Evidence for convergent nucleotide evolution and high allelic turnover rates at the complementary sex determiner (csd) gene of western and Asian honey bees

Our understanding of the impact of recombination, mutation, genetic drift and selection on the evolution of a single gene is still limited. Here we investigate the impact of all of these evolutionary forces at the complementary sex determiner (csd) gene which evolves under a balancing mode of selection. Females are heterozygous at the csd gene and males are hemizygous; diploid males are lethal and occur when csd is homozygous. Rare alleles thus have a selective advantage, are seldom lost by the effect of genetic drift and are maintained over extended periods of time when compared to neutral polymorphisms. Here, we report on the analysis of 17, 19 and 15 csd alleles of Apis cerana, Apis dorsata and Apis mellifera honey bees respectively. We observed great heterogeneity of synonymous (pi S) and nonsynonymous (pi N) polymorphisms across the gene, with a consistent peak in exon 6 and 7. We propose that exons 6 and 7 encode the potential specifying domain (csd-PSD) which has accumulated elevated nucleotide polymorphisms over time by balancing selection. We observed no direct evidence that balancing selection favors the accumulation of nonsynonymous changes at csd-PSD (pi N/pi S ratios are all < 1, ranging from 0.6 to 0.95). We observed an excess of shared nonsynonymous changes, which suggests that strong evolutionary constraints are operating at csd-PSD resulting in the independent accumulation of the same nonsynonymous changes in different alleles across species (convergent evolution). Analysis of a csd-PSD genealogy revealed relatively short average coalescence times (~6 million years), low average synonymous nucleotide diversity (pi S < 0.09) and a lack of trans-specific alleles which substantially contrasts with previously analyzed loci under strong balancing selection. We excluded the possibility of a burst of diversification after population bottlenecking and intragenic recombination as explanatory factors, leaving high turn-over rates as the explanation for this observation. By comparing observed allele richness and average coalescence times with a simplified model of csd-coalescence, we found that small long term population sizes (i.e. Ne <104), but not high mutation rates, can explain short maintenance times, implicating a strong impact of genetic drift on the molecular evolution of highly social honey bees

Challenges in the clinical measurement of ocular surface disease in glaucoma patients

Ocular surface disease (OSD) is common among glaucoma patients. Clinical assessment of OSD can be challenging. This review focuses on some of the limitations relating to both subjective and objective measures of OSD, including dry eye. A survey of the literature was conducted to identify the caveats associated with different methods of assessing OSD. The effect of preservatives on the ocular surface, with respect to glaucoma patients in particular, was also reviewed. Objective methods for assessing ocular surface health and disease include the Schirmer test, tear break-up time, fluorescein turnover, corneal and conjunctival staining, tear osmolarity, and vital dyes. These measures all have limitations in terms of their ability to grade the severity of OSD. Previous studies using the OSD Index showed a mild-to-moderate correlation to dry eye disease severity. Other scoring systems for dry eye have shown a relationship to patient symptom scores or quality of life. Due to the challenges clinicians face concerning both subjective and objective ocular surface health assessments, discerning clinical improvement in ocular surface disease can be a challenge. Further research is needed in order to optimize existing clinical methods and/or identify alternative techniques for assessing OSD in the glaucoma population

Spatial discontinuity of Optomotor-blind expression in the Drosophila wing imaginal disc disrupts epithelial architecture and promotes cell sorting

<p>Abstract</p> <p>Background</p> <p>Decapentaplegic (Dpp) is one of the best characterized morphogens, required for dorso-ventral patterning of the <it>Drosophila </it>embryo and for anterior-posterior (A/P) patterning of the wing imaginal disc. In the larval wing pouch, the Dpp target gene <it>optomotor-blind </it>(<it>omb</it>) is generally assumed to be expressed in a step function above a certain threshold of Dpp signaling activity.</p> <p>Results</p> <p>We show that the transcription factor Omb forms, in fact, a symmetrical gradient on both sides of the A/P compartment boundary. Disruptions of the Omb gradient lead to a re-organization of the epithelial cytoskeleton and to a retraction of cells toward the basal membrane suggesting that the Omb gradient is required for correct epithelial morphology. Moreover, by analysing the shape of <it>omb </it>gain- and loss-of-function clones, we find that Omb promotes cell sorting along the A/P axis in a concentration-dependent manner.</p> <p>Conclusions</p> <p>Our findings show that Omb distribution in the wing imaginal disc is described by a gradient rather than a step function. Graded Omb expression is necessary for normal cell morphogenesis and cell affinity and sharp spatial discontinuities must be avoided to allow normal wing development.</p

Regulating repression : roles for the Sir4 N-terminus in linker DNA protection and stabilization of epigenetic states

