Convergent CaMK and RacGEF signals control dendritic structure and function

Structural plasticity of excitatory synapses is a vital component of neuronal development, synaptic plasticity and behavior, and its malfunction underlies many neurodevelopmental and psychiatric disorders. However, the molecular mechanisms that control dendritic spine morphogenesis have only recently emerged. We summarize recent work that has revealed an important connection between calcium/calmodulin-dependent kinases (CaMKs) and guanine-nucleotide-exchange factors (GEFs) that activate the small GTPase Rac (RacGEFs) in controlling dendritic spine morphogenesis. These two groups of molecules function in neurons as a unique signaling cassette that transduces calcium influx into small GTPase activity and, thence, actin reorganization and spine morphogenesis. Through this pathway, CaMKs and RacGEFs amplify calcium signals and translate them into spatially and temporally regulated structural remodeling of dendritic spines.     

Pseudophosphorylation of tau at serine 422 inhibits caspase cleavage: in vitro evidence and implications for tangle formation in vivo

The tangles of Alzheimer's disease (AD) are comprised of the tau protein displaying numerous alterations, including phosphorylation at serine 422 (S422) and truncation at aspartic acid 421 (D421). Truncation at the latter site appears to result from activation of caspases, a class of proteases that cleave specifically at aspartic acid residues. It has been proposed that phosphorylation at or near caspase cleavage sites could regulate the ability of the protease to cleave at those sites. Here, we use tau pseudophosphorylated at S422 (S422E) to examine the effects of tau phosphorylation on its cleavage by caspase 3. We find that S422E tau is more resistant to proteolysis by caspase 3 than non-pseudophosphorylated tau. Additionally, we use antibodies directed against the phosphorylation site and against the truncation epitope to assess the presence of these epitopes in neurofibrillary tangles in the aged human brain. We show that phosphorylation precedes truncation during tangle maturation. Moreover, the distribution of the two epitopes suggests that a significant length of time (perhaps as much as two decades) elapses between S422 phosphorylation and cleavage at D421. We further conclude that tau phosphorylation at S422 may be a protective mechanism that inhibits cleavage in vivo.     

Applying behavioral-ecological theory to plant defense: light-dependent movement in Mimosa pudica suggests a trade-off between predation risk and energetic reward

Many animal species tolerate different amounts of predation risk based on environmental conditions and the individual's own condition, often accepting greater risk when energetically stressed. We studied the sensitive plant Mimosa pudica to see whether it too accepts greater risk of predation when less light energy is available. This plant displays a defensive behavior of rapidly folding its leaves when stimulated by touch, thereby decreasing visibility to herbivores. Averting herbivory involves a trade-off because leaf closure results in a reduction in light foraging. We manipulated the light environment of individual M. pudica plants and recorded the time it took a plant to reopen its leaves following stimulation as a measure of tolerance of predation risk. As predicted by theory, avoidance behavior was sustained longer under high light conditions than under more light-limited conditions. These findings suggest this species balances the risk and reward of antiherbivore behavior in relation to current environmental conditions and that behavioral-ecological theory is a useful framework for understanding plant responses to predators.     

Increased competition does not lead to increased phylogenetic overdispersion in a native grassland

That competition is stronger among closely related species and leads to phylogenetic overdispersion is a common assumption in community ecology. However, tests of this assumption are rare and field‐based experiments lacking. We tested the relationship between competition, the degree of relatedness, and overdispersion among plants experimentally and using a field survey in a native grassland. Relatedness did not affect competition, nor was competition associated with phylogenetic overdispersion. Further, there was only weak evidence for increased overdispersion at spatial scales where plants are likely to compete. These results challenge traditional theory, but are consistent with recent theories regarding the mechanisms of plant competition and its potential effect on phylogenetic structure. We suggest that specific conditions related to the form of competition and trait conservatism must be met for competition to cause phylogenetic overdispersion. Consequently, overdispersion as a result of competition is likely to be rare in natural communities.     

