Sortilin, SorCS1b, and SorLA Vps10p sorting receptors, are novel γ-secretase substrates

BACKGROUND: The mammalian Vps10p sorting receptor family is a group of 5 type I membrane homologs (Sortilin, SorLA, and SorCS1-3). These receptors bind various cargo proteins via their luminal Vps10p domains and have been shown to mediate a variety of intracellular sorting and trafficking functions. These proteins are highly expressed in the brain. SorLA has been shown to be down regulated in Alzheimer's disease brains, interact with ApoE, and modulate Aβ production. Sortilin has been shown to be part of proNGF mediated death signaling that results from a complex of Sortilin, p75(NTR )and proNGF. We have investigated and provide evidence for γ-secretase cleavage of this family of proteins. RESULTS: We provide evidence that these receptors are substrates for presenilin dependent γ-secretase cleavage. γ-Secretase cleavage of these sorting receptors is inhibited by γ-secretase inhibitors and does not occur in PS1/PS2 knockout cells. Like most γ-secretase substrates, we find that ectodomain shedding precedes γ-secretase cleavage. The ectodomain cleavage is inhibited by a metalloprotease inhibitor and activated by PMA suggesting that it is mediated by an α-secretase like cleavage. CONCLUSION: These data indicate that the α- and γ-secretase cleavages of the mammalian Vps10p sorting receptors occur in a fashion analogous to other known γ-secretase substrates, and could possibly regulate the biological functions of these proteins

Flow profiling of a surface acoustic wave nanopump

The flow profile in a capillary gap and the pumping efficiency of an acoustic micropump employing Surface Acoustic Waves is investigated both experimentally and theoretically. Such ultrasonic surface waves on a piezoelectric substrate strongly couple to a thin liquid layer and generate an internal streaming within the fluid. Such acoustic streaming can be used for controlled agitation during, e.g., microarray hybridization. We use fluorescence correlation spectroscopy and fluorescence microscopy as complementary tools to investigate the resulting flow profile. The velocity was found to depend on the applied power somewhat weaker than linearly and to decrease fast with the distance from the ultrasound generator on the chip.Comment: 12 pages 20 figure

Agency and the Pace of Adoption of New Techniques

We study the relation of financial contracting and the pace of technological advance in a dynamic agency theoretic model. A firm which is financed by outside shareholders but run by managers has the prospect of a process innovation which arrives stochastically. Adopting the innovation requires firing old management and hiring new with skills appropriate for the new technique. We show that subgame perfect equilibria in this game can be of two types. In "entrenchment" equilibrium once the new technique has been announced old style management raises their dividend payout sufficiently to preempt the innovation. In "maximum rent extraction" equilibrium' managers are unable or unwilling to match the impending productivity improvement and instead respond by increasing their perquisites for the remaining time of their tenure. We show that both equilibria involve several types of inefficiencies and can resuit in underinvestment in positive NPV projects. We discuss the role of financial innovation in reducing the inefficiencies identified.Contract, Corporate finance, Innovation, Governance

CDIO Projects in DTU’s B.Eng. in IT Study Program

Since the fall 2008 all B.Eng. study programs at the Technical University of Denmark have been based on the CDIO concept. The adoption of the CDIO standards and principles resulted in new or significantly revised study programs. As part of this effort design-build projects have been introduced on each of the first 4 semesters, and each semester-project spans several courses. The aim of this paper is to describe the four CDIO semester projects in the B.Eng. in IT study, and – along with similar papers describing the other six B.Eng. programs – to provide documentation to accompany an exposition with stands providing additional information and with students demonstrating their projects. The paper is narrowly focused on the IT-study program. At the time of writing this paper the students enrolled in 2008 have completed all four semesters in the new CDIO-based study plan, and the students enrolled in 2009 are currently in the process of finishing the 4 th semester. Consequently, the paper is reporting on curriculum development which has been implemented, and for which experiences have gained

Teachers' strategies for helping shy students: findings from a national survey in Norway

The goals of this study were to investigate strategies that teachers may use to help students with their shyness at school and to explore potential effects of demographic variables (i.e., teacher experience, class size, grade level) on teachers’ strategies. Participants were a national sample of N = 275 teachers (from 230 elementary schools) in Norway, who reported their frequency of use of different strategies and rated their perceived effectiveness for helping shy students across four domains: (1) encouraging oral participation; (2) promoting social relationships; (3) reducing anxiety; and (4) whole-class strategies. Across domains, common themes included teachers’ sensitivity to individual shy students, reduction of stress associated with novel situations, involving peers, focus on social skills, and building trusting relationships with shy students. Demographic variables had only limited effects on strategy use/effectiveness. Findings are discussed in relation to previous theory and research related to teachers’ strategies for assisting shy students at school

Spectroscopic evidence for an all-ferrous [4Fe–4S]0 cluster in the superreduced activator of 2-hydroxyglutaryl-CoA dehydratase from Acidaminococcus fermentans

The key enzyme of the fermentation of glutamate by Acidaminococcus fermentans, 2-hydroxyglutarylcoenzyme A dehydratase, catalyzes the reversible syn-elimination of water from (R)-2-hydroxyglutaryl-coenzyme A, resulting in (E)-glutaconylcoenzyme A. The dehydratase system consists of two oxygen-sensitive protein components, the activator (HgdC) and the actual dehydratase (HgdAB). Previous biochemical and spectroscopic studies revealed that the reduced [4Fe–4S]+ cluster containing activator transfers one electron to the dehydratase driven by ATP hydrolysis, which activates the enzyme. With a tenfold excess of titanium(III) citrate at pH 8.0 the activator can be further reduced, yielding about 50% of a superreduced [4Fe–4S]0 cluster in the all-ferrous state. This is inferred from the appearance of a new Mössbauer spectrum with parameters δ = 0.65 mm/s and ΔEQ = 1.51–2.19 mm/s at 140 K, which are typical of Fe(II)S4 sites. Parallel-mode electron paramagnetic resonance (EPR) spectroscopy performed at temperatures between 3 and 20 K showed two sharp signals at g = 16 and 12, indicating an integer-spin system. The X-band EPR spectra and magnetic Mössbauer spectra could be consistently simulated by adopting a total spin St = 4 for the all-ferrous cluster with weak zero-field splitting parameters D = −0.66 cm−1 and E/D = 0.17. The superreduced cluster has apparent spectroscopic similarities with the corresponding [4Fe–4S]0 cluster described for the nitrogenase Fe-protein, but in detail their properties differ. While the all-ferrous Fe-protein is capable of transferring electrons to the MoFe-protein for dinitrogen reduction, a similar physiological role is elusive for the superreduced activator. This finding supports our model that only one-electron transfer steps are involved in dehydratase catalysis. Nevertheless we discuss a common basic mechanism of the two diverse systems, which are so far the only described examples of the all-ferrous [4Fe–4S]0 cluster found in biology