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We develop a three-step methodology to restructure a product line by quantifying the restructuring's likely effects on revenues and costs: (i) Constructing migration lists to capture customer preferences and willingness to substitute; (ii) Explicitly capturing the (positive and negative) cost of complexity across different functional areas using statistical analysis of cost data; and (iii) Integrating these tools within a mathematical optimization program to produce a final product line, incorporating the possibility of differentiating products by lead-time (into different lanes). Our methodology is highly flexibleeach step can be tailored to a company's particular setting, data availability and strategic needs, so long as it produces the necessary output for the next step. We report on the successful application of our methodology to the Backhoe Loader product line at Caterpillar: In collaboration with Caterpillar we were able to significantly simplify this line, reducing the number of configurations from 37,920 to 135, in three lanes, while increasing sales by almost 7%. This article is protected by copyright. All rights reserved.

Nitric oxide (NO) plays an important role in innate host defense and inflammation. In response to infection, NO is generated by inducible nitric oxide synthase (iNOS), a gene product whose expression is highly modulated by different stimuli, including lipopolysaccharide (LPS) from gram-negative bacteria. We reported recently that LPS from Pseudomonas aeruginosa altered Na+transport in alveolar epithelial cells via a suramin-dependent process, indicating that LPS activated a purinergic response in these cells. To further study this question, in the present work, we tested whether iNOS mRNA and protein expression were modulated in response to LPS in alveolar epithelial cells. We found that LPS induced a 12-fold increase in iNOS mRNA expression via a transcription-dependent process in these cells. iNOS protein, NO, and nitrotyrosine were also significantly elevated in LPS-treated cells. Ca2+chelation and protein kinase C (PKCα-β1) inhibition suppressed iNOS mRNA induction by LPS, implicating Ca2+-dependent PKC signaling in this process. LPS evoked a significant increase of extracellular ATP. Because PKC activation is one of the signaling pathways known to mediate purinergic signaling, we evaluated the hypothesis that iNOS induction was ATP dependent. Although high suramin concentration inhibited iNOS mRNA induction, the process was not ATP dependent, since specific purinergic receptor antagonists could not inhibit the process. Altogether, these findings demonstrate that iNOS expression is highly modulated in alveolar epithelial cells by LPS via a Ca2+/PKCα-β1 pathway independent of ATP signaling.

Pseudomonas aeruginosa is a gram-negative bacterium that causes chronic infection in cystic fibrosis patients. We reported recently that P. aeruginosa modulates epithelial Na+ channel (ENaC) expression in experimental chronic pneumonia models. For this reason, we tested whether LPS from P. aeruginosa alters ENaC expression and activity in alveolar epithelial cells. We found that LPS induces a ∼60% decrease of ENaC apical current without significant changes in intracellular ENaC or surface protein expression. Because a growing body of evidence reports a key role for extracellular nucleotides in regulation of ion channels, we evaluated the possibility that modulation of ENaC activity by LPS involves extracellular ATP signaling. We found that alveolar epithelial cells release ATP upon LPS stimulation and that pretreatment with suramin, a P2Y2 purinergic receptor antagonist, inhibited the effect of LPS on ENaC. Furthermore, ET-18-OCH3, a PLC inhibitor, and Go-6976, a PKC inhibitor, were able to partially prevent ENaC inhibition by LPS, suggesting that the actions of LPS on ENaC current were mediated, in part, by the PKC and PLC pathways. Together, these findings demonstrate an important role of extracellular ATP signaling in the response of epithelial cells to LPS.

In 2004, Deere & Company's Commercial & Consumer Equipment Division (C&CE) engaged in a new logistics initiative to further enhance its outbound distribution network. The goal was to offer faster and more reliable replenishment to 2,500 North American independent dealers while keeping logistics costs in check by deploying different tactics during the peak (February–July) and offpeak (August–January) selling and shipping seasons. Deere and SmartOps worked together under a shared reward contract based on actual cost reductions accomplished (that are additive over the benefits that may have accrued for other reasons). Through careful analysis, validation, and verification of the data available, the team was able to develop detailed models of the current and alternative distribution systems. By formulating the key replenishment and transportation decisions and constraints as a mixed-integer mathematical program, the team was able to use powerful off-the-shelf solution software to find improvements. The ability to fix variables to perform what-if analysis also helped in the acceptance of the recommendations. Over a period of three years, Deere significantly improved service to 82% of their dealers (without any reduction in service to the other 18%) while reducing logistics costs by over $10 million. The novelty of this work stems from the dynamic seasonal optimization of Deere C&CE distribution network and replenishment decisions as a way of meeting service and cost reduction mandates, the creative use of tactical network optimization operations research models and what-if analysis to meet the implementation goals under time constraints and in the scrutiny given to the results.

