Neutral tumor evolution?

No abstract available

Unchanged muscle fiber conduction velocity relates to mild acidosis during exhaustive bicycling

Muscle fiber conduction velocity (MFCV) has often been shown to decrease during standardized fatiguing isometric contractions. However, several studies have indicated that the MFCV may remain constant during fatiguing dynamic exercise. It was investigated if these observations can be related to the absence of a large decrease in pH and if MFCV can be considered as a good indicator of acidosis, also during dynamic bicycle exercise. High-density surface electromyography (HDsEMG) was combined with read-outs of muscle energetics recorded by in vivo 31P magnetic resonance spectroscopy (MRS). Measurements were performed during serial exhausting bouts of bicycle exercise at three different workloads. The HDsEMG recordings revealed a small and incoherent variation of MFCV during all high-intensity exercise bouts. 31P MRS spectra revealed a moderate decrease in pH at the end of exercise (~0.3 units down to 6.8) and a rapid ancillary drop to pH 6.5 during recovery 30 s post-exercise. This additional degree of acidification caused a significant decrease in MFCV during cycling immediately after the rest period. From the data a significant correlation between MFCV and [H+] ([H+] = 10−pH) was calculated (p < 0.001, Pearson’s R = −0.87). Our results confirmed the previous observations of MFCV remaining constant during fatiguing dynamic exercise. A constant MFCV is in line with a low degree of acidification, considering the presence of a correlation between pH and MFCV after further increasing acidification

Differential susceptibility in youth: evidence that 5-HTTLPR x positive parenting is associated with positive affect ‘for better and worse'

Positive affect has been implicated in the phenomenological experience of various psychiatric disorders, vulnerability to develop psychopathology and overall socio-emotional functioning. However, developmental influences that may contribute to positive affect have been understudied. Here, we studied youths' 5-HTTLPR genotype and rearing environment (degree of positive and supportive parenting) to investigate the differential susceptibility hypothesis (DSH) that youth carrying short alleles of 5-HTTLPR would be more influenced and responsive to supportive and unsupportive parenting, and would exhibit higher and lower positive affect, respectively. Three independent studies tested this gene–environment interaction (GxE) in children and adolescents (age range 9–15 years; total N=1874). In study 1 (N=307; 54% girls), positive/supportive parenting was assessed via parent report, in study 2 (N=197; 58% girls) via coded observations of parent–child interactions in the laboratory and in study 3 (N=1370; 53% girls) via self report. Results from all the three studies showed that youth homozygous for the functional short allele of 5-HTTLPR were more responsive to parenting as environmental context in a ‘for better and worse' manner. Specifically, the genetically susceptible youth (that is, S'S' group) who experienced unsupportive, non-positive parenting exhibited low levels of positive affect, whereas higher levels of positive affect were reported by genetically susceptible youth under supportive and positive parenting conditions. These GxE findings are consistent with the DSH and may inform etiological models and interventions in developmental psychopathology focused on positive emotion, parenting and genetic susceptibility

Systematic Identification of Combinatorial Drivers and Targets in Cancer Cell Lines

There is an urgent need to elicit and validate highly efficacious targets for combinatorial intervention from large scale ongoing molecular characterization efforts of tumors. We established an in silico bioinformatic platform in concert with a high throughput screening platform evaluating 37 novel targeted agents in 669 extensively characterized cancer cell lines reflecting the genomic and tissue-type diversity of human cancers, to systematically identify combinatorial biomarkers of response and co-actionable targets in cancer. Genomic biomarkers discovered in a 141 cell line training set were validated in an independent 359 cell line test set. We identified co-occurring and mutually exclusive genomic events that represent potential drivers and combinatorial targets in cancer. We demonstrate multiple cooperating genomic events that predict sensitivity to drug intervention independent of tumor lineage. The coupling of scalable in silico and biologic high throughput cancer cell line platforms for the identification of co-events in cancer delivers rational combinatorial targets for synthetic lethal approaches with a high potential to pre-empt the emergence of resistance

