Scaffold-Hopping and Structure-Based Discovery of Potent, Selective, And Brain Penetrant <i>N</i>-(1<i>H</i>-Pyrazol-3-yl)pyridin-2-amine Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12)

Patel, Snahel,Harris, Seth F.,Gibbons, Paul,Deshmukh, Gauri,Gustafson, Amy,Kellar, Terry,Lin, Han,Liu, Xingrong,Liu, Yanzhou,Liu, Yichin,Ma, Changyou,Scearce-Levie, Kimberly,Ghosh, Arundhati Sengupta American Chemical Society 2015 Journal of medicinal chemistry Vol.58 No.20

<P>Recent data suggest that inhibition of dual leucine zipper kinase (DLK, MAP3K12) has therapeutic potential for treatment of a number of indications ranging from acute neuronal injury to chronic neurodegenerative disease. Thus, high demand exists for selective small molecule DLK inhibitors with favorable drug-like properties and good CNS penetration. Herein we describe a shape-based scaffold hopping approach to convert pyrimidine <B>1</B> to a pyrazole core with improved physicochemical properties. We also present the first crystal structures of DLK. By utilizing a combination of property and structure-based design, we identified inhibitor <B>11</B>, a potent, selective, and brain-penetrant inhibitor of DLK with activity in an in vivo nerve injury model.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2015/jmcmar.2015.58.issue-20/acs.jmedchem.5b01072/production/images/medium/jm-2015-01072j_0022.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jm5b01072'>ACS Electronic Supporting Info</A></P>

The Effects of Foreign Language Proficiency on Public Attitudes: Evidence From the Chinese-Speaking World

Yue Hu,Amy H. Liu 동아시아연구원 2020 Journal of East Asian Studies Vol.20 No.1

What explains public attitudes towards a former aggressor state? Conventional wisdom would suggest the prevalence of negative sentiments rooted in historical hatred. In this article we contend that when individuals are proficient in a foreign language—e.g. a lingua franca—they have an alternative channel through which they are exposed to positive narratives put forth by other parties regarding the former aggressor state. And as a result, their attitudes towards the former aggressor state are more positive than those held by their linguistically limited counterparts. To test our argument, we focus on public attitudes towards the Japanese in Mainland China, Singapore, and Taiwan—three Chinese-ethnic majority political units that experienced Japanese aggression leading up to and during World War II. Using survey data, we demonstrate that individuals who are proficient in the English language are much more likely to hold positive attitudes of the Japanese. These results are robust even when we consider whether some individuals are predisposed to being cosmopolitan; whether some individuals have more opportunities to learn English; and whether the linguistic effects are symptomatic of American soft power.

A novel attach-and-release mineral scale control strategy: Laboratory investigation of retention and release of scale inhibitor on pipe surface

Ping Zhang,Yuan Liu,Nan Zhang,Weng Fai Ip,Amy T. Kan,Mason B. Tomson 한국공업화학회 2019 Journal of Industrial and Engineering Chemistry Vol.70 No.-

A novel “attach-and-release” approach has been experimentally evaluated as an alternative scale controlstrategy for pipeflow system. Phosphonate scale inhibitor was initially attached to calcium carbonatemedium on the surface of the pipe. Subsequently, the retained inhibitor was released into theflowingfluid for scale control. A plug-flow tube reactor apparatus was adopted in laboratory studies. It shows thatformation of calcium-inhibitor precipitate accounts for the attachment of inhibitor and brine chemistrycan considerably impact the amount of inhibitor retained. This proposed strategy has the potential to beapplied in a pipeflow system to control scale deposition threat.

