Computer-Supported Resolution of Measurement Conflicts: A Case-Study in Materials Science

Resolving conflicts between different measurements ofa property of a physical system may be a key step in a discoveryprocess. With the emergence of large-scale databases and knowledgebases with property measurements, computer support for the task ofconflict resolution has become highly desirable. We will describe amethod for model-based conflict resolution and the accompanyingcomputer tool KIMA, which have been applied in a case-study inmaterials science. In order to be a useful aid to scientists, the toolneeds to be integrated with other tools in a computer-supporteddiscovery environment. We will give an outline of such acomputer-supported discovery environment and argue that its use mightlead to new ways of doing science, so-called computer regimes.     

Spontaneous functional correction of homozygous fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism.

Somatic mosaicism due to reversion of a pathogenic allele to wild type has been described in several autosomal recessive disorders. The best known mechanism involves intragenic mitotic recombination or gene conversion in compound heterozygous patients, whereby one allele serves to restore the wild-type sequence in the other. Here we document for the first time functional correction of a pathogenic microdeletion, microinsertion and missense mutation in homozygous Fanconi anaemia (FA) patients resulting from compensatory secondary sequence alterations in cis. The frameshift mutation 1615delG in FANCA was compensated by two additional single base-pair deletions (1637delA and 1641delT); another FANCA frameshift mutation, 3559insG, was compensated by 3580insCGCTG; and a missense mutation in FANCC(1749T-->G, Leu496Arg) was altered by 1748C-->T, creating a cysteine codon. Although in all three cases the predicted proteins were different from wild type, their cDNAs complemented the characteristic hypersensitivity of FA cells to crosslinking agents, thus establishing a functional correction to wild type.     

A radiation hybrid map of the zebrafish genome.

Recent large-scale mutagenesis screens have made the zebrafish the first vertebrate organism to allow a forward genetic approach to the discovery of developmental control genes. Mutations can be cloned positionally, or placed on a simple sequence length polymorphism (SSLP) map to match them with mapped candidate genes and expressed sequence tags (ESTs). To facilitate the mapping of candidate genes and to increase the density of markers available for positional cloning, we have created a radiation hybrid (RH) map of the zebrafish genome. This technique is based on somatic cell hybrid lines produced by fusion of lethally irradiated cells of the species of interest with a rodent cell line. Random fragments of the donor chromosomes are integrated into recipient chromosomes or retained as separate minichromosomes. The radiation-induced breakpoints can be used for mapping in a manner analogous to genetic mapping, but at higher resolution and without a need for polymorphism. Genome-wide maps exist for the human, based on three RH panels of different resolutions, as well as for the dog, rat and mouse. For our map of the zebrafish genome, we used an existing RH panel and 1,451 sequence tagged site (STS) markers, including SSLPs, cloned candidate genes and ESTs. Of these, 1,275 (87.9%) have significant linkage to at least one other marker. The fraction of ESTs with significant linkage, which can be used as an estimate of map coverage, is 81.9%. We found the average marker retention frequency to be 18.4%. One cR3000 is equivalent to 61 kb, resulting in a potential resolution of approximately 350 kb.     

Identification of the familial cylindromatosis tumour-suppressor gene

Familial cylindromatosis is an autosomal dominant genetic predisposition to multiple tumours of the skin appendages. The susceptibility gene (CYLD) has previously been localized to chromosome 16q and has the genetic attributes of a tumour-suppressor gene (recessive oncogene). Here we have identified CYLD by detecting germline mutations in 21 cylindromatosis families and somatic mutations in 1 sporadic and 5 familial cylindromas. All mutations predict truncation or absence of the encoded protein. CYLD encodes three cytoskeletal-associated-protein-glycine-conserved (CAP-GLY) domains, which are found in proteins that coordinate the attachment of organelles to microtubules. CYLD also has sequence homology to the catalytic domain of ubiquitin carboxy-terminal hydrolases (UCH).     

