The Realignment of Class Politics and Class Voting

Since the early days of the study of political behavior, class politics has been a key component. Initially researchers focused on simple manual versus nonmanual occupations and left versus right parties, and found consistent evidence of a strong effect of class on support for left-wing parties. This finding was assumed to be simply a matter of the redistributive preferences of the poor, an expression of the “democratic class struggle.” However, as the world became more complex, many established democracies developed more nuanced class structures and multidimensional party systems. How has this affected class politics? From the simple, but not deterministic pattern of left-voting workers, the early 21st century witnessed substantial realignment processes. Many remain faithful to social democratic (and to a lesser extent radical left) parties, but plenty of workers support radical right parties or have left the electoral arena entirely. To account for these changes, political scientists and sociologists have identified two mechanisms through which class voting occurs. The most frequently studied mechanism behind class voting is that classes have different attitudes, values, and ideologies, and political parties supply policies that appeal to different classes’ preferences. These ideologies are related not only to redistribution but also to newer issues such as immigration, which appear to some degree to have replaced competition over class-related inequality and the redistribution of wealth as the primary axis of class politics. A secondary mechanism is that members of different classes hold different social identities, and parties can connect to these identities by making symbolic class appeals or by descriptively representing a class. It follows that class realignment can occur either because the classes have changed their ideologies or identities, because the parties have changed their policies, class appeals, or personnel, or both. Early explanations focused on the classes themselves, arguing that they had become more similar in terms of living conditions, ideologies, and identities. However, later longitudinal studies failed to find such convergences taking place. The workers still have poorer, more uncertain, and shorter lives than their middle-class counterparts, identify more with the working class, and are more in favor of redistribution and opposed to immigration. While the classes are still distinctive, it seems that the parties have changed. Several social democratic parties have become less representative of working-class voters in terms of policies, rhetorical appeals, or the changing social composition of their activists and leaders. This representational defection is a response to the declining size of the working class, but not to the changing character or extent of class divisions in preferences. It is also connected to the exogeneous rise of new issues, on which these parties tend not to align with working-class preferences. By failing to represent the preferences or identities of many of their former core supporters, social democratic parties have initiated a supply-side driven process of realignment. This has primarily taken two forms; class–party realignments on both left and right and growing class inequalities in participation and representation.

Computational Studies on T2Rs Agonist-Based Anti–COVID-19 Drug Design

The expeditious and world pandemic viral disease of new coronavirus (SARS-CoV-2) has formed a prompt urgency to discover auspicious target-based ligand for the treatment of COVID-19. Symptoms of novel coronavirus disease (COVID-19) typically include dry cough, fever, and shortness of breath. Recent studies on many COVID-19 patients in Italy and the United Kingdom found increasing anosmia and ageusia among the COVID-19-infected patients. SARS-CoV-2 possibly infects neurons in the nasal passage and disrupts the senses of smell and taste, like other coronaviruses, such as SARS-CoV and MERS-CoV that could target the central nervous system. Developing a drug based on the T2Rs might be of better understanding and worth finding better molecules to act against COVID-19. In this research, we have taken a taste receptor agonist molecule to find a better core molecule that may act as the best resource to design a drug or corresponding derivatives. Based on the computational docking studies, the antibiotic tobramycin showed the best interaction against 6LU7 COVID-19 main protease. Aromatic carbonyl functional groups of the molecule established intermolecular hydrogen bonding interaction with GLN189 amino acid and it showed the two strongest carbonyl interactions with receptor protein resulting in a glide score of −11.159. To conclude, depending on the molecular recognition of the GPCR proteins, the agonist molecule can be recognized to represent the cell secondary mechanism; thus, it provides enough confidence to design a suitable molecule based on the tobramycin drug.

