The UNC-45 protein is a member of the UNC-45/CRO1/She4p (UCS) family that is required for myosin accumulation and thick filament assembly during muscle development in several model organisms. UNC-45 interacts with the chaperone Hsp90 and appears to be responsible for folding the myosin motor domain. However, additional factors that interact with UNC-45 during this process are poorly characterized. To approach this problem, we are using the Drosophila melanogaster model system together with co-immunoprecipitation and mass spectrometry to identify novel UNC-45 interacting proteins. We have generated a transgenic fly that expresses an UNC-45:GFP fusion protein under the control of a Drosophila UNC-45 promoter fragment. Similar to wild-type UNC-45, the recombinant fusion protein exhibits in vitro chaperone activity for the non-native substrate citrate synthase in thermal aggregation assays. The transgene is expressed at roughly 45% of endogenous levels and is capable of rescuing UNC-45 knockout flies in vivo. These data indicate that the tethered GFP moiety does not significantly alter or inhibit UNC-45 activity. The UNC-45:GFP fusion protein can be efficiently immunoprecipitated using anti-GFP Nano-Traps® (ChromoTek) and we are exploring conditions for the efficient pull-down of UNC-45 interacting partners using this ex vivo system. These putative binding partners will then be identified using mass spectrometry and interrogated in vivo using standard genetic techniques available to the Drosophila system. Identifying novel UNC-45 clients could further our understanding of the role of this highly conserved chaperone, while identification of co-chaperone partners could provide us with novel mechanistic insights. This work has been funded through R01 AR055958 to SIB and F32 AR067654 to DAS.

Ideally, a product’s price should strike a balance between extracting value for a firm and sharing some of that value with customers. Charging less than what is warranted by a product’s value “leaves money on the table”, but far greater long-run harm to the brand is caused when managers charge more than what is justified by the product’s benefits. This study examines the effect of environmental- and firm-level factors on managers’ judgment when setting prices. Using data collected from brand managers of major consumer goods companies, we found that managers are more inclined to charge unjustified prices in environments with less intense competition and in business units with a strong technological orientation. Brand strength is also positively related to the propensity to overprice, but this relationship diminishes as the brand becomes stronger.

At the beginning of the last decade, pharmaceutical companies provided a stark demonstration of poor portfolio management. Longer-term projects with the potential to deliver new drug platforms or technologies were given up for projects that were cheap, easy, and quick to deliver revenue. An industry built on high-stakes R&D began to channel a majority of its spending to projects that applied existing products to new diseases, developed me products, and created marketing-driven product extensions. Short-term profits spiked as planned, but by mid-decade, the pipelines of the largest pharmaceutical firms were depleted. This set off a feeding frenzy, as large corporations raced to gobble up smaller firms with more innovative early-stage pipelines. By the end of the decade, most of the big companies had been acquired, faced significant downsizing, or were fighting for their lives. Those remaining were left to lament the dearth of new products and the lack of innovation within the industry. Much of the blame for the meltdown of pharma can be attributed to poor resource-allocation decisions. Pharma projects are extremely high risk (fewer than 10 percent make it to market), expensive (a single project can cost hundreds of millions of dollars), and have long time frames (typically 3-8 years) (Mestre-Ferrandiz, Sussex, and Towse 2012). The combination of these factors means that getting project decisions right is critical to success for pharma companies. Carrying underperforming projects too long can take a crippling bite out of the R&D budget, yet innovative projects need to be given a chance to blossom into the next blockbuster. Furthermore, companies need to balance risky bets with safer ones and also satisfy short-term sales targets without sacrificing future growth. In order to properly balance these trade-offs, pharma companies recognized that they needed to think about projects collectively rather than individually. While most had operational portfolio processes that focused on allocating resources during project execution, very few had strategic portfolio processes that took a holistic approach as to which projects should be undertaken. Those companies that weathered this storm developed strategic portfolio processes that helped address these often-competing priorities. The portfolio teams at those companies that leveraged portfolio management most successfully used a relatively simple process (although, of course, there were some individual variations). The first, and most important, step in this process was to work with the executive team to understand the company's strategic objectives. The second step was to evaluate each project on an apples-to-apples basis, collecting sufficient data to enable the projects to be rolled into potential portfolios that can be measured against the strategic objectives. The third step was to vet the project data to ensure consistency and relative accuracy. The fourth step was to create a set of alternative portfolios that achieve the strategic objectives in different ways or to different degrees. And the fifth and final step was to select the best alternative from the possible portfolios. Although there were variations among companies in the timing and even the sequencing of these steps, these elements form the backbone of an effective process. The journey that a company takes to establish such a strategic portfolio process tends to take a number of years: Governance structures may need to be altered, valuation practices may require a more intense effort from a wide range of functional areas, and processes for communicating project decisions may need to be formalized. This case study illustrates how one client slowly but steadily enhanced its portfolio process over a six-year period, reaching a point where the portfolio management process is now an indispensible component of strategic decision making. (1) 2007: Asking the Wrong Questions In September of 2007, the executives of HealthPharm, a major pharmaceutical company, gathered for the annual portfolio review. …