The Gasser laboratory is supported by the Novartis Research Foundation and the EU training network Nucleosome 4D. SK was supported by an EMBO long-term fellowship, a Schrodinger fellowship from the FWF, and the Swiss SystemsX.ch initiative/C-CINA; HCF by an EMBO long-term fellowship.Silent information regulator proteins Sir2, Sir3, and Sir4 form a heterotrimeric complex that represses transcription at subtelomeric regions and homothallic mating type (HM) loci in budding yeast. We have performed a detailed biochemical and genetic analysis of the largest Sir protein, Sir4. The N-terminal half of Sir4 is dispensable for SIR-mediated repression of HM loci in vivo, except in strains that lack Yku70 or have weak silencer elements. For HM silencing in these cells, the C-terminal domain (Sir4C, residues 747-1,358) must be complemented with an N-terminal domain (Sir4N; residues 1-270), expressed either independently or as a fusion with Sir4C. Nonetheless, recombinant Sir4C can form a complex with Sir2 and Sir3 in vitro, is catalytically active, and has sedimentation properties similar to a full-length Sir4-containing SIR complex. Sir4C-containing SIR complexes bind nucleosomal arrays and protect linker DNA from nucleolytic digestion, but less effectively than wild-type SIR complexes. Consistently, full-length Sir4 is required for the complete repression of subtelomeric genes. Supporting the notion that the Sir4 N-terminus is a regulatory domain, we find it extensively phosphorylated on cyclin-dependent kinase consensus sites, some being hyperphosphorylated during mitosis. Mutation of two major phosphoacceptor sites (S63 and S84) derepresses natural subtelomeric genes when combined with a serendipitous mutation (P2A), which alone can enhance the stability of either the repressed or active state. The triple mutation confers resistance to rapamycin-induced stress and a loss of subtelomeric repression. We conclude that the Sir4 N-terminus plays two roles in SIR-mediated silencing: it contributes to epigenetic repression by stabilizing the SIR-mediated protection of linker DNA; and, as a target of phosphorylation, it can destabilize silencing in a regulated manner.Publisher PDFPeer reviewe

Note on Moufang-Noether currents

The derivative Noether currents generated by continuous Moufang tranformations are constructed and their equal-time commutators are found. The corresponding charge algebra turns out to be a birepresentation of the tangent Mal'ltsev algebra of an analytic Moufang loop.Comment: LaTeX2e, 6 pages, no figures, presented on "The XVth International Colloquium on Integrable Systems and Quantum Symmetries, Prague, 15-17 June, 2006

Risk-adapted Optimization in Intensity Modulated Proton Therapy (IMPT)

Due to the pronounced dose gradients generated by proton beams, proton treatment plans can be very sensitive to treatment uncertainties. However in IMPT many different solutions of the inverse problem exist which result in dose distributions of comparable quality. This thesis investigates methods to exploit this degeneracy of solutions to generate treatment plans which are robust to uncertainties. An investigation of the optimization algorithm in the used IMPT software KonRad revealed that the standard optimization algorithm is not capable to find the optimal treatment plan in a reasonable time. Thus several additional optimization algorithms were implemented and tested in KonRad. The best results were achieved using the L-BFGS algorithm. To rate the sensitivity to uncertainties of individual beamlet dose distributions the heterogeneity number H was developed. It was shown that H correlates with the dose calculation error introduced by the commonly employed pencil beam algorithm as well as with the sensitivity to setup errors of individual beamlets. Finally, the "worst case optimization" was developed to account for uncertainties during the inverse treatment planning. This technique was applied to account for range uncertainties, setup errors and a combination of both uncertainties. The treatment plans generated with this new method are much more robust to the respective uncertainties as conventional IMPT and even as conventional single-field proton plans

Особливості та умови формування властивостей техногенних ґрунтів

This work utilises general numerical magnetic resonance imaging MRI simulations to predict the spatial specificity of the blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signal. A Monte Carlo simulation approach was utilized on a microvascular structure consisting of randomly oriented cylinders representing blood vessels. This framework was employed to numerically investigate the spatial specificity, defined as ratio of pial vessel to microvascular signal, of the spin echo BOLD fMRI signal as a function of field strength, echo time and tissue types [grey matter (GM) and cerebrospinal fluid (CSF), respectively]. Spatial specificity of spin echo BOLD fMRI signal was determined to increase with field strength up to 16 T and with maximal specificity for echo time shorter than tissue T(2). In addition, it was found that, for large pial vessels, the extravascular signal decay could not be described using the oversimplified but nevertheless commonly employed mono-exponential signal decay approximation (MEA). Consequently, a recently proposed model relying on the MEA deviates substantially from our results on the spatial specificity. A refinement of this model is proposed based on an available, more detailed signal description. Finally, the effect of CSF on the spatial specificity was investigated. While a large spatial specificity of the spin echo BOLD fMRI signal is observed if a pial vessel is surrounded by grey matter, this is greatly reduced for a pial vessel situated on a GM/CSF interface, rendering the suppression of pial vessels on the cortex surface unlikely