Regulation of glycogen metabolism by the CRE-1, RCO-1 and RCM-1 proteins in Neurospora crassa. The role of CRE-1 as the central transcriptional regulator

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Nuclear proteins interacting with an AP-1/CRE-like promoter sequence in the human TNF$\alpha$ gene

Monocyte developmental heterogeneity is reflected at the cellular level by differential activation competence, at the molecular level by differential regulation of gene expression. LPS activates monocytes to produce tumor necrosis factor-$\alpha$ (TNF). Events occurring at the molecular level necessary for TNF regulation have not been elucidated, but depend both on activation signals and the maturation state of the cell: Peripheral blood monocytes produce TNF upon LPS stimulation, but only within the first 72 hours of culture. Expression of c-fos is associated with monocytic differentiation and activation; the fos-associated protein, c-jun, is also expressed during monocyte activation. Increased cAMP levels are associated with down regulation of macrophage function, including LPS-induced TNF transcription. Due to these associations, we studied a region of the TNF promoter which resembles the binding sites for both AP-1(fos/jun) and CRE-binding protein (or ATF) in order to identify potential molecular markers defining activation competent populations of monocytic cells.^ Nuclear protein binding studies using extracts from THP-1 monocytic cells stimulated with LPS, which stimulates, or dexamethasone (Dex) or pentoxyfilline (PTX), which inhibit TNF production, respectively, suggest that a low mobility doublet complex may be involved in regulation through this promoter region. PTX or Dex increase binding of these complexes equivalently over untreated cells; approximately two hours after LPS induction, the upper complex is undetectable. The upper complex is composed of ATF2 (CRE-BP1); the lower is a heterodimer of jun/ATF2. LPS induces c-jun and thus may enhance formation of jun-ATF2 complexes. The simultaneous presence of both complexes may reduce the amount of TNF transcription through competitive binding, while a loss of the upper (ATF2) and/or gain of the lower (jun-ATF2) allow increased transcription. AP-1 elements generally transduce signals involving PKC; the CRE mediates a cAMP response, involving PKA. Thus, this element has the potential of receiving signals through divergent signalling pathways. Our findings also suggest that cAMP-induced inhibition of macrophage functions may occur via down regulation of activation-associated genes through competitive binding of particular cAMP-responsive nuclear protein complexes. ^

Crédito rural : informe presentado al Grupo V del 1.er Congreso Ganadero-Agrícola celebrado bajo los auspicios de la Asociación Rural del Uruguay /

"Conclusiones aprobadas por el Congreso en la sesión del 8 de abril de 1895."

Unstructured strategic decision-making processes : CRE decision-making in the Italian consulting industry

This thesis aims at developing a better understanding of unstructured strategic decision making processes and the conditions for achieving successful decision outcomes. Specifically it focuses on the processes used to make CRE (Corporate Real Estate) decisions. The starting point for this thesis is that our knowledge of such processes is incomplete. A comprehensive study of the most recent CRE literature together with Behavioural Organization Theory has provided a research framework for the exploration of CRE recommended =best practice‘, and of how organizational variables impact on and shape these practices. To reveal the fundamental differences between CRE decision-making in practice and the prescriptive =best practice‘ advocated in the CRE literature, a study of seven Italian management consulting firms was undertaken addressing the aspects of content and process of decisions. This thesis makes its primary contribution by identifying the importance and difficulty of finding the right balance between problem complexity, process richness and cohesion to ensure a decision-making process that is sufficiently rich and yet quick enough to deliver a prompt outcome. While doing so, this research also provides more empirical evidence to some of the most established theories of decision-making while reinterpreting their mono-dimensional arguments in a multi-dimensional model of successful decision-making.

The concealed difficulties of aligning CRE decisions to corporate goals

Realisation of the importance of real estate asset strategic decision making has inspired a burgeoning corporate real estate management (CREM) literature. Much of this criticises the poor alignment between strategic business direction and the ‘enabling’ physical environment. This is based on the understanding that corporate real estate assets represent the physical resource base that supports business, and can either complement or impede that business. In the hope of resolving this problem, CRE authors advocate a deeper integration of strategic and corporate real estate decisions. However this recommendation appears to be based on a relatively simplistic theoretical approach to organization where decision-making tends to be viewed as a rationally managed event rather than a complex process. Defining decision making as an isolated event has led to an uncritical acceptance of two basic assumptions: ubiquitous, conflict-free rationality and profit maximisation. These assumptions have encouraged prescriptive solutions that clearly lack the sophistication necessary to come to grips with the complexity of the built and organizational environment. Alternatively, approaching CREM decision making from a more sophisticated perspective, such as that of the “Carnegie School”, leads to conceptualise it as a ‘process’, creating room for bounded rationality, multiple goals, intra-organizational conflict, environmental matching, uncertainty avoidance and problem searching. It is reasonable to expect that such an approach will result in a better understanding of the organizational context, which will facilitate the creation of organizational objectives, assist with the formation of strategies, and ultimately will aid decision.

