Notch signaling plays a fundamental role in cellular differentiation and has been linked to human diseases, including cancer. We report the use of comprehensive RNAi analyses to dissect Notch regulation and its connections to cellular pathways. A cell-based RNAi screen identified 900 candidate Notch regulators on a genome-wide scale. The subsequent use of a library of transgenic Drosophila expressing RNAi constructs enabled large-scale in vivo validation and confirmed 333 of 501 tested genes as Notch regulators. Mapping the phenotypic attributes of our data on an interaction network identified another 68 relevant genes and revealed several modules of unexpected Notch regulatory activity. In particular, we note an intriguing relationship to pyruvate metabolism, which may be relevant to cancer. Our study reveals a hitherto unappreciated diversity of tissue-specific modulators impinging on Notch and opens new avenues for studying Notch regulation and function in development and disease.

Previous research has shown that during recognition of frontal views of faces, the preferred landing positions of eye fixations are either on the nose or the eye region. Can these findings generalize to other facial views and a simpler perceptual task? An eye-tracking experiment investigated categorization of the sex of faces seen in four views. The results revealed a strategy, preferred in all views, which consisted of focusing gaze within an ‘infraorbital region’ of the face. This region was fixated more in the first than in subsequent fixations. Males anchored gaze lower and more centrally than females.

Background: The mitogen-activated protein kinases, MAPKs for short, constitute cascades of signalling pathways involved in the regulation of several cellular processes that include cell proliferation, differentiation and motility. They also intervene in neurological processes like fear conditioning and memory. Since little remains known about the MAPK-Activated Protein Kinase, MAPKAPK5, we constructed the first MAPKAPK knockin mouse model, using a constitutive active variant of MAPKAPK5 and analyzed the resulting mice for changes in anxiety-related behaviour. Methods: We performed primary SHIRPA observations during background breeding into the C57BL/6 background and assessed the behaviour of the background-bred animals on the elevated plus maze and in the light-dark test. Our results were analyzed using Chi-square tests and homoand heteroscedatic T-tests. Results: Female transgenic mice displayed increased amounts of head dips and open arm time on the maze, compared to littermate controls. In addition, they also explored further into the open arm on the elevated plus maze and were less active in the closed arm compared to littermate controls. Male transgenic mice displayed no differences in anxiety, but their locomotor activity increased compared to non-transgenic littermates. Conclusion: Our results revealed anxiety-related traits and locomotor differences between transgenic mice expressing constitutive active MAPKAPK5 and control littermates. Background The mitogen-activated protein kinases, MAPKs for short, constitute cascades of signalling pathways involved in the regulation of several cellular processes that include cell proliferation, differentiation, apoptosis, motility and embryogenesis. MAPKs also influence the development of cancer, inflammatory processes and most important in this article, neurological processes [1-4]. The MAPK pathway exists of a four component module where a MAPK kinase kinase (MAP3K) activates a MAPK kinase (MAP2K) by phosphorylation. The latter subsequently phosphorylates and activates a MAPK. This occurs on two residues within the TXY activation motif. MAPKs can in turn phosphorylate downstream targets like transcription factors but also other kinases, referred to as MAPK-activated protein kinases, MAPKAPKs or MKs. This branch of the MAPKs consists of 5 subfamilies: the ribosPublished: 12 November 2007 Behavioral and Brain Functions 2007, 3:58 doi:10.1186/1744-9081-3-58 Received: 28 September 2007 Accepted: 12 November 2007 This article is available from: http://www.behavioralandbrainfunctions.com/content/3/1/58 © 2007 Gerits et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

To perform a quantitative analysis with gene-arrays, one must take into account inaccuracies (experimental variations, biological variations and other measurement errors) which are seldom known. In this paper we investigated amplification and noise propagation related errors by measuring intensity dependent variations. Based on a set of control samples, we create confidence intervals for up and down regulations. We validated our method through a qPCR experiment and compared it to standard analysis methods (including loess normalization and filtering methods based on genetic variability). The results reveal that amplification related errors are a major concern.

BACKGROUND:The mitogen-activated protein kinases, MAPKs for short, constitute cascades of signalling pathways involved in the regulation of several cellular processes that include cell proliferation, differentiation and motility. They also intervene in neurological processes like fear conditioning and memory. Since little remains known about the MAPK-Activated Protein Kinase, MAPKAPK5, we constructed the first MAPKAPK knockin mouse model, using a constitutive active variant of MAPKAPK5 and analyzed the resulting mice for changes in anxiety-related behaviour.METHODS:We performed primary SHIRPA observations during background breeding into the C57BL/6 background and assessed the behaviour of the background-bred animals on the elevated plus maze and in the light-dark test. Our results were analyzed using Chi-square tests and homo- and heteroscedatic T-tests.RESULTS:Female transgenic mice displayed increased amounts of head dips and open arm time on the maze, compared to littermate controls. In addition, they also explored further into the open arm on the elevated plus maze and were less active in the closed arm compared to littermate controls. Male transgenic mice displayed no differences in anxiety, but their locomotor activity increased compared to non-transgenic littermates.CONCLUSION:Our results revealed anxiety-related traits and locomotor differences between transgenic mice expressing constitutive active MAPKAPK5 and control littermates.

