Tyrosine-1 of RNA Polymerase II CTD Controls Global Termination of Gene Transcription in Mammals

1. Download high-res image (146KB)
2. Download full-size image

     

Structural Architecture of the Nucleosome Remodeler ISWI Determined from Cross-Linking,Mass Spectrometry,SAXS, and Modeling

1. Download high-res image (219KB)
2. Download full-size image

     

Impact of Chiral Bioanalytical Methods on the Bioequivalence of Ibuprofen Products Containing Ibuprofen Lysinate and Ibuprofen Base

The purpose was to assess the impact of the use of a chiral bioanalytical method on the conclusions of a bioequivalence study that compared two ibuprofen suspensions with different rates of absorption. A comparison of the conclusion of bioequivalence between a chiral method and an achiral approach was made. Plasma concentrations of R‐ibuprofen and S‐ibuprofen were determined using a chiral bioanalytical method; bioequivalence was tested for R‐ibuprofen and for S‐ibuprofen separately and for the sum of both enantiomers as an approach for an achiral bioanalytical method. The 90% confidence interval (90% CI) that would have been obtained with an achiral bioanalytical method (90% CI: C_max: 117.69–134.46; AUC₀^t: 104.75–114.45) would have precluded the conclusion of bioequivalence. This conclusion cannot be generalized to the active enantiomer (90% CI: C_max: 103.36–118.38; AUC₀^t: 96.52–103.12), for which bioequivalence can be concluded, and/or the distomer (90% CI: C_max: 132.97–151.33; AUC₀^t: 115.91–135.77) for which a larger difference was observed. Chiral bioanalytical methods should be required when 1) the enantiomers exhibit different pharmacodynamics and 2) the exposure (AUC or C_max) ratio of enantiomers is modified by a difference in the rate of absorption. Furthermore, the bioequivalence conclusion should be based on all enantiomers, since the distomer(s) might not be completely inert, in contrast to what is required in the current regulatory guidelines. In those cases where it is unknown if the ratio between enantiomers is modified by changing the rate of absorption, chiral bioanalytical methods should be employed unless enantiomers exhibit the same pharmacodynamics. Chirality 28:429–433, 2016. © 2016 Wiley Periodicals, Inc.     

Fine scale prediction of ecological community composition using a two-step sequential Machine Learning ensemble

Prediction is one of the last frontiers in ecology. Indeed, predicting fine-scale species composition in natural systems is a complex challenge as multiple abiotic and biotic processes operate simultaneously to determine local species abundances. On the one hand, species intrinsic performance and their tolerance limits to different abiotic pressures modulate species abundances. On the other hand, there is growing recognition that species interactions play an equally important role in limiting or promoting such abundances within ecological communities. Here, we present a joint effort between ecologists and data scientists to use data-driven models to predict species abundances using reasonably easy to obtain data. We propose a sequential data-driven modeling approach that in a first step predicts the potential species abundances based on abiotic variables, and in a second step uses these predictions to model the realized abundances once accounting for species competition. Using a curated data set over five years we predict fine-scale species abundances in a highly diverse annual plant community. Our models show a remarkable spatial predictive accuracy using only easy-to-measure variables in the field, yet such predictive power is lost when temporal dynamics are taken into account. This result suggests that predicting future abundances requires longer time series analysis to capture enough variability. In addition, we show that these data-driven models can also suggest how to improve mechanistic models by adding missing variables that affect species performance such as particular soil conditions (e.g. carbonate availability in our case). Robust models for predicting fine-scale species composition informed by the mechanistic understanding of the underlying abiotic and biotic processes can be a pivotal tool for conservation, especially given the human-induced rapid environmental changes we are experiencing. This objective can be achieved by promoting the knowledge gained with classic modelling approaches in ecology and recently developed data-driven models.     

Biodiversity ensures plant–pollinator phenological synchrony against climate change

Climate change has the potential to alter the phenological synchrony between interacting mutualists, such as plants and their pollinators. However, high levels of biodiversity might buffer the negative effects of species‐specific phenological shifts and maintain synchrony at the community level, as predicted by the biodiversity insurance hypothesis. Here, we explore how biodiversity might enhance and stabilise phenological synchrony between a valuable crop, apple and its native pollinators. We combine 46 years of data on apple flowering phenology with historical records of bee pollinators over the same period. When the key apple pollinators are considered altogether, we found extensive synchrony between bee activity and apple peak bloom due to complementarity among bee species’ activity periods, and also a stable trend over time due to differential responses to warming climate among bee species. A simulation model confirms that high biodiversity levels can ensure plant–pollinator phenological synchrony and thus pollination function.     

Proteome dynamics at broken replication forks reveal a distinct ATM-directed repair response suppressing DNA double-strand break ubiquitination

1. Download : Download high-res image (232KB)
2. Download : Download full-size image

     

Mouse TRIP13/PCH2 Is Required for Recombination and Normal Higher-Order Chromosome Structure during Meiosis

Accurate chromosome segregation during meiosis requires that homologous chromosomes pair and become physically connected so that they can orient properly on the meiosis I spindle. These connections are formed by homologous recombination closely integrated with the development of meiosis-specific, higher-order chromosome structures. The yeast Pch2 protein has emerged as an important factor with roles in both recombination and chromosome structure formation, but recent analysis suggested that TRIP13, the mouse Pch2 ortholog, is not required for the same processes. Using distinct Trip13 alleles with moderate and severe impairment of TRIP13 function, we report here that TRIP13 is required for proper synaptonemal complex formation, such that autosomal bivalents in Trip13-deficient meiocytes frequently displayed pericentric synaptic forks and other defects. In males, TRIP13 is required for efficient synapsis of the sex chromosomes and for sex body formation. Furthermore, the numbers of crossovers and chiasmata are reduced in the absence of TRIP13, and their distribution along the chromosomes is altered, suggesting a role for TRIP13 in aspects of crossover formation and/or control. Recombination defects are evident very early in meiotic prophase, soon after DSB formation. These findings provide evidence for evolutionarily conserved functions for TRIP13/Pch2 in both recombination and formation of higher order chromosome structures, and they support the hypothesis that TRIP13/Pch2 participates in coordinating these key aspects of meiotic chromosome behavior.     

Cdc42-dependent actin dynamics controls maturation and secretory activity of dendritic cells

Cell division cycle 42 (Cdc42) is a member of the Rho guanosine triphosphatase family and has pivotal functions in actin organization, cell migration, and proliferation. To further study the molecular mechanisms of dendritic cell (DC) regulation by Cdc42, we used Cdc42-deficient DCs. Cdc42 deficiency renders DCs phenotypically mature as they up-regulate the co-stimulatory molecule CD86 from intracellular storages to the cell surface. Cdc42 knockout DCs also accumulate high amounts of invariant chain–major histocompatibility complex (MHC) class II complexes at the cell surface, which cannot efficiently present peptide antigens (Ag’s) for priming of Ag-specific CD4 T cells. Proteome analyses showed a significant reduction in lysosomal MHC class II–processing proteins, such as cathepsins, which are lost from DCs by enhanced secretion. As these effects on DCs can be mimicked by chemical actin disruption, our results propose that Cdc42 control of actin dynamics keeps DCs in an immature state, and cessation of Cdc42 activity during DC maturation facilitates secretion as well as rapid up-regulation of intracellular molecules to the cell surface.