Developments in Constitutional Law: The 1993-94 Term

This paper seeks to draw out four different, and often conflicting, themes that inform the Supreme Court of Canada\u27s constitutional decision making. Each theme expresses a conception of the Canadian state, and taken together they represent, arguably, the current range of dominant views regarding the appropriate role of the state in Canada: classical liberalism, federalism, social democracy and neo-liberalism. Explicit and implicit reliance upon these conceptions of the state can be understood as reflecting the Court\u27s concern to stay in step with its perception of contemporary social consensus on the large political issues lurking behind every constitutional question it addresses. The fact that four different and potentially conflicting themes are developed in answer to this question suggests that the members of the Court have not been able to identify what the social consensus is; or, far more likely, a social consensus does not exist on the desirable scope and content of state power, only competing ideals

Myeloid-Specific Rictor Deletion Induces M1 Macrophage Polarization and Potentiates In Vivo Pro-Inflammatory Response to Lipopolysaccharide

The phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) axis plays a central role in attenuating inflammation upon macrophage stimulation with toll-like receptor (TLR) ligands. The mechanistic target of rapamycin complex 2 (mTORC2) relays signal from PI3K to Akt but its role in modulating inflammation in vivo has never been investigated. To evaluate the role of mTORC2 in the regulation of inflammation in vivo, we have generated a mouse model lacking Rictor, an essential mTORC2 component, in myeloid cells. Primary macrophages isolated from myeloid-specific Rictor null mice exhibited an exaggerated response to TLRs ligands, and expressed high levels of M1 genes and lower levels of M2 markers. To determine whether the loss of Rictor similarly affected inflammation in vivo, mice were either fed a high fat diet, a situation promoting chronic but low-grade inflammation, or were injected with lipopolysaccharide (LPS), which mimics an acute, severe septic inflammatory condition. Although high fat feeding contributed to promote obesity, inflammation, macrophage infiltration in adipose tissue and systemic insulin resistance, we did not observe a significant impact of Rictor loss on these parameters. However, mice lacking Rictor exhibited a higher sensitivity to sceptic shock when injected with LPS. Altogether, these results indicate that mTORC2 is a key negative regulator of macrophages TLR signalling and that its role in modulating inflammation is particularly important in the context of severe inflammatory challenges. These observations suggest that approaches aimed at modulating mTORC2 activity may represent a possible therapeutic approach for diseases linked to excessive inflammation.Howard Hughes Medical Institute (Investigator)National Institutes of Health (U.S.) (NIH grant CA103866)National Institutes of Health (U.S.) (NIH grant CA129105)National Institutes of Health (U.S.) (NIH grant AI47389)Canadian Institutes of Health ResearchNatural Sciences and Engineering Research Council of CanadaFonds de la recherche en santé du Québe

Conceptualizing the Business Corporation: Insights from History

© 2020 Cambridge University Press. This paper has been accepted for publication and will appear in a revised form, subsequent to peer-review and/or editorial input by Cambridge University Press. This manuscript is made available under the terms of the Creative Commons Non-Commercial No-Derivatives License (CC-BY-NC-ND). For further information please see: https://creativecommons.org/licenses/by-nc-nd/4.0/The purpose of this symposium is to shed light on the genealogy of the idea of a business corporation, an economic institution which has long been regarded with a mixture of awe and apprehension. Each of the four original contributions addresses the history of some of its key features. In the process, each contributor reveals some of the insights that history has to teach us regarding the central concepts that inform contemporary debates about the nature of the corporation, the contours of the corporation’s purpose, the sources of corporate power, the functions of corporate law, the duties of directors, the status of shareholders, and the legitimacy of corporate rights.Peer reviewe

Personal investment in Japan and the U.S.A.: A study of worker motivation,

The Inventory of Personal Investment (IPI) was administered to 522 Japanese and 746 American workers to compare their work motivation and self-concepts. Eleven subscales were formed based on the IPI model and were found through factor analysis to be appropriate for the samples in both countries. Discriminant analyses of scale scores by subjects' nationality, gender, occupational strata, and age are reported. Findings included: (1) Japanese and American workers sampled emphasized different aspects of meaning as they perceive work and self, (2) Japanese and American women sampled exhibited similar profiles to one another, as did the two male subsamples, and (3) motivational profiles for various age groupings differed between the two samples. The results are related to previous research on Japanese and American workers.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30299/1/0000701.pd

mTORC1 is essential for early steps during Schwann cell differentiation of amniotic fluid stem cells and regulates lipogenic gene expression.

