Toxicity modelling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells

High attrition rates of novel anti-cancer drugs highlight the need for improved models to predict toxicity. Although polo-like kinase 1 (Plk1) inhibitors are attractive candidates for drug development, the role of Plk1 in primary cells remains widely unexplored. Therefore, we evaluated the utility of an RNA interference-based model to assess responses to an inducible knockdown (iKD) of Plk1 in adult mice. Here we show that Plk1 silencing can be achieved in several organs, although adverse events are rare. We compared responses in Plk1-iKD mice with those in primary cells kept under controlled culture conditions. In contrast to the addiction of many cancer cell lines to the non-oncogene Plk1, the primary cells' proliferation, spindle assembly and apoptosis exhibit only a low dependency on Plk1. Responses to Plk1-depletion, both in cultured primary cells and in our iKD-mouse model, correspond well and thus provide the basis for using validated iKD mice in predicting responses to therapeutic interventions

Relative validation of the KiGGS Food Frequency Questionnaire among adolescents in Germany

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to determine the relative validity of the self-administered Food Frequency Questionnaire (FFQ) "What do you eat?", which was used in the German National Health Interview and Examination Survey for Children and Adolescents (KiGGS 2003-2006).</p> <p>Methods</p> <p>The validation was conducted in the EsKiMo Nutrition Module, a subsample of KiGGS. The study population included 1,213 adolescents aged between 12 and 17. A modified diet history interview DISHES (Dietary Interview Software for Health Examination Studies) was used as the reference method. In order to compare the food groups, the data assessed with both instruments were aggregated to 40 similar food groups. The statistical analysis included calculating and comparing Spearman's correlation coefficients, calculating the mean difference between both methods, and ranking participants (quartiles) according to food group consumption, including weighted kappa coefficients. Correlations were also evaluated for relative body weight and socioeconomic status subgroups.</p> <p>Results</p> <p>In the total study population the Spearman correlation coefficients ranged from 0.22 for pasta/rice to 0.69 for margarine; most values were 0.50 and higher. The mean difference ranged between 1.4% for milk and 100.3% for pasta/rice. The 2.5 percentiles and 97.5 percentiles indicated a wide range of differences. Classifications in the same and adjacent quartile varied between 70.1% for pasta/rice and 90.8% for coffee. For most groups, Cohen's weighted kappa showed values between 0.21 and 0.60. Only for white bread and pasta/rice were values less than 0.20. Most of the 40 food groups showed acceptable to good correlations in all investigated subgroups concerning age, sex, body weight and socio-economic status.</p> <p>Conclusions</p> <p>The KiGGS FFQ showed fair to moderate ranking validity except for pasta/rice and white bread. However, the ability to assess absolute intakes is limited. The correlation coefficients for most food items were similar for normal weight and overweight as well as for different socio-economic status groups. Overall, the results of the relative validity were comparable to FFQs from the current literature.</p

Effects of variable magma supply on mid-ocean ridge eruptions : constraints from mapped lava flow fields along the Galápagos Spreading Center

Author Posting. © American Geophysical Union, 2012. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 13 (2012): Q08014, doi:10.1029/2012GC004163.Mapping and sampling of 18 eruptive units in two study areas along the Galápagos Spreading Center (GSC) provide insight into how magma supply affects mid-ocean ridge (MOR) volcanic eruptions. The two study areas have similar spreading rates (53 versus 55 mm/yr), but differ by 30% in the time-averaged rate of magma supply (0.3 × 106 versus 0.4 × 106 m3/yr/km). Detailed geologic maps of each study area incorporate observations of flow contacts and sediment thickness, in addition to sample petrology, geomagnetic paleointensity, and inferences from high-resolution bathymetry data. At the lower-magma-supply study area, eruptions typically produce irregularly shaped clusters of pillow mounds with total eruptive volumes ranging from 0.09 to 1.3 km3. At the higher-magma-supply study area, lava morphologies characteristic of higher effusion rates are more common, eruptions typically occur along elongated fissures, and eruptive volumes are an order of magnitude smaller (0.002–0.13 km3). At this site, glass MgO contents (2.7–8.4 wt. %) and corresponding liquidus temperatures are lower on average, and more variable, than those at the lower-magma-supply study area (6.2–9.1 wt. % MgO). The differences in eruptive volume, lava temperature, morphology, and inferred eruption rates observed between the two areas along the GSC are similar to those that have previously been related to variable spreading rates on the global MOR system. Importantly, the documentation of multiple sequences of eruptions at each study area, representing hundreds to thousands of years, provides constraints on the variability in eruptive style at a given magma supply and spreading rate.This work was supported by the National Science Foundation grants OCE08–49813, OCE08–50052, and OCE08– 49711.2013-02-2

