Microbes are not bound by sociobiology: Response to Kümmerli and Ross‐Gillespie (2013)

In recent years, sociobiology has been extended to microorganisms. Viewed through this lens, the microbial world is replete with cooperative behaviors. However, little attention has been paid to alternate hypotheses, making many studies self‐confirming. Somewhat apart is a recent analysis of pyoverdin production—a paradigmatic public good and social trait—by Pseudomonas, which has revealed discord between predictions arising from sociobiology and the biology of microbes. This led the authors, Zhang and Rainey (Z&R), to question the generality of the conclusion that pyoverdin is a social trait, and to question the fit between the sociobiology framework and microbiology. This has unsettled Kümmerli and Ross‐Gillespie (K&R), who in a recent “Technical Comment” assert that arguments presented by Z&R are flawed, their experiments technically mistaken, and their understanding of social evolution theory naive. We demonstrate these claims to be without substance and show the conclusions of K&R to be based on a lack of understanding of redox chemistry and on misinterpretation of data. We also point to evidence of cherry‐picking and raise the possibility of confirmation bias. Finally, we emphasize that the sociobiology framework applied to microbes is a hypothesis that requires rigorous and careful appraisal.     

Small molecule glutaminase inhibitors block glutamate release from stimulated microglia

Glutaminase plays a critical role in the generation of glutamate, a key excitatory neurotransmitter in the CNS. Excess glutamate release from activated macrophages and microglia correlates with upregulated glutaminase suggesting a pathogenic role for glutaminase. Both glutaminase siRNA and small molecule inhibitors have been shown to decrease excess glutamate and provide neuroprotection in multiple models of disease, including HIV-associated dementia (HAD), multiple sclerosis and ischemia. Consequently, inhibition of glutaminase could be of interest for treatment of these diseases. Bis-2-(5-phenylacetimido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) and 6-diazo-5-oxo-l-norleucine (DON), two most commonly used glutaminase inhibitors, are either poorly soluble or non-specific. Recently, several new BPTES analogs with improved physicochemical properties were reported. To evaluate these new inhibitors, we established a cell-based microglial activation assay measuring glutamate release. Microglia-mediated glutamate levels were significantly augmented by tumor necrosis factor (TNF)-α, phorbol 12-myristate 13-acetate (PMA) and Toll-like receptor (TLR) ligands coincident with increased glutaminase activity. While several potent glutaminase inhibitors abrogated the increase in glutamate, a structurally related analog devoid of glutaminase activity was unable to block the increase. In the absence of glutamine, glutamate levels were significantly attenuated. These data suggest that the in vitro microglia assay may be a useful tool in developing glutaminase inhibitors of therapeutic interest.     

Chemical changes in soil and soil solution after calcium silicate addition to a northern hardwood forest

Liming has been used to mitigate effects of acidic deposition in forest ecosystems. This study was designed to examine the effects of calcium (Ca) supply on the spatial patterns and the relations between soil and soil solution chemistry in a base-poor forest watershed. Watershed 1 at the Hubbard Brook Experimental Forest in New Hampshire, USA was experimentally treated with wollastonite (CaSiO₃) in October, 1999. Exchangeable Ca (Ex-Ca), soil pH_s (in 0.01 M CaCl₂), effective cation exchange capacity (CEC_e), and effective base saturation (BS_e) increased, while exchangeable acidity (Ex-Acid) decreased in organic soil horizons in 2000 and 2002. Mineral soils experienced either small increases in Ex-Ca, pH_s, CEC_e, BS_e, small decreases in Ex-Acid or no changes. Thus, most of the added Ca remained in the forest floor during the study period. Prior to the treatment the BS_e decreased with increasing elevation in organic and mineral soil horizons. This spatial pattern changed significantly in the forest floor after the treatment, suggesting that soils at higher elevations were more responsive to the chemical addition than at lower elevations. Soil solutions draining the forest floor responded to the treatment by increases in concentrations of Ca, dissolved silica, pH, and acid neutralizing capacity (ANC), and a decrease in inorganic monomeric Al (Al_i). Treatment effects diminished with increasing soil depth and decreasing elevation. Positive correlations between Ca/total monomeric Al (Al_m) in soil solution and Ex-Ca/Ex-Al ratios in soil indicated that changes in the chemistry of soils significantly influenced the chemistry of soil water, and that Ca derived from the dissolution of wollastonite mitigated the mobilization of Al within the experimental watershed.     

