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Abstract A promotional role for androgen receptor (AR) signaling in hepatocellular carcinogenesis is emerging. In pre-clinical models, including diethylnitrosamine- (DEN-) induced hepatocellular carcinoma (HCC), anti-androgen therapies delay hepatocarcinogenesis. However, pharmacologic anti-androgen therapy in advanced HCC patients fails, suggesting that AR plays a role in HCC onset. This study aims to characterize AR expression and function throughout DEN-induced liver inflammation and carcinogenesis and evaluate the efficacy of prophylactic AR antagonism to prevent hepatocarcinogenesis. We demonstrate that pharmacologic AR antagonism with enzalutamide inhibits hepatocellular carcinogenesis. With enzalutamide treatment, we observe decreased CYP2E1 expression, reducing DEN-induced hepatocyte death and DNA ethyl-adducts. AR protein expression analyses show that DEN causes an initial upregulation of AR in portal fibroblasts and leukocytes, but not hepatocytes, suggesting that hepatocyte-autonomous AR signaling is not essential for DEN-induced carcinogenesis. Ablating androgen signaling by surgical castration reduced pre-carcinogen Kupffer cell populations but did not alter DEN-mediated immune cell recruitment nor AR expression. In this study, we identified that anti-androgen interventions modulate mutagenic DNA adducts, tumour initiation, and immune cell composition. Additionally, we find that AR expression in hepatocytes is not present during nor required for early DEN-mediated carcinogenesis.

Liver transplant programs in Canada require a period of 6 months of abstinence from alcohol before considering a patient with liver disease secondary to alcohol for transplantation. Although some studies have demonstrated good outcomes following a transplant in carefully selected patients before the 6‐month abstinence period has been met, there have been arguments against this, including the claim that the public has a general negative perception of those with alcohol dependence. We performed a multicenter cross‐sectional survey to determine the perception of people in British Columbia, Canada, toward liver transplantation in patients with liver disease due to alcohol who have not demonstrated the capacity to remain abstinent from alcohol for 6 months. A total of 304 patient questionnaires were completed, and 83.1% agreed with a period of abstinence of 6 months. In those patients who were unlikely to survive 6 months without a transplant, 34.1% of respondents agreed with, 44.1% did not agree with, and 21.4% were neutral about, early transplantation; 42.8% would have less trust in the process of transplantation if a period of abstinence was not maintained, but relaxing the requirement for an abstinence period would not have an impact on the majority's decision to donate organs. Only 30.5% would support abandoning the abstinence criteria. Conclusion: Among patients followed at general gastroenterology, medicine, or transplant clinics, there is a willingness to relax the criteria in selected patients unlikely to survive without a transplant, although a general consensus remains in support of the existing 6‐month alcohol abstinence rule. A larger scale survey of all provinces in Canada would be required to assess support for such a change in policy.

Since the 1980s, within the broader context of studies on smart cities, there has been a growing body of academic research on networked cities and “computable cities” by authors including Manuel Castells (Castells, 1989; Castells & Cardoso, 2005), William Mitchell (1995), Michael Batty (2005, 2013), and Rob Kitchin (2011). Over the last decade, governments in Asia have displayed an appetite and commitment to construct large scale city developments from scratch—one of the most infamous being the smart entrepreneurial city of Songdo, South Korea. Using Songdo as a case study, this paper will examine, from an urban systems perspective, some of the challenges of using a green-city model led by networked technology. More specifically, this study intends to add to the growing body of smart city literature by using an external global event—the global financial crisis in 2008—to reveal what is missing from the smart city narrative in Songdo. The paper will use the definition of an urban system and internal subsystems by Bertuglia et al. (1987) and Bertuglia, Clarke and Wilson (1994) to reveal the sensitivity and resilience of a predetermined smart city narrative. For instance, what happens if the vision moves from the originally intended international-orientated population towards remarketing the city to attract a domestic middle-class population. The lens of the financial crisis in 2008 revealed that the inherent inflexibility of a closed-system approach in Songdo was not sufficiently resilient to external shocks. The shift towards a domestic middle-class population revealed the inequality in accessing the city services in a system designed with formalized and rigid inputs and outputs. By focusing predominantly on technology, the social dimensions of the city were not part of Songdo’s smart city vocabulary. Therefore, in adopting a technologically deterministic approach (Mullins & Shwayri, 2016) to achieving efficiency and combating environmental issues, Songdo’s green city model was found insufficient in its ability to cope with the complexity and dissonance that occurs in relation to “glocal” challenges facing cities today.