The Stability and Chloride Entrapping Capacity of ZnAl-NO2 LDH in High-Alkaline/Cementitious Environment

In this work, the ZnAl-NO2 LDH (layered double hydroxide) is investigated as a possible additive for mitigating the chloride-induced corrosion of steel in reinforced concrete. The investigation focused on the stability and chloride binding capacity of this LDH in the pH range typical of cementitious materials. Until pH = 12.5 the material was stable and effective in capturing chloride ions from the surrounding aqueous environment. For higher pH, precisely that of hydrated cement, the LDH was partially dissolved and OH− preferentially entrapped instead of Cl−. These results suggested that ZnAl-NO2 has excellent chloride entrapping capability at neutral pH, but this is reduced with increasing pH. However, when the LDH was incorporated into mortars, the chloride ingress was delayed, signifying that the dissolution of LDH leads to a secondary mechanism responsible for chloride capture.

The Law of the Sea, International Courts, and Judicialization

Dispute settlement is entrenched in the 1982 UN Convention on the Law of the Sea (UNCLOS) through the Part XV compulsory mechanisms. It is also reflected in UNCLOS's indication that delimitation of the exclusive economic zone or the continental shelf is to be by way of agreement between coastal states. While maritime boundary delimitation may be viewed as dominated by judicialization, that is not reflected in UNCLOS. The maritime boundary delimitation project unleashed by UNCLOS gave primacy to delimitation by agreement, with third party settlement under Part XV the secondary mechanism. The 2018 Australia/Timor-Leste maritime boundary settlement highlights how, even when Part XV third party mechanisms were used, the coastal states were able to reach agreement on a maritime boundary by negotiation, without recourse to judicialization.

Xanthine Oxidase Has a Protective Role during Heme Crisis By Binding and Degrading Heme

Xanthine oxidase (XO) is a key enzyme in the purine degradation pathway, catalyzing the catabolism of hypoxanthine to xanthine and xanthine to uric acid. A byproduct of these reactions is the generation of the reactive oxygen species (ROS), hydrogen peroxide and superoxide. XO is produced primarily in the liver; however, following hepatic stressors such as inflammation, hypoxia, or ischemia, XO is released from the liver and enters the circulation. XO can then bind distal endothelium via electrostatic interactions with glycosaminoglycans (GAGs). Current dogma believes that XO plays a harmful role in pathologies due to the increase in ROS production that can alter signaling pathways and damage endothelial cells. XO activity has been shown to be elevated in a number of hemolytic conditions including, sickle cell disease, malaria, and sepsis; however, the involvement of XO in these pathological conditions has not been fully elucidated. These conditions result in increased hemolysis, releasing free heme and hemoglobin into the circulation, inducing an inflammatory response, and damaging endothelial cells. Identifying the involvement of XO during heme crisis could improve our understanding of the pathologies associated with hemolytic conditions and lead to the identification or development of more effective treatment options. We hypothesized that XO has damaging properties under basal conditions; however, the presence of XO is crucial and protective during heme crisis by serving as a secondary mechanism of heme degradation when canonical heme degradation pathways are saturated. In order to explore the role of XO in heme crisis, we developed a novel heme crisis model in which we pre-treated mice with the clinically relevant dose of 10 mg/kg/day febuxostat, an FDA approved XO inhibitor, for five days in drinking water. Following inhibition of XO, the mice were challenged with two identical doses of hemin one hour apart and monitored for 24 hours. We observed a 20-fold increase in XO activity in the mice treated with 50 μmol/kg hemin. This increase was completely inhibited in the mice treated with febuxostat. Surprisingly, the febuxostat treated mice had worsened survival compared to the untreated mice. This suggests a protective role for XO during heme crisis. We hypothesized that XO has a protective role by preventing platelet activation and degrading excess free heme. To investigate this hypothesis, we used flow cytometry to quantify heme-induced platelet activation. Healthy human platelets were isolated and treated with 2.5 μM hemin, 10 mU/mL XO, 200 μM hypoxanthine, and 20 μM febuxostat. We observed 72% activation with heme alone, while incubation with XO and hypoxanthine resulted in almost complete prevention of platelet activation (16%). We were also able to partially restore platelet activation (45%) when febuxostat was added. Based on these results, we hypothesize that XO binds GAGs on the platelet surface and degrades heme in order to protect platelets from heme-induced activation. To assess the ability of XO to degrade heme, we tested whether XO binds heme. We performed computational modeling in which we identified a potential heme binding site in the FAD domain of XO with a kd = 128 nM. We confirmed heme-XO binding by performing a heme binding assay. We incubated heme (25 μM) alone, heme + XO (50 μM), and heme + XO + hypoxanthine (100 μM) for 20 minutes. Heme binding was assessed by dot blotting in nitrocellulose followed by chemiluminescent detection and dot density quantification. We observed a 2-fold increase in dot density when heme and XO were incubated and a 4-fold increase with heme, XO, and hypoxanthine. These results support a potential heme-XO interaction that is amplified when the enzyme is active. Lastly, we measured XO's ability to degrade heme using UV visible spectrophotometry. We incubated hemin, XO, and hypoxanthine together and measured the absorbance over 20 minutes. We observed a decrease in absorbance at 618 nm, indicative of heme degradation. In conclusion, contrary to the current dogma, we have identified a potential protective role for XO during hemolytic crisis. We found that febuxostat treatment worsened survival in heme challenged mice, XO prevented heme-induced platelet activation, identified a potential heme-XO binding site, and observed XO-induced heme degradation. XO may have a protective role in hemolytic conditions by serving as a secondary mechanism of heme degradation. Disclosures No relevant conflicts of interest to declare.

