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Bounded rationality

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https://www.readbyqxmd.com/read/28202514/mcl-1-degradation-is-required-for-targeted-therapeutics-to-eradicate-colon-cancer-cells
#1
Jingshan Tong, Peng Wang, Shuai Tan, Dongshi Chen, Zaneta Nikolovska-Coleska, Fangdong Zou, Jian Yu, Lin Zhang
The Bcl-2 family protein Mcl-1 is often degraded in cancer cells subjected to effective therapeutic treatment, and defective Mcl-1 degradation has been associated with intrinsic and acquired drug resistance. However, a causal relationship between Mcl-1 degradation and anticancer drug responses has not been directly established, especially in solid tumor cells where Mcl-1 inhibition alone is insufficient to trigger cell death. In this study, we present evidence that Mcl-1 participates directly in determining effective therapeutic responses in colon cancer cells...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28195463/target-elucidation-by-co-crystal-structures-of-nadh-ubiquinone-oxidoreductase-of-plasmodium-falciparum-pfndh2-with-small-molecule-to-eliminate-drug-resistant-malaria
#2
Yiqing Yang, You Yu, Xiaolu Li, Jing Li, Yue Wu, Jie Yu, Jingpeng Ge, Zhenghui Huang, Lubin Jiang, Yu Rao, Maojun Yang
Drug-resistant malarial strains have been continuously emerging recently, which posts a great challenge for the global health. Therefore, new anti-malarial drugs with novel targeting mechanisms are urgently needed for fighting drug-resistant malaria. NADH-ubiquinone oxidoreductase of Plasmodium falciparum (PfNDH2) represents a viable target for anti-malarial drug development. However, the absence of structural information of PfNDH2 limited rational drug design and further development. Herein, we report high resolution crystal structures of the PfNDH2 protein for the first time in Apo-, NADH- and RYL-552 (a new inhibitor)-bound states...
February 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28194151/structure-and-dynamics-of-antigenic-peptides-in-complex-with-tap
#3
REVIEW
Elisa Lehnert, Robert Tampé
The transporter associated with antigen processing (TAP) selectively translocates antigenic peptides into the endoplasmic reticulum. Loading onto major histocompatibility complex class I molecules and proofreading of these bound epitopes are orchestrated within the macromolecular peptide-loading complex, which assembles on TAP. This heterodimeric ABC-binding cassette (ABC) transport complex is therefore a major component in the adaptive immune response against virally or malignantly transformed cells. Its pivotal role predestines TAP as a target for infectious diseases and malignant disorders...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28159622/the-discovery-complex-crystal-structure-and-recognition-mechanism-of-a-novel-natural-pde4-inhibitor-from-selaginella-pulvinata
#4
Yiyou Huang, Xin Liu, Deyan Wu, Guihua Tang, Zengwei Lai, Xuehua Zheng, Yin Sheng, Hai-Bin Luo
Phosphodiesterase-4 (PDE4) is an important drug target for treatment of inflammation-related diseases. Till now, natural PDE4 inhibitors are rare and their co-crystal structures with PDE4 are hardly available. In the present study, selaginpulvilins K and L (1 and 2), two novel fluorene derivatives, were isolated from a traditional Chinese medicine Selaginella pulvinata and exhibited remarkable inhibition against phosphodiesterase-4D (PDE4D) at IC50 11 nM and 90 nM, respectively. Compound 1 also showed a good selectivity across PDE families with the selective fold ranging from 30 to 909...
January 31, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28157330/low-threshold-multiexciton-optical-gain-in-colloidal-cdse-cdte-core-crown-type-ii-nanoplatelet-heterostructures
#5
Qiuyang Li, Zihao Xu, James R McBride, Tianquan Lian
Colloidal cadmium chalcogenide core/crown type-II nanoplatelet heterostructures, such as CdSe/CdTe, are promising materials for lasing and light-emitting applications. Their rational design and improvement requires the understanding of the nature of single- and multiexciton states. Using pump fluence and wavelength-dependent ultrafast transient absorption spectroscopy, we have identified three spatially and energetically distinct excitons (in the order of increasing energy): interface-localized charge transfer exciton (XCT, with electron in the CdSe core bound to the hole in the CdTe crown), and CdTe crown-localized XCdTe and CdSe core-localized XCdSe excitons...
