Mammalian Mat1 subunit of Transcription Factor IIH in gene-specific and general transcription

All protein-encoding genes in eukaryotes are transcribed into messenger RNA (mRNA) by RNA Polymerase II (RNAP II), whose activity therefore needs to be tightly controlled. An important and only partially understood level of regulation is the multiple phosphorylations of RNAP II large subunit C-terminal domain (CTD). Sequential phosphorylations regulate transcription initiation and elongation, and recruit factors involved in co-transcriptional processing of mRNA. Based largely on studies in yeast models and in vitro, the kinase activity responsible for the phosphorylation of the serine-5 (Ser5) residues of RNAP II CTD has been attributed to the Mat1/Cdk7/CycH trimer as part of Transcription Factor IIH. However, due to the lack of good mammalian genetic models, the roles of both RNAP II Ser5 phosphorylation as well as TFIIH kinase in transcription have provided ambiguous results and the in vivo kinase of Ser5 has remained elusive. The primary objective of this study was to elucidate the role of mammalian TFIIH, and specifically the Mat1 subunit in CTD phosphorylation and general RNAP II-mediated transcription. The approach utilized the Cre-LoxP system to conditionally delete murine Mat1 in cardiomyocytes and hepatocytes in vivo and and in cell culture models. The results identify the TFIIH kinase as the major mammalian Ser5 kinase and demonstrate its requirement for general transcription, noted by the use of nascent mRNA labeling. Also a role for Mat1 in regulating general mRNA turnover was identified, providing a possible rationale for earlier negative findings. A secondary objective was to identify potential gene- and tissue-specific roles of Mat1 and the TFIIH kinase through the use of tissue-specific Mat1 deletion. Mat1 was found to be required for the transcriptional function of PGC-1 in cardiomyocytes. Transriptional activation of lipogenic SREBP1 target genes following Mat1 deletion in hepatocytes revealed a repressive role for Mat1apparently mediated via co-repressor DMAP1 and the DNA methyltransferase Dnmt1. Finally, Mat1 and Cdk7 were also identified as a negative regulators of adipocyte differentiation through the inhibitory phosphorylation of Peroxisome proliferator-activated receptor (PPAR) γ. Together, these results demonstrate gene- and tissue-specific roles for the Mat1 subunit of TFIIH and open up new therapeutic possibilities in the treatment of diseases such as type II diabetes, hepatosteatosis and obesity.

Strong spin-two interaction and general relativity

The concept of short range strong spin-two (f) field (mediated by massive f-mesons) and interacting directly with hadrons was introduced along with the infinite range (g) field in early seventies. In the present review of this growing area (often referred to as strong gravity) we give a general relativistic treatment in terms of Einstein-type (non-abelian gauge) field equations with a coupling constant Gf reverse similar, equals 1038 GN (GN being the Newtonian constant) and a cosmological term λf ƒ;μν (ƒ;μν is strong gravity metric and λf not, vert, similar 1028 cm− is related to the f-meson mass). The solutions of field equations linearized over de Sitter (uniformly curves) background are capable of having connections with internal symmetries of hadrons and yielding mass formulae of SU(3) or SU(6) type. The hadrons emerge as de Sitter “microuniverses” intensely curved within (radius of curvature not, vert, similar10−14 cm).The study of spinor fields in the context of strong gravity has led to Heisenberg's non-linear spinor equation with a fundamental length not, vert, similar2 × 10−14 cm. Furthermore, one finds repulsive spin-spin interaction when two identical spin-Image particles are in parallel configuration and a connection between weak interaction and strong gravity.Various other consequences of strong gravity embrace black hole (solitonic) solutions representing hadronic bags with possible quark confinement, Regge-like relations between spins and masses, connection with monopoles and dyons, quantum geons and friedmons, hadronic temperature, prevention of gravitational singularities, providing a physical basis for Dirac's two metric and large numbers hypothesis and projected unification with other basic interactions through extended supergravity.

A new general method for the introduction of the aldehyde function in aromatic compounds

Side chain bromination of aromatic amidomethylated compounds yields aldehydes.

