Role of Coagulation in Xenobiotic-Induced Liver Injury

The liver is a common target for xenobiotic-induced toxicity. Of importance, synthesis of soluble coagulation factors by the liver plays an essential role in hemostasis. Blood coagulation cascade activation is evident in both human patients and in animal models of liver injury. Several studies have shown that coagulation is not merely a process reactive to toxicity, but rather a critical determinant of liver disease pathogenesis. Previous studies have utilized global anticoagulation as a strategy to investigate the role of coagulation in liver injury. Currently, our understanding of the mechanisms whereby individual coagulation proteases contribute to hepatotoxicity is inadequate. Blood coagulation is initiated by tissue factor (TF), a transmembrane cellular receptor for the coagulation factor VII/VIIa. The TF:VIIa complex initiates a serine protease cascade, which culminates in the generation of the serine protease thrombin. Thrombin cleaves circulating fibrinogen to initiate fibrin clot formation. Additionally, thrombin signals to multiple cell types through activation of protease activated receptors (PARs), which can promote inflammation and platelet aggregation. The procoagulant response is balanced by several anticoagulant proteins and fibrin clot degradation is catalyzed by plasmin, the main endogenous fibrin degradation enzyme. The aim of this dissertation was to determine the role of several blood coagulation cascade components in the responses elicited by two model hepatotoxicants; &alpha-naphthylisothiocyanate (ANIT) a toxicant that damages bile duct epithelial cells (BDECs), and acetaminophen (APAP), a common analgesic that causes centrilobular hepatocellular necrosis at high doses. We found that TF-dependent generation of thrombin contributed to the progression of chronic ANIT-induced hepatic inflammation and fibrosis by a mechanism requiring PAR-1. PAR-1 activation amplified TGF-&beta1-induced &alphaV&beta6 integrin expression by BDECs, and activation of TGF-&beta signaling in vivo. This suggests a novel feed-forward mechanism whereby coagulation can promote fibrogenesis. In contrast, PAR-1 was not required for the acute hepatotoxic effects of ANIT. Rather, ANIT-induced liver injury occurred by a mechanism involving activation of PAR-4 on platelets and fibrin(ogen). The results highlight a differential contribution of thrombin signaling in acute and chronic cholestatic liver injury. Previous studies identified the primary inhibitor of fibrinolysis, plasminogen activator inhibitor-1 (PAI-1), as a key hepatoprotective factor in APAP-induced liver injury. Indeed, hepatic fibrin deposition is a prominent feature of APAP-induced hepatocellular necrosis. To our surprise, fibrin(ogen) did not contribute to acute APAP-induced liver injury. Of importance, plasminogen deficiency reduced APAP hepatotoxicity. Taken together, the results suggest that plasmin(ogen) promotes APAP-induced liver injury in a fibrin independent manner. Overall, these studies revealed novel pathways whereby elements of the coagulation cascade promote liver injury induced by two classical hepatotoxicants. The results suggest that individual coagulation cascade components may play divergent roles in different models of liver injury and potentially at different time points during injury development. Further studies systematically evaluating individual coagulation factors in animal models and human disease are required to fully understand the dynamic contribution that coagulation cascade proteins play in liver injury

Therapeutic Administration of the Direct Thrombin Inhibitor Argatroban Reduces Hepatic Inflammation in Mice with Established Fatty Liver Disease

Thrombin generation is increased in patients with nonalcoholic fatty liver disease (NAFLD) and in mouse models of diet-induced obesity. Deficiency in the thrombin receptor protease activated receptor-1 reduces hepatic inflammation and steatosis in mice fed a Western diet. However, it is currently unclear whether thrombin inhibitors can modify the pathogenesis of established NAFLD. We tested the hypothesis that thrombin inhibition could reverse hepatic steatosis and inflammation in mice with established diet-induced NAFLD. Low-density lipoprotein receptor–deficient LDLr−/− mice were fed a control diet or a Western diet for 19 weeks. Mice were given the direct thrombin inhibitor argatroban ∼15 mg/kg/day or its vehicle via a miniosmotic pump for the final 4 weeks of the study. Argatroban administration significantly reduced hepatic proinflammatory cytokine expression and reduced macrophage and neutrophil accumulation in livers of mice fed a Western diet. Argatroban did not significantly impact hepatic steatosis, as indicated by histopathology, Oil Red O staining, and hepatic triglyceride levels. Argatroban reduced serum triglyceride and cholesterol levels in mice fed a Western diet. Argatroban reduced both α-smooth muscle actin expression and Type 1 collagen mRNA levels in livers of mice fed a Western diet, indicating reduced activation of hepatic stellate cells. This study indicates that therapeutic intervention with a thrombin inhibitor attenuates hepatic inflammation and several profibrogenic changes in mice fed a Western diet

