Somatic point mutations in mtDNA control region are influenced by genetic background and associated with healthy aging: a GEHA stud

Tissue specific somatic mutations occurring in the mtDNA control region have been proposed to provide a survival advantage. Data on twins and on relatives of long-lived subjects suggested that the occurrence/accumulation of these mutations may be genetically influenced. To further investigate control region somatic heteroplasmy in the elderly, we analyzed the segment surrounding the nt 150 position (previously reported as specific of Leukocytes) in various types of leukocytes obtained from 195 ultra-nonagenarians sib-pairs of Italian or Finnish origin collected in the frame of the GEHA Project. We found a significant correlation of the mtDNA control region heteroplasmy between sibs, confirming a genetic influence on this phenomenon. Furthermore, many subjects showed heteroplasmy due to mutations different from the C150T transition. In these cases heteroplasmy was correlated within sibpairs in Finnish and northern Italian samples, but not in southern Italians. This suggested that the genetic contribution to control region mutations may be population specific. Finally, we observed a possible correlation between heteroplasmy and Hand Grip strength, one of the best markers of physical performance and of mortality risk in the elderly. Our study provides new evidence on the relevance of mtDNA somatic mutations in aging and longevity and confirms that the occurrence of specific point mutations in the mtDNA control region may represent a strategy for the age-related remodelling of organismal functions.

Molecular dynamics simulation model for the quantitative assessment of tool wear during single point diamond turning of cubic silicon carbide

Silicon carbide (SiC) is a material of great technological interest for engineering applications concerning hostile environments where silicon-based components cannot work (beyond 623 K). Single point diamond turning (SPDT) has remained a superior and viable method to harness process efficiency and freeform shapes on this harder material. However, it is extremely difficult to machine this ceramic consistently in the ductile regime due to sudden and rapid tool wear. It thus becomes non trivial to develop an accurate understanding of tool wear mechanism during SPDT of SiC in order to identify measures to suppress wear to minimize operational cost.

In this paper, molecular dynamics (MD) simulation has been deployed with a realistic analytical bond order potential (ABOP) formalism based potential energy function to understand tool wear mechanism during single point diamond turning of SiC. The most significant result was obtained using the radial distribution function which suggests graphitization of diamond tool during the machining process. This phenomenon occurs due to the abrasive processes between these two ultra hard materials. The abrasive action results in locally high temperature which compounds with the massive cutting forces leading to sp3–sp2 order–disorder transition of diamond tool. This represents the root cause of tool wear during SPDT operation of cubic SiC. Further testing led to the development of a novel method for quantitative assessment of the progression of diamond tool wear from MD simulations.

Phenotypic and genotypic variations within a single bacteriophage species.

Background: Although horizontal gene transfer plays a pivotal role in bacteriophage evolution, many lytic phage genomes are clearly shaped by vertical evolution. We investigated the influence of minor genomic deletions and insertions on various phage-related phenotypic and serological properties. Findings. We collected ten different isolates of Pseudomonas aeruginosa bacteriophage KMV. All sequenced genomes (42-43 kb, long direct terminal repeats) are nearly identical, which intuitively implied strongly similar infections cycles. However, their latent periods vary between 21 and 28 minutes and they are able to lyse between 5 and 58% of a collection of 107 clinical P. aeruginosa strains. We also noted that phages with identical tail structures displayed profound differences in host spectra. Moreover, point mutations in tail and spike proteins were sufficient to evade neutralization by two phage-specific antisera, isolated from rabbits. Conclusion: Although all analyzed phages are 83-97% identical at the genome level, they display a surprisingly large variation in various phenotypic properties. The small overlap in host spectrum and their ability to readily escape immune defences against a nearly identical phage are promising elements for the application of these phages in phage therapy. © 2011 Ceyssens et al; licensee BioMed Central Ltd.


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Mutations affecting the Rossman fold of isoleucyl-tRNA synthetase are correlated with low-level mupirocin resistance in Staphylococcus aureus.

The isoleucyl-tRNA synthetase (ileS) gene was sequenced in toto from 9 and in part from 31 Staphylococcus aureus strains with various degrees of susceptibility to mupirocin. All strains for which the mupirocin MIC was greater than 8 µg/ml contained point mutations affecting the Rossman fold via Val-to-Phe changes at either residue 588 (V588F) or residue 631 (V631F). The importance of the V588F mutation was confirmed by an allele-specific PCR survey of 32 additional strains. Additional mutations of uncertain significance were found in residues clustered on the surface of the IleS protein.

Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication.

The recently discovered aging-dependent large accumulation of point mutations in the human fibroblast mtDNA control region raised the question of their occurrence in postmitotic tissues. In the present work, analysis of biopsied or autopsied human skeletal muscle revealed the absence or only minimal presence of those mutations. By contrast, surprisingly, most of 26 individuals 53 to 92 years old, without a known history of neuromuscular disease, exhibited at mtDNA replication control sites in muscle an accumulation of two new point mutations, i.e., A189G and T408A, which were absent or marginally present in 19 individuals younger than 34 years. These two mutations were not found in fibroblasts from 22 subjects 64 to 101 years of age (T408A), or were present only in three subjects in very low amounts (A189G). Furthermore, in several older individuals exhibiting an accumulation in muscle of one or both of these mutations, they were nearly absent in other tissues, whereas the most frequent fibroblast-specific mutation (T414G) was present in skin, but not in muscle. Among eight additional individuals exhibiting partial denervation of their biopsied muscle, four subjects >80 years old had accumulated the two muscle-specific point mutations, which were, conversely, present at only very low levels in four subjects <or =40 years old. The striking tissue specificity of the muscle mtDNA mutations detected here and their mapping at critical sites for mtDNA replication strongly point to the involvement of a specific mutagenic machinery and to the functional relevance of these mutations.

A new model based approach for the prediction and optimisation of thermal homogeneity in single screw extrusion

In polymer extrusion, delivery of a melt which is homogenous in composition and temperature is important for good product quality. However, the process is inherently prone to temperature fluctuations which are difficult to monitor and control via single point based conventional thermo- couples. In this work, the die melt temperature profile was monitored by a thermocouple mesh and the data obtained was used to generate a model to predict the die melt temperature profile. A novel nonlinear model was then proposed which was demonstrated to be in good agreement with training and unseen data. Furthermore, the proposed model was used to select optimum process settings to achieve the desired average melt temperature across the die while improving the temperature homogeneity. The simulation results indicate a reduction in melt temperature variations of up to 60%.

Modelling relative motion to facilitate intra-limb coordination

The importance of relative motion information when modelling a novel motor skill was examined. Participants were assigned to one of four groups. Groups 1 and 2 viewed demonstrations of a skilled cricket bowler presented in either video or point light format. Group 3 observed a single point of light pertaining to the wrist of the skilled bowler only. Participants in Group 4 did not receive a demonstration and acted as controls. During 60 acquisition trials, participants in the demonstration groups viewed a model five times before each 10-trial block. Retention was examined the following day. Intra-limb coordination was assessed for the right elbow relative to the wrist in comparison to the model. The demonstration groups showed greater concordance with the model than the control group. However, the wrist group performed less like the model than the point light and video groups, who did not differ from each other. These effects were maintained in retention. Relative motion information aided the acquisition of intra-limb coordination, while making this information more salient (through point lights) provided no additional benefit. The motion of the models bowling arm was replicated more closely than the non-bowling arm, suggesting that information from the end-effector is prioritized during observation for later reproduction.

High-resolution organellar genome analysis of Triticum and Aegilops sheds new light on cytoplasm evolution in wheat

We have utilised polymorphic chloroplast microsatellites to analyse cytoplasmic relationships between accessions in the genera Triticum and Aegilops. Sequencing of PCR products revealed point mutations and insertions/deletions in addition to the standard repeat length expansion/contraction which most likely represent ancient synapomorphies. Phylogenetic analyses revealed three distinct groups of accessions. One of these contained all the non-Aegilops speltoides S-type cytoplasm species, another comprised almost exclusively A, C, D, M, N, T and U cytoplasm-type accessions and the third contained the polyploid Triticum species and all the Ae. speltoides accessions, further confirming that Ae. speltoides or a closely related but now extinct species was the original B-genome donor of cultivated polyploid wheat. Successive decreases in levels of genetic diversity due to domestication were also observed. Finally, we highlight the importance of elucidating longer-term evolutionary processes operating at microsatellite repeat loci.

