Sampling the self-assembly pathways of KFFE hexamers

The formation of amyloid fibrils is often encountered in Alzheimer's disease, type II diabetes, and transmissible spongiform encephalopathies. In the last few years, however, mounting evidence has suggested that the soluble oligomers of amyloid-forming peptides are also cytotoxic agents. Understanding the early pathway steps of amyloid self-assembly at atomic detail might therefore be crucial for the development of specific inhibitors to prevent amyloidosis in humans. Using the activation-relaxation technique and a generic energy model, we study in detail the aggregation of a hexamer of KFFE peptide. Our simulations show that a monomer remains disordered, but that six monomers placed randomly in an open box self-associate to adopt, with various orientations, three possible distant low-energy structures. Two of these structures show a double-layer beta-sheet organization, in agreement with the structure of amyloid fibrils as observed by x-ray diffraction, whereas the third one consists of a barrel-like curved single-layer hexamer. Based on these results, we propose a bidirectional growth mode of amyloid fibril, involving alternate lateral and longitudinal growths.     

The evolution of the phenotypic covariance matrix: evidence for selection and drift in Melanoplus

Phenotypic variation in trait means is a common observation for geographically separated populations. Such variation is typically retained under common garden conditions, indicating that there has been evolutionary change in the populations, as a result of selection and/or drift. Much less frequently studied is variation in the phenotypic covariance matrix (hereafter, P matrix), although this is an important component of evolutionary change. In this paper, we examine variation in the phenotypic means and P matrices in two species of grasshopper, Melanoplus sanguinipes and M. devastator. Using the P matrices estimated for 14 populations of M. sanguinipes and three populations of M. devastator we find that (1) significant differences between the sexes can be attributed to scaling effects; (2) there is no significant difference between the two species; (3) there are highly significant differences among populations that cannot be accounted for by scaling effects; (4) these differences are a consequence of statistically significant patterns of covariation with geographic and environmental factors, phenotypic variances and covariances increasing with increased temperature but decreasing with increased latitude and altitude. This covariation suggests that selection has been important in the evolution of the P matrix in these populations Finally, we find a significant positive correlation between the average difference between matrices and the genetic distance between the populations, indicating that drift has caused some of the variation in the P matrices.     

Changes in wheat DNA methylation pattern after chronic seed gamma-irradiation

Alterations of DNA methylation patterns of wheat two varieties--Odessa' albatross and Donetsk 48 have been studied. Seeds were irradiated for 4 months with low dose rate (3 x 10(-7) Gy/s). Six restriction endonucleases were used in the experiments. Primary distinction in DNA methylation patterns of the studied varieties has been demonstrated. The chronic irradiation resulted in the increase of methylation level on the sites of recognition for Glul and Sou3Al and in the decline of this index for the sites of recognition of GlaI and HpaII. The meaningful increase of chromosome aberration levels was demonstrated at the same accumulated dose of chronic irradiation. The role of changes of DNA methylation patterns in development of radiation damage and organism protective reactions is discussed.     

Host resistance does not explain variation in incidence of male-killing bacteria in <Emphasis Type="Italic">Drosophila bifasciata</Emphasis>

Background  

Selfish genetic elements that distort the sex ratio are found widely. Notwithstanding the number of records of sex ratio distorters, their incidence is poorly understood. Two factors can prevent a sex ratio distorter from invading: inability of the sex ratio distorter to function (failure of mechanism or transmission), and lack of drive if they do function (inappropriate ecology for invasion). There has been no test to date on factors causing variation in the incidence of sex ratio distorting cytoplasmic bacteria. We therefore examined whether absence of the male-killing Wolbachia infection in D. bifasciata in Hokkaido island of Japan, in contrast to the presence of infection on the proximal island of Honshu, was associated with failure of the infection to function properly on the Hokkaido genetic background.     

