Climate Change and Trophic Response of the Antarctic Bottom Fauna

BACKGROUND: As Earth warms, temperate and subpolar marine species will increasingly shift their geographic ranges poleward. The endemic shelf fauna of Antarctica is especially vulnerable to climate-mediated biological invasions because cold temperatures currently exclude the durophagous (shell-breaking) predators that structure shallow-benthic communities elsewhere. METHODOLOGY/PRINCIPAL FINDINGS: We used the Eocene fossil record from Seymour Island, Antarctic Peninsula, to project specifically how global warming will reorganize the nearshore benthos of Antarctica. A long-term cooling trend, which began with a sharp temperature drop approximately 41 Ma (million years ago), eliminated durophagous predators-teleosts (modern bony fish), decapod crustaceans (crabs and lobsters) and almost all neoselachian elasmobranchs (modern sharks and rays)-from Antarctic nearshore waters after the Eocene. Even prior to those extinctions, durophagous predators became less active as coastal sea temperatures declined from 41 Ma to the end of the Eocene, approximately 33.5 Ma. In response, dense populations of suspension-feeding ophiuroids and crinoids abruptly appeared. Dense aggregations of brachiopods transcended the cooling event with no apparent change in predation pressure, nor were there changes in the frequency of shell-drilling predation on venerid bivalves. CONCLUSIONS/SIGNIFICANCE: Rapid warming in the Southern Ocean is now removing the physiological barriers to shell-breaking predators, and crabs are returning to the Antarctic Peninsula. Over the coming decades to centuries, we predict a rapid reversal of the Eocene trends. Increasing predation will reduce or eliminate extant dense populations of suspension-feeding echinoderms from nearshore habitats along the Peninsula while brachiopods will continue to form large populations, and the intensity of shell-drilling predation on infaunal bivalves will not change appreciably. In time the ecological effects of global warming could spread to other portions of the Antarctic coast. The differential responses of faunal components will reduce the endemic character of Antarctic subtidal communities, homogenizing them with nearshore communities at lower latitudes

Analysis of cancer metabolism with high-throughput technologies

<p>Abstract</p> <p>Background</p> <p>Recent advances in genomics and proteomics have allowed us to study the nuances of the Warburg effect – a long-standing puzzle in cancer energy metabolism – at an unprecedented level of detail. While modern next-generation sequencing technologies are extremely powerful, the lack of appropriate data analysis tools makes this study difficult. To meet this challenge, we developed a novel application for comparative analysis of gene expression and visualization of RNA-Seq data.</p> <p>Results</p> <p>We analyzed two biological samples (normal human brain tissue and human cancer cell lines) with high-energy, metabolic requirements. We calculated digital topology and the copy number of every expressed transcript. We observed subtle but remarkable qualitative and quantitative differences between the citric acid (TCA) cycle and glycolysis pathways. We found that in the first three steps of the TCA cycle, digital expression of aconitase 2 (<it>ACO2</it>) in the brain exceeded both citrate synthase (<it>CS</it>) and isocitrate dehydrogenase 2 (<it>IDH2</it>), while in cancer cells this trend was quite the opposite. In the glycolysis pathway, all genes showed higher expression levels in cancer cell lines; and most notably, digital gene expression of glyceraldehyde-3-phosphate dehydrogenase (<it>GAPDH</it>) and enolase (<it>ENO</it>) were considerably increased when compared to the brain sample.</p> <p>Conclusions</p> <p>The variations we observed should affect the rates and quantities of ATP production. We expect that the developed tool will provide insights into the subtleties related to the causality between the Warburg effect and neoplastic transformation. Even though we focused on well-known and extensively studied metabolic pathways, the data analysis and visualization pipeline that we developed is particularly valuable as it is global and pathway-independent.</p

Continuum Molecular Simulation of Large Conformational Changes during Ion–Channel Gating