Presidential Electoral Cycles and Corruption Charges

Amick Joe,Bukovansky Mlada,Liu Amy H 동아시아연구원 2022 Journal of East Asian Studies Vol.22 No.2

Anti-corruption efforts are inherently political. Corruption charges can be levied against political opponents as an instrument of repression; they can also be used against troublesome allies in the same party coalition to further consolidate power. In this paper, we focus on Indonesia and ask: Do major corruption charges follow a presidential electoral cycle—and if so, how? We contend charges against prominent members of the government coalition are more likely to happen before an election, allowing the government to replace intra-party rivals with loyal allies. Conversely, charges against prominent opposition members are more likely to happen after an election when fears of retaliation are low, opportunities for credit-claiming are high, and there is an incentive to remove veto players who may inhibit implementing the government’s agenda. To test this argument, we use an original, newly assembled dataset of all major corruption charges—i.e., those involving high-profile politicians and garnering international attention—in Indonesia from 1998–2015 as reported in the Associated Press. We find a significant and robust relationship between the electoral calendar and major corruption charges. This relationship is robust across presidential administrations. These results yield insights into how anti-corruption efforts can become a political tool and counsel caution about the effectiveness of “good governance,” especially in new democracies. Finally, we discuss how contextual political factors external to Indonesia’s anti-corruption commission, reinforce this empirical pattern.

Identification of novel therapeutic targets in acute leukemias with NRAS mutations using a pharmacologic approach

Nonami, Atsushi,Sattler, Martin,Weisberg, Ellen,Liu, Qingsong,Zhang, Jianming,Patricelli, Matthew P.,Christie, Amanda L.,Saur, Amy M.,Kohl, Nancy E.,Kung, Andrew L.,Yoon, Hojong,Sim, Taebo,Gray, Natha American Society of Hematology 2015 Blood Vol.125 No.20

<P>Oncogenic forms of NRAS are frequently associated with hematologic malignancies and other cancers, making them important therapeutic targets. Inhibition of individual downstream effector molecules (eg, RAF kinase) have been complicated by the rapid development of resistance or activation of bypass pathways. For the purpose of identifying novel targets in NRAS-transformed cells, we performed a chemical screen using mutant NRAS transformed Ba/F3 cells to identify compounds with selective cytotoxicity. One of the compounds identified, GNF-7, potently and selectively inhibited NRAS-dependent cells in preclinical models of acute myelogenous leukemia and acute lymphoblastic leukemia. Mechanistic analysis revealed that its effects were mediated in part through combined inhibition of ACK1/AKT and of mitogen-activated protein kinase kinase kinase kinase 2 (germinal center kinase). Similar to genetic synthetic lethal approaches, these results suggest that small molecule screens can be used to identity novel therapeutic targets in cells addicted to RAS oncogenes.</P>

A spatial-based explanation for institutional trust in Georgia: Evidence from the maternal healthcare system

Siegel David,Byelousova Anastasiya,Gupta Parth,Liu Amy H,Pizzi Elise,Sanchez Michael,Shengelia Lela,Unapkoshvili Mariana,Wang Lyndsey,Wierschke Katherina 한양대학교 아태지역연구센터 2022 Journal of Eurasian Studies Vol.13 No.1

When an institution is not easily accessible—for example, it is geographically far—it can be hard for institutional trust to develop. The institution is not only unavailable, but it can also be seen as inappropriate, non-affordable, unapproachable, and unacceptable. In this paper, we examine whether reducing distance to medical facilities and professionals can improve trust in the maternal healthcare system. We do so by focusing on developments in Georgia. Since 2013, the government has aggressively closed the distance to service access not by building more facilities or hiring more staff per se, but by upgrading and funding existing facilities and professionals in a national network to better coordinate service provisions at the local levels. Employing an original survey, we match GPS coordinates to measure distance and use regression analysis to demonstrate how ensuring every woman has access to maternal healthcare at the right place at the right time has improved institutional trust in the system. The implications highlight results that are generalizable beyond both the country and maternal healthcare.