Composite MR image reconstruction and unaliasing for general trajectories using neural networks

In rapid parallel magnetic resonance imaging, the problem of image reconstruction is challenging. Here, a novel image reconstruction technique for data acquired along any general trajectory in neural network framework, called ``Composite Reconstruction And Unaliasing using Neural Networks'' (CRAUNN), is proposed. CRAUNN is based on the observation that the nature of aliasing remains unchanged whether the undersampled acquisition contains only low frequencies or includes high frequencies too. Here, the transformation needed to reconstruct the alias-free image from the aliased coil images is learnt, using acquisitions consisting of densely sampled low frequencies. Neural networks are made use of as machine learning tools to learn the transformation, in order to obtain the desired alias-free image for actual acquisitions containing sparsely sampled low as well as high frequencies. CRAUNN operates in the image domain and does not require explicit coil sensitivity estimation. It is also independent of the sampling trajectory used, and could be applied to arbitrary trajectories as well. As a pilot trial, the technique is first applied to Cartesian trajectory-sampled data. Experiments performed using radial and spiral trajectories on real and synthetic data, illustrate the performance of the method. The reconstruction errors depend on the acceleration factor as well as the sampling trajectory. It is found that higher acceleration factors can be obtained when radial trajectories are used. Comparisons against existing techniques are presented. CRAUNN has been found to perform on par with the state-of-the-art techniques. Acceleration factors of up to 4, 6 and 4 are achieved in Cartesian, radial and spiral cases, respectively. (C) 2010 Elsevier Inc. All rights reserved.

Development of radiosynthesis methods for 18F-labelled radiopharmaceuticals : General considerations and production of a dopamine transporter radioligand

Positron emission tomography (PET) is a molecular imaging technique that utilises radiopharmaceuticals (radiotracers) labelled with a positron-emitting radionuclide, such as fluorine-18 (18F). Development of a new radiotracer requires an appropriate radiosynthesis method: the most common of which with 18F is nucleophilic substitution with [18F]fluoride ion. The success of the labelling reaction is dependent on various factors such as the reactivity of [18F]fluoride, the structure of the target compound in addition to the chosen solvent. The overall radiosynthesis procedure must be optimised in terms of radiochemical yield and quality of the final product. Therefore, both quantitative and qualitative radioanalytical methods are essential in developing radiosynthesis methods. Furthermore, biological properties of the tracer candidate need to be evaluated by various pre-clinical studies in animal models. In this work, the feasibility of various nucleophilic 18F-fluorination strategies were studied and a labelling method for a novel radiotracer, N-3-[18F]fluoropropyl-2beta-carbomethoxy-3beta-4-fluorophenyl)nortropane ([18F]beta-CFT-FP), was optimised. The effect of solvent was studied by labelling a series of model compounds, 4-(R1-methyl)benzyl R2-benzoates. 18F-Fluorination reactions were carried out both in polar aprotic and protic solvents (tertiary alcohols). Assessment of the 18F-fluorinated products was studied by mass spectrometry (MS) in addition to conventional radiochromatographic methods, using radiosynthesis of 4-[18F]fluoro-N-[2-[1-(2-methoxyphenyl)-1-piperazinyl]ethyl-N-2-pyridinyl-benzamide (p-[18F]MPPF) as a model reaction. Labelling of [18F]beta-CFT-FP was studied using two 18F-fluoroalkylation reagents, [18F]fluoropropyl bromide and [18F]fluoropropyl tosylate, as well as by direct 18F-fluorination of sulfonate ester precursor. Subsequently, the suitability of [18F]beta-CFT-FP for imaging dopamine transporter (DAT) was evaluated by determining its biodistribution in rats. The results showed that protic solvents can be useful co-solvents in aliphatic 18F-fluorinations, especially in the labelling of sulfonate esters. Aromatic 18F-fluorination was not promoted in tert-alcohols. Sensitivity of the ion trap MS was sufficient for the qualitative analysis of the 18F-labelled products; p-[18F]MPPF was identified from the isolated product fraction with a mass-to-charge (m/z) ratio of 435 (i.e. protonated molecule [M+H]+). [18F]beta-CFT-FP was produced most efficiently via [18F]fluoropropyl tosylate, leading to sufficient radiochemical yield and specific radioactivity for PET studies. The ex vivo studies in rats showed fast kinetics as well as the specific uptake of [18F]beta-CFT-FP to the DAT rich brain regions. Thus, it was concluded that [18F]beta-CFT-FP has potential as a radiotracer for imaging DAT by PET.

A geodesic constant method for computing high-frequency mutual coupling between antennas on general quadric cylinders

A Geodesic Constant Method (GCM) is outlined which provides a common approach to ray tracing on quadric cylinders in general, and yields all the surface ray-geometric parameters required in the UTD mutual coupling analysis of conformal antenna arrays in the closed form. The approach permits the incorporation of a shaping parameter which permits the modeling of quadric cylindrical surfaces of desired sharpness/flatness with a common set of equations. The mutual admittance between the slots on a general parabolic cylinder is obtained as an illustration of the applicability of the GCM.