Meta-analysis of multidecadal biodiversity trends in Europe

Local biodiversity trends over time are likely to be decoupled from global trends, as local processes may compensate or counteract global change. We analyze 161 long-term biological time series (15-91 years) collected across Europe, using a comprehensive dataset comprising similar to 6,200 marine, freshwater and terrestrial taxa. We test whether (i) local long-term biodiversity trends are consistent among biogeoregions, realms and taxonomic groups, and (ii) changes in biodiversity correlate with regional climate and local conditions. Our results reveal that local trends of abundance, richness and diversity differ among biogeoregions, realms and taxonomic groups, demonstrating that biodiversity changes at local scale are often complex and cannot be easily generalized. However, we find increases in richness and abundance with increasing temperature and naturalness as well as a clear spatial pattern in changes in community composition (i.e. temporal taxonomic turnover) in most biogeoregions of Northern and Eastern Europe. The global biodiversity decline might conceal complex local and group-specific trends. Here the authors report a quantitative synthesis of longterm biodiversity trends across Europe, showing how, despite overall increase in biodiversity metric and stability in abundance, trends differ between regions, ecosystem types, and taxa.peerReviewe

Sequential treatment of ADHD in mother and child (AIMAC study): importance of the treatment phases for intervention success in a randomized trial

Background: The efficacy of parent-child training (PCT) regarding child symptoms may be reduced if the mother has attention-deficit/hyperactivity disorder (ADHD). The AIMAC study (ADHD in Mothers and Children) aimed to compensate for the deteriorating effect of parental psychopathology by treating the mother (Step 1) before the beginning of PCT (Step 2). This secondary analysis was particularly concerned with the additional effect of the Step 2 PCT on child symptoms after the Step 1 treatment. Methods: The analysis included 143 mothers and children (aged 6–12 years) both diagnosed with ADHD. The study design was a two-stage, two-arm parallel group trial (Step 1 treatment group [TG]: intensive treatment of the mother including psychotherapy and pharmacotherapy; Step 1 control group [CG]: supportive counseling only for mother; Step 2 TG and CG: PCT). Single- and multi-group analyses with piecewise linear latent growth curve models were applied to test for the effects of group and phase. Child symptoms (e.g., ADHD symptoms, disruptive behavior) were rated by three informants (blinded clinician, mother, teacher). Results: Children in the TG showed a stronger improvement of their disruptive behavior as rated by mothers than those in the CG during Step 1 (Step 1: TG vs. CG). In the CG, according to reports of the blinded clinician and the mother, the reduction of children’s disruptive behavior was stronger during Step 2 than during Step 1 (CG: Step 1 vs. Step 2). In the TG, improvement of child outcome did not differ across treatment steps (TG: Step 1 vs. Step 2). Conclusions: Intensive treatment of the mother including pharmacotherapy and psychotherapy may have small positive effects on the child’s disruptive behavior. PCT may be a valid treatment option for children with ADHD regarding disruptive behavior, even if mothers are not intensively treated beforehand. Trial registration: ISRCTN registry ISRCTN73911400. Registered: 29 March 2007