A modeling framework was developed to simulate large and gradual conformational changes within a macromolecule (protein) when its low amplitude high frequency vibrations are not concerned. Governing equations were derived as alternative to Langevin and Smoluchowski equations and used to simulate gating conformational changes of the Kv7.1 ion-channel over the time scale of its gating process (tens of milliseconds). The alternative equations predict the statistical properties of the motion trajectories with good accuracy and do not require the force field to be constant over the diffusion length, as assumed in Langevin equation. The open probability of the ion–channel was determined considering cooperativity of four subunits and solving their concerted transition to the open state analytically. The simulated open probabilities for a series of voltage clamp tests produced current traces that were similar to experimentally recorded currents

Computational Identification of Uncharacterized Cruzain Binding Sites

Chagas disease, caused by the unicellular parasite Trypanosoma cruzi, claims 50,000 lives annually and is the leading cause of infectious myocarditis in the world. As current antichagastic therapies like nifurtimox and benznidazole are highly toxic, ineffective at parasite eradication, and subject to increasing resistance, novel therapeutics are urgently needed. Cruzain, the major cysteine protease of Trypanosoma cruzi, is one attractive drug target. In the current work, molecular dynamics simulations and a sequence alignment of a non-redundant, unbiased set of peptidase C1 family members are used to identify uncharacterized cruzain binding sites. The two sites identified may serve as targets for future pharmacological intervention

Novel Allosteric Sites on Ras for Lead Generation

Aberrant Ras activity is a hallmark of diverse cancers and developmental diseases. Unfortunately, conventional efforts to develop effective small molecule Ras inhibitors have met with limited success. We have developed a novel multi-level computational approach to discover potential inhibitors of previously uncharacterized allosteric sites. Our approach couples bioinformatics analysis, advanced molecular simulations, ensemble docking and initial experimental testing of potential inhibitors. Molecular dynamics simulation highlighted conserved allosteric coupling of the nucleotide-binding switch region with distal regions, including loop 7 and helix 5. Bioinformatics methods identified novel transient small molecule binding pockets close to these regions and in the vicinity of the conformationally responsive switch region. Candidate binders for these pockets were selected through ensemble docking of ZINC and NCI compound libraries. Finally, cell-based assays confirmed our hypothesis that the chosen binders can inhibit the downstream signaling activity of Ras. We thus propose that the predicted allosteric sites are viable targets for the development and optimization of new drugs

Understanding biomolecular motion, recognition, and allostery by use of conformational ensembles

We review the role conformational ensembles can play in the analysis of biomolecular dynamics, molecular recognition, and allostery. We introduce currently available methods for generating ensembles of biomolecules and illustrate their application with relevant examples from the literature. We show how, for binding, conformational ensembles provide a way of distinguishing the competing models of induced fit and conformational selection. For allostery we review the classic models and show how conformational ensembles can play a role in unravelling the intricate pathways of communication that enable allostery to occur. Finally, we discuss the limitations of conformational ensembles and highlight some potential applications for the future

Oxidized iron in garnets from the mantle transition zone

The oxidation state of iron in Earth’s mantle is well known to depths of approximately 200 km, but has not been characterized in samples from the lowermost upper mantle (200–410 km depth) or the transition zone (410–660 km depth). Natural samples from the deep (>200 km) mantle are extremely rare, and are usually only found as inclusions in diamonds. Here we use synchrotron Mössbauer source spectroscopy complemented by single-crystal X-ray diffraction to measure the oxidation state of Fe in inclusions of ultra-high pressure majoritic garnet in diamond. The garnets show a pronounced increase in oxidation state with depth, with Fe3+/(Fe3++ Fe2+) increasing from 0.08 at approximately 240 km depth to 0.30 at approximately 500 km depth. The latter majorites, which come from pyroxenitic bulk compositions, are twice as rich in Fe3+ as the most oxidized garnets from the shallow mantle. Corresponding oxygen fugacities are above the upper stability limit of Fe metal. This implies that the increase in oxidation state is unconnected to disproportionation of Fe2+ to Fe3+ plus Fe0. Instead, the Fe3+ increase with depth is consistent with the hypothesis that carbonated fluids or melts are the oxidizing agents responsible for the high Fe3+ contents of the inclusions