Algebraic and hamiltonian approaches to isostokes deformations

We study a generalization of the isomonodromic deformation to the case of connections with irregular singularities. We call this generalization Isostokes Deformation. A new deformation parameter arises: one can deform the formal normal forms of connections at irregular points. We study this part of the deformation, giving an algebraic description. Then we show how to use loop groups and hypercohomology to write explicit hamiltonians. We work on an arbitrary complete algebraic curve, the structure group is an arbitrary semisimiple group.Comment: 23 pages, minor corrections in the introduction, references expande

Frobenius manifold structures on the spaces of abelian integrals

Frobenius manifold structures on the spaces of abelian integrals were constructed by I. Krichever. We use D-modules, deformation theory, and homological algebra to give a coordinate-free description of these structures. It turns out that the tangent sheaf multiplication has a cohomological origin, while the Levi-Civita connection is related to 1-dimensional isomonodromic deformations.Comment: Expanded version. The case of an abelian integral with multiple poles is treated. Other minor improvements. Final versio

Irregular Wakimoto modules and the Casimir connection

We study some non-highest weight modules over an affine Kac-Moody algebra at non-critical level. Roughly speaking, these modules are non-commutative localizations of some non-highest weight "vacuum" modules. Using free field realization, we embed some rings of differential operators in endomorphism rings of our modules. These rings of differential operators act on a localization of the space of coinvariants of any module over the Kac-Moody algebra with respect to a certain level subalgebra. In a particular case this action is identified with the Casimir connection.Comment: Final version, available at Springerlink.co

Identification of Leishmania major UDP-Sugar Pyrophosphorylase Inhibitors Using Biosensor-Based Small Molecule Fragment Library Screening

Leishmaniasis is a neglected disease that is caused by different species of the protozoan parasite Leishmania, and it currently affects 12 million people worldwide. The antileishmanial therapeutic arsenal remains very limited in number and efficacy, and there is no vaccine for this parasitic disease. One pathway that has been genetically validated as an antileishmanial drug target is the biosynthesis of uridine diphosphate-glucose (UDP-Glc), and its direct derivative UDP-galactose (UDP-Gal). De novo biosynthesis of these two nucleotide sugars is controlled by the specific UDP-glucose pyrophosphorylase (UGP). Leishmania parasites additionally express a UDP-sugar pyrophosphorylase (USP) responsible for monosaccharides salvage that is able to generate both UDP-Gal and UDP-Glc. The inactivation of the two parasite pyrophosphorylases UGP and USP, results in parasite death. The present study reports on the identification of structurally diverse scaffolds for the development of USP inhibitors by fragment library screening. Based on this screening, we selected a small set of commercially available compounds, and identified molecules that inhibit both Leishmania major USP and UGP, with a half-maximal inhibitory concentration in the 100 µM range. The inhibitors were predicted to bind at allosteric regulation sites, which were validated by mutagenesis studies. This study sets the stage for the development of potent USP inhibitors

A proof of the Grothendieck-Serre conjecture on principal bundles over regular local rings containing infinite fields

Let R be a regular local ring, containing an infinite field. Let G be a reductive group scheme over R. We prove that a principal G-bundle over R is trivial, if it is trivial over the fraction field of R.Comment: Section "Formal loops and affine Grassmannians" is removed as this is now covered in arXiv:1308.3078. Exposition is improved and slightly restructured. Some minor correction

Mechanism and specificity of pentachloropseudilin-mediated inhibition of myosin motor activity.

Here, we report that the natural compound pentachloropseudilin (PClP) acts as a reversible and allosteric inhibitor of myosin ATPase and motor activity. IC(50) values are in the range from 1 to 5 μm for mammalian class-1 myosins and greater than 90 μm for class-2 and class-5 myosins, and no inhibition was observed with class-6 and class-7 myosins. We show that in mammalian cells, PClP selectively inhibits myosin-1c function. To elucidate the structural basis for PClP-induced allosteric coupling and isoform-specific differences in the inhibitory potency of the compound, we used a multifaceted approach combining direct functional, crystallographic, and in silico modeling studies. Our results indicate that allosteric inhibition by PClP is mediated by the combined effects of global changes in protein dynamics and direct communication between the catalytic and allosteric sites via a cascade of small conformational changes along a conserved communication pathway

Kinetic properties and small-molecule inhibition of human myosin-6.

