Novel characteristics of the biological properties of the yeast Saccharomyces cerevisiae eukaryotic initiation factor 2A

Eukaryotic initiation factor 2A (eIF2A) has been shown to direct binding of the initiator methionyl-tRNA (Met-tRNA(i)) to 40 S ribosomal subunits in a codon-dependent manner, in contrast to eIF2, which requires GTP but not the AUG codon to bind initiator tRNA to 40 S subunits. We show here that yeast eIF2A genetically interacts with initiation factor eIF4E, suggesting that both proteins function in the same pathway. The double eIF2A/eIF4E-ts mutant strain displays a severe slow growth phenotype, which correlated with the accumulation of 85% of the double mutant cells arrested at the G(2)/M border. These cells also exhibited a disorganized actin cytoskeleton and elevated actin levels, suggesting that eIF2A might be involved in controlling the expression of genes involved in morphogenic processes. Further insights into eIF2A function were gained from the studies of eIF2A distribution in ribosomal fractions obtained from either an eIF5BDelta (fun12Delta) strain or a eIF3b-ts (prt1-1) strain. It was found that the binding of eIF2A to 40 and 80 S ribosomes was not impaired in either strain. We also found that eIF2A functions as a suppressor of Ure2p internal ribosome entry site-mediated translation in yeast cells. The regulation of expression from the URE2 internal ribosome entry site appears to be through the levels of eIF2A protein, which has been found to be inherently unstable with a half-life of approximately 17 min. It was hypothesized that this instability allows for translational control through the level of eIF2A protein in yeast cells.

Revolution in sales:The impact of social media and related technology on the selling environment

Over the years several articles have tracked the impact of technology on various aspects of the sales domain. However, the advent of social media and technologies related to social media has gone largely unnoticed in the literature. This article first provides brief attention to changing aspects of technology within the sales environment, leading to the identification of social media as a dominant new selling tool. A qualitative approach (focus groups) is employed to explore the breadth of current technology usage by sales managers and salespeople. Analysis of the data, collected in the United States and the United Kingdom, reveals six major themes: connectivity, relationships, selling tools, generational, global, and sales/marketing interface. Results provide evidence of a revolution in the buyer-seller relationship that includes some unanticipated consequences both for sales organization performance and needed future research contributions.

Linking performance outcomes to salesperson organizational citizenship behavior in an industrial sales setting

More than ever before, firms in the industrial marketplace are focusing on the contribution of the salesperson and selling role to organizational success. Considerable recent research shows that not only in-role but also extra-role behaviors-organizational citizenship behaviors (OCBs)-are important in modeling salesperson performance. Yet, to date little effort has focused on examining the impact of OCB on relevant performance outcomes. Employing a sample of 207 industrial field salespeople from two companies and industries across the United States, this study reveals differences in impact of OCB on four diverse performance outcome types. The findings are discussed in terms of managerial applicability to industrial sales organizations, and a resulting set of next research steps is presented.

Tracking and updating academic research in selling and sales management:a decade later

This study examines the state of academic research in selling and sales management (S&SM) from the years 2003-7, ten years after the data collected by Moncrief, Marshall, and Watkins (2000). Sales articles are reviewed that appeared in 19 marketing journals and evidence is provided on the state of the S&SM discipline by comparing the number of authors, authorships, and publications versus a comparable five-year period a decade ago. Of interest are the universities that produce and employ faculty in S&SM and to identify those schools and geographic regions that are publishing the majority of articles. Publication distribution trends across journals are also examined. A dramatic increase in non-U.S. authors and authorships is noted versus the prior study. Overall, the findings indicate that, perhaps contrary to some popular misconceptions, the state of S&SM research is healthy, vibrant, and evolving.

Alogliptin after acute coronary syndrome in patients with type 2 diabetes

Background - To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome. Methods - We randomly assigned patients with type 2 diabetes and either an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days to receive alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy. The study design was a double-blind, noninferiority trial with a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results - A total of 5380 patients underwent randomization and were followed for up to 40 months (median, 18 months). A primary end-point event occurred in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) (hazard ratio, 0.96; upper boundary of the one-sided repeated confidence interval, 1.16; P<0.001 for noninferiority). Glycated hemoglobin levels were significantly lower with alogliptin than with placebo (mean difference, -0.36 percentage points; P<0.001). Incidences of hypoglycemia, cancer, pancreatitis, and initiation of dialysis were similar with alogliptin and placebo. Conclusions - Among patients with type 2 diabetes who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin as compared with placebo. (Funded by Takeda Development Center Americas; EXAMINE ClinicalTrials.gov number, NCT00968708.)

