DEXA screening: are we doing too much?

Reconsider the intervals at which you recommend rescreening for osteoporosis; for postmenopausal women with a baseline of normal bone mineral density (BMD) or mild osteopenia, a 15-year interval is probably sufficient. Strength of recommendation B: Based on a single cohort study

Cobalt-Porphyrin Catalyzed Electrochemical Reduction of Carbon Dioxide in Water II: Mechanism from First Principles

We apply first principles computational techniques to analyze the two-electron, multi-step, electrochemical reduction of CO2 to CO in water using cobalt porphyrin as a catalyst. Density Functional Theory calculations with hybrid functionals and dielectric continuum solvation are used to determine the steps at which electrons are added. This information is corroborated with ab initio molecular dynamics simulations in an explicit aqueous environment which reveal the critical role of water in stabilizing a key intermediate formed by CO2 bound to cobalt. Using potential of mean force calculations, the intermediate is found to spontaneously accept a proton to form a carboxylate acid group at pH<9.0, and the subsequent cleavage of a C-OH bond to form CO is exothermic and associated with a small free energy barrier. These predictions suggest that the proposed reaction mechanism is viable if electron transfer to the catalyst is sufficiently fast. The variation in cobalt ion charge and spin states during bond breaking, DFT+U treatment of cobalt 3d orbitals, and the need for computing electrochemical potentials are emphasized.Comment: 33 pages, 7 figure

Ab initio molecular dynamics study of manganese porphine hydration and interaction with nitric oxide

The authors use ab initio molecular dynamics and the density functional theory+U (DFT+U) method to compute the hydration environment of the manganese ion in manganese (II) and manganese (III) porphines (MnP) dispersed in liquid water. These are intended as simple models for more complex water soluble porphyrins, which have important physiological and electrochemical applications. The manganese ion in Mn(II)P exhibits significant out-of-porphine plane displacement and binds strongly to a single H2O molecule in liquid water. The Mn in Mn(III)P is on average coplanar with the porphine plane and forms a stable complex with two H2O molecules. The residence times of these water molecules exceed 15 ps. The DFT+U method correctly predicts that water displaces NO from Mn(III)P-NO, but yields an ambiguous spin state for the MnP(II)-NO complex.Comment: 10 pages, 6 figure

Foraging environment determines the genetic architecture and evolutionary potential of trophic morphology in cichlid fishes

Phenotypic plasticity allows organisms to change their phenotype in response to shifts in the environment. While a central topic in current discussions of evolutionary potential, a comprehensive understanding of the genetic underpinnings of plasticity is lacking in systems undergoing adaptive diversification. Here, we investigate the genetic basis of phenotypic plasticity in a textbook adaptive radiation, Lake Malawi cichlid fishes. Specifically, we crossed two divergent species to generate an F3 hybrid mapping population. At early juvenile stages, hybrid families were split and reared in alternate foraging environments that mimicked benthic/scraping or limnetic/sucking modes of feeding. These alternate treatments produced a variation in morphology that was broadly similar to the major axis of divergence among Malawi cichlids, providing support for the flexible stem theory of adaptive radiation. Next, we found that the genetic architecture of several morphological traits was highly sensitive to the environment. In particular, of 22 significant quantitative trait loci (QTL), only one was shared between the environments. In addition, we identified QTL acting across environments with alternate alleles being differentially sensitive to the environment. Thus, our data suggest that while plasticity is largely determined by loci specific to a given environment, it may also be influenced by loci operating across environments. Finally, our mapping data provide evidence for the evolution of plasticity via genetic assimilation at an important regulatory locus, ptch1. In all, our data address long-standing discussions about the genetic basis and evolution of plasticity. They also underscore the importance of the environment in affecting developmental outcomes, genetic architectures, morphological diversity and evolutionary potential

Insulin-dependent GLUT4 trafficking is not regulated by protein SUMOylation in L6 myocytes

Type-II Diabetes Mellitus (T2DM) is one of the fastest growing public health issues today, consuming 12% of worldwide health budgets and affecting an estimated 400 million people. One of the key pathological traits of this disease is insulin resistance at ‘glucose sink’ tissues (mostly skeletal muscle), and this remains one of the features of this disease most intractable to therapeutic intervention. Several lines of evidence have implicated the post-translational modification,SUMOylation, in insulin signalling and insulin resistance in skeletal muscle. In this study, we examined this possibility by manipulation of cellular SUMOylation levels using multiple different tools, and assaying the effect on insulin-stimulated GLUT4 surface expression in differentiated L6 rat myocytes. Although insulin stimulation of L6 myocytes produced a robust decrease in total cellular SUMO1-ylation levels, manipulating cellular SUMOylation had no effect on insulin-responsive GLUT4 surface trafficking using any of the tools we employed. Whilst we cannot totally exclude the possibility that SUMOylation plays a role in the insulin signalling pathway in human health and disease, our data strongly argue that GLUT4 trafficking in response to insulin is not regulated by protein SUMOylation, and that SUMOylation does not therefore represent a viable therapeutic target for the treatment of insulin resistance

Conserved but flexible modularity in the zebrafish skull: implications for craniofacial evolvability

