Race and Authoritarianism in American Politics Parker, Christopher Sebastian; Towler, Christopher C
Annual review of political science,
05/2019, Letnik:
22, Številka:
1
Journal Article
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Authoritarianism, it seems, is alive and well these days. The Trump administration's blatant dismissal of democratic norms has many wondering whether it fits the authoritarian model. This review ...offers a framework for understanding authoritarianism in the American past, as well as the American present. Starting in the early twentieth century, this analysis seeks to provide a better understanding of how authoritarianism once existed in enclaves in the Jim Crow South, where it was intended to dominate blacks in the wake of emancipation. Confining the definition of authoritarianism to regime rule, however, leaves little room for a discussion of more contemporary authoritarianism, at the micro level. This review shifts focus to an assessment of political psychology's concept of authoritarianism and how it ultimately drives racism. Ultimately, we believe a tangible connection exists between racism and authoritarianism. Even so, we question the mechanism. Along the way, we also discuss the ways in which communities of color, often the targets of authoritarianism, resist the intolerance to which they have been exposed. We conclude with a discussion of why we believe, despite temporal and spatial differences as well as incongruous levels of analysis, that micro- and macro-level authoritarianism have much in common.
Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the ...survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists; however it codes for a less stable SMN protein. In recent years, significant progress has been made toward disease modifying treatments for SMA by modulating SMN2 pre-mRNA splicing. Herein, we describe the discovery of LMI070/branaplam, a small molecule that stabilizes the interaction between the spliceosome and SMN2 pre-mRNA. Branaplam (1) originated from a high-throughput phenotypic screening hit, pyridazine 2, and evolved via multiparameter lead optimization. In a severe mouse SMA model, branaplam treatment increased full-length SMN RNA and protein levels, and extended survival. Currently, branaplam is in clinical studies for SMA.
SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an ...important role in the programmed cell death pathway (PD-1/PD-L1). Because it is an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter, and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition, and several new protein–ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.
The polymorphism of the simple amino acid glycine has been known for almost a century. It is also known that in aqueous solutions, at the isoelectric point (pI 5.9), the metastable α polymorph ...crystallizes, while the stable γ form of glycine only nucleates at high and low pH. Despite the importance of understanding the process by which crystals nucleate, the solution and solid-state chemistry underlying this simple observation have never been explored. In this contribution, we have combined solution chemistry, crystallization, and crystallographic data to investigate the mechanisms by which this effect occurs. It is concluded that solution speciation and the consequent interactions between charged species and developing crystal nuclei determine the structural outcome of the crystallization process.
Soluble guanylate cyclase (sGC), the endogenous receptor for nitric oxide (NO), has been implicated in several diseases associated with oxidative stress. In a pathological oxidative environment, the ...heme group of sGC can be oxidized becoming unresponsive to NO leading to a loss in the ability to catalyze the production of cGMP. Recently a dysfunctional sGC/NO/cGMP pathway has been implicated in contributing to elevated intraocular pressure associated with glaucoma. Herein we describe the discovery of molecules specifically designed for topical ocular administration, which can activate oxidized sGC restoring the ability to catalyze the production of cGMP. These efforts culminated in the identification of compound (+)-23, which robustly lowers intraocular pressure in a cynomolgus model of elevated intraocular pressure over 24 h after a single topical ocular drop and has been selected for clinical evaluation.
Salt screening and selection is a well established approach for improving the properties of drug candidates, including dissolution rate and bioavailability. Typically during early development only ...small amounts of compound are available for solid state profiling, including salt screening. In order to probe large areas of experimental space, high-throughput screening is utilized and is often designed in a way to search for suitable crystallization parameters within hundreds or even thousands of conditions. However, the hit rate in these types of screens can be very low.
In order to allow for selection of a salt form early within the drug development process whilst using smaller amounts of compounds, a screening procedure taking into account the compounds properties and the driving forces for salt formation is described. Experiments were carried out on the model compounds clotrimazole, cinnarizine itraconazole and atropine. We found an increase in crystalline hit rate for water-insoluble drugs crystallized from solutions that included at least 10% aqueous content.
Conversely it was observed that compounds with greater water solubility did not benefit from aqueous content in salt screening, instead organic solvents lead to more crystalline screening hits. Results from four model compounds show that the inclusion of an aqueous component to the salt reaction can enhance the chance of salt formation and significantly improve the crystalline hit rate for low water soluble drugs.
The crystallization and subsequent polymorphic transformation from the β to the α form of glycine has been studied using optical microscopy, X-ray diffraction, and Fourier transform infrared ...spectroscopy techniques. The crystal structure and morphology of β glycine have been determined, and the influence of solvent, solubility, and process scale on its solvent-mediated transformation to the α form was quantified. It is concluded that for the low solubility environments used in this study, the rate-determining step in the transformation process is the dissolution rate of the metastable β polymorph.
Crystallization from solutions is an important technique for a wide range of industries. One of the prime requirements for crystallization is that molecular aggregation or clustering occurs prior to ...the formation of stable nuclei. Despite this, very little work has been carried out to investigate the nature of supersaturated solutions and the structure of prenucleation clusters. In this study, we have probed molecular assemblies in solution, using spectroscopic techniques, to search for structural features common to both solutions and solids. For the systems studied, it was found that, although solute−solute interactions could be detected in solution, there was generally a limited relationship with the solid forms, and therefore, these assemblies were not predictive of the polymorph initially crystallized.
Amorphous solids and crystalline salts are both of interest as a means of improving the dissolution characteristics and apparent solubility of poorly water soluble active pharmaceutical ingredients ...which have low bioavailability in humans. The theory and selection of both crystalline drug substance salt forms and amorphous products have been extensively studied. However, less is known about the impact of different counterions on the properties of amorphous drug substance salts. In this study, several salts of either nicardipine or propranolol were prepared and characterized with respect to glass transition temperature, crystallization tendency and moisture sorption behavior. Although the moisture sorption behavior and crystallization tendency varied depending on the counterion used, no trends were readily apparent. The glass transition temperature was found to be dependent on the counterion used to form the salt, and was higher in all instances for the salts than for the neutral compound. Several molecular descriptors were calculated for the various counterions, and multivariate analysis was used to build a model that successfully correlated T g with a number of these parameters. Important parameters which influenced T g included counterion pK a and electrophilicity index. In conclusion, it is apparent that, as for crystalline salts, the counterion has an effect on the properties of amorphous materials.
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