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Bounded rationality

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https://www.readbyqxmd.com/read/28104818/structure-and-activation-of-c1-the-complex-initiating-the-classical-pathway-of-the-complement-cascade
#1
Simon A Mortensen, Bjoern Sander, Rasmus K Jensen, Jan Skov Pedersen, Monika M Golas, Jens C Jensenius, Annette G Hansen, Steffen Thiel, Gregers R Andersen
The complement system is an important antimicrobial and inflammation-generating component of the innate immune system. The classical pathway of complement is activated upon binding of the 774-kDa C1 complex, consisting of the recognition molecule C1q and the tetrameric protease complex C1r2s2, to a variety of activators presenting specific molecular patterns such as IgG- and IgM-containing immune complexes. A canonical model entails a C1r2s2 with its serine protease domains tightly packed together in the center of C1 and an intricate intramolecular reaction mechanism for activation of C1r and C1s, induced upon C1 binding to the activator...
January 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28094587/applying-theories-to-better-understand-socio-political-challenges-in-implementing-evidence-based-work-disability-prevention-strategies
#2
Christian Ståhl, Katia Costa-Black, Patrick Loisel
PURPOSE: This article explores and applies theories for analyzing socio-political aspects of implementation of work disability prevention (WDP) strategies. METHOD: For the analysis, theories from political science are explained and discussed in relation to case examples from three jurisdictions (Sweden, Brazil and Québec). RESULTS: Implementation of WDP strategies may be studied through a conceptual framework that targets: (1) the institutional system in which policy-makers and other stakeholders reside; (2) the ambiguity and conflicts regarding what to do and how to do it; (3) the bounded rationality, path dependency and social systems of different stakeholders; and (4) coalitions formed by different stakeholders and power relations between them...
January 17, 2017: Disability and Rehabilitation
https://www.readbyqxmd.com/read/28081485/the-elucidation-of-non-classical-mhc-class-ii-antigen-processing-through-the-study-of-viral-antigens
#3
REVIEW
Asha Purnima Veerappan Ganesan, Laurence C Eisenlohr
By convention, CD4(+) T cells are activated predominantly by Major Histocompatibility Complex class II-bound peptides derived from extracellular (exogenous) antigens. It has been known for decades that alternative sources of antigen, particularly those synthesized within the antigen-presenting cell, can also supply peptides but the impact on TCD4+ responses, sometimes considerable, has only recently become appreciated. This review focuses on the contributions that studies of viral antigen have made to this shift in perspective, concluding with discussions of relevance to rational vaccine design, autoimmunity and cancer immunotherapy...
January 9, 2017: Current Opinion in Virology
https://www.readbyqxmd.com/read/28070724/identification-of-potential-glutaminyl-cyclase-inhibitors-from-lead-like-libraries-by-in-silico-and-in-vitro-fragment-based-screening
#4
Mária Szaszkó, István Hajdú, Beáta Flachner, Krisztina Dobi, Csaba Magyar, István Simon, Zsolt Lőrincz, Zoltán Kapui, Tamás Pázmány, Sándor Cseh, György Dormán
A glutaminyl cyclase (QC) fragment library was in silico selected by disconnection of the structure of known QC inhibitors and by lead-like 2D virtual screening of the same set. The resulting fragment library (204 compounds) was acquired from commercial suppliers and pre-screened by differential scanning fluorimetry followed by functional in vitro assays. In this way, 10 fragment hits were identified ([Formula: see text]5 % hit rate, best inhibitory activity: 16 [Formula: see text]). The in vitro hits were then docked to the active site of QC, and the best scoring compounds were analyzed for binding interactions...
January 9, 2017: Molecular Diversity
https://www.readbyqxmd.com/read/28068644/mitigating-17%C3%AE-ethynylestradiol-water-contamination-through-binding-and-photosensitization-by-dissolved-humic-substances
#5
Dong Ren, Bin Huang, Benqin Yang, Xuejun Pan, Dionysios D Dionysiou
Photodegradation is an important abiotic pathway transforming organic pollutants in natural waters. Humic substances (HS), including humic and fulvic acids, are capable of accelerating the photodegradation of steroid estrogens. However, how the photodegradtion of the emerging pollutants influenced by HS is not clear. Thus, we studied the roles and mechanisms of HS in inducing the photodegradation of 17α-ethynylestradiol (EE2). HS generally induces EE2 photodegradation through binding and reactive species generation...