Probing the Huntingtin 1-17 Membrane Anchor on a Phospholipid Bilayer by Using All-Atom Simulations

Mislocalization and aggregation of the huntingtin protein are related to Huntington’s disease. Its first exon—more specifically the first 17 amino acids (Htt17)—is crucial for the physiological and pathological functions of huntingtin. It regulates huntingtin’s activity through posttranslational modifications and serves as an anchor to membrane-containing organelles of the cell. Recently, structure and orientation of the Htt17 membrane anchor were determined using a combined solution and solid-state NMR approach. This prompted us to refine this model by investigating the dynamics and thermodynamics of this membrane anchor on a POPC bilayer using all-atom, explicit solvent molecular dynamics and Hamiltonian replica exchange. Our simulations are combined with various experimental measurements to generate a high-resolution atomistic model for the huntingtin Htt17 membrane anchor on a POPC bilayer. More precisely, we observe that the single α-helix structure is more stable in the phospholipid membrane than the NMR model obtained in the presence of dodecylphosphocholine detergent micelles. The resulting Htt17 monomer has its hydrophobic plane oriented parallel to the bilayer surface. Our results further unveil the key residues interacting with the membrane in terms of hydrogen bonds, salt-bridges, and nonpolar contributions. We also observe that Htt17 equilibrates at a well-defined insertion depth and that it perturbs the physical properties—order parameter, thickness, and area per lipid—of the bilayer in a manner that could favor its dimerization. Overall, our observations reinforce and refine the NMR measurements on the Htt17 membrane anchor segment of huntingtin that is of fundamental importance to its biological functions.     

An approach to rapid processing of camera trap images with minimal human input

1. Camera traps have become an extensively utilized tool in ecological research, but the manual processing of images created by a network of camera traps rapidly becomes an overwhelming task, even for small camera trap studies.
2. We used transfer learning to create convolutional neural network (CNN) models for identification and classification. By utilizing a small dataset with an average of 275 labeled images per species class, the model was able to distinguish between species and remove false triggers.
3. We trained the model to detect 17 object classes with individual species identification, reaching an accuracy up to 92% and an average F1 score of 85%. Previous studies have suggested the need for thousands of images of each object class to reach results comparable to those achieved by human observers; however, we show that such accuracy can be achieved with fewer images.
4. With transfer learning and an ongoing camera trap study, a deep learning model can be successfully created by a small camera trap study. A generalizable model produced from an unbalanced class set can be utilized to extract trap events that can later be confirmed by human processors.

     

A comparison of two methods for constructing evolutionary distances from a weighted contribution of transition and transversion differences

Since the initial work of Jukes and Cantor (1969), a number of procedures have been developed to estimate the expected number of nucleotide substitutions corresponding to a given observed level of nucleotide differentiation assuming particular evolutionary models. Unlike the proportion of different sites, the expected number of substitutions that would have occurred grows linearly with time and therefore has had great appeal as an evolutionary distance. Recently, however, a number of authors have tried to develop improved statistical approaches for generating and evaluating evolutionary distances (Schoniger and von Haeseler 1993; Goldstein and Polock 1994; Tajima and Takezaki 1994). These studies clearly show that the estimated number of nucleotide substitutions is generally not the best estimator for use in reconstruction of phylogenetic relationships. The reason for this is that there is often a large error associated with the estimation of this number. Therefore, even though its expectation is correct (i.e., on average the expected number of substitutions is proportional to time- -but see Tajima 1993), it is not expected to be as useful as estimators designed to have a lower variance.      

The [3H]Tryptamine Receptor in Human Brain: Kinetics, Distribution, and Pharmacologic Profile

Abstract: The kinetics and distribution of [³H]tryptamine binding sites in human brain were investigated. Specific [³H]tryptamine binding in frontal cortex was of nanomolar affinity, reversible, saturable, and best fit to a single-site model. A heterogeneous distribution for this binding site was demonstrated, with the highest density observed in hippocampus, thalamus ≫ caudate nucleus, frontal cortex, pons, temporal cortex > globus pallidus/putamen, cerebellum. The similarities in kinetics and distribution of the [³H]tryptamine binding site in human and rat brain indicate that these two binding sites represent homologous structures. However, the present displacement studies using various ligands (indoleamines and other tryptophan metabolites, phenylethylamines, and miscellaneous drugs) and salts (Na⁺, K⁺, Ca²⁺, Mg²⁺, Cu²⁺) indicate stereospecific displacement as well as a rank-order potency profile that is different from that reported for the rat [³H]tryptamine binding site. This suggests the presence of distinct species-dependent [³H]tryptamine binding site subtypes. Taken together with the documented electrophysiological and behavioral evidence of tryptamine-mediated effects in the rat and the recent report of a significant loss of these binding sites in human portal systemic encephalopathy, as well as the present demonstration of an effect of guanine nucleotides on [³H]-tryptamine binding affinity, these findings suggest that these binding sites might be functional receptors. The implied role of tryptamine in neuropsychiatric disorders is supported by this demonstration of a receptor for [³H]-tryptamine in human brain.     