North American ice-sheet dynamics and the onset of 100,000-year glacial cycles

The onset of major glaciations in the Northern Hemisphere about 2.7 million years ago was most probably induced by climate cooling during the late Pliocene epoch. These glaciations, during which the Northern Hemisphere ice sheets successively expanded and retreated, are superimposed on this long-term climate trend, and have been linked to variations in the Earth's orbital parameters. One intriguing problem associated with orbitally driven glacial cycles is the transition from 41,000-year to 100,000-year climatic cycles that occurred without an apparent change in insolation forcing. Several hypotheses have been proposed to explain the transition, both including and excluding ice-sheet dynamics. Difficulties in finding a conclusive answer to this palaeoclimatic problem are related to the lack of sufficiently long records of ice-sheet volume or sea level. Here we use a comprehensive ice-sheet model and a simple ocean-temperature model to extract three-million-year mutually consistent records of surface air temperature, ice volume and sea level from marine benthic oxygen isotopes. Although these records and their relative phasings are subject to considerable uncertainty owing to limited availability of palaeoclimate constraints, the results suggest that the gradual emergence of the 100,000-year cycles can be attributed to the increased ability of the merged North American ice sheets to survive insolation maxima and reach continental-scale size. The oversized, wet-based ice sheet probably responded to the subsequent insolation maximum by rapid thinning through increased basal-sliding, thereby initiating a glacial termination. Based on our assessment of the temporal changes in air temperature and ice volume during individual glacials, we demonstrate the importance of ice dynamics and ice-climate interactions in establishing the 100,000-year glacial cycles, with enhanced North American ice-sheet growth and the subsequent merging of the ice sheets being key elements.     

Towards new β-lactam antibiotics

Antibiotics have had a profound impact on human health and belong to one of the largest-selling classes of drugs worldwide. Introduced into industrial production only some half century ago, these miracle drugs have been the main contributors to the recent increase in human life expectancy. However, the accelerated emergence of bacteria that are resistant to multiple antibiotic types now appears as the most serious threat to continuing success in the treatment of infectious diseases. Recent advances in our knowledge of the structures and mechanisms of enzymes in the biosynthetic pathways of penicillins and cephalosporins, amongst the most important antibiotics in current use, have identified a common structural core together with common iron- and cosubstrate-binding motifs. The diversity in the catalytic specificities of these oxygenases using very similar structural platforms suggests that altering the substrate and product specificities of these enzymes should be possible in the laboratory. This opens up new avenues for industrial production and medical utilisation.     

Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter.

Leukoencephalopathy with vanishing white matter (VWM) is an inherited brain disease that occurs mainly in children. The course is chronic-progressive with additional episodes of rapid deterioration following febrile infection or minor head trauma. We have identified mutations in EIF2B5 and EIF2B2, encoding the epsilon- and beta-subunits of the translation initiation factor eIF2B and located on chromosomes 3q27 and 14q24, respectively, as causing VWM. We found 16 different mutations in EIF2B5 in 29 patients from 23 families. We also found two distantly related individuals who were homozygous with respect to a missense mutation in EIF2B2, affecting a conserved amino acid. Three other patients also had mutations in EIF2B2. As eIF2B has an essential role in the regulation of translation under different conditions, including stress, this may explain the rapid deterioration of people with VWM under stress. Mutant translation initiation factors have not previously been implicated in disease.     

A Property of the CHAID Partitioning Method for Dichotomous Randomized Response Data and Categorical Predictors

In this paper, we present empirical and theoretical results on classification trees for randomized response data. We considered a dichotomous sensitive response variable with the true status intentionally misclassified by the respondents using rules prescribed by a randomized response method. We assumed that classification trees are grown using the Pearson chi-square test as a splitting criterion, and that the randomized response data are analyzed using classification trees as if they were not perturbed. We proved that classification trees analyzing observed randomized response data and estimated true data have a one-to-one correspondence in terms of ranking the splitting variables. This is illustrated using two real data sets.     

PLATFORM SELECTION FOR COMPLEX SYSTEMS:BUILDING AUTOMATION SYSTEMS

Automation systems for buildings interconnect components and technologies from the information technology industry and the telecommunications industry.In these industries,existing platforms and new platforms（that are designed to make building automation systems work） compete for market acceptance and consequently several platform battles among suppliers for building automation networking are being waged.It is unclear what the outcome of these battles will be and also which factors are important in achieving platform dominance.Taking the fuzziness of decision makers＇ judgments into account,a fuzzy multi-criteria decision-making methodology called the Fuzzy Analytic Hierarchy Process is applied to investigate the importance of such factors in platform battles for building automation networking.We present the relative importance of the factors for three types of platforms（subsystem platforms,system platforms,and evolved subsystem platforms）.The results provide a first indication that the set of important factors differs per type of platform.For example,when focusing on other stakeholders,for subsystem platforms,the previous installed base is of importance;for system platforms,the diversity of the network of stakeholders is essential;and for evolved subsystem platforms,the judiciary is an important factor.