Background Two-dimensional gel electrophoresis (2DE) is a powerful technique to examine post-translational modifications of complexly modulated proteins. Currently, spot detection is a necessary step to assess relations between spots and biological variables. This often proves time consuming and difficult when working with non-perfect gels. We developed an analysis technique to measure correlation between 2DE images and biological variables on a pixel by pixel basis. After image alignment and normalization, the biological parameters and pixel values are replaced by their specific rank. These rank adjusted images and parameters are then put into a standard linear Pearson correlation and further tested for significance and variance. Results We validated this technique on a set of simulated 2DE images, which revealed also correct working under the presence of normalization factors. This was followed by an analysis of p53 2DE immunoblots from cancer cells, known to have unique signaling networks. Since p53 is altered through these signaling networks, we expected to find correlations between the cancer type (acute lymphoblastic leukemia and acute myeloid leukemia) and the p53 profiles. A second correlation analysis revealed a more complex relation between the differentiation stage in acute myeloid leukemia and p53 protein isoforms. Conclusion The presented analysis method measures relations between 2DE images and external variables without requiring spot detection, thereby enabling the exploration of biosignatures of complex signaling networks in biological systems.

The anti-oncogene TP53 is frequently mutated in human cancer, but in hematological malignancies this is a rare feature. In acute myeloid leukemia (AML) more than 90% of the patients comprise wild type TP53 in their cancer cells, but if TP53 is mutated or deleted the disease is often found to be chemoresistant. In this review we define proteomics of the oncogene product p53 as the study of proteins in the p53 regulating signaling networks, as well as the protein study of members of the p53 family itself. Various messenger RNA splice forms as well as a multitude of post-translational modifications give a high number of protein isoforms in the p53 family. Some of the proteomic techniques allow detection of various isoforms, such as two-dimensional gel electrophoresis in combination with tandem mass spectrometry (MS/MS) and this methodology may therefore increasingly be used as a diagnostic tool in human disease. We introduce the p53 protein as an illustration of the complexity of post-translational modifications that may affect one highly connected protein and discuss the possible impact in AML diagnostics if the p53 profile is reflecting cell stress and status of signal transduction systems of the malignancy.

2-DE is a powerful technique to discriminate post-translationally modified protein isoforms. However, all steps of 2-DE preparation and gel-staining may introduce unwanted artefacts, including inconsistent variation of background intensity over the entire 2-DE gel image. Background intensity variations limit the accuracy of gel orientation, overlay alignment and spot detection methods. We present a compact and efficient denoising algorithm that adaptively enhances the image contrast and then, through thresholding and median filtering, removes the gray-scale range covering the background. Applicability of the algorithm is demonstrated on immunoblots, isotope-labeled gels, and protein-stained gels. Validation is performed in contexts of (i) automatic gel orientation based on Hough transformation, (ii) overlay alignment based on cross correlation and (iii) spot detection. In gel stains with low background variability, e.g. Sypro Ruby, denoising will lower the spot detection sensitivity. In gel regions with high background levels denoising enhances spot detection. We propose that the denoising algorithm prepares images with high background for further automatic analysis, without requiring manual input on a gel-to-gel basis.

Multiple signaling networks target the anti-oncogene TP53 protein product by complex posttranslational modulation, regulating stress responses like cell cycle arrest or cell death. The relation between wild type p53 protein and chemotherapy response is not fully understood. We have examined the relationship between the p53 protein profile of patient cancer cells and clinical data in samples from 39 acute myeloid leukemia and 8 acute lymphoblastic leukemia patients. The p53 profile was determined by two-dimensional gel electrophoresis immunoblot, recognizing the amino-terminal region that is modified by DNA damage activated kinases. Survival of patients correlated with strong expression of ∆p53, while αp53 correlated with short survival. A similar but more significant correlation was found when remission response two weeks after chemotherapy was used as the clinical parameter. Conversely, the independent marker for disease relapse, Flt3 length mutation of the receptor tyrosine kinase Flt3, correlated with prominent αp53 isoforms. Inhibition of Flt3 by the kinase inhibitor PKC412 and down-regulation by small interfering RNA increased the pro-survival/proremission ∆p53. These lines of evidence suggest that examinations of the p53 protein can decipher cell signaling network perturbations that direct clinical outcome in cancer, and that targeted signaling network therapy is reflected in the p53 profile.