Novel EGF pathway regulators modulate C. elegans healthspan and lifespan via EGF receptor,PLC‐γ, and IP3R activation

Improving health of the rapidly growing aging population is a critical medical, social, and economic goal. Identification of genes that modulate healthspan, the period of mid‐life vigor that precedes significant functional decline, will be an essential part of the effort to design anti‐aging therapies. Because locomotory decline in humans is a major contributor to frailty and loss of independence and because slowing of movement is a conserved feature of aging across phyla, we screened for genetic interventions that extend locomotory healthspan of Caenorhabditis elegans. From a group of 54 genes previously noted to encode secreted proteins similar in sequence to extracellular domains of insulin receptor, we identified two genes for which RNAi knockdown delayed age‐associated locomotory decline, conferring a high performance in advanced age phenotype (Hpa). Unexpectedly, we found that hpa‐1 and hpa‐2 act through the EGF pathway, rather than the insulin signaling pathway, to control systemic healthspan benefits without detectable developmental consequences. Further analysis revealed a potent role of EGF signaling, acting via downstream phospholipase C‐γplc‐3 and inositol‐3‐phosphate receptor itr‐1, to promote healthy aging associated with low lipofuscin levels, enhanced physical performance, and extended lifespan. This study identifies HPA‐1 and HPA‐2 as novel negative regulators of EGF signaling and constitutes the first report of EGF signaling as a major pathway for healthy aging. Our data raise the possibility that EGF family members should be investigated for similar activities in higher organisms.     

Evidence for the local evolution of mechanisms underlying limb regeneration in salamanders

The most extensive regenerative ability in adult vertebrates is found in the salamanders. Although it is often suggested that regeneration is an ancestral property for vertebrates, our studies on the cell-surface three-finger-protein Prod 1 provide clear evidence for the importance of local evolution of limb regeneration in salamanders. Prod 1 is implicated in both patterning and growth in the regeneration of limbs. It interacts with well-conserved proteins such as the epidermal growth-factor receptor and the anterior gradient protein that are widely expressed in phylogeny. A detailed analysis of the structure and sequence of Prod 1 in relation to other vertebrate three-finger proteins in mammals and zebra fish supports the view that it is a salamander-specific protein. This is the first example of a taxon-specific protein that is clearly implicated in the mechanisms of regeneration. We propose the hypothesis that regeneration depends on the activity of taxon-specific components in orchestrating a cellular machinery that is extensively conserved between regenerating and non-regenerating taxa. This hypothesis has significant implications for our outlook on regeneration in vertebrates, as well as for the strategies employed in extending regenerative ability in mammals.     

An Overview of the Development,Status, and Application of Equilibrium Partitioning Sediment Benchmarks for PAH Mixtures

This article provides an overview of the development, theoretical basis, regulatory status, and application of the U.S. Environmental Protection Agency's (USEPA's) Equilibrium Partitioning Sediment Benchmarks (ESBs) for PAH mixtures. ESBs are compared to other sediment quality guidelines (SQGs) for PAHs. Data that examine the ability of the ESB approach to predict toxic effects to invertebrates are discussed. A USEPA draft methodology for the development of site-specific ESBs that takes into account the limited bioavailability of PAHs at certain sites is discussed. Research is presented that compares the ability of ESBs and site-specific ESBs to predict the toxicity of sediments collected from manufactured gas plants (MGPs). Site-specific ESBs that accounted for adsorption of PAHs onto black carbon were better predictors of the toxicity of sediments from MGP sites than ESBs that did not account for adsorption to black carbon.     

Candidate genes versus genome-wide associations: which are better for detecting genetic susceptibility to infectious disease?

Technological developments allow increasing numbers of markers to be deployed in case-control studies searching for genetic factors that influence disease susceptibility. However, with vast numbers of markers, true 'hits' may become lost in a sea of false positives. This problem may be particularly acute for infectious diseases, where the control group may contain unexposed individuals with susceptible genotypes. To explore this effect, we used a series of stochastic simulations to model a scenario based loosely on bovine tuberculosis. We find that a candidate gene approach tends to have greater statistical power than studies that use large numbers of single nucleotide polymorphisms (SNPs) in genome-wide association tests, almost regardless of the number of SNPs deployed. Both approaches struggle to detect genetic effects when these are either weak or if an appreciable proportion of individuals are unexposed to the disease when modest sample sizes (250 each of cases and controls) are used, but these issues are largely mitigated if sample sizes can be increased to 2000 or more of each class. We conclude that the power of any genotype-phenotype association test will be improved if the sampling strategy takes account of exposure heterogeneity, though this is not necessarily easy to do.