Framework for the Integration of Service and Technology Strategies

Organised by: Cranfield UniversityAfter sales service is a highly profitable business for manufacturers of technology-driven products. Due to this fact competitors want to share in high profit margins. At the same time after sales business has to deal with an increasing range of variants of products and technologies, shorter life cycles and changing customer demands. In spite of these manifold challenges, often neither after sales departments are involved in the early product development stage nor are customer demands and technical parameters considered in the service development processes entirely. Therefore an integration of service and technology strategies is necessary. This paper presents a framework for this integration that visualises the complex interdependencies and interfaces between service as well as product and motor vehicle workshop technologies.Mori Seiki – The Machine Tool Compan

LC-MS based quantification of 2’-ribosylated nucleosides Ar(p) and Gr(p) in tRNA

RNA nucleosides are often naturally modified into complex non-canonical structures with key biological functions. Here we report LC-MS quantification of the Ar(p) and Gr(p) 2'-ribosylated nucleosides in tRNA using deuterium labelled standards, and the first detection of Gr(p) in complex fungi

Spatial normalization for voxel-based lesion symptom mapping: impact of registration approaches

BackgroundVoxel-based lesion symptom mapping (VLSM) assesses the relation of lesion location at a voxel level with a specific clinical or functional outcome measure at a population level. Spatial normalization, that is, mapping the patient images into an atlas coordinate system, is an essential pre-processing step of VLSM. However, no consensus exists on the optimal registration approach to compute the transformation nor are downstream effects on VLSM statistics explored. In this work, we evaluate four registration approaches commonly used in VLSM pipelines: affine (AR), nonlinear (NLR), nonlinear with cost function masking (CFM), and enantiomorphic registration (ENR). The evaluation is based on a standard VLSM scenario: the analysis of statistical relations of brain voxels and regions in imaging data acquired early after stroke onset with follow-up modified Rankin Scale (mRS) values.Materials and methodsFluid-attenuated inversion recovery (FLAIR) MRI data from 122 acute ischemic stroke patients acquired between 2 and 3 days after stroke onset and corresponding lesion segmentations, and 30 days mRS values from a European multicenter stroke imaging study (I-KNOW) were available and used in this study. The relation of the voxel location with follow-up mRS was assessed by uni- as well as multi-variate statistical testing based on the lesion segmentations registered using the four different methods (AR, NLR, CFM, ENR; implementation based on the ANTs toolkit).ResultsThe brain areas evaluated as important for follow-up mRS were largely consistent across the registration approaches. However, NLR, CFM, and ENR led to distortions in the patient images after the corresponding nonlinear transformations were applied. In addition, local structures (for instance the lateral ventricles) and adjacent brain areas remained insufficiently aligned with corresponding atlas structures even after nonlinear registration.ConclusionsFor VLSM study designs and imaging data similar to the present work, an additional benefit of nonlinear registration variants for spatial normalization seems questionable. Related distortions in the normalized images lead to uncertainties in the VLSM analyses and may offset the theoretical benefits of nonlinear registration

Changes of bivalent chromatin coincide with increased expression of developmental genes in cancer

Bivalent (poised or paused) chromatin comprises activating and repressing histone modifications at the same location. This combination of epigenetic marks at promoter or enhancer regions keeps genes expressed at low levels but poised for rapid activation. Typically, DNA at bivalent promoters is only lowly methylated in normal cells, but frequently shows elevated methylation levels in cancer samples. Here, we developed a universal classifier built from chromatin data that can identify cancer samples solely from hypermethylation of bivalent chromatin. Tested on over 7,000 DNA methylation data sets from several cancer types, it reaches an AUC of 0.92. Although higher levels of DNA methylation are often associated with transcriptional silencing, counter-intuitive positive statistical dependencies between DNA methylation and expression levels have been recently reported for two cancer types. Here, we re-analyze combined expression and DNA methylation data sets, comprising over 5,000 samples, and demonstrate that the conjunction of hypermethylation of bivalent chromatin and up-regulation of the corresponding genes is a general phenomenon in cancer. This up-regulation affects many developmental genes and transcription factors, including dozens of homeobox genes and other genes implicated in cancer. Thus, we reason that the disturbance of bivalent chromatin may be intimately linked to tumorigenesis

The use of information theory in evolutionary biology

Information is a key concept in evolutionary biology. Information is stored in biological organism's genomes, and used to generate the organism as well as to maintain and control it. Information is also "that which evolves". When a population adapts to a local environment, information about this environment is fixed in a representative genome. However, when an environment changes, information can be lost. At the same time, information is processed by animal brains to survive in complex environments, and the capacity for information processing also evolves. Here I review applications of information theory to the evolution of proteins as well as to the evolution of information processing in simulated agents that adapt to perform a complex task.Comment: 25 pages, 7 figures. To appear in "The Year in Evolutionary Biology", of the Annals of the NY Academy of Science

Transfer RNA in Decoding and the Wobble Hypothesis

Translation of the genetic code stored in messenger ribonucleic acid (RNA) requires significantly fewer transfer RNAs (35–45) than there are codons (61, amino acid specifying). This is achieved through an increased flexibility in the allowable base-pair interactions between the messenger RNA and the transfer RNA involving the third position of the codon and the first position of the corresponding anticodon. The rules governing this RNA:RNA interaction were originally summarised in Crick's ‘wobble hypothesis’. Covalent modification of the first base of an anticodon of a transfer RNA can profoundly affect the degree of flexibility in its base-pairing potential by either extending or restricting such interactions. Recent studies suggest that the rate at which a codon is processed by the ribosome is influenced by whether or not decoding of that codon is via wobble base interactions. Yet, in spite of this flexibility and different rates of processing, decoding by transfer RNAs is achieved with considerable accuracy

