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Bounded rationality

Joel L Kaar
Widespread interest in the use of room-temperature ionic liquids (RTILs) as solvents in anhydrous biocatalytic reactions has largely been met with underwhelming results. Enzymes are frequently inactivated in RTILs as a result of the influence of solvent on the enzyme's microenvironment, be it through interacting with the enzyme or enzyme-bound water molecules. The purpose of this chapter is to present a rational approach to mediate RTIL-enzyme interactions, which is essential if we are to realize the advantages of RTILs over conventional solvents for biocatalysis in full...
2017: Methods in Molecular Biology
Blake T Riley, Olga Ilyichova, Mauricio G S Costa, Benjamin T Porebski, Simon J de Veer, Joakim E Swedberg, Itamar Kass, Jonathan M Harris, David E Hoke, Ashley M Buckle
The kallikrein-related peptidase (KLK) family of proteases is involved in many aspects of human health and disease. One member of this family, KLK4, has been implicated in cancer development and metastasis. Understanding mechanisms of inactivation are critical to developing selective KLK4 inhibitors. We have determined the X-ray crystal structures of KLK4 in complex with both sunflower trypsin inhibitor-1 (SFTI-1) and a rationally designed SFTI-1 derivative to atomic (~1 Å) resolution, as well as with bound nickel...
October 21, 2016: Scientific Reports
Yumiko Mizukoshi, Koh Takeuchi, Misa Arutaki, Yuji Tokunaga, Takeshi Takizawa, Hiroyuki Hanzawa, Ichio Shimada
The thermodynamic properties of a ligand in the bound state affect its binding specificity. Strict binding specificity can be achieved by introducing multiple spatially defined interactions, such as hydrogen bonds and van der Waals interactions, into the ligand-receptor interface. These introduced interactions are characterized by restricted local dynamics and improved surface complementarity in the bound state. In this study, we experimentally evaluated the local dynamics and the surface complementarity of weak-affinity ligands in the receptor-bound state by forbidden coherence transfer analysis in free-bound exchange systems (Ex-FCT), using the interaction between a ligand, a myocyte-enhancer factor 2A (MEF2A) docking peptide, and a receptor, p38α, as a model system...
October 20, 2016: Angewandte Chemie
Kevin J Boudreau, Eva C Guinan, Karim R Lakhani, Christoph Riedl
Selecting among alternative projects is a core management task in all innovating organizations. In this paper, we focus on the evaluation of frontier scientific research projects. We argue that the "intellectual distance" between the knowledge embodied in research proposals and an evaluator's own expertise systematically relates to the evaluations given. To estimate relationships, we designed and executed a grant proposal process at a leading research university in which we randomized the assignment of evaluators and proposals to generate 2,130 evaluator-proposal pairs...
October 2016: Management Science
Marion A David, Stéphane Orlowski, Roger K Prichard, Shaima Hashem, François André, Anne Lespine
Macrocyclic lactones (ML) are important anthelmintics used in animals and humans against parasite nematodes, but their therapeutic success is compromised by the spread of ML resistance. Some ABC transporters, such as p-glycoproteins (Pgps), are selected and overexpressed in ML-resistant nematodes, supporting a role for some drug efflux proteins in ML resistance. However, the role of such proteins in ML transport remains to be clarified at the molecular level. Recently, Caenorhabditis elegans Pgp-1 (Cel-Pgp-1) has been crystallized, and its drug-modulated ATPase function characterized in vitro revealed Cel-Pgp-1 as a multidrug transporter...
September 15, 2016: International Journal for Parasitology, Drugs and Drug Resistance
Shoichiro Horita, Yayoi Nomura, Yumi Sato, Tatsuro Shimamura, So Iwata, Norimichi Nomura
Pembrolizumab is an FDA-approved therapeutic antibody that targets the programmed cell death-1 (PD-1) to block the immune checkpoint pathway for the treatment of various types of cancer. It receives remarkable attention due to the high degree of efficacy. Very recently, the crystal structure of the Fab fragment of pembrolizumab (PemFab) in complex with the extracellular domain of human PD-1 (PD-1ECD) was reported at a resolution of 2.9 Å. However, this relatively low-resolution structural data fails to provide sufficient information on interfacial water molecules at the binding interface that substantially contribute to affinity and specificity between the therapeutic antibody and target...
October 13, 2016: Scientific Reports
Chun-Chieh Wang, Hao-Ching Chang, Yei-Chen Lai, Huayi Fang, Chieh-Chin Li, Hung-Kai Hsu, Zong-Yan Li, Tien-Sung Lin, Ting-Shen Kuo, Frank Neese, Shengfa Ye, Yun-Wei Chiang, Ming-Li Tsai, Wen-Feng Liaw, Way-Zen Lee
Bubbling O2 into a THF solution of Co(II)(BDPP) (1) at -90 °C generates an O2 adduct, Co(BDPP)(O2) (3). The resonance Raman and EPR investigations reveal that 3 contains a low spin cobalt(III) ion bound to a superoxo ligand. Significantly, at -90 °C, 3 can react with 2,2,6,6-tetramethyl-1-hydroxypiperidine (TEMPOH) to form a structurally characterized cobalt(III)-hydroperoxo complex, Co(BDPP)(OOH) (4) and TEMPO(•). Our findings show that cobalt(III)-superoxo species are capable of performing hydrogen atom abstraction processes...