Targeting microglial polarization to improve TBI outcomes.

: Traumatic brain injury (TBI) is still the worldwide leading cause of mortality and morbidity in young adults. Improved safety measures and advances in critical care have improved chances of surviving a TBI, however, numerous secondary mechanisms contribute to the injury in the weeks and months that follow TBI. The past 4 decades of research have addressed many of the metabolic impairments sufficient to mitigate mortality, however, an enduring secondary mechanism, i.e. neuroinflammation, has been intractable to current therapy. Neuroinflammation is particularly difficult to target with pharmacological agents due to lack of specificity, the blood brain barrier, and an incomplete understanding of the protective and pathologic influences of inflammation in TBI. Recent insights into TBI pathophysiology have established microglial activation as a hallmark of all types of TBI. The inflammatory response to injury is necessary and beneficial while the death of activated microglial is not. This review presents new insights on the therapeutic and maladaptive features of the immune response after TBI with emphasis on microglial polarization, followed by a discussion of potential targets for pharmacologic and non-pharmacologic treatments. In aggregate, this review presents a rationale for guiding TBI inflammation towards neural repair and regeneration rather than secondary injury and degeneration, which we posit could improve outcomes and reduce lifelong disease burden in TBI survivors.

Strain-hardenability of new strengthened TRIP/TWIP titanium alloys

A new Ti-Cr based alloy has been developed to reach a TWIP (TWinning Induced Plasticity) effect as the main deformation mechanism. This new composition, involving Fe addition, was derived from a classical TRIP/TWIP alloy Ti-8.5Cr-1.5Al (wt%) (TCA). The main objective is to achieve an optimized strength/hardenability combination by limiting the TRIP (TRansformation Induced Plasticity) effect whose critical resolved shear stress lowers the plasticity threshold. This new alloy Ti-7Cr-1Al-xFe (wt%) (TCAF) displays excellent mechanical properties, with an increased yield strength (with respect to TCA alloy), a very high work-hardening rate and an extremely high fracture strength (UTS=1415MPa), while maintaining an excellent ductility (ε=0.38 at fracture). Both mechanical (tensile tests) and microstructural characterization at different scales (EBSD, XRD) have been performed, evidencing a dense network of fine {332}<113> mechanical twins as well as the presence of stress-induced martensite plates at twins intersections, as a secondary mechanism.

