Application of regulatory sequence analysis and metabolic network analysis to the interpretation of gene expression data

We present two complementary approaches for the interpretation of clusters of co-regulated genes, such as those obtained from DNA chips and related methods. Starting from a cluster of genes with similar expression profiles, two basic questions can be asked: 1. Which mechanism is responsible for the coordinated transcriptional response of the genes? This question is approached by extracting motifs that are shared between the upstream sequences of these genes. The motifs extracted are putative cis-acting regulatory elements. 2. What is the physiological meaning for the cell to express together these genes? One way to answer the question is to search for potential metabolic pathways that could be catalyzed by the products of the genes. This can be done by selecting the genes from the cluster that code for enzymes, and trying to assemble the catalyzed reactions to form metabolic pathways. We present tools to answer these two questions, and we illustrate their use with selected examples in the yeast Saccharomyces cerevisiae. The tools are available on the web (http://ucmb.ulb.ac.be/bioinformatics/rsa-tools/; http://www.ebi.ac.uk/research/pfbp/; http://www.soi.city.ac.uk/~msch/)

Processing of quantitative information, investigated with fMRI.

Ever since the discovery of the ‘number neurons’, the neural representation of quantity in the brain has been thought of as a number-selective coding system. In such a system, the neuron is activated by a specific quantity but numerically close quantities also activate the neuron. Recent fMRI studies also confirmed the existence of a number-selective system in humans. Several computational modelling studies predicted a number-sensitive coding stage as a necessary preceding stage to the number-selective neurons (Verguts & Fias, 2004). In this coding scheme, the coding is analogous to the number it represents. This can be implemented by neurons that respond monotonically to number (e.g., more strongly for larger numbers). Recently, the biological reality of such a system has been demonstrated by use of single-cell recording, in the lateral intraparietal area (LIP) of the macaque monkey. In this thesis, we searched for evidence of number-sensitive coding in humans. Using a priming paradigm, we found behavioural evidence for a number-sensitive system in humans for small non-symbolic numerosities (1 to 5). Using event-related fMRI, we showed number-sensitive activation in the human LIP area in the same number range. Remarkably, we could not extend these results for larger numerosities (2 to 64). Whereas the lack of results in the behavioural priming experiment could be due to an insensitivity of the method, this was not a plausible explanation in the fMRI experiment, as the activity measured in human LIP significantly decreased for numerosities larger than 8. We therefore concluded that the number-sensitive system is liable to a capacity limit for higher numerosities, which could be caused by the use of lateral inhibition. We further suggest that the implementation of this lateral inhibition is dependent on the particular task set, and that the capacity limit is not present (or less stringent) when numerosity is not behaviourally relevant. This could explain the finding of number-sensitive neurons for larger numerosities in monkeys. Finally, we suggest that a different mechanism is employed when numerical value of large numerosities is relevant. This leads to the conclusion that dot patterns in the small and large number range are processed differently

LEDAcrypt: QC-LDPC Code-Based Cryptosystems with Bounded Decryption Failure Rate

We consider the QC-LDPC code-based cryptosystems named LEDAcrypt, which are under consideration by NIST for the second round of the post-quantum cryptography standardization initiative. LEDAcrypt is the result of the merger of the key encapsulation mechanism LEDAkem and the public-key cryptosystem LEDApkc, which were submitted to the first round of the same competition. We provide a detailed quantification of the quantum and classical computational efforts needed to foil the cryptographic guarantees of these systems. To this end, we take into account the best known attacks that can be mounted against them employing both classical and quantum computers, and compare their computational complexities with the ones required to break AES, coherently with the NIST requirements. Assuming the original LEDAkem and LEDApkc parameters as a reference, we introduce an algorithmic optimization procedure to design new sets of parameters for LEDAcrypt. These novel sets match the security levels in the NIST call and make the C reference implementation of the systems exhibit significantly improved figures of merit, in terms of both running times and key sizes. As a further contribution, we develop a theoretical characterization of the decryption failure rate (DFR) of LEDAcrypt cryptosystems, which allows new instances of the systems with guaranteed low DFR to be designed. Such a characterization is crucial to withstand recent attacks exploiting the reactions of the legitimate recipient upon decrypting multiple ciphertexts with the same private key, and consequentially it is able to ensure a lifecycle of the corresponding key pairs which can be sufficient for the wide majority of practical purposes