The effects of radiation on sperm swimming behavior depend on plasma oxidative status in the barn swallow (Hirundo rustica)

Sperm are highly susceptible to reactive oxygen species (ROS) that can damage sperm DNA and structure, resulting in reduced fertilizing capacity. Exposure to radioactive contamination can also impair sperm swimming behavior and fertilizing ability, both through a reduction of sperm DNA integrity and via an increased generation of reactive oxygen species (ROS). However, the relationship between individual oxidative status and sperm swimming behavior has never been investigated in any wild population of animals exposed to radioactive contamination. We studied the motility of sperm collected from barn swallows, Hirundo rustica, breeding under different levels of radioactive contamination following the Chernobyl accident in 1986, in relation to individual oxidative status. We tested the hypothesis that the degree of impairment of sperm swimming behavior by radioactive contamination depended on plasma antioxidant capacity, the level of reactive oxygen metabolites (ROMs) and oxidative stress (sensu Costantini et al. 2006), a better oxidative status being associated with higher sperm motility. Sperm behavior parameters were subjected to principal component (PC) analysis, which extracted four PCs explaining 86% of the variance in sperm motility. PC2, representing sperm with high track velocity and ample lateral head displacement, was significantly predicted by the interaction between radiation level and either oxidative damage or oxidative stress. Contrary to our predictions, the highest values of PC2 were associated with relatively high radiation levels, particularly for high levels of either ROMs or oxidative stress. In addition, there was a tendency for values of PC3 (representing the percent of motile sperm) and PC4 (representing slow sperm with high beat cross frequency) to depend on the interaction between radiation level and total plasma antioxidant protection. Our results confirm the importance of oxidative status in determining the genetic and physiological outcome of exposure to radioactive contamination, complementing previous studies relating sperm abnormality to circulating levels of specific antioxidants. Our results also complement previous evidence that oxidative damage of sperm was negatively related to sperm motility, thus indicating a possible trade-off in quenching pro-oxidant compounds in the plasma and the seminal fluid.     

Complex folding pathways in a simple beta-hairpin

The determination of the folding mechanisms of proteins is critical to understand the topological change that can propagate Alzheimer and Creutzfeld-Jakobs diseases, among others. The computational community has paid considerable attention to this problem; however, the associated time scale, typically on the order of milliseconds or more, represents a formidable challenge. Ab initio protein folding from long molecular dynamics simulations or ensemble dynamics is not feasible with ordinary computing facilities and new techniques must be introduced. Here we present a detailed study of the folding of a 16-residue beta-hairpin, described by a generic energy model and using the activation-relaxation technique. From a total of 90 trajectories at 300 K, three folding pathways emerge. All involve a simultaneous optimization of the complete hydrophobic and hydrogen bonding interactions. The first two pathways follow closely those observed by previous theoretical studies (folding starting at the turn or by interactions between the termini). The third pathway, never observed by previous all-atom folding, unfolding, and equilibrium simulations, can be described as a reptation move of one strand of the beta-sheet with respect to the other. This reptation move indicates that non-native interactions can play a dominant role in the folding of secondary structures. Furthermore, such a mechanism mediated by non-native hydrogen bonds is not available for study by unfolding and Gō model simulations. The exact folding path followed by a given beta-hairpin is likely to be influenced by its sequence and the solvent conditions. Taken together, these results point to a more complex folding picture than expected for a simple beta-hairpin.