Creating research collaboration among the global community of sales scholars:key takeaways from the 2013 AMA faculty consortium

Within the contemporary business milieu, the discipline of selling and sales management has taken on a more prominent role in recent years. Myriad factors have contributed to the rise of interest in sales including globalization, technology, more sophisticated analytical approaches and new opportunities for co-creation of value between organizations and their customers. Over the past three decades, seven faculty consortia in sales have served as milestones to document the progress 2of the field, particularly the evolution of academic research. This article provides key takeaways from the most recent American Marketing Association (AMA) Faculty Consortium in Selling and Sales Management, which had the overarching goal of fostering new opportunities for building intercontinental research teams to effectively address the substantive issues for the future of the field. © 2014 Pi Sigma Epsilon National Educational Foundation.

Social media and related technology:drivers of change in managing the contemporary sales force

The selling environment has undergone tremendous transformation over the past 2 decades. Perhaps the greatest change has centered on changes and advancements in technology. The latest dramatic change has been the rapidly increasing use of social media and other related technologies in the business-to-business realm. The sales world began the use of technology through the use of Web 1.0, which was primarily webpage oriented; now we see the world of social media as the paradigm of how firms should implement technology. Although there has been some recent emphasis on how marketing might implement social media into their strategies and how the individual salesperson might implement social media into his or her daily selling routine, no substantive discussion on how social media is affecting the role of the sales manager has appeared in the literature. This article systematically examines how social media is impacting the sales management function and, in fact, may be dramatically revolutionizing the position. To help the marketing and sales organization better understand the changing sales world, we present eight lessons that every sales manager needs to embrace.

Drug repurposing screen identifies Foxo1-dependent angiopoietin-2 regulation in sepsis

Objective: The recent withdrawal of a targeted sepsis therapy has diminished pharmaceutical enthusiasm for developing novel drugs for the treatment of sepsis. Angiopoietin-2 is an endothelial-derived protein that potentiates vascular inflammation and leakage and may be involved in sepsis pathogenesis. We screened approved compounds for putative inhibitors of angiopoietin-2 production and investigated underlying molecular mechanisms. Design: Laboratory and animal research plus prospective placebo-controlled randomized controlled trial (NCT00529139) and retrospective analysis (NCT00676897). Setting: Research laboratories of Hannover Medical School and Harvard Medical School. Patients: Septic patients/C57Bl/6 mice and human endothelial cells. Interventions: Food and Drug Administration-approved library screening. Measurements and Main Results: In a cell-based screen of more than 650 Food and Drug Administration-approved compounds, we identified multiple members of the 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor drug class (referred to as statins) that suppressed angiopoietin-2. Simvastatin inhibited 3-hydroxy-3-methyl-glutaryl-CoA reductase, which in turn activated PI3K-kinase. Downstream of this signaling, PI3K-dependent phosphorylation of the transcription factor Foxo1 at key amino acids inhibited its ability to shuttle to the nucleus and bind cis-elements in the angiopoietin-2 promoter. In septic mice, transient inhibition of angiopoietin-2 expression by liposomal siRNA in vivo improved absolute survival by 50%. Simvastatin had a similar effect, but the combination of angiopoietin-2 siRNA and simvastatin showed no additive benefit. To verify the link between statins and angiopoietin-2 in humans, we performed a pilot matched case-control study and a small randomized placebo-controlled trial demonstrating beneficial effects on angiopoietin-2. Conclusions: 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors may operate through a novel Foxo1-angiopoietin-2 mechanism to suppress de novo production of angiopoietin-2 and thereby ameliorate manifestations of sepsis. Given angiopoietin-2's dual role as a biomarker and candidate disease mediator, early serum angiopoietin-2 measurement may serve as a stratification tool for future trials of drugs targeting vascular leakage.

The C-terminus of Raf-1 acts as a 14-3-3-dependent activation switch

The Raf-1 protein kinase is a major activator of the ERK MAPK pathway, which links signaling by a variety of cell surface receptors to the regulation of cell proliferation, survival, differentiation and migration. Signaling by Raf-1 is regulated by a complex and poorly understood interplay between phosphorylation events and protein-protein interactions. One important mode of Raf-1 regulation involves the phosphorylation-dependent binding of 14-3-3 proteins. Here, we have examined the mechanism whereby the C-terminal 14-3-3 binding site of Raf-1, S621, controls the activation of MEK-ERK signaling. We show that phosphorylation of S621 turns over rapidly and is enriched in the activated pool of endogenous Raf-1. The phosphorylation on this site can be mediated by Raf-1 itself but also by other kinase(s). Mutations that prevent the binding of 14-3-3 proteins to S621 render Raf-1 inactive by specifically disrupting its capacity to bind to ATP, and not by gross conformational alteration as indicated by intact MEK binding. Phosphorylation of S621 correlates with the inhibition of Raf-1 catalytic activity in vitro, but 14-3-3 proteins can completely reverse this inhibition. Our findings suggest that 14-3-3 proteins function as critical cofactors in Raf-1 activation, which induce and maintain the protein in a state that is competent for both ATP binding and MEK phosphorylation.