Uncovering the DNA methylome in chronic lymphocytic leukemia

Over the past two decades, aberrant DNA methylation has emerged as a key player in the pathogenesis of chronic lymphocytic leukemia (CLL), and knowledge regarding its biological and clinical consequences in this disease has evolved rapidly. Since the initial studies relating DNA hypomethylation to genomic instability in CLL, a plethora of reports have followed showing the impact of DNA hypermethylation in silencing vital single gene promoters and the reversible nature of DNA methylation through inhibitor drugs. With the recognition that DNA hypermethylation events could potentially act as novel prognostic and treatment targets in CLL, the search for aberrantly methylated genes, gene families and pathways has ensued. Subsequently, the advent of microarray and next-generation sequencing technologies has supported the hunt for such targets, allowing exploration of the methylation landscape in CLL at an unprecedented scale. In light of these analyses, we now understand that different CLL prognostic subgroups are characterized by differential methylation profiles; we recognize DNA methylation of a number of signaling pathways genes to be altered in CLL, and acknowledge the role of DNA methylation outside of traditional CpG island promoters as fundamental players in the regulation of gene expression. Today, the significance and timing of altered DNA methylation within the complex epigenetic network of concomitant epigenetic messengers such as histones and miRNAs is an intensive area of research. In CLL, it appears that DNA methylation is a rather stable epigenetic mark occurring rather early in the disease pathogenesis. However, other consequences, such as how and why aberrant methylation marks occur, are less explored. In this review, we will not only provide a comprehensive summary of the current literature within the epigenetics field of CLL, but also highlight some of the novel findings relating to when, where, why and how altered DNA methylation materializes in CLL.     

Does phylogenetic relatedness influence the strength of competition among vascular plants?

A widely assumed but largely untested hypothesis central to ecology and evolutionary biology has been Charles Darwin's suggestion that closely related species will be more ecologically similar, and thus will compete more strongly with each other than they will with more distantly related species. We provide one of the first direct tests of the “competition-relatedness hypothesis” by combining two data sets: the relative competitive ability of 50 vascular plant species competing against 92 competitor species measured in five multi-species experiments, and measures of the phylogenetic relatedness of these species. In contrast to Darwin's assertion, there were weak relationships between the strength of competition and phylogenetic relatedness. Across all species studied, the competition-relatedness relationship was weak and not significant. This overall lack of pattern masked different responses of monocot and eudicot focal (phytometer) species. When monocots served as the focal (phytometer) species, the intensity of competition increased with the phylogenetic distance separating species, while competition decreased with phylogenetic distance for eudicot phytometers. These results were driven by the monocot-eudicot evolutionary split, such that monocots were poor competitors against eudicots, while eudicots are most strongly suppressed by other eudicots. There was no relationship between relatedness and competition for eudicots competing with other eudicots, while monocots did compete more intensely with closely related monocots than with distantly related monocots. Overall, the relationships between competition intensity and relatedness were weak compared to the strong and consistent relationships between competitive ability and functional traits such as plant size that have been reported by other studies. We suggest that Darwin's assertion that competition will be strongest among closely related species is not supported by empirical data, at least for the 142 vascular plant species in this study.     

Specification, annotation, visualization and simulation of a large rule-based model for ERBB receptor signaling

ABSTRACT: BACKGROUND: Mathematical/computational models are needed to understand cell signaling networks, which are complex. Signaling proteins contain multiple functional components and multiple sites of post-translational modification. The multiplicity of components and sites of modification ensures that interactions among signaling proteins have the potential to generate myriad protein complexes and post-translational modification states. As a result, the number of chemical species that can be populated in a cell signaling network, and hence the number of equations in an ordinary differential equation model required to capture the dynamics of these species, is prohibitively large. To overcome this problem, the rule-based modeling approach has been developed for representing interactions within signaling networks efficiently and compactly through coarse-graining of the chemical kinetics of molecular interactions. RESULTS: Here, we provide a demonstration that the rule-based modeling approach can be used to specify and simulate a large model for ERBB receptor signaling that accounts for site-specific details of protein-protein interactions. The model is considered large because it corresponds to a reaction network containing more reactions than can be practically enumerated. The model encompasses activation of ERK and Akt, and it can be simulated using a network-free simulator, such as NFsim, to generate time courses of phosphorylation for 55 individual serine, threonine, and tyrosine residues. The model is annotated and visualized in the form of an extended contact map. CONCLUSIONS: With the development of software that implements novel computational methods for calculating the dynamics of large-scale rule-based representations of cellular signaling networks, it is now possible to build and analyze models that include a significant fraction of the protein interactions that comprise a signaling network, with incorporation of the site-specific details of the interactions. Modeling at this level of detail is important for understanding cellular signaling.