A review of elliptical and disc galaxy structure, and modern scaling laws

A century ago, in 1911 and 1913, Plummer and then Reynolds introduced their models to describe the radial distribution of stars in `nebulae'. This article reviews the progress since then, providing both an historical perspective and a contemporary review of the stellar structure of bulges, discs and elliptical galaxies. The quantification of galaxy nuclei, such as central mass deficits and excess nuclear light, plus the structure of dark matter halos and cD galaxy envelopes, are discussed. Issues pertaining to spiral galaxies including dust, bulge-to-disc ratios, bulgeless galaxies, bars and the identification of pseudobulges are also reviewed. An array of modern scaling relations involving sizes, luminosities, surface brightnesses and stellar concentrations are presented, many of which are shown to be curved. These 'redshift zero' relations not only quantify the behavior and nature of galaxies in the Universe today, but are the modern benchmark for evolutionary studies of galaxies, whether based on observations, N-body-simulations or semi-analytical modelling. For example, it is shown that some of the recently discovered compact elliptical galaxies at 1.5 < z < 2.5 may be the bulges of modern disc galaxies.Comment: Condensed version (due to Contract) of an invited review article to appear in "Planets, Stars and Stellar Systems"(www.springer.com/astronomy/book/978-90-481-8818-5). 500+ references incl. many somewhat forgotten, pioneer papers. Original submission to Springer: 07-June-201

The stellar and sub-stellar IMF of simple and composite populations

The current knowledge on the stellar IMF is documented. It appears to become top-heavy when the star-formation rate density surpasses about 0.1Msun/(yr pc^3) on a pc scale and it may become increasingly bottom-heavy with increasing metallicity and in increasingly massive early-type galaxies. It declines quite steeply below about 0.07Msun with brown dwarfs (BDs) and very low mass stars having their own IMF. The most massive star of mass mmax formed in an embedded cluster with stellar mass Mecl correlates strongly with Mecl being a result of gravitation-driven but resource-limited growth and fragmentation induced starvation. There is no convincing evidence whatsoever that massive stars do form in isolation. Various methods of discretising a stellar population are introduced: optimal sampling leads to a mass distribution that perfectly represents the exact form of the desired IMF and the mmax-to-Mecl relation, while random sampling results in statistical variations of the shape of the IMF. The observed mmax-to-Mecl correlation and the small spread of IMF power-law indices together suggest that optimally sampling the IMF may be the more realistic description of star formation than random sampling from a universal IMF with a constant upper mass limit. Composite populations on galaxy scales, which are formed from many pc scale star formation events, need to be described by the integrated galactic IMF. This IGIMF varies systematically from top-light to top-heavy in dependence of galaxy type and star formation rate, with dramatic implications for theories of galaxy formation and evolution.Comment: 167 pages, 37 figures, 3 tables, published in Stellar Systems and Galactic Structure, Vol.5, Springer. This revised version is consistent with the published version and includes additional references and minor additions to the text as well as a recomputed Table 1. ISBN 978-90-481-8817-

Demographic responses of Daphnia magna fed transgenic Bt-maize

The food/feed quality of a variety of genetically modified (GM) maize expressing Cry1Ab Bt-toxin was tested over the life-cycle of Daphnia magna, an arthropod commonly used as model organism in ecotoxicological studies. Demographic responses were compared between animals fed GM or unmodified (UM) near isogenic maize, with and without the addition of predator smell. Age-specific data on survival and birth rates were integrated and analysed using life tables and Leslie matrices. Survival, fecundity and population growth rate (PGR) data generally disfavoured transgenic Bt-maize as feed for D. magna compared to animals fed the unmodified (UM) near isogenic line of maize. Decomposition of age-specific effects revealed that the most important contributions to a reduced PGR in the GM-fed group came from both fecundity and survival differences early in life. We conclude that juvenile and young adult stages are the most sensitive experimental units and should be prioritized in future research. These stages are often omitted in toxicological/ecotoxicological studies and in feeding trials

Comparative Genomic Analyses of Copper Transporters and Cuproproteomes Reveal Evolutionary Dynamics of Copper Utilization and Its Link to Oxygen