October 11, 2016: Journal of the American Chemical Society
Malay Patra, Kristof Zarschler, Hans-Jürgen Pietzsch, Holger Stephan, Gilles Gasser
Tumour pretargeting is a promising strategy for cancer diagnosis and therapy allowing for the rational use of long circulating, highly specific monoclonal antibodies (mAbs) for both non-invasive cancer radioimmunodetection (RID) and radioimmunotherapy (RIT). In contrast to conventional RID/RIT where the radionuclides and oncotropic vector molecules are delivered as presynthesised radioimmunoconjugates, the pretargeting approach is a multistep procedure that temporarily separates targeting of certain tumour-associated antigens from delivery of diagnostic or therapeutic radionuclides...
September 27, 2016: Chemical Society Reviews
Chung-Hsuan Huang, Marcio S Carvalho, Satish Kumar
Transfer of liquid from one surface to another plays a key role in printing processes. During liquid transfer, a liquid bridge is formed and then undergoes significant extensional motion while its contact lines are free to move on the bounding solid surfaces. In this work, we develop one-dimensional (1D) slender-jet and two-dimensional (2D) axisymmetric models of this phenomenon and compare the resulting predictions with previously published experimental data. For very low capillary numbers (Ca) (quasi-static stretching), predictions from both models of the amount of liquid transferred agree well with the experimental data, provided that the difference in receding contact angles (|Δθr|) between the two surfaces is sufficiently large...
September 13, 2016: Soft Matter
Megan Dearnley, Nicholas P Reynolds, Peter Cass, Xiaohu Wei, Shuning Shi, A Aalam Mohammed, Tam Le, Pathiraja Gunatillake, Mark L Tizard, San H Thang, Tracey M Hinton
The translation of siRNA into clinical therapies has been significantly delayed by issues surrounding the delivery of naked siRNA to target cells. Here we investigate siRNA delivery by cationic acrylic polymers developed by Reversible Addition Fragmentation chain Transfer (RAFT) mediated free radical polymerization. We investigated cell uptake and gene silencing of a series of siRNA-star polymer complexes both in the presence and absence of a protein "corona". Using a multidisciplinary approach including quantitative nanoscale mechanical-atomic force microscopy, dynamic light scattering and nanoparticle tracking analysis we have characterized the nanoscale morphology, stiffness and surface charge of the complexes with and without the protein corona...
October 6, 2016: Biomacromolecules
Huaqun Zhang, Cameron McGlone, Matthew M Mannion, Richard C Page
The ubiquitin ligase CHIP catalyzes covalent attachment of ubiquitin to unfolded proteins chaperoned by the heat shock proteins Hsp70/Hsc70 and Hsp90. CHIP interacts with Hsp70/Hsc70 and Hsp90 by binding of a C-terminal IEEVD motif found in Hsp70/Hsc70 and Hsp90 to the tetratricopeptide repeat (TPR) domain of CHIP. Although recruitment of heat shock proteins to CHIP via interaction with the CHIP-TPR domain is well established, alterations in structure and dynamics of CHIP upon binding are not well understood...
October 5, 2016: Biomolecular NMR Assignments
Suzanne G Mays, C Denise Okafor, Richard J Whitby, Devrishi Goswami, J Oacutezef Stec, Autumn R Flynn, Michael C Dugan, Nathan T Jui, Patrick R Griffin, Eric A Ortlund
Liver receptor homolog 1 (NR5A2, LRH-1) is an orphan nuclear hormone receptor that regulates diverse biological processes, including metabolism, proliferation, and the resolution of endoplasmic reticulum stress. While preclinical and cellular studies demonstrate that LRH-1 has great potential as a therapeutic target for metabolic diseases and cancer, development of LRH-1 modulators has been difficult. Recently, systematic modifications to one of the few known chemical scaffolds capable of activating LRH-1 failed to improve efficacy substantially...
September 30, 2016: Journal of Biological Chemistry
Amritaj Patra, Qianqian Zhang, F Peter Guengerich, Martin Egli
O6-Methyl-2(prime)-deoxyguanosine (O6-MeG) is a ubiquitous DNA lesion, formed not only by xenobiotic carcinogens but also by the endogenous methylating agent S-adenosylmethionine. It can introduce mutations during DNA replication, with different DNA polymerases displaying different ratios of correct or incorrect incoporation opposite this nucleoside. Of the "translesion" Y-family human DNA polymerases (hpols), hpol η is most efficient in incorporating equal numbers of correct and incorrect C and T bases. However, the mechanistic basis for this specific yet indescriminate activity is not known...