General model of a foam bed reactor

A general model of a foam bed reactor has been developed which rigorously accounts for the extent of gas absorption with chemical reaction occurring in both the storage and foam sections. Its applicability extends to a wide spectrum of reaction velocities. The possibilities of the predominance of the bulk-liquid reaction in the storage section or the absorption with reaction in the foam section can be handled as merely special cases of the general analysis. The importance of foam for carrying out a particular gas-liquid reaction is characterised by a criterion in terms of the fractional rate of reaction in the foam section. Trends of variations in the concentrations of dissolved free A, solute B, and gas-phase A with time of operation of the reactor are presented. The nature of the variation in the fractional rate of reaction in the foam section with time, at different reaction velocities, and the effect of the liquid flow rate (across the storage section) on the transience are also illustrated. Finally, the predictions of the general model have been validated using the available experimental data on the oxidation of sodium sulphide in a foam bed reactor. The agreement between the experimental and the present theoretical information is fairly good, apart from being more insightful than all the previous models of this reactor.

Bearing capacity factors of circular foundations for a general c-phi soil using lower bound finite elements limit analysis

By using the lower bound limit analysis in conjunction with finite elements and linear programming, the bearing capacity factors due to cohesion, surcharge and unit weight, respectively, have been computed for a circular footing with different values of phi. The recent axisymmetric formulation proposed by the authors under phi = 0 condition, which is based on the concept that the magnitude of the hoop stress (sigma(theta)) remains closer to the least compressive normal stress (sigma(3)), is extended for a general c-phi soil. The computational results are found to compare quite well with the available numerical results from literature. It is expected that the study will be useful for solving various axisymmetric geotechnical stability problems. Copyright (C) 2010 John Wiley & Sons, Ltd.

A canonical formulation of the direct position kinematics problem for a general 6-6 stewart platform

This paper deals with the direct position kinematics problem of a general 6-6 Stewart platform, the complete solution of which is not reported in the literature until now and even establishing the number of possible solutions for the general case has remained an unsolved problem for a long period. Here a canonical formulation of the direct position kinematics problem for a general 6-6 Stewart platform is presented. The kinematic equations are expressed as a system of six quadratic and three linear equations in nine unknowns, which has a maximum of 64 solutions. Thus, it is established that the mechanism, in general, can have up to 64 closures. Further reduction of the system is shown arriving at a set of three quartic equations in three unknowns, the solution of which will yield the assembly configurations of the general Stewart platform with far less computational effort compared to earlier models.

A formula for the solution of general Abel integral equation

A new formula for the solution of the general Abel Integral equation is derived, and an important special case is checked with the known result.

A general procedure for modified crack closure integral in 3D problems with cracks

In linear elastic fracture mechanics (LEFM), Irwin's crack closure integral (CCI) is one of the signficant concepts for the estimation of strain energy release rates (SERR) G, in individual as well as mixed-mode configurations. For effective utilization of this concept in conjunction with the finite element method (FEM), Rybicki and Kanninen [Engng Fracture Mech. 9, 931 938 (1977)] have proposed simple and direct estimations of the CCI in terms of nodal forces and displacements in the elements forming the crack tip from a single finite element analysis instead of the conventional two configuration analyses. These modified CCI (MCCI) expressions are basically element dependent. A systematic derivation of these expressions using element stress and displacement distributions is required. In the present work, a general procedure is given for the derivation of MCCI expressions in 3D problems with cracks. Further, a concept of sub-area integration is proposed which facilitates evaluation of SERR at a large number of points along the crack front without refining the finite element mesh. Numerical data are presented for two standard problems, a thick centre-cracked tension specimen and a semi-elliptical surface crack in a thick slab. Estimates for the stress intensity factor based on MCCI expressions corresponding to eight-noded brick elements are obtained and compared with available results in the literature.

The Shannon Cipher System With a Guessing Wiretapper: General Sources

The Shannon cipher system is studied in the context of general sources using a notion of computational secrecy introduced by Merhav and Arikan. Bounds are derived on limiting exponents of guessing moments for general sources. The bounds are shown to be tight for i.i.d., Markov, and unifilar sources, thus recovering some known results. A close relationship between error exponents and correct decoding exponents for fixed rate source compression on the one hand and exponents for guessing moments on the other hand is established.