Cis-regulatory module detection using constraint programming

We propose a method for finding CRMs in a set of co-regulated genes. Each CRM consists of a set of binding sites of transcription factors. We wish to find CRMs involving the same transcription factors in multiple sequences. Finding such a combination of transcription factors is inherently a combinatorial problem. We solve this problem by combining the principles of itemset mining and constraint programming. The constraints involve the putative binding sites of transcription factors, the number of sequences in which they co-occur and the proximity of the binding sites. Genomic background sequences are used to assess the significance of the modules. We experimentally validate our approach and compare it with state-of-the-art techniques

A Revised Publication Model for ECML PKDD

ECML PKDD is the main European conference on machine learning and data mining. Since its foundation it implemented the publication model common in computer science: there was one conference deadline; conference submissions were reviewed by a program committee; papers were accepted with a low acceptance rate. Proceedings were published in several Springer Lecture Notes in Artificial (LNAI) volumes, while selected papers were invited to special issues of the Machine Learning and Data Mining and Knowledge Discovery journals. In recent years, this model has however come under stress. Problems include: reviews are of highly variable quality; the purpose of bringing the community together is lost; reviewing workloads are high; the information content of conferences and journals decreases; there is confusion among scientists in interdisciplinary contexts. In this paper, we present a new publication model, which will be adopted for the ECML PKDD 2013 conference, and aims to solve some of the problems of the traditional model. The key feature of this model is the creation of a journal track, which is open to submissions all year long and allows for revision cycles.Comment: 13 page

Inter- and intracellular resistance and vulnerability in motor neuron diseases

Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are fatal diseases presenting with degeneration and loss of lower motor neurons in the brainstem and spinal cord. However, oculomotor and trochlear motor neurons that control eye movement, are resistant until late stages of disease. Moreover, individual motor neurons degenerate in a distinct pattern. Firstly, the distal synapse between motor neuron and muscle, the neuromuscular junction (NMJ), becomes denervated. Subsequently, the neuron degenerates in a retrograde manner, until the cell body in the spinal cord is lost later in disease. This highlights the distal axon and NMJ as the most vulnerable subcellular compartment of motor neurons. We set out to investigate the mechanisms that underlie the resistance of oculomotor neurons, as well as the differential vulnerability within motor neurons themselves. We first validated the resistance of oculomotor neurons in two mouse models of ALS and SMA in Paper I. Next, we performed a large transcriptomic screen of differentially vulnerable motor pools in SMA mice throughout disease progression in Paper II. We used laser capture microdissection (LCM) to dissect motor neurons from different pools in the brainstem and spinal cord. Here we revealed pathways and transcripts that were enriched only in the resistant oculomotor neurons that serve to prevent them from going into apoptosis, as well as promote their regeneration. We showed that applying one of the oculomotor-enriched transcripts, Gdf15, to vulnerable spinal motor neurons derived from stem cells improved their survival. Next, in Paper III we utilised in vitro approaches and generated a model of oculomotor resistance in ALS by deriving both spinal and oculomotor neurons from mouse embryonic stem cells. Here we found that in vitro oculomotor neurons are more resistant to excitotoxic stress and have increased levels of prosurvival Akt-signaling, which also held up in LCM-dissected post-mortem human spinal and oculomotor neurons. To investigate the vulnerability of the distal axon, we generated a technique called Axon-Seq in Paper IV, that allows transcriptomic profiling of isolated motor axons by culturing motor neurons in microfluidic chambers. We subsequently used this technique in Paper V to show that human stem cell-derived motor neurons carrying ALS-causative mutations in FUS and TDP-43 showed unique transcriptome dysregulation in somas and axons. This implies that different pathways of degeneration are at play between subcellular compartments, and provides novel targets for therapeutic intervention directed at different compartments of the motor neuron

Strategisch gedrag, planning en prestatie: Een inductieve studie binnen de computerbranche

Long Range Planning;Computer Industry;computer science

Understanding the Role of Willingness to Cannibalize in New Service Development

The objective of the present study is to develop a model of explaining new service development behavior using the concept of willingness to cannibalize existing sales, current capabilities and prior investments. The paper is structured as follows. First, we review the literature relevant for our work. Second, we explain our conceptual model. Next, we report on the research method used and present empirical evidence from 217 service firms. We close with a discussion and recommendations for future research.

De Miles and Snow-typologie: Een exploratieve studie in de meubelbranche

Furniture Industry;industrieen

Unveiling combinatorial regulation through the combination of ChIP information and in silico cis-regulatory module detection

Computationally retrieving biologically relevant cis-regulatory modules (CRMs) is not straightforward. Because of the large number of candidates and the imperfection of the screening methods, many spurious CRMs are detected that are as high scoring as the biologically true ones. Using ChIP-information allows not only to reduce the regions in which the binding sites of the assayed transcription factor (TF) should be located, but also allows restricting the valid CRMs to those that contain the assayed TF (here referred to as applying CRM detection in a query-based mode). In this study, we show that exploiting ChIP-information in a query-based way makes in silico CRM detection a much more feasible endeavor. To be able to handle the large datasets, the query-based setting and other specificities proper to CRM detection on ChIP-Seq based data, we developed a novel powerful CRM detection method 'CPModule'. By applying it on a well-studied ChIP-Seq data set involved in self-renewal of mouse embryonic stem cells, we demonstrate how our tool can recover combinatorial regulation of five known TFs that are key in the self-renewal of mouse embryonic stem cells. Additionally, we make a number of new predictions on combinatorial regulation of these five key TFs with other TFs documented in TRANSFAC