January 3, 2017: Journal of Hazardous Materials
https://www.readbyqxmd.com/read/28060514/targeted-covalent-inhibition-of-grb2-sos1-interaction-through-proximity-induced-conjugation-in-breast-cancer-cells
#6
Yongsheng Yu, Yunyu Nie, Qian Feng, Jiale Qu, Rui Wang, Liming Bian, Jiang Xia
Targeted covalent inhibitors of protein-protein interactions differ from reversible inhibitors in that the former bind and covalently bond the target protein at a specific site of the target. The site specificity is the result of the proximity of two reactive groups at the bound state, for example one mild electrophile in the inhibitor and a natural cysteine in the target close to the ligand binding site. Only a few pharmaceutically relevant proteins have this structural feature. Grb2, a key adaptor protein in maintaining the ERK activity via binding Sos1 to activated RTKs, is one: the N-terminal SH3 domain of Grb2 (Grb2N-SH3) carries a unique solvent-accessible cysteine Cys32 close to its Sos1-binding site...
January 6, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28035828/a-hepatic-carcinoma-selective-nucleic-acid-nanovector-assembled-by-endogenous-molecules-based-on-modular-strategy
#7
Fang Xie, Luchen Zhang, Jinliang Peng, Chong Li, Jun Pu, Yuhong Xu, Zixiu Du
We rationally formulated a nucleic acid nano-vector platform utilizing endogenous molecules in the following steps: nucleic acids are initially packed by a multifunctional peptide and a cationic liposome to form positively charged ternary complexes through electrostatic interaction; then the ternary complexes were coated with hyaluronic acid (HA) to form negatively charged quaternary nanocomplexes (Q-complexes). Among the components of Q-complexes, the multifunctional peptide was composed of a polysixteen-arginine (R16) and a hepatic tumor-targeted cell penetrating peptide (KRPTMRFRYTWNPMK); the cationic lipid component included DOTAP and fusogenic lipid DOPE; the HA component shielded the cationic ternary complexes and actively targeted the CD44 overexpressed on the surface of tumor cells...
December 30, 2016: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28032978/exploring-the-structural-compliancy-versus-specificity-of-the-estrogen-receptor-using-isomeric-three-dimensional-ligands
#8
Naina Sharma, Kathryn E Carlson, Jerome C Nwachukwu, Sathish Srinivasan, Abhishek Sharma, Kendall W Nettles, John A Katzenellenbogen
The estrogen receptors (ERs) bind with high affinity to many structurally diverse ligands by significantly distorting the contours of their ligand-binding pockets. This raises a question: To what degree is ER able to distinguish between structurally related regioisomers and enantiomers? We have explored the structural compliance and specificity of ERα with a set of ligands having a 7-oxa-bicyclo[2.2.1]hept-5-ene sulfonate core and basic side chains typical of selective ER modulators (SERMs). These ligands have two regioisomers, each of which is a racemate of enantiomers...
December 29, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/28029774/the-structure-of-murine-n-1-acetylspermine-oxidase-reveals-molecular-details-of-vertebrate-polyamine-catabolism
#9
Tove Sjögren, Carola M Wassvik, Arjan Snijder, Anna Aagaard, Taichi Kumanomidou, Louise Barlind, Tim P Kaminski, Akiko Kashima, Takehiro Yokota, Ola Fjellström
N(1)-Acetylspermine oxidase (APAO) catalyzes the conversion of N(1)-acetylspermine or N(1)-acetylspermidine to spermidine or putrescine, respectively, with concomitant formation of N-acetyl-3-aminopropanal and hydrogen peroxide. Here we present the structure of murine APAO in its oxidized holo form and in complex with substrate. The structures provide a basis for understanding molecular details of substrate interaction in vertebrate APAO, highlighting a key role for an asparagine residue in coordinating the N(1)-acetyl group of the substrate...
January 12, 2017: Biochemistry
https://www.readbyqxmd.com/read/28026921/n-a-and-n-d-oligomer-and-partner-specification-by-asparagine-in-coiled-coil-interfaces
#10
Jordan M Fletcher, Gail J Bartlett, Aimee L Boyle, Jonathan J Danon, Laura E Rush, Andrei N Lupas, Derek N Woolfson
The α-helical coiled coil is one of the best-studied protein-protein interaction motifs. As a result, sequence-to-structure relationships are available for the prediction of natural coiled-coil sequences and the de novo design of new ones. However, coiled coils adopt a wide range of oligomeric states and topologies, and our understanding of the specification of these and the discrimination between them remains incomplete. Gaps in our knowledge assume more importance as coiled coils are used increasingly to construct biomimetic systems of higher complexity; for this, coiled-coil components need to be robust, orthogonal and transferable between contexts...
