The importance of a new product development (NPD) process: getting started.

In order to achieve a successful new product, and certainly the successful implementation of a new product into a company, it is necessary to have a structured and documented approach to New Product Development (NPD), therefore providing a clear roadmap for the development of new products. This review highlights the NPD process, from concept to consumer, and what the key success drivers are, such as; the quest for real product superiority and success, and the need for cross-functional teams; in order for a company to succeed and use new products as a source for competitive advantage

Subcellular localisation modulates ubiquitylation and degradation of Ascl1.

The proneural transcription factor Ascl1 is a master regulator of neurogenesis, coordinating proliferation and differentiation in the central nervous system. While its expression is well characterised, post-translational regulation is much less well understood. Here we demonstrate that a population of chromatin-bound Ascl1 can be found associated with short chains of ubiquitin while cytoplasmic Ascl1 harbours much longer ubiquitin chains. Only cytoplasmic ubiquitylation targets Ascl1 for destruction, which occurs by conjugation of ubiquitin to lysines in the basic helix-loop-helix domain of Ascl1 and requires the E3 ligase Huwe1. In contrast, chromatin-bound Ascl1 associated with short ubiquitin-chains, which can occur on lysines within the N-terminal region or the bHLH domain and is not mediated by Huwe1, is not targeted for ubiquitin-mediated destruction. We therefore offer further insights into post-translational regulation of Ascl1, highlighting complex regulation of ubiquitylation and degradation in the cytoplasm and on chromatin.This work was funded by MRC Research Grants (MR/K018329/1 and MR/L021129/1) and received core support from Wellcome Trust and MRC Cambridge Stem Cell Institute

Multi-site phosphorylation controls the neurogenic and myogenic activity of E47.

The superfamily of basic-Helix-Loop-Helix (bHLH) transcription factors influence cell fate in all three embryonic germ layers, and the tissue-specific class II factors have received prominent attention for their potent ability to direct differentiation during development and in cellular reprogramming. The activity of many class II bHLH proteins driving differentiation, and the inhibitory class VI bHLH factor Hes1, is controlled by phosphorylation on multiple sites by Cyclin-dependent kinases (Cdks). As class II proteins are generally thought to be active through hetero-dimerisation with the ubiquitously expressed class I E proteins, regulation of class I transcription factors such as E47 may influence the activity of multiple tissue-specific bHLH proteins. Using differentiation of nerve and muscle in Xenopus frog embryos as a model system, we set out to explore whether with the ubiquitously expressed class I E protein E47 that hetero-dimerises with Class II bHLHs to control their activity, is also regulated by multi-site phosphorylation. We demonstrate that E47 can be readily phosphorylated by Cdks on multiple sites in vitro, while ectopically-expressed E47 exists in multiple phosphorylated forms in Xenopus embryos. Preventing multi-site phosphorylation using a phospho-mutant version of E47 enhances the neurogenic and myogenic activity of three different class II bHLH reprogramming factors, and also when E47 acts in hetero-dimerisation with endogenous proteins. Mechanistically, unlike phospho-regulation of class II bHLH factors, we find that preventing phosphorylation of E47 increases the amount of chromatin-bound E47 protein but without affecting its overall protein stability. Thus, multi-site phosphorylation is a conserved regulatory mechanism across the bHLH superfamily that can be manipulated to enhance cellular differentiation.This work was supported by Medical Research Council Research Grants MR/L021129/1 and MR/K018329 and AP receives core funding from Wellcome and MRC at the Wellcome-MRC Cambridge Stem Cell Institute. LH is supported by a Peterhouse Research Fellowship

Cooling of cryogenic electron bilayers via the Coulomb interaction

Heat dissipation in current-carrying cryogenic nanostructures is problematic because the phonon density of states decreases strongly as energy decreases. We show that the Coulomb interaction can prove a valuable resource for carrier cooling via coupling to a nearby, cold electron reservoir. Specifically, we consider the geometry of an electron bilayer in a silicon-based heterostructure, and analyze the power transfer. We show that across a range of temperatures, separations, and sheet densities, the electron-electron interaction dominates the phonon heat-dissipation modes as the main cooling mechanism. Coulomb cooling is most effective at low densities, when phonon cooling is least effective in silicon, making it especially relevant for experiments attempting to perform coherent manipulations of single spins.Comment: 9 pages, 5 figure

The origin of switching noise in GaAs/AlGaAs lateral gated devices

We have studied the origin of switching (telegraph) noise at low temperature in lateral quantum structures defined electrostatically in GaAs/AlGaAs heterostructures by surface gates. The noise was measured by monitoring the conductance fluctuations around $e^2/h$ on the first step of a quantum point contact at around 1.2 K. Cooling with a positive bias on the gates dramatically reduces this noise, while an asymmetric bias exacerbates it. We propose a model in which the noise originates from a leakage current of electrons that tunnel through the Schottky barrier under the gate into the doped layer. The key to reducing noise is to keep this barrier opaque under experimental conditions. Bias cooling reduces the density of ionized donors, which builds in an effective negative gate voltage. A smaller negative bias is therefore needed to reach the desired operating point. This suppresses tunnelling from the gate and hence the noise. The reduction in the density of ionized donors also strengthens the barrier to tunneling at a given applied voltage. Support for the model comes from our direct observation of the leakage current into a closed quantum dot, around $10^{-20} \mathrm{A}$ for this device. The current was detected by a neighboring quantum point contact, which showed monotonic steps in time associated with the tunneling of single electrons into the dot. If asymmetric gate voltages are applied, our model suggests that the noise will increase as a consequence of the more negative gate voltage applied to one of the gates to maintain the same device conductance. We observe exactly this behaviour in our experiments.Comment: 8 pages, 7 figure

Municipal Ethical Standards: The Need for a New Approach Report

The New York State Commission on Government Integrity investigated numerous situations throughout the state that revealed just how bad the current law is. Our findings and a pro- posed municipal ethics act that we drafted to correct the law\u27s deficiencies are contained in the following report, Municipal Ethical Standards: The Need for a New Approach. Our pro- posed Act would set out the minimum ethical standards that should be observed in every municipality throughout the state. The premise here is that there are certain basic features to good government that make sense for all governments, no matter what their size or location - rural or suburban, upstate or downstate. If the proposed Act became law, localities would be able to enact more stringent regulations if they wanted to, but no local government could have standards that fell below the floor put in place by the Act. The Governor has had a bill introduced in the Legislature that is patterned after the law we proposed. The State Assembly has held public hearings on the bill and it is hopeful that in the 1990 legislative session, New Yorkers will get the strong municipal ethics law they need and deserve