Myosin-6 is an actin-based motor protein that moves its cargo towards the minus-end of actin filaments. Mutations in the gene encoding the myosin-6 heavy chain and changes in the cellular abundance of the protein have been linked to hypertrophic cardiomyopathy, neurodegenerative diseases, and cancer. Here, we present a detailed kinetic characterization of the human myosin-6 motor domain, describe the effect of 2,4,6-triiodophenol on the interaction of myosin-6 with F-actin and nucleotides, and show how addition of the drug reduces the number of myosin-6-dependent vesicle fusion events at the plasma membrane during constitutive secretion

A theoretical entropy score as a single value to express inhibitor selectivity

<p>Abstract</p> <p>Background</p> <p>Designing maximally selective ligands that act on individual targets is the dominant paradigm in drug discovery. Poor selectivity can underlie toxicity and side effects in the clinic, and for this reason compound selectivity is increasingly monitored from very early on in the drug discovery process. To make sense of large amounts of profiling data, and to determine when a compound is sufficiently selective, there is a need for a proper quantitative measure of selectivity.</p> <p>Results</p> <p>Here we propose a new theoretical entropy score that can be calculated from a set of IC₅₀data. In contrast to previous measures such as the 'selectivity score', Gini score, or partition index, the entropy score is non-arbitary, fully exploits IC₅₀data, and is not dependent on a reference enzyme. In addition, the entropy score gives the most robust values with data from different sources, because it is less sensitive to errors. We apply the new score to kinase and nuclear receptor profiling data, and to high-throughput screening data. In addition, through analyzing profiles of clinical compounds, we show quantitatively that a more selective kinase inhibitor is not necessarily more drug-like.</p> <p>Conclusions</p> <p>For quantifying selectivity from panel profiling, a theoretical entropy score is the best method. It is valuable for studying the molecular mechanisms of selectivity, and to steer compound progression in drug discovery programs.</p

ИНТИМАЛЬНАЯ САРКОМА ЛЕГОЧНОЙ АРТЕРИИ, ПРОТЕКАЮЩАЯ ПОД МАСКОЙ ТРОМБОЭМБОЛИИ ЛЕГОЧНОЙ АРТЕРИИ: РЕЗУЛЬТАТЫ ХИРУРГИЧЕСКОГО ЛЕЧЕНИЯ

HighlightsThe article describes a rare case of surgical treatment of pulmonary artery intimal sarcoma. The authors analyzed the causes for incorrect diagnosis of pulmonary embolism in detail, and proposed alternative options for distinguishing the diseases under consideration. Moreover, the authors analyzed different surgical treatment modalities of intracardial sarcomas, and demonstrated the prospect of using molecular hydrogen as a component of an anesthetics during surgical interventions with cardiopulmonary bypass. AbstractThe article describes a rare clinical case of a patient with pulmonary artery sarcoma. The absence of specific symptoms of sarcoma, as well as features of developing cardiovascular and respiratory failure, characteristic of pulmonary embolism, contributed to the incorrect diagnosis. The article analyzes the main problems of primary diagnostics, and proposes new parameters for evaluating manifesting symptoms and the results of additional examination, which should improve the results of surgical treatment of malignant tumors.Основные положенияВ статье представлен редкий случай хирургического лечения интимальной саркомы легочной артерии. Детально проанализированы причины гипердиагностики тромбоэмболии легочной артерии, а также предложены альтернативные варианты дифференциальной верификации рассматриваемых заболеваний. Рассмотрены возможные варианты хирургического лечения сарком внутрикардиальной локализации. Кроме этого, продемонстрирована перспектива применения молекулярного водорода в качестве компонента анестезиологического пособия при выполнении оперативных вмешательств в условиях искусственного кровообращения. РезюмеВ статье описано редкое клиническое наблюдение пациентки с саркомой легочной артерии. Отсутствие специфических симптомов саркомы, а также особенности развивающейся сердечно-сосудистой и дыхательной недостаточности, характерные для тромбоэмболии легочной артерии, способствовали постановке неправильного диагноза. В работе проанализированы основные проблемы первичной диагностики, а также предложены параметры оценки манифестирующих симптомокомплексов и результатов объективных методов обследования, что в свете повышенной онкологической настороженности позволит улучшить результаты хирургического лечения злокачественных заболеваний сердца