The highly rearranged mitochondrial genomes of the crabs Maja crispata and Maja squinado (Majidae) and gene order evolution in Brachyura

Abstract We sequenced the mitochondrial genomes of the spider crabs Maja crispata and Maja squinado (Majidae, Brachyura). Both genomes contain the whole set of 37 genes characteristic of Bilaterian genomes, encoded on both \u3b1- and \u3b2-strands. Both species exhibit the same gene order, which is unique among known animal genomes. In particular, all the genes located on the \u3b2-strand form a single block. This gene order was analysed together with the other nine gene orders known for the Brachyura. Our study confirms that the most widespread gene order (BraGO) represents the plesiomorphic condition for Brachyura and was established at the onset of this clade. All other gene orders are the result of transformational pathways originating from BraGO. The different gene orders exhibit variable levels of genes rearrangements, which involve only tRNAs or all types of genes. Local homoplastic arrangements were identified, while complete gene orders remain unique and represent signatures that can have a diagnostic value. Brachyura appear to be a hot-spot of gene order diversity within the phylum Arthropoda. Our analysis, allowed to track, for the first time, the fully evolutionary pathways producing the Brachyuran gene orders. This goal was achieved by coupling sophisticated bioinformatic tools with phylogenetic analysis

Improved systematic tRNA gene annotation allows new insights into the evolution of mitochondrial tRNA structures and into the mechanisms of mitochondrial genome rearrangements

Transfer RNAs (tRNAs) are present in all types of cells as well as in organelles. tRNAs of animal mitochondria show a low level of primary sequence conservation and exhibit ‘bizarre’ secondary structures, lacking complete domains of the common cloverleaf. Such sequences are hard to detect and hence frequently missed in computational analyses and mitochondrial genome annotation. Here, we introduce an automatic annotation procedure for mitochondrial tRNA genes in Metazoa based on sequence and structural information in manually curated covariance models. The method, applied to re-annotate 1876 available metazoan mitochondrial RefSeq genomes, allows to distinguish between remaining functional genes and degrading ‘pseudogenes’, even at early stages of divergence. The subsequent analysis of a comprehensive set of mitochondrial tRNA genes gives new insights into the evolution of structures of mitochondrial tRNA sequences as well as into the mechanisms of genome rearrangements. We find frequent losses of tRNA genes concentrated in basal Metazoa, frequent independent losses of individual parts of tRNA genes, particularly in Arthropoda, and wide-spread conserved overlaps of tRNAs in opposite reading direction. Direct evidence for several recent Tandem Duplication-Random Loss events is gained, demonstrating that this mechanism has an impact on the appearance of new mitochondrial gene orders

A single methyltransferase YefA (RlmCD) catalyses both m5U747 and m5U1939 modifications in Bacillus subtilis 23S rRNA

Methyltransferases that use S-adenosylmethionine (AdoMet) as a cofactor to catalyse 5-methyl uridine (m5U) formation in tRNAs and rRNAs are widespread in Bacteria and Eukaryota, and are also found in certain Archaea. These enzymes belong to the COG2265 cluster, and the Gram-negative bacterium Escherichia coli possesses three paralogues. These comprise the methyltransferases TrmA that targets U54 in tRNAs, RlmC that modifies U747 in 23S rRNA and RlmD that is specific for U1939 in 23S rRNA. The tRNAs and rRNAs of the Gram-positive bacterium Bacillus subtilis have the same three m5U modifications. However, as previously shown, the m5U54 modification in B. subtilis tRNAs is catalysed in a fundamentally different manner by the folate-dependent enzyme TrmFO, which is unrelated to the E. coli TrmA. Here, we show that methylation of U747 and U1939 in B. subtilis rRNA is catalysed by a single enzyme, YefA that is a COG2265 member. A recombinant version of YefA functions in an E. coli m5U-null mutant adding the same two rRNA methylations. The findings suggest that during evolution, COG2265 enzymes have undergone a series of changes in target specificity and that YefA is closer to an archetypical m5U methyltransferase. To reflect its dual specificity, YefA is renamed RlmCD

Crystal structure of human selenocysteine tRNA

Selenocysteine (Sec) is the 21st amino acid in translation. Sec tRNA (tRNASec) has an anticodon complementary to the UGA codon. We solved the crystal structure of human tRNASec. tRNASec has a 9-bp acceptor stem and a 4-bp T stem, in contrast with the 7-bp acceptor stem and the 5-bp T stem in the canonical tRNAs. The acceptor stem is kinked between the U6:U67 and G7:C66 base pairs, leading to a bent acceptor-T stem helix. tRNASec has a 6-bp D stem and a 4-nt D loop. The long D stem includes unique A14:U21 and G15:C20a pairs. The D-loop:T-loop interactions include the base pairs G18:U55 and U16:U59, and a unique base triple, U20:G19:C56. The extra arm comprises of a 6-bp stem and a 4-nt loop. Remarkably, the D stem and the extra arm do not form tertiary interactions in tRNASec. Instead, tRNASec has an open cavity, in place of the tertiary core of a canonical tRNA. The linker residues, A8 and U9, connecting the acceptor and D stems, are not involved in tertiary base pairing. Instead, U9 is stacked on the first base pair of the extra arm. These features might allow tRNASec to be the target of the Sec synthesis/incorporation machineries