BpmDj Is a program for DJ's. It helps to select songs and play them. To achieve this the program relies on a number of signal processing techniques. One of the available techniques compares song spectra. Both a standard spectrum analysis is performed as well as a distri- bution analysis ('echo' characteristics). In this short article we describe how this property is calculated and how it is further used in song comparison. We also present a short analysis of the structure of the space using correlation techniques. Referring: Wvb05) Werner Van Belle; Observations on Spectrum and Spectrum Histograms in BpmDj; Department Computer Science, Norut IT, University Tromsø; Published by online pub- lications, Malmvegen206, 9022Krokelvdalen, Norway; Onlineathttp://bio6.itek.norut.no/papers/;

Today mobile devices can interact with their environment through wireless communication. Wireless communication has a limited communication range; which introduces two major problems, currently not captured in distributed middleware. First, they are less reliable than their wired variants and secondly they are extremely dynamic. Both problems complicate the development of mobile software. In this paper we extend the operational semantics of the actor model to capture these two properties. We do this by adding a signle new concept to the model: the mailbox. This paper provides a foundation for new implementations of the actor language and frameworks that are usable in the context of wireless network environments. Refering: DVB04] Werner Van Belle, Jessie Dedecker; The Ambient Actor Model; Programming Technology Lab, Vrije Universiteit Brussel; Computer Science Department University of Tromso; Published by online publications, Malmvegen 206, 9022 Tromso; Online at

Today mobile devices can interact with their environment through wireless communication. Wireless communication has a limited communication range, which introduces two major problems, currently not captured in distributed middleware. Firstly, they are less reliable and secondly they are extremely dynamic. Both problems complicate the development of mobile software. In this paper we extend the operational semantics of the actor model to capture these two properties by adding a single new concept to the model: the mailbox. This paper provides a foundation for new implementations of the actor language and frameworks that are usable in the context of mobile ad-hoc networks.

As mobile devices become more powerful, interprocess communication becomes increasingly more important. Unfortunately, this larger freedom of mobility gives rise to unknown environments. In these environments, processes that want to communicate with each other will be unable to do so because of protocol conflicts. Although conflicting protocols can be remedied by using adaptors, the number of possible combinations of different protocols increases dramatically. Therefore we propose a technique to generate protocol adaptors automatically. This is realised by means of genetically engineered classifier systems that use Petri nets as a specification for the underlying protocols. This paper reports on an experiment that validates this approach.

This paper describes an experiment with mobility in multi-agent systems. The setting is a virtual machine that supports reification of the computational state of a running process. The objective is to investigate how this feature facilitates telescripting and to speculate on how languages like Java should evolve to include the resulting notion of strong migration

This paper reports on our experiences in the field of mobile components. In the past 4 years we developed a mobile component system, which allowed us to experiment with code mobility in distributed systems. These experiments have given us a unique opportunity to study two major issues in mobile component systems. The first issue is how to develop and provide a robust mobile component architecture. The second issue is how to write code in these kinds of systems. This paper discusses our experience in both of the above.

Component-oriented programming (COP) and component-based development (CBD) have become rather mature software development approaches in the last years, with both quite good conceptual and technological support. In spite of this rapid growth, the concepts used when talking about components are not always well-defined and can lead to misconception, misunderstanding and confusion. Although the general, abstract definition of a component, as defined at WCOP'96 [1] A software component is a unit of composition with contractually specified interfaces and explicit context dependencies only. A software component can be deployed independently and is subject to composition by third parties. is widely accepted, a lot of confusion can arise when characteristics of components are described. For instance, a number of people disagree on the fact whether a component should always be stateless[2,3], or whether it could also be stateful[4].

This paper describes an experiment with mobility in multi-agent systems. The setting is a virtual machine that supports reification of the computational state of a running process. The objective is to investigate how this feature facilitates telescripting and to speculate on how languages like Java should evolve to include the resulting notion of strong migration. Mobile Agent Systems An agent is a persistent and autonomous software component. It can be thought of as a process executed by some virtual machine but it is mainly intended to provide a particular service. Viewed as processes, agents run concurrently on one or more machines and have their own data space and computational state. We talk about multi agents if two or more agents, represented by processes, are able to communicate with each other. Depending on the agent system this communication can be performed by means of the available technology (Remote Procedure Call, Remote Method Invocation, etc.). In our particular setup, we will require our communication mechanism to support asynchronous remote message passing. A mobile agent is an agent which is able to move between different machines, or in a more abstract sense, between locations. We will discuss migration in the following section. A mobile multi agent system is a software artefact specified in a language that provides sufficient expressiveness and flexibility to allow the construction of multiple interacting mobile agents. This includes routing of messages between agent systems and providing an interconnection with