OVERVIEW: A case study shows a six-year timeline of how a life sciences company enhanced its R&D portfolio management process and, in doing so, improved its decision-making processes. The company aligned the portfolio with its longterm strategic objectives and shifted its focus from selecting the best projects to selecting the best set of projects that would meet the strategic objectives. Over the duration of the case study, the company made a number of significant decisions based on the new approach, and the improved portfolio process is credited by the CEO and board of directors with playing a strong role in driving these decisions.

BACKGROUND:Trauma patients consume many resources in the emergency department (ED), but what effect their care may have upon other patients seeking care is unclear.OBJECTIVE:We sought to determine whether the presentation of trauma patients to the ED diverts staff and resources away from non-trauma patients. We hypothesized that the admission of trauma patients to the ED would result in longer times to physician evaluation and completion of laboratory and imaging studies, as well as a longer length of stay in the ED.METHODS:This retrospective study reviewed and compared the charts of two groups of non-trauma ED patients. The group affected by trauma arrived up to 30 min after a trauma activation. The group unaffected by trauma arrived >3 h before or 3 h after a trauma activation. Times from arrival to initial MD evaluation, X-ray study, and computed tomography (CT) scan were documented. Median times from order to completion of laboratory results and imaging were compared, as well as total ED lengths of stay (LOS).RESULTS:Median time from arrival to MD evaluation for patients affected by a trauma activation was almost twice as long as for unaffected patients (42 vs. 23 min, respectively; p < 0.001). Times from arrival to X-ray study, CT scan order, and laboratory results were all significantly greater for patients affected by a trauma activation (p < 0.001). For patients who required admission to the hospital, the affected group had a median LOS that was increased by 16 min (224 vs. 208 min, respectively) when compared to unaffected patients (p = 0.04).CONCLUSION:In the setting studied, the arrival of a trauma patient delayed physician evaluation and diagnostic testing. It only modestly increased the ED LOS for patients needing hospital admission.

The quality of the next generation of business leaders will be determined by the ways in which business schools respond to a host of dramatic changes emerging in the environment of higher education. While specific initiatives will vary widely, one thing seems certain: business schools will need to be more nimble, more innovative, and more efficient than ever before. The Kelley School of Business, Indiana University has consistently been at the forefront of business education. Over the past century, the School has developed a set of capabilities that has enabled it to capitalize on the forces that have shaped the evolution of business education. In this article, we review several significant trends affecting the future of business education and share the success principles that we believe are most applicable to thriving in the new world that is on our doorstep.

The National Highway Traffic Safety Administration's statute at 49 U.S.C. 30118, Notification of Defects and Noncompliance, and 49 U.S.C. 30120, Remedies for Defects and Noncompliance, generally requires manufacturers of motor vehicles and items of replacement equipment to conduct a notification and remedy campaign (recall) when their products are determined to contain a safety- related defect or a noncompliance with a Federal motor vehicle safety standard (FMVSS). Those sections require a manufacturer of motor vehicles or motor vehicle equipment to notify distributors, dealers, and purchasers if any of the manufacturer's products are determined to either contain a safety-related defect or fail to comply with an applicable FMVSS. The manufacturer is under a concomitant obligation to remedy such defect or noncompliance. Pursuant to 49