September 30, 2016: Journal of Biological Chemistry
Shuiping Luo, Pei Kang Shen
Multimetallic nanoframes with three-dimensional (3D) catalytic surfaces represent an emerging class of efficient nanocatalysts. However, it still remains a challenge in engineering nanoframes via simple and economical methods. Herein, we report a facile one-pot synthetic strategy to synthesize Pt-Cu nanoframes bounded with multiple high-index facets as highly active electrooxidation catalysts. Two distinct octopod nanoframes, namely, concave PtCu2 octopod nanoframes (PtCu2 CONFs) and ultrathin PtCu octopod nanoframes (PtCu UONFs) were successfully synthesized by simply changing the feeding Pt and Cu precursors...
October 4, 2016: ACS Nano
Xiaoying Liang, Hai Chen, Yanni Wang, Shixiong Song
The belief-desire-intention (BDI) model has been widely used to construct reasoning systems for complex tasks in dynamic environments. We have designed a capabilities and abilities (CA)-BDI farmer decision-making model, which is an extension of the BDI architecture and includes internal representations for farmer household Capabilities and Abilities. This model is used to explore farmer learning mechanisms and to simulate the bounded rational decisions made by farmer households. Our case study focuses on the Gaoqu Commune of Mizhi County, Shaanxi Province, China, where scallion is one of the main cash crops...
2016: SpringerPlus
Shogo Nakano, Kazuyuki Yasukawa, Takaki Tokiwa, Takeshi Ishikawa, Erika Ishitsubo, Naoya Matsuo, Sohei Ito, Hiroaki Tokiwa, Yasuhisa Asano
Elucidation of the molecular mechanism of amine oxidases (AOx) will help to extend their reactivity by rational design and their application to deracemization of various amine compounds. To date, several studies have been performed on S-selective AOx, but relatively few have focused on R-selective AOx. In this study, we sought to elucidate the mechanism of pkAOx, an R-selective AOx that we designed by introducing the Y228L and R283G mutations into d-amino acid oxidase from pig kidney. Four crystal structures of the substrate-bound protein and first-principles calculations based on the correlated fragment molecular orbital (FMO) indicated that two aromatic residues, Tyr224 and Phe242, form stable π-π stacking interaction with substrates...
October 10, 2016: Journal of Physical Chemistry. B
Ewa A Mirecka, Sophie Feuerstein, Lothar Gremer, Gunnar F Schröder, Matthias Stoldt, Dieter Willbold, Wolfgang Hoyer
In type 2 diabetes, the formation of islet amyloid consisting of islet amyloid polypeptide (IAPP) is associated with reduction in β-cell mass and contributes to the failure of islet cell transplantation. Rational design of inhibitors of IAPP amyloid formation has therapeutic potential, but is hampered by the lack of structural information on inhibitor complexes of the conformationally flexible, aggregation-prone IAPP. Here we characterize a β-hairpin conformation of IAPP in complex with the engineered binding protein β-wrapin HI18...
2016: Scientific Reports
Min Xie, Farhad Vesuna, Saritha Tantravedi, Guus M Bol, Marise R Heerma van Voss, Katriana Nugent, Reem Malek, Kathleen L Gabrielson, Paul J Van Diest, Phuoc T Tran, Venu Raman
Despite advances in diagnosis and treatment, prostate cancer is the most prevalent cancer in males and the second-highest cause of cancer-related mortality in men. We identified an RNA helicase gene, DDX3 (DDX3X), which is over-expressed in prostate cancers, and whose expression is directly correlated with high Gleason scores. Knockdown of DDX3 in aggressive prostate cancer cell lines DU145 and 22Rv1 resulted in significantly reduced clonogenicity. To target DDX3, we rationally designed a small molecule, RK-33, which docks into the ATP-binding domain of DDX3...
September 12, 2016: Cancer Research
Kevin A Henry, Traian Sulea, Henk van Faassen, Greg Hussack, Enrico O Purisima, C Roger MacKenzie, Mehdi Arbabi-Ghahroudi
Staphylococcal protein A (SpA) and streptococcal protein G (SpG) affinity chromatography are the gold standards for purifying monoclonal antibodies (mAbs) in therapeutic applications. However, camelid VHH single-domain Abs (sdAbs or VHHs) are not bound by SpG and only sporadically bound by SpA. Currently, VHHs require affinity tag-based purification, which limits their therapeutic potential and adds considerable complexity and cost to their production. Here we describe a simple and rapid mutagenesis-based approach designed to confer SpA binding upon a priori non-SpA-binding VHHs...
2016: PloS One
Michael N Lombardo, Narendran G-Dayanandan, Dennis L Wright, Amy C Anderson
Multidrug-resistant Enterobacteriaceae, notably Escherichia coli and Klebsiella pneumoniae, have become major health concerns worldwide. Resistance to effective therapeutics is often carried by class I and II integrons that can confer insensitivity to carbapenems, extended spectrum β-lactamases, the antifolate trimethoprim, fluoroquinolones, and aminoglycosides. Specifically of interest to the study here, a prevalent gene (dfrA1) coding for an insensitive dihydrofolate reductase (DHFR) confers 190- or 1000-fold resistance to trimethoprim for K...
February 12, 2016: ACS Infectious Diseases
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