December 27, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/28025809/the-human-orexin-hypocretin-receptor-crystal-structures
#11
Jie Yin, Daniel M Rosenbaum
The human orexin/hypocretin receptors (hOX1R and hOX2R) are G protein-coupled receptors (GPCRs) that mediate the diverse functions of the orexin/hypocretin neuropeptides. Orexins/hypocretins produced by neurons in the lateral hypothalamus stimulate their cognate GPCRs in multiple regions of the central nervous system to control sleep and arousal, circadian rhythms, metabolism, reward pathways, and other behaviors. Dysfunction of orexin/hypocretin signaling is associated with human disease, and the receptors are active targets in a number of therapeutic areas...
December 27, 2016: Current Topics in Behavioral Neurosciences
https://www.readbyqxmd.com/read/28005385/design-and-synthesis-of-a-series-of-l-trans-4-substituted-prolines-as-selective-antagonists-for-the-ionotropic-glutamate-receptors-including-functional-and-x-ray-crystallographic-studies-of-new-subtype-selective-kainic-acid-receptor-subtype-1-gluk1-antagonist
#12
Niels Krogsgaard-Larsen, Claudia G Delgar, Karina Koch, Patricia M G E Brown, Charlotte Møller, Liwei Han, Tri H V Huynh, Stinne W Hansen, Birgitte Nielsen, Derek Bowie, Darryl S Pickering, Jette Sandholm Kastrup, Karla Frydenvang, Lennart Bunch
Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (Ki = 4 μM). In a functional assay, 1b displayed full antagonist activity with IC50 = 6 ± 2 μM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1...
December 22, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28002402/structural-basis-of-an-essential-interaction-between-influenza-polymerase-and-pol-ii-ctd
#13
Maria Lukarska, Guillaume Fournier, Alexander Pflug, Patricia Resa-Infante, Stefan Reich, Nadia Naffakh, Stephen Cusack
The heterotrimeric influenza polymerase (FluPol), comprising subunits PA, PB1 and PB2, binds to the conserved 5' and 3' termini (the 'promoter') of each of the eight single-stranded viral RNA (vRNA) genome segments and performs both transcription and replication of vRNA in the infected cell nucleus. To transcribe viral mRNAs, FluPol associates with cellular RNA polymerase II (Pol II), which enables it to take 5'-capped primers from nascent Pol II transcripts. Here we present a co-crystal structure of bat influenza A polymerase bound to a Pol II C-terminal domain (CTD) peptide mimic, which shows two distinct phosphoserine-5 (SeP5)-binding sites in the polymerase PA subunit, accommodating four CTD heptad repeats overall...
December 21, 2016: Nature
https://www.readbyqxmd.com/read/27998977/a-novel-mechanism-causing-familial-hypercholesterolemia-the-proprotein-convertase-subtilisin-kexin-type-9-resistant-arg410ser-ldl-receptor-mutation
#14
Delia Susan-Resiga, Emmanuelle Girard, Robert Scott Kiss, Rachid Essalmani, Josée Hamelin, Marie-Claude Asselin, Zuhier Awan, Chutikarn Butkinaree, Alexandre Fleury, Armand Soldera, Yves L Dory, Alexis Baass, Nabil G Seidah
Familial hypercholesterolemia (FH) is characterized by severely elevated low-density lipoprotein (LDL) cholesterol. Herein, we identified an FH patient presenting novel compound heterozygote mutations R410S and G592E of the LDL receptor (LDLR). The patient responded modestly to maximum rosuvastatin plus ezetimibe therapy, even in combination with a PCSK9-monoclonal-antibody injection. Using cell biology and molecular-dynamics simulations, we aimed to define the underlying mechanism(s) by which these LDLR mutations affect LDL metabolism and lead to hypercholesterolemia...
December 20, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27991903/structural-basis-for-targeted-dna-cytosine-deamination-and-mutagenesis-by-apobec3a-and-apobec3b
#15
Ke Shi, Michael A Carpenter, Surajit Banerjee, Nadine M Shaban, Kayo Kurahashi, Daniel J Salamango, Jennifer L McCann, Gabriel J Starrett, Justin V Duffy, Özlem Demir, Rommie E Amaro, Daniel A Harki, Reuben S Harris, Hideki Aihara
APOBEC-catalyzed cytosine-to-uracil deamination of single-stranded DNA (ssDNA) has beneficial functions in immunity and detrimental effects in cancer. APOBEC enzymes have intrinsic dinucleotide specificities that impart hallmark mutation signatures. Although numerous structures have been solved, mechanisms for global ssDNA recognition and local target-sequence selection remain unclear. Here we report crystal structures of human APOBEC3A and a chimera of human APOBEC3B and APOBEC3A bound to ssDNA at 3.1-Å and 1...