February 7, 2017: ACS Nano
https://www.readbyqxmd.com/read/28157128/cobalt-ii-chloride-adducts-with-acetonitrile-propan-2-ol-and-tetrahydrofuran-considerations-on-nuclearity-reactivity-and-synthetic-applications
#6
Danilo Stinghen, André Luis Rüdiger, Siddhartha O K Giese, Giovana G Nunes, Jaísa F Soares, David L Hughes
High-spin cobalt(II) complexes are considered useful building blocks for the synthesis of single-molecule magnets (SMM) because of their intrinsic magnetic anisotropy. In this work, three new cobalt(II) chloride adducts with labile ligands have been synthesized from anhydrous CoCl2, to be subsequently employed as starting materials for heterobimetallic compounds. The products were characterized by elemental, spectroscopic (EPR and FT-IR) and single-crystal X-ray diffraction analyses. trans-Tetrakis(acetonitrile-κN)bis(tetrahydrofuran-κO)cobalt(II) bis[(acetonitrile-κN)trichloridocobaltate(II)], [Co(C2H3N)4(C4H8O)2][CoCl3(C2H3N)]2, (1), comprises mononuclear ions and contains both acetonitrile and tetrahydrofuran (thf) ligands, The coordination polymer catena-poly[[tetrakis(propan-2-ol-κO)cobalt(II)]-μ-chlorido-[dichloridocobalt(II)]-μ-chlorido], [Co2Cl4(C3H8O)4], (2'), was prepared by direct reaction between anhydrous CoCl2 and propan-2-ol in an attempt to rationalize the formation of the CoCl2-alcohol adduct (2), probably CoCl2(HO(i)Pr)m...
February 1, 2017: Acta Crystallographica. Section C, Structural Chemistry
https://www.readbyqxmd.com/read/28130301/structural-and-biochemical-studies-of-novel-aldo-keto-reductases-for-the-biocatalytic-conversion-of-3-hydroxybutanal-to-1-3-butanediol
#7
Taeho Kim, Robert Flick, Joseph Brunzelle, Alex Singer, Elena Evdokimova, Greg Brown, Jeong Chan Joo, George A Minasov, Wayne F Anderson, Radhakrishnan Mahadevan, Alexei Savchenko, Alexander F Yakunin
: The non-natural alcohol 1,3-butanediol (1,3-BDO) is a valuable building block for the synthesis of various polymers. One of the potential pathways for the biosynthesis of 1,3-BDO includes the biotransformation of acetaldehyde to 1,3-BDO via 3-hydroxybutanal (3-HB) using aldolases and aldo-keto reductases. This pathway requires an aldo-keto reductase (AKR) selective for 3-HB, but inactive toward acetaldehyde, so it can be used for one pot synthesis. In this work, we screened over 20 purified uncharacterized AKRs for 3-HB reduction and identified 10 enzymes with significant activity and nine proteins with detectable activity...
January 27, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28126742/binding-of-nadp-triggers-an-open-to-closed-transition-in-a-mycobacterial-fabg-%C3%AE-ketoacyl-acp-reductase
#8
Mickael Blaise, Niel Van Wyk, Francoise Banères-Roquet, Yann Guérardel, Laurent Kremer
The ketoacyl-acyl carrier protein (ACP) reductase FabG catalyzes the NADPH/NADH-dependent reduction of b-ketoacyl-ACP substrates to b-hydroxyacyl-ACP products, the first reductive step in the fatty acid biosynthesis elongation cycle. FabG proteins are ubiquitous in bacteria and are part of the type II fatty acid synthase system (FAS-II). Mining the Mycobacterium smegmatis genome uncovered several putative FabG-like proteins. Among them, we identified MSMEG_6753 whose gene was found adjacent to MSMEG_6754 , encoding a recently characterized enoyl-CoA dehydratase and to MSMEG_6755 , encoding another potential reductase...