Cephalosporin-3’-diazeniumdiolate NO-donor prodrug PYRRO-C3D enhances azithromycin susceptibility of non-typeable Haemophilus influenzae biofilms

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Objectives: PYRRO-C3D is a cephalosporin-3-diazeniumdiolate nitric oxide (NO)-donor prodrug designed to selectively deliver NO to bacterial infection sites. The objective of this study was to assess the activity of PYRRO-C3D against non-typeable Haemophilus influenzae (NTHi) biofilms and examine the role of NO in reducing biofilm-associated antibiotic tolerance. Methods: The activity of PYRRO-C3D on in vitro NTHi biofilms was assessed through CFU enumeration and confocal microscopy. NO release measurements were performed using an ISO-NO probe. NTHi biofilms grown on primary ciliated respiratory epithelia at an air-liquid interface were used to investigate the effects of PYRRO-C3D in the presence of host tissue. Label-free LC/MS proteomic analyses were performed to identify differentially expressed proteins following NO treatment. Results: PYRRO-C3D specifically released NO in the presence of NTHi, while no evidence of spontaneous NO release was observed when the compound was exposed to primary epithelial cells. NTHi lacking β-lactamase activity failed to trigger NO release. Treatment significantly increased the susceptibility of in vitro NTHi biofilms to azithromycin, causing a log-fold reduction in viability (p<0.05) relative to azithromycin alone. The response was more pronounced for biofilms grown on primary respiratory epithelia, where a 2-log reduction was observed (p<0.01). Label-free proteomics showed that NO increased expression of sixteen proteins involved in metabolic and transcriptional/translational functions. Conclusions: NO release from PYRRO-C3D enhances the efficacy of azithromycin against NTHi biofilms, putatively via modulation of NTHi metabolic activity. Adjunctive therapy with NO mediated through PYRRO-C3D represents a promising approach for reducing biofilm associated antibiotic tolerance

Domain specific software design for decision aiding

McDonnell Aircraft Company (MCAIR) is involved in many large multi-discipline design and development efforts of tactical aircraft. These involve a number of design disciplines that must be coordinated to produce an integrated design and a successful product. Our interpretation of a domain specific software design (DSSD) is that of a representation or framework that is specialized to support a limited problem domain. A DSSD is an abstract software design that is shaped by the problem characteristics. This parallels the theme of object-oriented analysis and design of letting the problem model directly drive the design. The DSSD concept extends the notion of software reusability to include representations or frameworks. It supports the entire software life cycle and specifically leads to improved prototyping capability, supports system integration, and promotes reuse of software designs and supporting frameworks. The example presented in this paper is the task network architecture or design which was developed for the MCAIR Pilot's Associate program. The task network concept supported both module development and system integration within the domain of operator decision aiding. It is presented as an instance where a software design exhibited many of the attributes associated with DSSD concept

Change blindness: eradication of gestalt strategies

Arrays of eight, texture-defined rectangles were used as stimuli in a one-shot change blindness (CB) task where there was a 50% chance that one rectangle would change orientation between two successive presentations separated by an interval. CB was eliminated by cueing the target rectangle in the first stimulus, reduced by cueing in the interval and unaffected by cueing in the second presentation. This supports the idea that a representation was formed that persisted through the interval before being 'overwritten' by the second presentation (Landman et al, 2003 Vision Research 43149–164]. Another possibility is that participants used some kind of grouping or Gestalt strategy. To test this we changed the spatial position of the rectangles in the second presentation by shifting them along imaginary spokes (by ±1 degree) emanating from the central fixation point. There was no significant difference seen in performance between this and the standard task [F(1,4)=2.565, p=0.185]. This may suggest two things: (i) Gestalt grouping is not used as a strategy in these tasks, and (ii) it gives further weight to the argument that objects may be stored and retrieved from a pre-attentional store during this task