A theoretical thermodynamic investigation of cascade reactions in dinuclear octa-azacryptates involving carbon dioxide

This paper investigates the thermodynamics of gas-phase CO₂ cascade uptake-reactions in the form of carbonate or monomethylcarbonate anions in the host cavity of various dinuclear octa-azacryptates of m-CH₂C₆H₄CH₂ and 2,5-furano-spaced hosts, L ¹ and L ² cryptands, using density functional theory (DFT). The cascade process involves two stages, namely the formation of dinuclear cryptate complexes, and the subsequent formation of either μ-carbonato cryptate complexes or μ-monomethylcarbonato cryptates. The geometric and electronic structures were also investigated to determine the parameters that affect the stability of the complexes. Natural bond orbital (NBO) analysis was used to investigate the interactions between the trapped anion and its host. Ion selectivity was studied in terms of the formation of dinuclear cryptate complexes, while the basicity and nucleophilicity of cryptands towards Lewis acids was also studied, and good agreement was found vis-à-vis available experimental data.     

Effects of pelvic stabilization on lumbar muscle activity during dynamic exercise

Many commonly utilized low-back exercise devices offer mechanisms to stabilize the pelvis and to isolate the lumbar spine, but the value of these mechanisms remains unclear. The purpose of this study was to examine the effect of pelvic stabilization on the activity of the lumbar and hip extensor muscles during dynamic back extension exercise. Fifteen volunteers in good general health performed dynamic extension exercise in a seated upright position on a lumbar extension machine with and without pelvic stabilization. During exercise, surface electromyographic activity of the lumbar multifidus and biceps femoris was recorded. The activity of the multifidus was 51% greater during the stabilized condition, whereas there was no difference in the activity of the biceps femoris between conditions. This study demonstrates that pelvic stabilization enhances lumbar muscle recruitment during dynamic exercise on machines. Exercise specialists can use these data when designing exercise programs to develop low back strength.     

Structural characterization of proteins using residue environments

A primary challenge for structural genomics is the automated functional characterization of protein structures. We have developed a sequence-independent method called S-BLEST (Structure-Based Local Environment Search Tool) for the annotation of previously uncharacterized protein structures. S-BLEST encodes the local environment of an amino acid as a vector of structural property values. It has been applied to all amino acids in a nonredundant database of protein structures to generate a searchable structural resource. Given a query amino acid from an experimentally determined or modeled structure, S-BLEST quickly identifies similar amino acid environments using a K-nearest neighbor search. In addition, the method gives an estimation of the statistical significance of each result. We validated S-BLEST on X-ray crystal structures from the ASTRAL 40 nonredundant dataset. We then applied it to 86 crystallographically determined proteins in the protein data bank (PDB) with unknown function and with no significant sequence neighbors in the PDB. S-BLEST was able to associate 20 proteins with at least one local structural neighbor and identify the amino acid environments that are most similar between those neighbors.     

Bioinformatics approaches and resources for single nucleotide polymorphism functional analysis

Since the initial sequencing of the human genome, many projects are underway to understand the effects of genetic variation between individuals. Predicting and understanding the downstream effects of genetic variation using computational methods are becoming increasingly important for single nucleotide polymorphism (SNP) selection in genetics studies and understanding the molecular basis of disease. According to the NIH, there are now more than four million validated SNPs in the human genome. The volume of known genetic variations lends itself well to an informatics approach. Bioinformaticians have become very good at functional inference methods derived from functional and structural genomics. This review will present a broad overview of the tools and resources available to collect and understand functional variation from the perspective of structure, expression, evolution and phenotype. Additionally, public resources available for SNP identification and characterisation are summarised.     

A chemical polymorphism in a multitrophic setting: thyme monoterpene composition and food web structure

We investigated the effects of chemical variation in thyme (Thymus vulgaris L.) on its interactions with competitors, herbivores, and herbivore predators. Four different thyme monoterpene phenotypes (chemotypes) were grown in a 4x2x2 factorial of chemotype, caging (sham half-cages vs. full cages), and competition (control vs. the grass Bromus madritensis L.). Cages reduced numbers of arthropod predators. Thyme-feeding aphids Aphis serpylli Koch passed through full cage walls to increase more than fourfold. As a result, freed from their predators, aphids had a large negative effect on thyme size and flowering. Similarly, competition from Bromus had a negative effect on thyme size and flowering. Individual effects of aphids and competition were nonadditive, however, and their combined effect was significantly less than that predicted by a multiplicative null model. Differential thyme sizes among chemotypes were not mediated by herbivores or competitors, but differential flowering was due to the effects of chemotype on aphids. We thus document differential selection by aphids among thyme chemotypes and the influence of Bromus on the strength of these negative effects of aphids.     