Sorption behavior of cationic and anionic dyes from aqueous solution on different types of activated carbons

The effect of dye molecular charges on their adsorption from solution was investigated by using different types of activated carbon adsorbents. Two types of model systems were used representing cationic and anionic dyes. Screening investigations using single point tests were used throughout the study. Cationic dyes, of which Methylene Blue is an example, showed a higher adsorption tendency towards activated carbon over anionic dyes represented by an ate-type reactive compound. Of the number of activated carbons tested, only one of the adsorbents showed an exception to this behavior, and a good relation was observed between Methylene Blue capacity and activated carbon performance. The high capacity of cationic dyes in comparison to anionic dyes was also evident in the results obtained by a preliminary kinetic study carried out on the selected systems. Surface net charge of activated carbon and the nature of attractions between the molecules were suggested to be one of the reasons attributed for this behavior.

High tech start-ups in University Science Park incubators: The relationship between the start-up’s lifecycle progression and use of the incubator’s resources

University Science Park incubators (USIs) have emerged as a means by which Government, academia and business can develop high technology business firms (spin out HTBFs) from initial conception through to becoming established small firms, which are ready to move beyond the Science Park confines. Although there is considerable literature on how USIs can be improved and developed there is a paucity of studies, which explore how lifecycle development within HTBFs in USIs can affect how they use the unique resources and opportunities of the USI. Moreover, there is a focus on single point in time studies, which do not adequately investigate the longitudinal dynamics of HTBF lifecycle development within USIs. Therefore, the aim of this paper is to explore the longitudinal use of the unique resources of the USI by HTBFs at different lifecycle stages. The research methodology involved 18 HTBFs within two separate USIs. A series of longitudinal interviews and focus groups were conducted with HTBFs and USI staff over a 36-month period. NUD*IST software was used in developing the coding and analysis of transcripts. The results show that a HTBF's propensity to make effective use of the USI's resources and support increases as the lifecycle stage of the company increases and the small-firm searches for independence and autonomy. Therefore, further research is required to investigate the following two outstanding questions; firstly, which usage pattern is associated with the HTBF's ultimate success or failure in the marketplace? And secondly, are there any services missing from the observed array that the USI could provide to enhance the HTBF's degree of ultimate success? © 2007 Elsevier Ltd. All rights reserved.

Evidence That Interspecies Polymorphism in the Human and Rat Cholecystokinin Receptor-2 Affects Structure of the Binding Site for the Endogenous Agonist Cholecystokinin

The cholecystokinin (CCK) receptor-2 exerts very important central and peripheral functions by binding the neuropeptides cholecystokinin or gastrin. Because this receptor is a potential therapeutic target, great interest has been devoted to the identification of efficient antagonists. However, interspecies genetic polymorphism that does not alter cholecystokinin-induced signaling was shown to markedly affect activity of synthetic ligands. In this context, precise structural study of the agonist binding site on the human cholecystokinin receptor-2 is a prerequisite to elucidating the molecular basis for its activation and to optimizing properties of synthetic ligands. In this study, using site-directed mutagenesis and molecular modeling, we delineated the binding site for CCK on the human cholecystokinin receptor-2 by mutating amino acids corresponding to that of the rat homolog. By doing so, we demonstrated that, although resembling that of rat homolog, the human cholecystokinin receptor-2 binding site also displays important distinct structural features that were demonstrated by susceptibility to several point mutations (F120A, Y189A, H207A). Furthermore, docking of CCK in the human and rat cholecystokinin receptor-2, followed by dynamic simulations, allowed us to propose a plausible structural explanation of the experimentally observed difference between rat and human cholecystokinin-2 receptors.

Fronts, jumps and secondary introductions suggested as different invasion patterns in marine species, with an increase in spread rates over time

Not all introduced (invasive) species in a region will spread from a single point of introduction. Long-distance dispersal or further introductions can obscure the pattern of spread, but the regional importance of such processes is difficult to gauge. These difficulties are further compounded when information on the multiple scale process of invasive species range expansion is reduced to one-dimensional estimates of spread (e. g. km yr(-1)). We therefore compared the results of two different metrics of range expansion: maximum linear rate of spread and accumulation of occupied grid squares (50 x 50 km) over time. An analysis of records for 54 species of introduced marine macrophytes in the Mediterranean and northeast Atlantic revealed cases where the invasion process was probably missed (e. g. Atlantic Bonnemaisonia hamifera) and suggested cases of secondary introductions or erratic jump dispersal (Dasysiphonia sp. and Womersleyella setacea). A majority of species analysed showed evidence for an accumulation of invaded sites without a clear invasion front. Estimates of spread rate are increasing for more recent introductions. The increase is greater than can be accounted for by temporally varying search effort and implies a historical increase in vector efficiency and/or a decreased resistance of native communities to invasion.