Learning a functional grammar of protein domains using natural language word embedding techniques

In this paper, using Word2vec, a widely-used natural language processing method, we demonstrate that protein domains may have a learnable implicit semantic “meaning” in the context of their functional contributions to the multi-domain proteins in which they are found. Word2vec is a group of models which can be used to produce semantically meaningful embeddings of words or tokens in a fixed-dimension vector space. In this work, we treat multi-domain proteins as “sentences” where domain identifiers are tokens which may be considered as “words.” Using all InterPro (Finn et al. 2017) pfam domain assignments we observe that the embedding could be used to suggest putative GO assignments for Pfam (Finn et al. 2016) domains of unknown function.     

A Bayesian nonparametric testing procedure for paired samples

We propose a Bayesian hypothesis testing procedure for comparing the distributions of paired samples. The procedure is based on a flexible model for the joint distribution of both samples. The flexibility is given by a mixture of Dirichlet processes. Our proposal uses a spike-slab prior specification for the base measure of the Dirichlet process and a particular parametrization for the kernel of the mixture in order to facilitate comparisons and posterior inference. The joint model allows us to derive the marginal distributions and test whether they differ or not. The procedure exploits the correlation between samples, relaxes the parametric assumptions, and detects possible differences throughout the entire distributions. A Monte Carlo simulation study comparing the performance of this strategy to other traditional alternatives is provided. Finally, we apply the proposed approach to spirometry data collected in the United States to investigate changes in pulmonary function in children and adolescents in response to air polluting factors.     

Combined Force-Torque Spectroscopy of Proteins by Means of Multiscale Molecular Simulation

Assessing the structural properties of large proteins is important to gain an understanding of their function in, e.g., biological systems or biomedical applications. We propose a method to examine the mechanical properties of proteins subject to applied forces by means of multiscale simulation. Both stretching and torsional forces are considered, and these may be applied independently of each other. As a proof of principle, we apply torsional forces to a coarse-grained continuum model of the antibody protein immunoglobulin G using fluctuating finite element analysis and use it to identify the area of strongest deformation. This region is essential to the torsional properties of the molecule as a whole because it represents the softest, most deformable domain. Zooming in, this part of the molecule is subjected to torques and stretching forces using molecular dynamics simulations on an atomistically resolved level to investigate its torsional properties. We calculate the torsional resistance as a function of the rotation of the domain while subjecting it to various stretching forces. From this, we assess how the measured twist-torque profiles develop with increasing stretching force and show that they exhibit torsion stiffening, in qualitative agreement with experimental findings. We argue that combining the twist-torque profiles for various stretching forces effectively results in a combined force-torque spectroscopy analysis, which may serve as a mechanical signature for a biological macromolecule.     

Random epigenetic modulation of CHO cells by repeated knockdown of DNA methyltransferases increases population diversity and enables sorting of cells with higher production capacities

Chinese hamster ovary (CHO) cells produce a large share of today's biopharmaceuticals. Still, the generation of satisfactory producer cell lines is a tedious undertaking. Recently, it was found that CHO cells, when exposed to new environmental conditions, modify their epigenome, suggesting that cells adapt their gene expression pattern to handle new challenges. The major aim of the present study was to employ artificially induced, random changes in the DNA-methylation pattern of CHO cells to diversify cell populations and consequently increase the finding of cell lines with improved cellular characteristics. To achieve this, DNA methyltransferases and/or the ten-eleven translocation enzymes were downregulated by RNA interference over a time span of ∼16 days. Methylation analysis of the resulting cell pools revealed that the knockdown of DNA methyltransferases was highly effective in randomly demethylating the genome. The same approach, when applied to stable CHO producer cells resulted in (a) an increased productivity diversity in the cell population, and (b) a higher number of outliers within the population, which resulted in higher specific productivity and titer in the sorted cells. These findings suggest that epigenetics play a previously underestimated, but actually important role in defining the overall cellular behavior of production clones.     

Microhabitat contributes to microgeographic divergence in threespine stickleback

Since the New Synthesis, most migration-selection balance theory has predicted that there should be negligible differentiation over small spatial scales (relative to dispersal), because gene flow should erode any effect of divergent selection. Nevertheless, there are classic examples of microgeographic divergence, which theory suggests can arise under specific conditions: exceptionally strong selection, phenotypic plasticity in philopatric individuals, or nonrandom dispersal. Here, we present evidence of microgeographic morphological variation within lake and stream populations of threespine stickleback (Gasterosteus aculeatus). It seems reasonable to assume that a given lake or stream population of fish is well-mixed. However, we found this assumption to be untenable. We examined trap-to-trap variation in 34 morphological traits measured on stickleback from 16 lakes and 16 streams. Most traits varied appreciably among traps within populations. Both between-trap distance and microhabitat characteristics such as depth and substrate explained some of the within-population morphological variance. Microhabitat was also associated with genotype at particular loci but there was no genetic isolation by distance, implying that heritable habitat preferences may contribute to microgeographic variation. Our study adds to growing evidence that microgeographic divergence can occur across small spatial scales within individuals’ daily dispersal neighborhood where gene flow is expected to be strong.     

Species delimitation based on integrative approach suggests reallocation of genus in Hypostomini catfish (Siluriformes,Loricariidae)

Hydrobiologia - Integrative approaches are particularly useful to resolve taxonomic uncertainties in species-rich groups that have undergone explosive radiation, such as Hypostomini (suckermouth...     

α-Synuclein facilitates endocytosis by elevating the steady-state levels of phosphatidylinositol 4,5-bisphosphate

α-Synuclein (α-Syn) is a protein implicated in the pathogenesis of Parkinson''s disease (PD). It is an intrinsically disordered protein that binds acidic phospholipids. Growing evidence supports a role for α-Syn in membrane trafficking, including, mechanisms of endocytosis and exocytosis, although the exact role of α-Syn in these mechanisms is currently unclear. Here we investigate the associations of α-Syn with the acidic phosphoinositides (PIPs), phosphatidylinositol 4,5-bisphosphate (PI(4,5)P₂) and phosphatidylinositol 3,4-bisphosphate (PI(3,4)P₂). Our results show that α-Syn colocalizes with PIP₂ and the phosphorylated active form of the clathrin adaptor protein 2 (AP2) at clathrin-coated pits. Using endocytosis of transferrin as an indicator for clathrin-mediated endocytosis (CME), we find that α-Syn involvement in endocytosis is specifically mediated through PI(4,5)P₂ levels on the plasma membrane. In accord with their effects on PI(4,5)P₂ levels, the PD associated A30P, E46K, and A53T mutations in α-Syn further enhance CME in neuronal and nonneuronal cells. However, lysine to glutamic acid substitutions at the KTKEGV repeat domain of α-Syn, which interfere with phospholipid binding, are ineffective in enhancing CME. We further show that the rate of synaptic vesicle (SV) endocytosis is differentially affected by the α-Syn mutations and associates with their effects on PI(4,5)P₂ levels, however, with the exception of the A30P mutation. This study provides evidence for a critical involvement of PIPs in α-Syn–mediated membrane trafficking.