Role of FGFR2b expression and signaling in keratinocyte differentiation. Sequential involvement of PKCδ and PKCα

The tumor suppressor epithelial isoform of the fibroblast growth factor receptor 2 (FGFR2b) induces human keratinocyte early differentiation. Moreover, protein kinases C (PKCs) are known to regulate the differentiation program in several cellular contexts, including keratinocytes. Therefore, in this paper we propose to clarify if FGFR2b could play a role also in the late steps of keratinocyte differentiation and to assess if this receptor-induced process would sequentially involve PKCδ and PKCα isoforms. Immunofluorescence, biochemical, and molecular approaches, performed on 2D cultures or 3D organotypic rafts of human keratinocytes overexpressing FGFR2b by stable transduction, showed that receptor signaling induced the precocious onset and an accelerated progression of keratinocyte differentiation, indicating that FGFR2b is a crucial regulator of the entire program of keratinocyte differentiation. In addition, the use of specific inhibitors and gene silencing approaches through specific siRNA demonstrated that PKCδ controls the onset of FGFR2b-triggered differentiation, while PKCα plays a role restricted to the terminal stages of the process. Molecular analysis revealed that the two PKC isoforms sequentially act via induction of KLF4 and DLX3, two transcription factors linked by negative loops to p63, suggesting that p63 would represent the hub molecule at the crossroad of an intricate signaling network downstream FGFR2b, involving multiple PKC-induced transcription factors

Some path-following techniques for solution of nonlinear equations and comparison with parametric differentiation

Some path-following techniques are described and compared with other methods. Use of multipurpose techniques that can be used at more than one stage of the path-following computation results in a system that is relatively simple to understand, program, and use. Comparison of path-following methods with the method of parametric differentiation reveals definite advantages for the path-following methods. The fact that parametric differentiation has found a broader range of applications indicates that path-following methods have been underutilized

Optimal cure cycle design for autoclave processing of thick composites laminates: A feasibility study

The thermal analysis and the calculation of thermal sensitivity of a cure cycle in autoclave processing of thick composite laminates were studied. A finite element program for the thermal analysis and design derivatives calculation for temperature distribution and the degree of cure was developed and verified. It was found that the direct differentiation was the best approach for the thermal design sensitivity analysis. In addition, the approach of the direct differentiation provided time histories of design derivatives which are of great value to the cure cycle designers. The approach of direct differentiation is to be used for further study, i.e., the optimal cycle design

THE VALUE OF AGRICULTURAL ECONOMICS EXTENSION PROGRAMMING: AN APPLICATION OF CONTINGENT VALUATION

We use the contingent valuation method to estimate participant willingness to pay for agricultural economics extension programming. The data, collected as part of standard evaluation forms for the Ohio State University's 2001 Agricultural Outlook and Policy program series, and subsequent analysis suggest participant benefits exceeded departmental costs of conducting the program (benefit-cost ratios of 1.07 under conservative assumptions and 1.74 under moderate assumptions). We also use the data to explore the revenue generation potential from alternative program pricing and discuss the potential for developing differentiated programs to reach distinct audience segments. Additional research necessary before implementing alternative pricing or program differentiation plans is also discussed.Teaching/Communication/Extension/Profession,

Functional programming framework for GRworkbench

The software tool GRworkbench is an ongoing project in visual, numerical General Relativity at The Australian National University. Recently, the numerical differential geometric engine of GRworkbench has been rewritten using functional programming techniques. By allowing functions to be directly represented as program variables in C++ code, the functional framework enables the mathematical formalism of Differential Geometry to be more closely reflected in GRworkbench . The powerful technique of `automatic differentiation' has replaced numerical differentiation of the metric components, resulting in more accurate derivatives and an order-of-magnitude performance increase for operations relying on differentiation

Expression of the FGFR2c mesenchymal splicing variant in human keratinocytes inhibits differentiation and promotes invasion

The altered isoform switching of the fibroblast growth factor receptor 2 (FGFR2) and aberrant expression of the mesenchymal FGFR2c isoform in epithelial cells is involved in cancer progression. We have recently described that the ectopic expression of FGFR2c in normal human keratinocytes induces epithelial-mesenchymal transition and leads to invasiveness and anchorage-independent growth. Here, we extended our analysis to the effects of this FGFR2c forced expression on human keratinocyte differentiation and stratification. Our findings demonstrated that, differently from cells overexpressing the epithelial splicing variant FGFR2b, keratinocytes ectopically expressing FGFR2c are not able to form a monolayer and display decreased expression of early differentiation markers. This impaired ability to enter the differentiation program is related to the up-modulation of the transcription factor ΔNp63. In addition, FGFR2c-expressing keratinocytes undergo defective stratification and invasion of the collagen matrix in 3D organotypic cultures, further suggesting their tumorigenic potential. Taken together, our results support the hypothesis that the receptor switching and the consequent appearance of the mesenchymal FGFR2c variant in the epithelial context would drive early steps of carcinogenesis, unbalancing the p63/FGFR interplay, and altering the paracrine response to the microenvironment

Red Queen Pricing Effects in E-Retail Markets

A standard “solution” offered to the deleterious effects of all-out price competition is for firms to engage in differentiation strategies. This solution, however, depends critically on the inability of rivals to imitate a successful differentiation strategy. With imitation, we show how “Red Queen” pricing effects can arise: All firms have an incentive to vertically differentiate and increase markups, yet imitation by rivals drives prices down toward pre-differentiation levels. Thus, the price premia arising from differentiation strategies in eretailing critically depend on the number of other firms that imitate the strategies. Based on data from Shopper.com, we find that an online firm that unilaterally differentiates itself from its rivals by participating in CNet’s Certified Merchant program enjoys a 5 to 17 percent price premium. However, when other firms also follow this strategy, the price premium vanishes.Pricing, Product Differentiation, Red Queen Effect, Internet, Reputation

A Novel Role of Cdk9/CyclinT2 complexes in skeletal muscle and Rhabdomyosarcoma cells

Cyclin dependent kinase 9 (Cdk9) is a member of the cyclin dependent kinase family. The regulatory units of Cdk9 are the T family Cyclins (T1, T2) and Cyclin K1. Cyclin T2 has two forms termed CycT2a and CycT2b that arise by an alternative splicing of the primary transcript. Previous studies underscored a crucial role for Cdk9 in association of Cyclin T2 during skeletal myogenesis. Upon induction of muscle differentiation, MyoD recruits Cdk9/CycT2 on musclespecific gene promoter sequences. This complex is able to phosphorylate the C-terminal domain of RNA polymerase II, enhancing Myod function and promoting myogenic differentiation. Rhabdomyosarcoma (RMS), one of the most common childhood solid tumor, arises from muscle precursor cells and fails to complete both the differentiation program both the irreversibly cell cycle exit, resulting in uncontrolled proliferation and incomplete myogenesis. In RMS, Cdk9 fails to phosphorylate MyoD and the ability of MyoD to arrest cell proliferation and to activate the myogenic program is repressed. The result of this study confirmed the involvement of Cdk9/ CyclinT2 complexes during the myogenesis. Both isoforms of Cyclin T2 are able to activate the myogenic program at different stages of differentiation but CycT2b have a predominant role of in particular during the latest stages. Moreover we demonstred that EZH2 is probably responsible to inhibition of Cdk9 in RMS cells and her overexpression contribuite to inhibition of myogenesis