Morphological variation is the outward manifestation of development and provides fodder for adaptive evolution. Because of this contingency, evolution is often thought to be biased by developmental processes and functional interactions among structures, which are statistically detectable through forms of covariance among traits. This can take the form of substructures of integrated traits, termed modules, which together comprise patterns of variational modularity. While modularity is essential to an understanding of evolutionary potential, biologists currently have little understanding of its genetic basis and its temporal dynamics over generations. To address these open questions, we compared patterns of craniofacial modularity among laboratory strains, defined mutant lines and a wild population of zebrafish ( ). Our findings suggest that relatively simple genetic changes can have profound effects on covariance, without greatly affecting craniofacial shape. Moreover, we show that instead of completely deconstructing the covariance structure among sets of traits, mutations cause shifts among seemingly latent patterns of modularity suggesting that the skull may be predisposed towards a limited number of phenotypes. This new insight may serve to greatly increase the evolvability of a population by providing a range of 'preset' patterns of modularity that can appear readily and allow for rapid evolution

Modularity of the Oral Jaws Is Linked to Repeated Changes in the Craniofacial Shape of African Cichlids

The African cichlids of the East-African rift-lakes provide one of the most dramatic examples of adaptive radiation known. It has long been thought that functional decoupling of the oral and pharyngeal jaws in cichlids has facilitated their explosive evolution. Recent research has also shown that craniofacial evolution from radiations in lakes Victoria, Malawi, and Tanganyika has occurred along a shared primary axis of shape divergence, whereby the preorbital region of the skull changes in a manner that is, relatively independent from other head regions. We predicted that the preorbital region would comprise a variational module and used an extensive dataset from each lake that allowed us to test this prediction using a model selection approach. Our findings supported the presence of a preorbital module across all lakes, within each lake, and for Malawi, within sand and rock-dwelling clades. However, while a preorbital module was consistently present, notable differences were also observed among groups. Of particular interest, a negative association between patterns of variational modularity was observed between the sand and rock-dwelling clades, a patter consistent with character displacement. These findings provide the basis for further experimental research involving the determination of the developmental and genetic bases of these patterns of modularity

Density functional theory and DFT+U study of transition metal porphines adsorbed on Au(111) surfaces and effects of applied electric fields

We apply Density Functional Theory (DFT) and the DFT+U technique to study the adsorption of transition metal porphine molecules on atomistically flat Au(111) surfaces. DFT calculations using the Perdew-Burke-Ernzerhof (PBE) exchange correlation functional correctly predict the palladium porphine (PdP) low-spin ground state. PdP is found to adsorb preferentially on gold in a flat geometry, not in an edgewise geometry, in qualitative agreement with experiments on substituted porphyrins. It exhibits no covalent bonding to Au(111), and the binding energy is a small fraction of an eV. The DFT+U technique, parameterized to B3LYP predicted spin state ordering of the Mn d-electrons, is found to be crucial for reproducing the correct magnetic moment and geometry of the isolated manganese porphine (MnP) molecule. Adsorption of Mn(II)P on Au(111) substantially alters the Mn ion spin state. Its interaction with the gold substrate is stronger and more site-specific than PdP. The binding can be partially reversed by applying an electric potential, which leads to significant changes in the electronic and magnetic properties of adsorbed MnP, and ~ 0.1 Angstrom, changes in the Mn-nitrogen distances within the porphine macrocycle. We conjecture that this DFT+U approach may be a useful general method for modeling first row transition metal ion complexes in a condensed-matter setting.Comment: 14 pages, 6 figure

Limits of Principal Components Analysis for Producing a Common Trait Space: Implications for Inferring Selection, Contingency, and Chance in Evolution

&lt;b&gt;Background&lt;/b&gt; Comparing patterns of divergence among separate lineages or groups has posed an especially difficult challenge for biologists. Recently a new, conceptually simple methodology called the “ordered-axis plot” approach was introduced for the purpose of comparing patterns of diversity in a common morphospace. This technique involves a combination of principal components analysis (PCA) and linear regression. Given the common use of these statistics the potential for the widespread use of the ordered axis approach is high. However, there are a number of drawbacks to this approach, most notably that lineages with the greatest amount of variance will largely bias interpretations from analyses involving a common morphospace. Therefore, without meeting a set of a priori requirements regarding data structure the ordered-axis plot approach will likely produce misleading results.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methodology/Principal Findings&lt;/b&gt; Morphological data sets from cichlid fishes endemic to Lakes Tanganyika, Malawi, and Victoria were used to statistically demonstrate how separate groups can have differing contributions to a common morphospace produced by a PCA. Through a matrix superimposition of eigenvectors (scale-free trajectories of variation identified by PCA) we show that some groups contribute more to the trajectories of variation identified in a common morphospace. Furthermore, through a set of randomization tests we show that a common morphospace model partitions variation differently than group-specific models. Finally, we demonstrate how these limitations may influence an ordered-axis plot approach by performing a comparison on data sets with known alterations in covariance structure. Using these results we provide a set of criteria that must be met before a common morphospace can be reliably used.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions/Significance&lt;/b&gt; Our results suggest that a common morphospace produced by PCA would not be useful for producing biologically meaningful results unless a restrictive set of criteria are met. We therefore suggest biologists be aware of the limitations of the ordered-axis plot approach before employing it on their own data, and possibly consider other, less restrictive methods for addressing the same question