TDP-43 is intercellularly transmitted across axon terminals

Transactive response DNA-binding protein 43 kD (TDP-43) is an aggregation-prone prion-like domain-containing protein and component of pathological intracellular aggregates found in most amyotrophic lateral sclerosis (ALS) patients. TDP-43 oligomers have been postulated to be released and subsequently nucleate TDP-43 oligomerization in recipient cells, which might be the molecular correlate of the systematic symptom spreading observed during ALS progression. We developed a novel protein complementation assay allowing quantification of TDP-43 oligomers in living cells. We demonstrate the exchange of TDP-43 between cell somata and the presence of TDP-43 oligomers in microvesicles/exosomes and show that microvesicular TDP-43 is preferentially taken up by recipient cells where it exerts higher toxicity than free TDP-43. Moreover, studies using microfluidic neuronal cultures suggest both anterograde and retrograde trans-synaptic spreading of TDP-43. Finally, we demonstrate TDP-43 oligomer seeding by TDP-43-containing material derived from both cultured cells and ALS patient brain lysate. Thus, using an innovative detection technique, we provide evidence for preferentially microvesicular uptake as well as both soma-to-soma "horizontal" and bidirectional "vertical" synaptic intercellular transmission and prion-like seeding of TDP-43.status: publishe

Links across ecological scales: Plant biomass responses to elevated CO2_2

The degree to which elevated CO$_2$ concentrations (e[CO$_2$]) increase the amount of carbon (C) assimilated by vegetation plays a key role in climate change. However, due to the short-term nature of CO$_2$ enrichment experiments and the lack of reconciliation between different ecological scales, the effect of e[CO$_2$] on plant biomass stocks remains a major uncertainty in future climate projections. Here, we review the effect of e[CO$_2$] on plant biomass across multiple levels of ecological organization, scaling from physiological responses to changes in population-, community-, ecosystem-, and global-scale dynamics. We find that evidence for a sustained biomass response to e[CO$_2$] varies across ecological scales, leading to diverging conclusions about the responses of individuals, populations, communities, and ecosystems. While the distinct focus of every scale reveals new mechanisms driving biomass accumulation under e[CO$_2$], none of them provides a full picture of all relevant processes. For example, while physiological evidence suggests a possible long-term basis for increased biomass accumulation under e[CO$_2$] through sustained photosynthetic stimulation, population-scale evidence indicates that a possible e[CO$_2$]-induced increase in mortality rates might potentially outweigh the effect of increases in plant growth rates on biomass levels. Evidence at the global scale may indicate that e[CO$_2$] has contributed to increased biomass cover over recent decades, but due to the difficulty to disentangle the effect of e[CO$_2$] from a variety of climatic and land-use-related drivers of plant biomass stocks, it remains unclear whether nutrient limitations or other ecological mechanisms operating at finer scales will dampen the e[CO$_2$] effect over time. By exploring these discrepancies, we identify key research gaps in our understanding of the effect of e[CO$_2$] on plant biomass and highlight the need to integrate knowledge across scales of ecological organization so that large-scale modeling can represent the finer-scale mechanisms needed to constrain our understanding of future terrestrial C storage.ISSN:1354-1013ISSN:1365-248

Accurate mass–time tag library for LC/MS-based metabolite profiling of medicinal plants

We report the development and testing of an accurate mass–time tag library for plant natural product profiling. [Display omitted] ► The development of an accurate mass–time tag approach for the identification of plant natural products is reported. ► LC/MS and MS/MS data sets were integrated into online spectral search tools and repositories. ► The utility was demonstrated by the detection of active principles in 27 medicinal plant species. We report the development and testing of an accurate mass–time (AMT) tag approach for the LC/MS-based identification of plant natural products (PNPs) in complex extracts. An AMT tag library was developed for approximately 500 PNPs with diverse chemical structures, detected in electrospray and atmospheric pressure chemical ionization modes (both positive and negative polarities). In addition, to enable peak annotations with high confidence, MS/MS spectra were acquired with three different fragmentation energies. The LC/MS and MS/MS data sets were integrated into online spectral search tools and repositories (Spektraris and MassBank), thus allowing users to interrogate their own data sets for the potential presence of PNPs. The utility of the AMT tag library approach is demonstrated by the detection and annotation of active principles in 27 different medicinal plant species with diverse chemical constituents