CRE workshop part I : comprehending the context

CRE (Corporate Real Estate) decisions should not simply deal with the management of individual facilities, but should especially be concerned with the relationships that a facility has with the corporate business strategy and with the larger real estate markets. Both the practice and the research of CRE management have historically tended to emphasize real estate issues and ignore the corporation’s business issues, causing real estate strategies to be disconnected from the goal and priorities of the corporation’s senior management. With regard to office cycles, a large number of econometric models have been proposed during the last 20 years. However, evidence from historical data and previous research in the field of real estate forecasting seem to agree only on one thing: the existence of interconnected property cycles that are concentrated on vacancy rates (demand). Vacancy also represents the linkage between the inadequacy of existing CRE strategies and the inability of existing econometric models to correctly forecast office rent cycles. Business cycles, across different industry sectors, have decreased from 5-7 years to 1-3 years today, yet corporations are still entering into leases of 5-10 years, causing hidden vacancy levels to rise. Possibly, once CRE strategies are totally in tune with the overall business, hidden vacancy will fade away providing forecasters with better quality data. The aim of this paper is not to investigate whether and when the supply-side will eventually evolve to provide flexible occupancy arrangements to accommodate corporate agility requirements, but rather to propose a general framework for corporations to improve the decision making process of their CRE executives, while emphasizing the importance of understanding the context as a precondition to effective real estate involvements.

A baseline study of Australia's community recycling enterprises(CRE)

This report presents the findings on a baseline study of Australia's community recycling enterprises(CREs). The study sought to document the activities and impacts of these enterprises and to understand the conditions under which they succeed. The purposes of the research were to generate evidence that can contribute to the development of practice and policy support for CREs, and to provide information that is useful to community groups wishing to establish new CREs. The study included a review of the existing literature in relation to CREs, an online survey of Australian CREs, and in-depth case studies of three CREs from various regions within Australia

Competing Actions of Type 1 Angiotensin II Receptors Expressed on T Lymphocytes and Kidney Epithelium during Cisplatin-Induced AKI.

Inappropriate activation of the renin-angiotensin system (RAS) contributes to many CKDs. However, the role of the RAS in modulating AKI requires elucidation, particularly because stimulating type 1 angiotensin II (AT1) receptors in the kidney or circulating inflammatory cells can have opposing effects on the generation of inflammatory mediators that underpin the pathogenesis of AKI. For example, TNF-α is a fundamental driver of cisplatin nephrotoxicity, and generation of TNF-α is suppressed or enhanced by AT1 receptor signaling in T lymphocytes or the distal nephron, respectively. In this study, cell tracking experiments with CD4-Cre mT/mG reporter mice revealed robust infiltration of T lymphocytes into the kidney after cisplatin injection. Notably, knockout of AT1 receptors on T lymphocytes exacerbated the severity of cisplatin-induced AKI and enhanced the cisplatin-induced increase in TNF-α levels locally within the kidney and in the systemic circulation. In contrast, knockout of AT1 receptors on kidney epithelial cells ameliorated the severity of AKI and suppressed local and systemic TNF-α production induced by cisplatin. Finally, disrupting TNF-α production specifically within the renal tubular epithelium attenuated the AKI and the increase in circulating TNF-α levels induced by cisplatin. These results illustrate discrepant tissue-specific effects of RAS stimulation on cisplatin nephrotoxicity and raise the concern that inflammatory mediators produced by renal parenchymal cells may influence the function of remote organs by altering systemic cytokine levels. Our findings suggest selective inhibition of AT1 receptors within the nephron as a promising intervention for protecting patients from cisplatin-induced nephrotoxicity.

Heme oxygenase-1 derived carbon monoxide permits maturation of myeloid cells

Critical functions of the immune system are maintained by the ability of myeloid progenitors to differentiate and mature into macrophages. We hypothesized that the cytoprotective gas molecule carbon monoxide (CO), generated endogenously by heme oxygenases (HO), promotes differentiation of progenitors into functional macrophages. Deletion of HO-1, specifically in the myeloid lineage (Lyz-Cre:Hmox1(flfl)), attenuated the ability of myeloid progenitors to differentiate toward macrophages and decreased the expression of macrophage markers, CD14 and macrophage colony-stimulating factor receptor (MCSFR). We showed that HO-1 and CO induced CD14 expression and efficiently increased expansion and differentiation of myeloid cells into macrophages. Further, CO sensitized myeloid cells to treatment with MCSF at low doses by increasing MCSFR expression, mediated partially through a PI3K-Akt-dependent mechanism. Exposure of mice to CO in a model of marginal bone marrow transplantation significantly improved donor myeloid cell engraftment efficiency, expansion and differentiation, which corresponded to increased serum levels of GM-CSF, IL-1α and MCP-1. Collectively, we conclude that HO-1 and CO in part are critical for myeloid cell differentiation. CO may prove to be a novel therapeutic agent to improve functional recovery of bone marrow cells in patients undergoing irradiation, chemotherapy and/or bone marrow transplantation.

ENaC-mediated alveolar fluid clearance and lung fluid balance depend on the channel-activating protease 1.

Sodium transport via epithelial sodium channels (ENaC) expressed in alveolar epithelial cells (AEC) provides the driving force for removal of fluid from the alveolar space. The membrane-bound channel-activating protease 1 (CAP1/Prss8) activates ENaC in vitro in various expression systems. To study the role of CAP1/Prss8 in alveolar sodium transport and lung fluid balance in vivo, we generated mice lacking CAP1/Prss8 in the alveolar epithelium using conditional Cre-loxP-mediated recombination. Deficiency of CAP1/Prss8 in AEC induced in vitro a 40% decrease in ENaC-mediated sodium currents. Sodium-driven alveolar fluid clearance (AFC) was reduced in CAP1/Prss8-deficient mice, due to a 48% decrease in amiloride-sensitive clearance, and was less sensitive to beta(2)-agonist treatment. Intra-alveolar treatment with neutrophil elastase, a soluble serine protease activating ENaC at the cell surface, fully restored basal AFC and the stimulation by beta(2)-agonists. Finally, acute volume-overload increased alveolar lining fluid volume in CAP1/Prss8-deficient mice. This study reveals that CAP1 plays a crucial role in the regulation of ENaC-mediated alveolar sodium and water transport and in mouse lung fluid balance.