Controlling Switching in Bistable [2]Catenanes by Combining Donor–Acceptor and Radical–Radical Interactions

Zhu, Zhixue,Fahrenbach, Albert C.,Li, Hao,Barnes, Jonathan C.,Liu, Zhichang,Dyar, Scott M.,Zhang, Huacheng,Lei, Juying,Carmieli, Raanan,Sarjeant, Amy A.,Stern, Charlotte L.,Wasielewski, Michael R.,Sto American Chemical Society 2012 JOURNAL OF THE AMERICAN CHEMICAL SOCIETY - Vol.134 No.28

<P>Two redox-active bistable [2]catenanes composed of macrocyclic polyethers of different sizes incorporating both electron-rich 1,5-dioxynaphthalene (DNP) and electron-deficient 4,4′-bipyridinium (BIPY<SUP>2+</SUP>) units, interlocked mechanically with the tetracationic cyclophane cyclobis(paraquat-<I>p</I>-phenylene) (CBPQT<SUP>4+</SUP>), were obtained by donor–acceptor template-directed syntheses in a threading-followed-by-cyclization protocol employing Cu(I)-catalyzed azide–alkyne 1,3-dipolar cycloadditions in the final mechanical-bond forming steps. These bistable [2]catenanes exemplify a design strategy for achieving redox-active switching between two translational isomers, which are driven (i) by donor–acceptor interactions between the CBPQT<SUP>4+</SUP> ring and DNP, or (ii) radical–radical interactions between CBPQT<SUP>2(•+)</SUP> and BIPY<SUP>•+</SUP>, respectively. The switching processes, as well as the nature of the donor–acceptor interactions in the ground states and the radical–radical interactions in the reduced states, were investigated by single-crystal X-ray crystallography, dynamic <SUP>1</SUP>H NMR spectroscopy, cyclic voltammetry, UV/vis spectroelectrochemistry, and electron paramagnetic resonance (EPR) spectroscopy. The crystal structure of one of the [2]catenanes in its trisradical tricationic redox state provides direct evidence for the radical–radical interactions which drive the switching processes for these types of mechanically interlocked molecules (MIMs). Variable-temperature <SUP>1</SUP>H NMR spectroscopy reveals a degenerate rotational motion of the BIPY<SUP>2+</SUP> units in the CBPQT<SUP>4+</SUP> ring for both of the two [2]catenanes, that is governed by a free energy barrier of 14.4 kcal mol<SUP>–1</SUP> for the larger catenane and 17.0 kcal mol<SUP>–1</SUP> for the smaller one. Cyclic voltammetry provides evidence for the reversibility of the switching processes which occurs following a three-electron reduction of the three BIPY<SUP>2+</SUP> units to their radical cationic forms. UV/vis spectroscopy confirms that the processes driving the switching are (i) of the donor–acceptor type, by the observation of a 530 nm charge-transfer band in the ground state, and (ii) of the radical–radical ilk in the switched state as indicated by an intense visible absorption (ca. 530 nm) and near-infrared (ca. 1100 nm) bands. EPR spectroscopic data reveal that, in the switched state, the interacting BIPY<SUP>•+</SUP> radical cations are in a fast exchange regime. In general, the findings lay the foundations for future investigations where this radical–radical recognition motif is harnessed in bistable redox-active MIMs in order to achieve close to homogeneous populations of co-conformations in both the ground and switched states.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jacsat/2012/jacsat.2012.134.issue-28/ja3037355/production/images/medium/ja-2012-037355_0011.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/ja3037355'>ACS Electronic Supporting Info</A></P>

Converging Evidence for Efficacy from Parallel EphB4-Targeted Approaches in Ovarian Carcinoma

Spannuth, Whitney A.,Mangala, Lingegowda S.,Stone, Rebecca L.,Carroll, Amy R.,Nishimura, Masato,Shahzad, Mian M.K.,Lee, Sun-Joo,Moreno-Smith, Myrthala,Nick, Alpa M.,Liu, Ren,Jennings, Nicholas B.,Lin, American Association for Cancer Research 2010 Molecular Cancer Therapeutics Vol.9 No.8