Summary We have recently demonstrated that a novel angiotensin II (Ang II) type 1 receptor-associated protein, GLP induces cellular hypertrophy and Ang II stimulated GLP mRNA expression in a time-, dose-, and AT1 receptor-dependent manner in rat immortalized renal proximal tubular cells (IRPTCs). The present studies investigated which signaling pathways are involved in Ang II stimulated GLP mRNA expression in IRPTCs. Cellular GLP mRNA expression was determined by reverse transcription polymerase chain reaction. The effect of Ang II was blocked by epidermal growth factor receptor inhibitor, AG1478, PKC inhibitor, GF109203X, MAPK kinase inhibitor, PD98059, antioxidants, taurine and tiron, and NADH/NADPH oxidase inhibitor, DPI, whereas, no effects were observed on Ang II-induced GLP mRNA expression with p38 MAPK inhibitors, SB203580 and PD169316, and Janus kinase 2 inhibitor, AG490. IRPTCs stably expressing GLP gene significantly increased reactive oxygen species (ROS) generation compared to control IRPTCs analyzed by lucigenin assay. Furthermore, NADH/NADPH oxidase inhibitor, DPI, and antioxidants taurine and tiron inhibited GLP-induced total protein content and de novo protein synthesis. These studies demonstrated that the stimulatory action of Ang II on GLP mRNA expression in IRPTCs is mediated by multiple signal mechanisms, transactivation of EGF receptor and subsequent MAPK activation, PKC activation and ROS generation. Furthermore, the cellular hypertrophic effect of GLP gene in IRPTCs is mediated at least in part via ROS generation.

The carboxyl terminus of the type 1 angiotensin II receptor (AT 1 ) plays an important role in receptor phosphorylation, desensitization, and internalization. The yeast two-hybrid system was employed to isolate proteins associated with the carboxyl terminal region of the AT 1A receptor. In the present study, we report the isolation of a novel protein, ARAP1, which promotes recycling of AT 1A to the plasma membrane in HEK-293 cells. ARAP1 cDNA encodes a 493-amino-acid protein and its mRNA is ubiquitously expressed in rat tissues. A complex of ARAP1 and AT 1A was observed by immunoprecipitation and Western blotting in HEK-293 cells. In the presence of ARAP1, recycled AT 1A showed a significant Ca 2+ release response to a second stimulation by Ang II 30 min after the first treatment. Immunocytochemical analysis revealed co-localization of recycled AT 1A and ARAP1 in the plasma membrane 45 min after the initial exposure to Ang II. Taken together, these results indicate a role for ARAP1 in the recycling of the AT 1 receptor to the plasma membrane with presumable concomitant recovery of receptor signal functions.

In the past few years, the electronics industry has undergone an explosion in new products and technologies. This fierce global competition has resulted in the decision by many companies to outsource manufacturing in order to concentrate on research and development, marketing, and sales. This has given rise to a number of companies who solely provide electronics manufacturing services. Exchange of information between product developers and contract manufacturers, especially information about product demand, is critical to the success of this business model. In this paper, we analyze forecast data obtained from a local contract manufacturer in order to better understand forecast variability and its reasons. We find that forecast variability tends to increase as the production period approaches, despite common belief that forecasts get better with time. We also discuss the impact that chronic material unavailability and product mix have on forecast variability. Finally, we see that unmet demand pushed in the next production period can distort forecasts and result in unrealistic expectations.

Caterpillar recently embarked on an ambitious program to radically change how it markets and sells key products of its Building Construction Products division (BCP). The goal was to move from a strict build-to-order strategy, in which customers selected one of millions of possible configurations, to a Lane Strategy in which the majority of their customers would choose machines from just over 100 configurations. To successfully make such a radical change Caterpillar needed to quantify how customers would potentially react to the new strategy, and how such a drastic simplification of their product line would affect their manufacturing, sales, and service costs. We embarked on a study with Caterpillar to explicitly model customers' reactions to reduced product lines, to estimate the (positive and negative) effect such variety has on Caterpillar's costs - the cost of complexity - and ultimately help them design and implement this strategy for their flagship BCP product, the Backhoe Loader. Based on our analysis, Caterpillar began implementing the new strategy with their 2010 price list, moving completely to the new strategy in 2011. Since that time Caterpillar has expanded their Lane strategy throughout all of their product lines, fundamentally remaking their business.

In this paper, we propose a Bayesian statistical approach to cycle time modeling. Three models of cycle time in complex manufacturing environments are proposed. These models capture changes in cycle time mean and variance at different levels of work-in-process. We model cycle time mean during a period as a two-segment piecewise linear function of the period's work-in-process and consider three variance models. The challenge is to estimate the breakpoint between the two segments, and the parameters of each model. To accomplish this, we use the Gibbs sampler and Metropolis-Hastings algorithm to perform a Bayesian analysis. With three competing models, Bayesian model selection is used to identify the most plausible and model averaging is performed on the selected model. We compare the resulting model to an analytical non-linear model on an example and provide some insights.