Experimental Tests of Steel Unstiffened Double Side Joints with Flush and Extended End Plate

Experimental tests of steel unstiffened double side bolted end-plate joints have been presented. The main aim of the conducted tests was to check the behavior of joints in an accidental situation and possibility of creating secondary mechanism, i.e. catenary action in the scenario of column loss. Two types of end plate joints were tested: flush end-plate (FP) and extended end-plate (EP) with different thickness and different number of bolt rows in each. The tests were carried out on an isolated cross beam-column-beam type system until joint failure. During tests the available moment resistance and rotation capacity of bending joints and also values of tension forces in the beam were determined. The joints with extended end-plate have demonstrated higher bending and rotational capacity than flush end-plate. Significant deformation of column flanges, web and end plate were observed. The fracture of bolts was the failure mode of joints. Obtained results of axial force values in beam exceeded standard requirement what confirmed that the joints with unstiffened web column, flush or extended end-plate possess the ability of development the catenary action.

A Novel Mechanism for Zika Virus Host-Cell Binding

Zika virus (ZIKV) recently emerged in the Western Hemisphere with previously unrecognized or unreported clinical presentations. Here, we identify two putative binding mechanisms of ancestral and emergent ZIKV strains featuring the envelope (E) protein residue asparagine 154 (ASN154) and viral phosphatidylserine (PS). Synthetic peptides representing the region containing ASN154 from strains PRVABC59 (Puerto Rico 2015) and MR_766 (Uganda 1947) were exposed to neuronal cells and fibroblasts to model ZIKV E protein/cell interactions and bound MDCK or Vero cells and primary neurons significantly. Peptides significantly inhibited Vero cell infectivity by ZIKV strains MR_766 and PRVABC59, indicating that this region represents a putative binding mechanism of ancestral African ZIKV strains and emergent Western Hemisphere strains. Pretreatment of ZIKV strains MR_766 and PRVABC59 with the PS-binding protein annexin V significantly inhibited replication of PRVABC59 but not MR_766, suggesting that Western hemisphere strains may additionally be capable of utilizing PS-mediated entry to infect host cells. These data indicate that the region surrounding E protein ASN154 is capable of binding fibroblasts and primary neuronal cells and that PS-mediated entry may be a secondary mechanism for infectivity utilized by Western Hemisphere strains.

Next-Generation Multimodality of Nanomedicine Therapy: Size and Structure Dependence of Folic Acid Conjugated Copolymers Actively Target Cancer Cells in Disabling Cell Division and Inducing Apoptosis

Nanomedicine as a multimodality treatment of cancer utilizes the advantages of nanodelivery systems of drugs. They are superior to the clinical administration of different therapeutic agents in several aspects, including simultaneous delivery of drugs to the active site, precise ratio control of the loading drugs and overcoming multidrug resistance. The role of nanopolymer size and structural shape on the internalization process and subsequent intracellular toxicity is limited. Here, the size and shape dependent mechanism of a functionalized copolymer was investigated using folic acid (FA) covalently bonded to the copolymer poly (styrene-alt-maleic anhydride) (SMA) on its hydrophilic exterior via a biological linker 2,4-diaminobutyric acid (DABA) to target folic acid receptors (FR) overly expressed on cancer cells actively. We recently reported that unloaded FA-DABA-SMA copolymers significantly reduced cancer cell viability, suggesting a secondary therapeutic mechanism of action of the copolymer carrier post-internalization. Here, we investigated the size and shape dependent secondary mechanism of unloaded 350 kDa and 20 kDa FA-DABA-SMA. The 350 kDa and 20 kDa copolymers actively target folic acid receptors (FR) to initialize internationalization, but only the large size and sheet shaped copolymer disables cell division by intracellular disruptions of essential oncogenic proteins including p53, STAT-3 and c-Myc. Furthermore, the 350 kDa FA-DABA-SMA activates early and late apoptotic events in both PANC-1 and MDA-MB-231 cancer cells. These findings indicate that the large size and structural sheet shape of the 350 kDa FA-DABA-SMA copolymer facilitate multimodal tumor targeting mechanisms together with the ability to internalize hydrophobic chemotherapeutics to disable critical oncogenic proteins controlling cell division and to induce apoptosis. The significance of these novel findings reveals copolymer secondary cellular targets and therapeutic actions that extend beyond the direct delivery of chemotherapeutics. This report offers novel therapeutic insight into the intracellular activity of copolymers critically dependent on the size and structural shape of the nanopolymers.