Copper is an essential trace element in many organisms and is utilized in all domains of life. It is often used as a cofactor of redox proteins, but is also a toxic metal ion. Intracellular copper must be carefully handled to prevent the formation of reactive oxygen species which pose a threat to DNA, lipids, and proteins. In this work, we examined patterns of copper utilization in prokaryotes by analyzing the occurrence of copper transporters and copper-containing proteins. Many organisms, including those that lack copper-dependent proteins, had copper exporters, likely to protect against copper ions that inadvertently enter the cell. We found that copper use is widespread among prokaryotes, but also identified several phyla that lack cuproproteins. This is in contrast to the use of other trace elements, such as selenium, which shows more scattered and reduced usage, yet larger selenoproteomes. Copper transporters had different patterns of occurrence than cuproproteins, suggesting that the pathways of copper utilization and copper detoxification are independent of each other. We present evidence that organisms living in oxygen-rich environments utilize copper, whereas the majority of anaerobic organisms do not. In addition, among copper users, cuproproteomes of aerobic organisms were larger than those of anaerobic organisms. Prokaryotic cuproproteomes were small and dominated by a single protein, cytochrome c oxidase. The data are consistent with the idea that proteins evolved to utilize copper following the oxygenation of the Earth

Comparative Analysis of mRNA Targets for Human PUF-Family Proteins Suggests Extensive Interaction with the miRNA Regulatory System

Genome-wide identification of mRNAs regulated by RNA-binding proteins is crucial to uncover post-transcriptional gene regulatory systems. The conserved PUF family RNA-binding proteins repress gene expression post-transcriptionally by binding to sequence elements in 3′-UTRs of mRNAs. Despite their well-studied implications for development and neurogenesis in metazoa, the mammalian PUF family members are only poorly characterized and mRNA targets are largely unknown. We have systematically identified the mRNAs associated with the two human PUF proteins, PUM1 and PUM2, by the recovery of endogenously formed ribonucleoprotein complexes and the analysis of associated RNAs with DNA microarrays. A largely overlapping set comprised of hundreds of mRNAs were reproducibly associated with the paralogous PUM proteins, many of them encoding functionally related proteins. A characteristic PUF-binding motif was highly enriched among PUM bound messages and validated with RNA pull-down experiments. Moreover, PUF motifs as well as surrounding sequences exhibit higher conservation in PUM bound messages as opposed to transcripts that were not found to be associated, suggesting that PUM function may be modulated by other factors that bind conserved elements. Strikingly, we found that PUF motifs are enriched around predicted miRNA binding sites and that high-confidence miRNA binding sites are significantly enriched in the 3′-UTRs of experimentally determined PUM1 and PUM2 targets, strongly suggesting an interaction of human PUM proteins with the miRNA regulatory system. Our work suggests extensive connections between the RBP and miRNA post-transcriptional regulatory systems and provides a framework for deciphering the molecular mechanism by which PUF proteins regulate their target mRNAs

Moving to capture children’s attention: developing a methodology for measuring visuomotor attention

Attention underpins many activities integral to a child’s development. However, methodological limitations currently make large-scale assessment of children’s attentional skill impractical, costly and lacking in ecological validity. Consequently we developed a measure of ‘Visual Motor Attention’ (VMA) - a construct defined as the ability to sustain and adapt visuomotor behaviour in response to task-relevant visual information. In a series of experiments, we evaluated the capability of our method to measure attentional processes and their contributions in guiding visuomotor behaviour. Experiment 1 established the method’s core features (ability to track stimuli moving on a tablet-computer screen with a hand-held stylus) and demonstrated its sensitivity to principled manipulations in adults’ attentional load. Experiment 2 standardised a format suitable for use with children and showed construct validity by capturing developmental changes in executive attention processes. Experiment 3 tested the hypothesis that children with and without coordination difficulties would show qualitatively different response patterns, finding an interaction between the cognitive and motor factors underpinning responses. Experiment 4 identified associations between VMA performance and existing standardised attention assessments and thereby confirmed convergent validity. These results establish a novel approach to measuring childhood attention that can produce meaningful functional assessments that capture how attention operates in an ecologically valid context (i.e. attention's specific contribution to visuomanual action)