Antigen-Drug Conjugates as a Novel Therapeutic Class for the Treatment of Antigen-Specific Autoimmune Disorders

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Molecular Pharmaceutics, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see doi.org/10.1021/acs.molpharmaceut.9b00063.Multiple sclerosis represents the world’s most common cause of neurological disability in young people and is attributed to a loss of immune tolerance toward proteins of the myelin sheath. Typical treatment options for MS patients involve immunomodulatory drugs, which act non-specifically, resulting in global immunosuppression. The study discussed herein aims to demonstrate the efficacy of antigen-specific immunotherapies involving conjugation of disease causing auto-antigen, PLP139–151, and a potent immunosuppressant, dexamethasone. Antigen-drug conjugates (AgDCs) were formed using copper-catalyzed azide-alkyne cycloaddition chemistry with the inclusion of a hydrolyzable linker to maintain activity of released dexamethasone. Subcutaneous administration of this antigen-drug conjugate to SJL mice induced with experimental autoimmune encephalomyelitis protected the mice from symptom onset throughout the 25-day study, demonstrating enhanced efficacy in comparison to dexamethasone treatment. These results highlight the benefits of co-delivery of auto-antigens with immunosuppressant drugs as AgDCs for the treatment of autoimmune diseases.National Institutes of Health Graduate Training Program in Dynamic Aspects of Chemical Biology Grant (T32 GM008545)Howard Rytting pre-doctoral fellowship from the Department of Pharmaceutical Chemistry at the University of KansasNational Institutes of Health Biotechnology Training Grant (NIH0073415)NIH Shared Instrumentation Grant # S10RR024664NSF Major Research Instrumentation Award # 162592

The H alpha Galaxy Survey VI. Star-forming companions of nearby field galaxies

We present a search for star-forming satellite galaxies that are close enough to their parent galaxies to be considered analogues of the Magellanic Clouds. Our search technique relied on the detection of the satellites in continuum-subtracted narrow-band H alpha imaging of the central galaxies, which removes most of the background and foreground line-of-sight companions, thus giving a high probability that we are detecting true satellites. The search was performed for 119 central galaxies at distances between 20 and 40 Mpc, although spatial incompleteness means that we have effectively searched 53 full satellite-containing volumes. We find only 9 probable star-forming satellites, around 9 different central galaxies, and 2 possible satellites. After incompleteness correction, this is equivalent to 0.17/0.21 satellites per central galaxy. The Small Magellanic Cloud is just below the median values of both star formation rate and R-band luminosity of the 9 probable satellites. The Large Magellanic Cloud, however, has a higher R-band luminosity than any of the 9 and is only exceeded in star formation rate by the one satellite that appears to be undergoing a tidally-induced starburst. Thus the Milky Way appears to be quite unusual, both in having two star-forming satellite galaxies and in the high luminosity of the Large Magellanic Cloud.Comment: 13 pages, accepted for publication in A&

The Host Galaxies of Type Ia Supernovae Discovered by the Palomar Transient Factory

We present spectroscopic observations of the host galaxies of 82 low-redshift type Ia supernovae (SNe Ia) discovered by the Palomar Transient Factory (PTF). We determine star-formation rates, gas-phase stellar metallicities, and stellar masses and ages of these objects. As expected, strong correlations between the SN Ia light-curve width (stretch) and the host age mass metallicity are found: fainter, faster-declining events tend to be hosted by older massive metal-rich galaxies. There is some evidence that redder SNe Ia explode in higher metallicity galaxies, but we found no relation between the SN colour and host galaxy extinction based on the Balmer decrement, suggesting that the colour variation of these SNe does not primarily arise from this source. SNe Ia in higher-mass metallicity galaxies also appear brighter after stretch colour corrections than their counterparts in lower mass hosts, and the stronger correlation is with gas-phase metallicity suggesting this may be the more important variable. We also compared the host stellar mass distribution to that in galaxy targeted SN surveys and the high-redshift untargeted Supernova Legacy Survey (SNLS). SNLS has many more low mass galaxies, while the targeted searches have fewer. This can be explained by an evolution in the galaxy stellar mass function, coupled with a SN delay-time distribution proportional to t1. Finally, we found no significant difference in the mass--metallicity relation of our SN Ia hosts compared to field galaxies, suggesting any metallicity effect on the SN Ia rate is small

