bonded layer of μ-1,1 azide bridged Cu dimers in 1; a network of two different types of dimers (Cu1-Cu2 & Cu3-Cu3') involving μ-1,1; μ-1,3; μ-1,1,3; & μ-1,1,3,3 azide bridges in 2; a ladder structure in which μ-1,1 azide bridges form the rungs and μ-1,3 azide bridges form the rails of the ladder in 3; and a 1-D polymer chain involving μ-1,1 azide bridges in 4. Consistent with the bridge geometry, compounds 1 & 2 display ferromagnetic interactions, while 3 & 4 display antiferromagnetic interactions. The rather unexpected antiferromagnetic interactions in 3, in spite of μ-1,1 azide bridged rungs may be due to the crossover near the bridge angle. The ferromagnetic interactions in 1 and 2 are supported by DFT calculations.

Concepts: Structure, Magnetism, Ferromagnetism, Copper, Antiferromagnetism, 4-Aminopyridine, Bridge, Contract bridge

0

Receptor tyrosine kinases (RTK) have been demonstrated to signal via regulated intramembrane proteolysis (RIP), in which ectodomain shedding and subsequent intramembrane cleavage by gamma-secretase leads to release of a soluble intracellular receptor fragment with functional activity. For most RTKs, however, it is not known whether they can exploit this new signaling mechanism or not. Here we used a system-wide screen to address the frequency of susceptibility to gamma-secretase cleavage among human RTKs. The screen covering 45 of the 55 human RTKs identified 12 new as well as all 9 previously published gamma-secretase substrates. The screen was biochemically validated by demonstrating that the release of a soluble intracellular fragment from endogenous AXL was dependent on the sheddase ADAM10 and the gamma-secretase component presenilin-1. Functional analysis of the cleavable RTKs indicated that proliferation promoted by overexpression of the TAM family members AXL or TYRO3 was dependent on gamma-secretase cleavage. Taken together, these data indicate that gamma-secretase-mediated cleavage provides an additional signaling mechanism for numerous human RTKs.

Concepts: Signal transduction, Receptor tyrosine kinase, Protein kinase, Signal, Vector space, Demonstration, Contract bridge

0

Implantable cardioverter defibrillators (ICDs) provide a significant mortality benefit for appropriately selected patients with advanced heart failure. ICDs are associated with a mortality benefit when used in patients with a pulsatile left ventricular assist device (LVAD). It is unclear whether patients with a continuous-flow LVAD (CF-LVAD) derive the same benefit. We sought to determine if the presence of an ICD provided a mortality benefit during CF-LVAD support as a bridge to transplantation.

Concepts: Cardiology, Heart, Implantable cardioverter-defibrillator, Propensity score, Ventricular fibrillation, Ventricular assist device, Bridge, Contract bridge

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Remember the name: Melanie Davies, RCN Nurse of the Year 2017 and a truly extraordinary woman. She has transformed care for people with learning disabilities on her ward, driven through changes across her hospital and health board in south Wales, and inspired others to follow suit across the country.

Concepts: Health care, Educational psychology, Nursing, Wales, Contract bridge, Merthyr Tydfil

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The value of stereoelectronic guidelines is illustrated by the discovery of a convenient, ozone-free synthesis of bridged secondary ozonides from 1,5-dicarbonyl compounds and H2 O2 . The tetraoxane products generally formed in reactions of carbonyl and dicarbonyl compounds with H2 O2 were not detected because the structural distortions imposed on the tetraoxacyclohexane subunit in [3.2.2]tetraoxanonanes by the three-carbon bridge leads to the partial deactivation of anomeric effects. The new procedure is readily scalable to produce gram quantities of the ozonides. This reaction enables the selective preparation of ozonides without the use of ozone.

Concepts: Chemical reaction, Bridge, Contract bridge

0

Animal development is characterized by signaling events that occur at precise locations and times within the embryo, but determining when and where such precision is needed for proper embryogenesis has been a long-standing challenge. Here we address this question for extracellular signal regulated kinase (Erk) signaling, a key developmental patterning cue. We describe an optogenetic system for activating Erk with high spatiotemporal precision in vivo. Implementing this system in Drosophila, we find that embryogenesis is remarkably robust to ectopic Erk signaling, except from 1 to 4 hr post-fertilization, when perturbing the spatial extent of Erk pathway activation leads to dramatic disruptions of patterning and morphogenesis. Later in development, the effects of ectopic signaling are buffered, at least in part, by combinatorial mechanisms. Our approach can be used to systematically probe the differential contributions of the Ras/Erk pathway and concurrent signals, leading to a more quantitative understanding of developmental signaling.

Concepts: Embryo, Developmental biology, Signal, Embryology, Zygote, Morphogenesis, Drosophila embryogenesis, Contract bridge

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Activation of extracellular signal regulated kinase (ERK) is used by many signaling pathways to control tissue patterning in a broad range of multicellular organisms. In this issue of Developmental Cell, Johnson et al. (2017) provide an optogenetic approach to manipulate this pathway with high precision and explore its signaling code.

Concepts: DNA, Cell, Signal transduction, Developmental biology, Cellular differentiation, Signal, Multicellular organism, Contract bridge

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Recognition of linear polyubiquitin by specific ubiquitin-binding proteins plays an important role in mediating nuclear factor-κB (NF-κB) signaling. A20 binding proteins, ABINs, recognize linear polyubiquitin and A20 through UBAN and AHD1, respectively, for the inhibition of NF-κB activation. Here we report the crystal structure of the AHD1-UBAN fragment of ABIN2 in complex with linear tri-ubiquitin, which reveals a 2:1 stoichiometry of the complex. Structural analyses together with mutagenesis, pull-down, and isothermal titration calorimetry assays show that the hABIN2:tri-ubiquitin interaction is mainly through the primary ubiquitin-binding site, and also through the secondary ubiquitin-binding site under a high local protein concentration. Surprisingly, three ubiquitin units could form a right-handed helical trimer to bridge two ABIN2 dimers. The residues around the M1-linkage are crucial for ABIN2 to recognize tri-ubiquitin. The tri-ubiquitin bridging two ABIN2 dimers model suggests a possible higher-order signaling complex assembled between M1-linked polyubiquitinated proteins, ubiquitin-binding proteins, and effector signaling proteins in signal transduction.

Concepts: Protein, Protein structure, Molecular biology, Structure, Signal, Biochemistry, Inhibitor, Contract bridge