Mechanical stimulation and mitogen-activated protein kinase signaling independently regulate osteogenic differentiation and mineralization by calcifying vascular cells

Ectopic calcification of vascular tissue is associated with several cardiovascular pathologies and likely involves active regulation by vascular smooth muscle cells and osteoblast-like vascular cells. This process often occurs in sites with altered mechanical environments, suggesting a role for mechanical stimuli in calcification. In this study, we investigated the effect of mechanical stimulation on the proliferation, osteogenic differentiation, calcification, and mitogen-activated protein kinase (MAPK) signaling in calcifying vascular cells (CVCs), a subpopulation of aortic smooth muscle cells putatively involved in vascular calcification. Application of equibiaxial cyclic strain (7%, 0.25 Hz) to CVCs had no effect on cell proliferation, but accelerated alkaline phosphatase expression and significantly increased mineralization by 3.1-fold over unstrained cells. Fluid motion in the absence of strain also enhanced mineralization, but to a lesser degree. Because MAPK pathways mediate mechanically regulated osteoblast differentiation, we tested whether similar signaling was involved in mineralization by CVCs. In static cultures, pharmacological inhibition of the extracellular signal-regulated kinase (ERK1/2), p38 MAPK, and c-Jun N-terminal kinase pathways significantly attenuated mineral production by as much as -94%, compared with uninhibited CVCs. Strikingly, although mechanical stimulation activated each of the MAPK pathways, inhibition of these pathways had no effect on the mechanically induced enhancement of alkaline phosphatase activity or mineralization. These novel data indicate that mechanical signals regulate calcification by CVCs, and although MAPK signaling is critical to CVC osteogenic differentiation and mineralization, it is not involved directly in transduction of mechanical signals to regulate these processes under the conditions utilized in this study.     

Monomeric recombinant TCR ligand reduces relapse rate and severity of experimental autoimmune encephalomyelitis in SJL/J mice through cytokine switch

Our previous studies demonstrated that oligomeric recombinant TCR ligands (RTL) can treat clinical signs of experimental autoimmune encephalomyelitis (EAE) and induce long-term T cell tolerance against encephalitogenic peptides. In the current study, we produced a monomeric I-A(s)/PLP 139-151 peptide construct (RTL401) suitable for use in SJL/J mice that develop relapsing disease after injection of PLP 139-151 peptide in CFA. RTL401 given i.v. or s.c. but not empty RTL400 or free PLP 139-151 peptide prevented relapses and significantly reduced clinical severity of EAE induced by PLP 139-151 peptide in SJL/J or (C57BL/6 x SJL)F(1) mice, but did not inhibit EAE induced by PLP 178-191 or MBP 84-104 peptides in SJL/J mice, or MOG 35-55 peptide in (C57BL/6 x SJL/J)F(1) mice. RTL treatment of EAE caused stable or enhanced T cell proliferation and secretion of IL-10 in the periphery, but reduced secretion of inflammatory cytokines and chemokines. In CNS, there was a modest reduction of inflammatory cells, reduced expression of very late activation Ag-4, lymphocyte function-associated Ag-1, and inflammatory cytokines, chemokines, and chemokine receptors, but enhanced expression of Th2-related factors, IL-10, TGF-beta3, and CCR3. These results suggest that monomeric RTL therapy induces a cytokine switch that curbs the encephalitogenic potential of PLP 139-151-specific T cells without fully preventing their entry into CNS, wherein they reduce the severity of inflammation. This mechanism differs from that observed using oligomeric RTL therapy in other EAE models. These results strongly support the clinical application of this novel class of peptide/MHC class II constructs in patients with multiple sclerosis who have focused T cell responses to known encephalitogenic myelin peptides.     

The ecosystem-service chain and the biological diversity crisis

The losses that are being incurred of the Earth''s biological diversity, at all levels, are now staggering. The trend lines for future loss are steeply upward as new adverse drivers of change come into play. The political processes for matching this crisis are now inadequate and the science needs to address this issue are huge and slow to fulfil, even though strong advances have been made. A more integrated approach to evaluating biodiversity in terms that are meaningful to the larger community is needed that can provide understandable metrics of the consequences to society of the losses that are occurring. Greater attention is also needed in forecasting likely diversity-loss scenarios in the near term and strategies for alleviating detrimental consequences. At the international level, the Convention on Biological Diversity must be revisited to make it more powerful to meet the needs that originally motivated its creation. Similarly, at local and regional levels, an ecosystem-service approach to conservation can bring new understanding to the value, and hence the need for protection, of the existing natural capital.