The small-molecule inhibitor Exo2 {4-hydroxy-3-methoxy-(5,6,7,8-tetrahydrol[1]benzothieno[2,3-d]pyrimidin-4-yl)hydraz-one benzaldehyde} has been reported to disrupt the Golgi apparatus completely and to stimulate Golgi–ER (endoplasmic reticulum) fusion in mammalian cells, akin to the well-characterized fungal toxin BFA (brefeldin A). It has also been reported that Exo2 does not affect the integrity of the TGN (trans-Golgi network), or the direct retrograde trafficking of the glycolipid-binding cholera toxin from the TGN to the ER lumen. We have examined the effects of BFA and Exo2, and found that both compounds are indistinguishable in their inhibition of anterograde transport and that both reagents significantly disrupt the morphology of the TGN in HeLa and in BS-C-1 cells. However, Exo2, unlike BFA, does not induce tubulation and merging of the TGN and endosomal compartments. Furthermore, and in contrast with its effects on cholera toxin, Exo2 significantly perturbs the delivery of Shiga toxin to the ER. Together, these results suggest that the likely target(s) of Exo2 operate at the level of the TGN, the Golgi and a subset of early endosomes, and thus Exo2 provides a more selective tool than BFA for examining membrane trafficking in mammalian cells.

Following gyro failures in April 2001 and April 2003, HST Pointing Control System engineers designed reduced-gyro control laws to extend the spacecraft science mission. The Two-Gyro Science (TGS) and One-Gyro Science (OGS) control laws were designed and implemented using magnetometers, star trackers, and Fine Guidance Sensors in succession to control vehicle rate about the missing gyro axes. Both TGS and OGS have demonstrated on-orbit pointing stability of 7 milli-arcseconds or less, which depends upon the guide star magnitude used by the Fine Guidance Sensor. This paper describes the design, implementation, and on-orbit performance of the TGS and OGS control law fine-pointing modes using Fixed Head Star Trackers and Fine Guidance Sensors, after successfully achieving coarse-pointing control using magnetometers.

Retrograde transport allows proteins and lipids to leave the endocytic pathway to reach other intracellular compartments, such as trans-Golgi network (TGN)/Golgi membranes, the endoplasmic reticulum and, in some instances, the cytosol. Here, we have used RNA interference against the SNARE proteins syntaxin 5 and syntaxin 16, combined with recently developed quantitative trafficking assays, morphological approaches and cell intoxication analysis to show that these SNARE proteins are not only required for efficient retrograde transport of Shiga toxin, but also for that of an endogenous cargo protein – the mannose 6-phosphate receptor – and for the productive trafficking into cells of cholera toxin and ricin. We have found that the function of syntaxin 16 was specifically required for, and restricted to, the retrograde pathway. Strikingly, syntaxin 5 RNA interference protected cells particularly strongly against Shiga toxin. Since our trafficking analysis showed that apart from inhibiting retrograde endosome-to-TGN transport, the silencing of syntaxin 5 had no additional effect on Shiga toxin endocytosis or trafficking from TGN/Golgi membranes to the endoplasmic reticulum, we hypothesize that syntaxin 5 also has trafficking-independent functions. In summary, our data demonstrate that several cellular and exogenous cargo proteins use elements of the same SNARE machinery for efficient retrograde transport between early/recycling endosomes and TGN/Golgi membranes.

Previous research has shown that the monetary value of a promotion (promotion depth) affects choice during the promotion period. However, as promotion depth increases, consumers might lower their expectations of future price, which in turn may threaten future choice when prices return to normal levels. This research examines how promotion frame (percentage off versus cents off) moderates the effect of promotion depth on postpromotion price expectations and choice. The findings indicate that compared with cents-off promotions, high-depth percentage-off promotions lead to higher postpromotion price expectations. Likewise, postpromotion choice is higher when high-depth promotions are framed in percentage-off than cents-off terms. The authors examine the process underlying the effect of promotion frame on price expectations and find that frame affects (1) consumers' perceptions of the promoted price and (2) the weight they place on the promoted price.