January 26, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28118518/pentagonal-bipyramid-fe-ii-complexes-robust-ising-spin-units-towards-heteropolynuclear-nano-magnets
#9
Arun Kumar Bar, Nayanmoni Gogoi, Céline Pichon, Durga Prasad Goli, Mehrez Thlijeni, Carine Duhayon, Nicolas Suaud, Nathalie Guihéry, Anne-Laure Barra, S Ramasesha, Jean-Pascal Sutter
Pentagonal bipyramid Fe(II) complexes have been investigated in order to evaluate their potential as Ising-spin building units for the preparation of hetero-polynuclear species likely to behave as SMMs. The monometallic complexes result from association of a divalent metal ion with pentadentate ligands having 2,6-diacetylpyridine bis(hydrazone) core. Their magnetic anisotropy established by magnetometry revealed zero-field splitting (ZFS) parameter D ranging between -4 and -13 cm-1 which was found to be modulated by the apical ligands (ROH versus Cl)...
January 24, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28117977/interactions-and-attachment-pathways-between-functionalized-gold-nanorods
#10
Shu Fen Tan, Utkarsh Anand, Utkur Mirsaidov
Nanoparticle (NP) self-assembly has been recognized as an important technological process for forming ordered nanostructures. However, the detailed dynamics of the assembly processes remain poorly understood. Using in situ liquid cell transmission electron microscopy, we describe the assembly modes of gold (Au) nanorods (NRs) in solution mediated by hydrogen bonding between NR-bound cysteamine linker molecules. Our observations reveal that by tuning the linker concentration, two different NR assembly modes can be achieved...
January 31, 2017: ACS Nano
https://www.readbyqxmd.com/read/28113647/backstepping-design-of-adaptive-neural-fault-tolerant-control-for-mimo-nonlinear-systems
#11
Hui Gao, Yongduan Song, Changyun Wen
In this paper, an adaptive controller is developed for a class of multi-input and multioutput nonlinear systems with neural networks (NNs) used as a modeling tool. It is shown that all the signals in the closed-loop system with the proposed adaptive neural controller are globally uniformly bounded for any external input in L[₀,∞]. In our control design, the upper bound of the NN modeling error and the gains of external disturbance are characterized by unknown upper bounds, which is more rational to establish the stability in the adaptive NN control...
August 24, 2016: IEEE Transactions on Neural Networks and Learning Systems
https://www.readbyqxmd.com/read/28112319/a-ni-based-mof-for-selective-detection-and-removal-of-hg-2-in-aqueous-medium-a-facile-strategy
#12
Shibashis Halder, John Mondal, Joaquín Ortega-Castro, Antonio Frontera, Partha Roy
The uncoordinated sulfur atom of the thiocyanato ligand of a 3D metallo-organic framework (MOF), [Ni(3-bpd)2(NCS)2]n (1), where 3-bpd is 1,4-bis(3-pyridyl)-2,3-diaza-1,3-butadiene, has been explored for selective visual detection and effective removal of Hg(2+) in aqueous medium. [Ni(3-bpd)2(NCS)2]n has been synthesized under ambient conditions and characterized by elemental analysis, FT-IR spectroscopy, UV-vis spectroscopy, FE-SEM and EDX, XPS and X-ray single crystal diffraction analysis. 1 shows two thiocyanato moieties bound to the hexacoordinated metal center with N atoms whereas the sulfur end remains uncoordinated...
January 23, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/28108630/macropinocytosis-of-nab-paclitaxel-drives-macrophage-activation-in-pancreatic-cancer
#13
Jane E Cullis, Despina Siolas, Antonina Avanzi, Sugata Barui, Anirban Maitra, Dafna Bar-Sagi
Pancreatic cancer is a devastating disease that is largely refractory to currently available treatment strategies. Therapeutic resistance is partially attributed to the dense stromal reaction of PDAC tumors that includes a pervasive infiltration of immunosuppressive (M2) macrophages. Nab-paclitaxel (trade name Abraxane) is a nanoparticle albumin-bound formulation of paclitaxel that, in combination with gemcitabine, is currently the first line treatment for pancreatic cancer. Here, we show that macrophages internalized nab-paclitaxel via macropinocytosis...
January 20, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28104818/structure-and-activation-of-c1-the-complex-initiating-the-classical-pathway-of-the-complement-cascade
#14
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 31, 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
#15
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
#16
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
#17
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...
February 2017: Molecular Diversity
https://www.readbyqxmd.com/read/28068644/mitigating-17%C3%AE-ethynylestradiol-water-contamination-through-binding-and-photosensitization-by-dissolved-humic-substances
#18
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
#19
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
#20
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
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