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Fray is a serine/threonine kinase expressed by the peripheral glia of Drosophila, whose function is required for normal axonal ensheathment. Null fray mutants die early in larval development and have nerves with severe swelling and axonal defasciculation. The phenotype is associated with a failure of the ensheathing glia to correctly wrap peripheral axons. When the fray cDNA is expressed in the ensheathing glia of fray mutants, normal nerve morphology is restored. Fray belongs to a novel family of Ser/Thr kinases, the PF kinases, whose closest relatives are the PAK kinases. Rescue of the Drosophila mutant phenotype with PASK, the rat homolog of Fray, demonstrates a functional homology among these proteins and suggests that the Fray signaling pathway is widely conserved.

The nervous system is protected by blood barriers that use multiple systems to control extracellular solute composition, osmotic pressure, and fluid volume. In the human nervous system, misregulation of the extracellular volume poses serious health threats. Here we show that the glial cells that form the Drosophila blood-nerve barrier have a conserved molecular mechanism that regulates extracellular volume: the Serine/Threonine kinase Fray, which we previously showed is an ortholog of mammalian PASK/SPAK; and the Na-K-Cl cotransporter NCC69, which we show is an ortholog of human NKCC1. In mammals, PASK/SPAK binds to NKCC1 and regulates its activity. In Drosophila, larvae mutant for NCC69 develop a peripheral neuropathy, where fluid accumulates between glia and axons. The accumulation of fluid has no detectable impact on action potential conduction, suggesting that the role of NCC69 is to maintain volume or osmotic homeostasis. Drosophila NCC69 has kinetics similar to human NKCC1, and NKCC1 can rescue NCC69, suggesting that they function in a conserved physiological mechanism. We show that fray and NCC69 are coexpressed in nerve glia, interact in a yeast-twohybrid assay, and have an essentially identical bulging nerve phenotype. We propose that normally functioning nerves generate extracellular solutes that are removed by NCC69 under the control of Fray. This mechanism may perform a similar role in humans, given that NKCC1 is expressed at the blood-brain barrier.

The Cilkview scalability analyzer is a software tool for profiling, estimating scalability, and benchmarking multithreaded Cilk++ applications. Cilkview monitors logical parallelism during an instrumented execution of the Cilk++ application on a single processing core. As Cilkview executes, it analyzes logical dependencies within the computation to determine its work and span (criticalpath length). These metrics allow Cilkview to estimate parallelism and predict how the application will scale with the number of processing cores. In addition, Cilkview analyzes scheduling overhead using the concept of a "burdened dag," which allows it to diagnose performance problems in the application due to an insufficient grain size of parallel subcomputations.Cilkview employs the Pin dynamic-instrumentation framework to collect metrics during a serial execution of the application code. It operates directly on the optimized code rather than on a debug version. Metadata embedded by the Cilk++ compiler in the binary executable identifies the parallel control constructs in the executing application. This approach introduces little or no overhead to the program binary in normal runs.Cilkview can perform real-time scalability benchmarking automatically, producing gnuplot-compatible output that allows developers to compare an application's performance with the tool's predictions. If the program performs beneath the range of expectation, the programmer can be confident in seeking a cause such as insufficient memory bandwidth, false sharing, or contention, rather than inadequate parallelism or insufficient grain size.

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