This paper introduces a new adaptive kanban-type pull control mechanism which determines when to release or reorder raw parts based on customer demands, inventory and backorders. This system differs from the traditional kanban system in that the number of kanban cards is allowed to change with respect to the inventory and backorder levels. However, the number of cards in the system remains limited, thereby restricting the amount of work-in-process (WIP) in the system. In this paper, we show how to evaluate the performance of this system for the case of a single-stage, single-product kanban system where the demands arrive according to a Poisson process and processing times are exponential random variables. We show that our adaptive system under such conditions can outperform the traditional kanban pull control mechanism while remaining easy to implement. In addition, we present simulation results and show the benefits of this system under variable demand means.

This paper considers the problem of configuring a printed circuit board (PCB) assembly line experiencing uncertainty in demand and capacity. The PCB assembly process involves a single line of automatic placement machines, a variety of board types, and a number of component types. The line is set up only once, at the beginning of a production cycle, to eliminate setups between board types. Using this strategy, the line therefore can assemble all different types of PCBs without feeder changes. The problem then becomes to partition component types to the different machines in the hope of processing all boards quickly with a good workload balance. In this paper, the board demands and machine breakdowns are random but follow some probability distribution, which can be predicted from past observations of the system. We formulate this problem as a stochastic mixed-integer programming formulation with the objective of minimizing the expected makespan for assembling all PCBs during a production cycle. The results obtained indicate significant improvement over the existing methods. We hope that this research will provide more PCB assembly facilities with models and techniques to hedge against variable forecasts and capacity plans

Planning releases and prioritizing work in manufacturing facilities must be done with the often conflicting goals of meeting due dates and minimizing in-process inventory. The ideal system is one in which the planner can enter the current logistical configuration and let the system evaluate the configurations' feasibility by developing a schedule. If a feasible schedule is obtained, the system reports on the schedule derived, otherwise it provides diagnostic information suggesting how the situation can be improved. The user can then decide to keep the current schedule, at the risk of missing due dates, or might choose to modify the inputs (e.g. renegotiate a due date, schedule overtime), retest them with the system, and continue until an acceptable work plan has been established. Our procedure, MRP-C, performs the necessary operations needed at the core of such a decision-support system. MRP-C generates good schedules for finite capacity production scheduling problems when all demands can be met within capacity limitations. Otherwise, it detects scheduling infeasibilities if the instance has no feasible schedule, provides analysis on the possible causes of the infeasibilities and suggests modifications of the input to make the schedule feasible.

Objective: We have identified 2 distinct gene expression patterns (CRS1 and CRS2) in cultured epithelial cells obtained from surgical biopsies in CRS patients with and without nasal polyps (NP), which may better classify this disorder. We wished to compare the cellular infiltrate in CRS when assessed by molecular and clinical phenotypes.Method: Surgical biopsies taken from 20 CRS patients and 10 controls were divided according to their molecular signature as determined from epithelial cell cultures. Immunohistochemistry (IHC) for neutrophil elastase (NE) and major basic protein (MBP) was used to identify neutrophils and eosinophils in the epithelial and submucosal areas.Results: Groups were analyzed statistically using ANOVA and t test to identify significant differences between groups. When biopsies were assessed as function of the clinical phenotypes of CRSwNP compared with CRSsNP, while there were equal increases in the number of eosinophils and neutrophils cells in CRS patients compared with the contr...

Angiotensin II stimulates cellular hypertrophy in cultured vascular smooth muscle and renal proximal tubular cells. This effect is believed to be one of earliest morphological changes of heart and renal failure. However, the precise molecular mechanism involved in angiotensin II-induced hypertrophy is poorly understood. In the present study we report the isolation of a novel angiotensin II type 1 receptor-associated protein. It encodes a 531-amino acid protein. Its mRNA is detected in all human tissues examined but highly expressed in the human kidney, pancreas, heart, and human embryonic kidney cells as well as rat vascular smooth muscle and renal proximal tubular cells. Protein synthesis and relative cell size analyzed by flow cytometry studies indicate that overexpression of the novel angiotensin II type 1 receptor-associated protein induces cellular hypertrophy in cultured rat vascular smooth muscle and renal proximal tubular cells. In contrast, the hypertrophic effects was reversed in renal proximal tubular cell lines expressing the novel gene in the antisense orientation and its dominant negative mutant, which lacks the last 101 amino acids in its carboxyl-terminal tail. The hypertrophic effects are at least in part mediated via protein kinase B activation or cyclin-dependent kinase inhibitor, p27(kip1) protein expression level in vascular smooth muscle, and renal proximal tubular cells. Moreover, angiotensin II could not stimulate cellular hypertrophy in renal proximal tubular cells expressing the novel gene in the antisense orientation and its mutant. These findings may provide new molecular mechanisms to understand hypertrophic agents such as angiotensin II-induced cellular hypertrophy.