Landscape genetics investigations examine how the availability and configuration of habitat influence genetic structure of plants and animals. We used landscape genetics to evaluate the role that forest connectivity plays in determining genetic structure of the federally-threatened Northern Spotted Owl (Strix occidentalis caurina) using genotypes of 339 Northern Spotted Owls obtained for 10 microsatellite loci. Spatial clustering analyses identified a distinct genetic cluster at the southern extent of the region examined. This cluster could not be linked to landscape connectivity patterns and suggested that post-Pleistocene processes were involved with its development rather than contemporary landscape configuration. We also compared matrices of pairwise inter-individual genetic distances with resistance distances derived from a circuit-theory based framework. Resistance distances were obtained for an idealized raster map that reflected continuous unimpeded dispersal habitat across the landscape along with five empirically-derived raster maps reflecting the 1870's, 1940's, 1986, 1994, and 2012. Resistance distances from the idealized map served as surrogates for linear geographic distances. Relative to idealized conditions, resistance distances were ~250% higher in the 1940's and ~200% higher from 1986 onward. Resistance distances from the 1870's were ~40% higher than idealized conditions. Inter-individual genetic distances were most highly correlated with resistance distances from the idealized map rather than any of the empirical maps. Two hypotheses explain our results. First, our results may reflect temporal lags between the onset of large-scale habitat alterations and their novel effects on genetic structure in long-lived species such as Northern Spotted Owls. Second, because Northern Spotted Owls disperse over long distances, our results may indicate that forest habitat has never been sufficiently fragmented to the point where connectivity was disrupted. The second hypothesis could indicate that forest management practices mandated by the Northwest Forest Plan succeeded with one of its primary goals. However, our results do not represent a complete portrayal of the status of Northern Spotted Owls given detection of significant population declines and bottlenecks in other studies. Future investigations based on computer simulations may help distinguish between hypotheses.

Every year in Virginia, many teachers instruct students that capitalism is a system in which government stays out of the way. The author of this review, being a former high school teacher in Virginia, taught this very concept. Nevertheless, Sven Beckert tells a different story in his book Empire of Cotton: A Global History. Beckert argues that not only was the state involved in the development of capitalism, but also “the needs of nation-states were not conflicting”, meaning that in many instances capitalism intertwined with goals of the state. He uses a commodity, cotton, as a centerpiece to exemplify his point. From the onset, the reader may think they are embarking on a history of cotton, but that is not Beckert’s goal. His goal is to tell the story of capitalism, by focusing on a topicthat everyone knows something about: cotton.

This is a review of Empire of Cotton: A Global History by Sven Beckert. This review discusses how Beckert argues that not only was the state involved in the development of capitalism, but in many instances capitalism intertwined with goals of the state. Beckert uses a commodity, cotton, as a centerpiece to exemplify his point. From the onset, the reader may think they are embarking on a history of cotton, but that is not Beckert’s goal. His goal is to tell the story of capitalism, by focusing on a topic that everyone knows something about: cotton.

Mathematical models of cardiac function at the cellular level include three major components, such as electrical activity, Ca(2+) dynamics, and cellular shortening. We developed a model for mouse ventricular myocyte contraction which is based on our previously published comprehensive models of action potential and Ca(2+) handling mechanisms. The model was verified with extensive experimental data on mouse myocyte contraction at room temperature. In the model, we implemented variable sarcomere length and indirect modulation of the tropomyosin transition rates by Ca(2+) and troponin. The resulting model described well steady-state force-calcium relationships, dependence of the contraction force on the sarcomere length, time course of the contraction force and myocyte shortening, frequency dependence of the contraction force and cellular contraction, and experimentally measured derivatives of the myocyte length variation. We emphasized the importance of the inclusion of variable sarcomere length into a model for ventricular myocyte contraction. Differences in contraction force and cell shortening for epicardial and endocardial ventricular myocytes were investigated. Model applicability for the experimental studies and model limitations were discussed.

Activating mutations in Ras (N- and K-) are the most common point mutations found in patients with multiple myeloma (MM) and are associated with poor clinical outcome. We sought to directly examine the role of Ras activation in MM pathogenesis and used two different tissue-specific Cre recombinase mouse lines (Cγ1-Cre and AID-Cre), to generate mice with mutant Kras (Kras(G12D) ) activated specifically in germinal center B-cells. We also generated mice with activation of the Kras(G12D) allele in a tumor-prone Arf-null genetic background. Surprisingly, we observed no significant disruption in B-cell homeostasis in any of these models by serum immunoglobulin ELISA, SPEP, flow cytometry and histological examination. We observed development of non-overlapping tumor types due to off-target Cre expression, but despite successful recombination in germinal center and later B-cell populations, we observed no B-cell phenotype. Together, these data demonstrate that Ras activation is not sufficient to transform primary germinal center B-cells, even in an Arf-null context, and that the temporal order of mutation acquisition may be critical for myeloma development. Specific pathways, yet to be identified, are required before Kras can contribute to the development of MM.