December 19, 2016: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27988421/voltage-gated-sodium-channels-viewed-through-a-structural-biology-lens
#16
REVIEW
Thomas Clairfeuille, Hui Xu, Christopher M Koth, Jian Payandeh
Voltage-gated sodium (Nav) channels initiate and propagate action potentials in excitable cells, and are frequently dysregulated or mutated in human disease. Despite decades of intense physiological and biophysical research, eukaryotic Nav channels have so far eluded high-resolution structure determination because of their biochemical complexity. Recently, simpler bacterial voltage-gated sodium (BacNav) channels have provided templates to understand the structural basis of voltage-dependent activation, inactivation, ion selectivity, and drug block in eukaryotic Nav and related voltage-gated calcium (Cav) channels...
December 15, 2016: Current Opinion in Structural Biology
https://www.readbyqxmd.com/read/27981404/two-new-mononuclear-copper-ii-dipeptide-complexes-of-2-2-pyridyl-benzoxazole-dna-interaction-antioxidation-and-in-vitro-cytotoxicity-studies
#17
Qian Gan, Yongyu Qi, Yahong Xiong, Yinlian Fu, Xueyi Le
Two new mononuclear mixed ligand copper(II) complexes [Cu(PBO)(Gly-gly)(H2O)]·ClO4·1.5H2O (1) and [Cu(PBO)(Gly-L-leu)(H2O)]·ClO4 (2) (PBO is 2-(2'-pyridyl)benzoxazole, Gly-gly and Gly-L-leu are Glycyl-glycine anion and Glycyl-L-leucine anion, respectively), have been prepared and characterized by various analytical and spectral techniques. The interactions of the complexes with DNA were investigated using multi-spectroscopic methods (absorption, emission, circular dichroism), viscometry and electrochemical titration as well as molecular docking technique...
December 15, 2016: Journal of Fluorescence
https://www.readbyqxmd.com/read/27934233/modeling-membrane-protein-ligand-binding-interactions-the-human-purinergic-platelet-receptor
#18
D'Artagnan Greene, Wesley M Botello-Smith, Alec Follmer, Li Xiao, Eleftherios Lambros, Ray Luo
Membrane proteins, due to their roles as cell receptors and signaling mediators, make prime candidates for drug targets. The computational analysis of protein-ligand binding affinities has been widely employed as a tool in rational drug design efforts. Although efficient implicit solvent-based methods for modeling globular protein-ligand binding have been around for many years, the extension of such methods to membrane protein-ligand binding is still in its infancy. In this study, we extended the widely used Amber/MMPBSA method to model membrane protein-ligand systems, and we used it to analyze protein-ligand binding for the human purinergic platelet receptor (P2Y12R), a prominent drug target in the inhibition of platelet aggregation for the prevention of myocardial infarction and stroke...
December 8, 2016: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/27933956/rational-design-of-thermodynamic-and-kinetic-binding-profiles-by-optimizing-surface-water-networks-coating-protein-bound-ligands
#19
Stefan G Krimmer, Jonathan Cramer, Michael Betz, Veronica Fridh, Robert Karlsson, Andreas Heine, Gerhard Klebe
A previously studied congeneric series of thermolysin inhibitors addressing the solvent-accessible S2' pocket with different hydrophobic substituents showed modulations of the surface water layers coating the protein-bound inhibitors. Increasing stabilization of water molecules resulted in an enthalpically more favorable binding signature, overall enhancing affinity. Based on this observation, we optimized the series by designing tailored P2' substituents to improve and further stabilize the surface water network...
December 8, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27933949/sulfonamide-based-inhibitors-of-aminoglycoside-acetyltransferase-eis-abolish-resistance-to-kanamycin-in-mycobacterium-tuberculosis
#20
Atefeh Garzan, Melisa J Willby, Keith D Green, Chathurada S Gajadeera, Caixia Hou, Oleg V Tsodikov, James E Posey, Sylvie Garneau-Tsodikova
A two-drug combination therapy where one drug targets an offending cell and the other targets a resistance mechanism to the first drug is a time-tested, yet underexploited approach to combat or prevent drug resistance. By high-throughput screening, we identified a sulfonamide scaffold that served as a pharmacophore to generate inhibitors of Mycobacterium tuberculosis acetyltransferase Eis, whose upregulation causes resistance to the aminoglycoside (AG) antibiotic kanamycin A (KAN) in Mycobacterium tuberculosis...
December 8, 2016: Journal of Medicinal Chemistry
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