Schwann cell development is hallmarked by the induction of a lipogenic profile. Here we used amniotic fluid stem (AFS) cells and focused on the mechanisms occurring during early steps of differentiation along the Schwann cell lineage. Therefore, we initiated Schwann cell differentiation in AFS cells and monitored as well as modulated the activity of the mechanistic target of rapamycin (mTOR) pathway, the major regulator of anabolic processes. Our results show that mTOR complex 1 (mTORC1) activity is essential for glial marker expression and expression of Sterol Regulatory Element-Binding Protein (SREBP) target genes. Moreover, SREBP target gene activation by statin treatment promoted lipogenic gene expression, induced mTORC1 activation and stimulated Schwann cell differentiation. To investigate mTORC1 downstream signaling we expressed a mutant S6K1, which subsequently induced the expression of the Schwann cell marker S100b, but did not affect lipogenic gene expression. This suggests that S6K1 dependent and independent pathways downstream of mTORC1 drive AFS cells to early Schwann cell differentiation and lipogenic gene expression. In conclusion our results propose that future strategies for peripheral nervous system regeneration will depend on ways to efficiently induce the mTORC1 pathway

Atomic-Level Characterization of the Activation Mechanism of SERCA by Calcium

We have performed molecular dynamics (MD) simulations to elucidate, in atomic detail, the mechanism by which the sarcoplasmic reticulum Ca2+-ATPase (SERCA) is activated by Ca2+. Crystal structures suggest that activation of SERCA occurs when the cytoplasmic head-piece, in an open (E1) conformation stabilized by Ca2+, undergoes a large-scale open-to-closed (E1 to E2) transition that is induced by ATP binding. However, spectroscopic measurements in solution suggest that these structural states (E1 and E2) are not tightly coupled to biochemical states (defined by bound ligands); the closed E2 state predominates even in the absence of ATP, in both the presence and absence of Ca2+. How is this loose coupling consistent with the high efficiency of energy transduction in the Ca2+-ATPase? To provide insight into this question, we performed long (500 ns) all-atom MD simulations starting from the open crystal structure, including a lipid bilayer and water. In both the presence and absence of Ca2+, we observed a large-scale open-to-closed conformational transition within 400 ns, supporting the weak coupling between structural and biochemical states. However, upon closer inspection, it is clear that Ca2+ is necessary and sufficient for SERCA to reach the precise geometrical arrangement necessary for activation of ATP hydrolysis. Contrary to suggestions from crystal structures, but in agreement with solution spectroscopy, the presence of ATP is not required for this activating transition. Principal component analysis showed that Ca2+ reshapes the free energy landscape of SERCA to create a path between the open conformation and the activated closed conformation. Thus the malleability of the free energy landscape is essential for SERCA efficiency, ensuring that ATP hydrolysis is tightly coupled to Ca2+ transport. These results demonstrate the importance of real-time dynamics in the formation of catalytically competent conformations of SERCA, with broad implications for understanding enzymatic catalysis in atomic detail

The Conundrum of Order: The Concept of Governance from an Interdisciplinary Perspective

The term governance has made an impressive career in a number of disciplines concerned with regulation, order and law. This chapter draws on insights from legal studies, sociology, political science, anthropology, history and geography to paint a multifaceted picture of existing, competing and complementing approaches to the concept of governance. For reasons of space, the chapter can but point to the different variations on a theme, as governance occupies an ambivalent place in past and present discourses on political (or, legal or economic) order and society. It is argued that beyond pointing to crucial phases of methodological and theoretical transformation within different disciplines such as the often perceived transition ‘from government to governance’, governance is itself a deeply interdisciplinary concept