Normal modes and discovery of high-order cross-frequencies in the DBV white dwarf GD 358

We present a detailed mode identification performed on the 1994 Whole Earth Telescope (WET) run on GD 358. The results are compared with that obtained for the same star from the 1990 WET data. The two temporal spectra show very few qualitative differences, although amplitude changes are seen in most modes, including the disappearance of the mode identified as k=14 in the 1990 data. The excellent coverage and signal-to-noise ratio obtained during the 1994 run lead to the secure identification of combination frequencies up to fourth order, i.e. peaks that are sums or differences of up to four parent frequencies, including a virtually complete set of second-order frequencies, as expected from harmonic distortion. We show how the third-order frequencies are expected to affect the triplet structure of the normal modes by back-interacting with them. Finally, a search for ℓ=2 modes was unsuccessful, not verifying the suspicion that such modes had been uncovered in the 1990 data set

A search for non-virialized axionic dark matter

Cold dark matter in the Milky Way halo may have structure defined by flows with low velocity dispersion. The Axion Dark Matter eXperiment high resolution channel is especially sensitive to axions in such low velocity dispersion flows. Results from a combined power spectra analysis of the high resolution channel axion search are presented along with a discussion of the assumptions underlying such an analysis. We exclude KSVZ axion dark matter densities of {\rho} > 0.2 GeV/cm^3 and DFSZ densities of {\rho} > 1.4 GeV/cm^3 over a mass range of m_a = 3.3{\mu}eV to 3.69{\mu}eV for models having velocity dispersions of {\Delta}{\beta} < 3x10^-6.Comment: 4 pages, 4 figures, Accepted to be published in PRD Rapid Communication

Protease-Activated Receptor 1 and Hematopoietic Cell Tissue Factor Are Required for Hepatic Steatosis in Mice Fed a Western Diet

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of obesity and metabolic syndrome and contributes to increased risk of cardiovascular disease and liver-related morbidity and mortality. Indeed, obese patients with metabolic syndrome generate greater amounts of thrombin, an indication of coagulation cascade activation. However, the role of the coagulation cascade in Western diet–induced NAFLD has not been investigated. Using an established mouse model of Western diet–induced NAFLD, we tested whether the thrombin receptor protease-activated receptor 1 (PAR-1) and hematopoietic cell–derived tissue factor (TF) contribute to hepatic steatosis. In association with hepatic steatosis, plasma thrombin-antithrombin levels and hepatic fibrin deposition increased significantly in C57Bl/6J mice fed a Western diet for 3 months. PAR-1 deficiency reduced hepatic inflammation, particularly monocyte chemoattractant protein-1 expression and macrophage accumulation. In addition, PAR-1 deficiency was associated with reduced steatosis in mice fed a Western diet, including reduced liver triglyceride accumulation and CD36 expression. Similar to PAR-1 deficiency, hematopoietic cell TF deficiency was associated with reduced inflammation and reduced steatosis in livers of low-density lipoprotein receptor–deficient mice fed a Western diet. Moreover, hematopoietic cell TF deficiency reduced hepatic fibrin deposition. These studies indicate that PAR-1 and hematopoietic cell TF are required for liver inflammation and steatosis in mice fed a Western diet

A 'Performative' Social Movement: The Emergence of Collective Contentions within Collaborative Governance

The enmeshment of urban movements in networks of collaborative governance has been characterised as a process of co-option in which previously disruptive contentions are absorbed by regimes and reproduced in ways that do not threaten the stability of power relations. Applying a theoretical framework drawn from feminist philosopher Judith Butler this paper directs attention to the development of collective oppositional identities that remain embedded in conventional political processes. In a case study of the English tenants' movement, it investigates the potential of regulatory discourses that draw on market theories of performative voice to offer the collectivising narratives and belief in change that can generate the emotional identification of a social movement. The paper originates the concept of the ‘performative social movement’ to denote the contentious claims that continue to emerge from urban movements that otherwise appear quiescent