Structure of Cross-Bridges in Vertebrate Skeletal Muscle Activated by Photolysis of Caged Ca2+

In order to understand the contraction mechanism in vertebrate skeletal muscle, one must correlate the structural and mechanical details of the cross-bridge cycle on the millisecond time scale. Using electron microscopy, I investigated the structure of cross-bridges in fibers activated by photolysis of caged ca2+ and then ultra­rapidly frozen and freeze substituted with tannic acid and OsO4. Sections from relaxed fibers show helical tracks, presumed to be rnyosin heads, on the thick filament surface. Optical diffraction patterns show strong meridional spots and layer lines up to the 6th order of the 429 Å repeat, indicating preservation and resolution of periodic structures smaller than 100 Å . Following photo-release of ca2+, the myosin 1/429 Å-1 layer line becomes less intense, and higher orders disappear, both with a time course which precedes the rise in tension. Å 1/360 Å-1 layer line appears early in contraction ( 12-15 ms) and becomes stronger at later times. The intensity of the 1/143 Å_-1 meridional spot decreases initially and then increases to greater than its value in relaxed fibers, while it broadens six-fold laterally. The 1/430 Å-1 meridional spot is present during contraction but markedly weakened. The 1/215 Å-1 meridional spot is weak or absent. These results are consistent with time resolved X-ray diffraction data on the periodic structures within the fiber. The intensification of the 1/360 Å-1 layer line, with a concomitant decrease in the intensity of the 1/429 Å-1 layer line, supports the view that at least some cross­bridges decorate the thin filament during contraction with an act in based set of periodicities, but not to the same degree as is seen in rigor. The lateral spread of the 1/ 143 Å-1 meridional spot indicates a disorder of axial coherence among thick filaments during tension development. In sections along the (1,1) plane of activated fibers, the individual cross-bridges have a wide range of shapes and angles, perpendicular to the fiber axis or pointing toward or away from the Z-line. Fibers frozen at 12-15 ms, 30-35 ms, and 210-220 ms after photolysis all show surprisingly similar cross-bridges. Thus, a highly variable distribution of cross-bridge shapes and angles is established early in contraction

Architectures for Dynamic Data Scaling in 2/4/8K Pipeline FFT Cores

This paper presents architectures for supporting dynamic data scaling in pipeline fast Fourier transforms (FFTs), suitable when implementing large size FFTs in applications such as digital video broadcasting and digital holographic imaging. In a pipeline FFT, data is continuously streaming and must, hence, be scaled without stalling the dataflow. We propose a hybrid floating-point scheme with tailored exponent datapath, and a co-optimized architecture between hybrid floating point and block floating point (BFP) to reduce memory requirements for 2-D signal processing. The presented co-optimization generates a higher signal-to-quantization-noise ratio and requires less memory than for instance convergent BFP. A 2048-point pipeline FFT has been fabricated in a standard-CMOS process from AMI Semiconductor (Lenart and Öwall, 2003), and a field-programmable gate array prototype integrating a 2-D FFT core in a larger design shows that the architecture is suitable for image reconstruction in digital holographic imaging

A hybrid interconnect network-on-chip and a transaction level modeling approach for reconfigurable computing

This paper presents a hybrid interconnect network consisting of a local network with dedicated wires and a global hierarchical network. A distributed memory approach enables the possibility to use generic memory banks as routing buffers, simplifies the implementation and reduces the area requirements of routers. A SystemC simulation environment (SCENIC) has been developed to simulate and instrument models, and to setup different topologies and scenarios. Modules are designed as transaction level models to improve design time and simulation speed

Modeling and exploration of a reconfigurable architecture for digital holographic imaging

The use of coarse-grain reconfigurable architectures (CGRA) is a suitable alternative for hardware acceleration in many application areas, including digital holographic imaging. In this paper, we propose a CGRA-based system with an array of processing and memory cells, which communicate using a local and a global communication network, and a stream memory controller to manage data transfers to external memory. We present our SystemC-based exploration environment (SCENIC) and methodology used to construct and evaluate systems containing reconfigurable architectures. A case study illustrates the advantages with rapid system level exploration to find and solve bottlenecks in complex designs prior to RTL description

Asymmetric function theory

The classical theory of symmetric functions has a central position in algebraic combinatorics, bridging aspects of representation theory, combinatorics, and enumerative geometry. More recently, this theory has been fruitfully extended to the larger ring of quasisymmetric functions, with corresponding applications. Here, we survey recent work extending this theory further to general asymmetric polynomials.Comment: 36 pages, 8 figures, 1 table. Written for the proceedings of the Schubert calculus conference in Guangzhou, Nov. 201

Littlewood-Richardson coefficients for reflection groups

In this paper we explicitly compute all Littlewood-Richardson coefficients for semisimple or Kac-Moody groups G, that is, the structure coefficients of the cohomology algebra H^*(G/P), where P is a parabolic subgroup of G. These coefficients are of importance in enumerative geometry, algebraic combinatorics and representation theory. Our formula for the Littlewood-Richardson coefficients is given in terms of the Cartan matrix and the Weyl group of G. However, if some off-diagonal entries of the Cartan matrix are 0 or -1, the formula may contain negative summands. On the other hand, if the Cartan matrix satisfies $a_{ij}a_{ji}\ge 4$ for all $i,j$, then each summand in our formula is nonnegative that implies nonnegativity of all Littlewood-Richardson coefficients. We extend this and other results to the structure coefficients of the T-equivariant cohomology of flag varieties G/P and Bott-Samelson varieties Gamma_\ii(G).Comment: 51 pages, AMSLaTeX, typos correcte

Evidence-based guidelines for the pharmacological treatment of postmenopausal osteoporosis: a consensus document by the Belgian Bone Club

Several drugs are available for the management of postmenopausal osteoporosis. This may, in daily practice, confuse the clinician. This manuscript offers an evidence-based update of previous treatment guidelines, with a critical assessment of the currently available efficacy data on all new chemical entities which were granted a marketing authorization. Osteoporosis is widely recognized as a major public health concern. The availability of new therapeutic agents makes clinical decision-making in osteoporosis more complex. Nation-specific guidelines are needed to take into consideration the specificities of each and every health care environment. The present manuscript is the result of a National Consensus, based on a systematic review and a critical appraisal of the currently available literature. It offers an evidence-based update of previous treatment guidelines, with the aim of providing clinicians with an unbiased assessment of osteoporosis treatment effect

Determination of Alkali and Halide Monovalent Ion Parameters for Use in Explicitly Solvated Biomolecular Simulations

Alkali (Li+, Na+, K+, Rb+, and Cs+) and halide (F−, Cl−, Br−, and I−) ions play an important role in many biological phenomena, roles that range from stabilization of biomolecular structure, to influence on biomolecular dynamics, to key physiological influence on homeostasis and signaling. To properly model ionic interaction and stability in atomistic simulations of biomolecular structure, dynamics, folding, catalysis, and function, an accurate model or representation of the monovalent ions is critically necessary. A good model needs to simultaneously reproduce many properties of ions, including their structure, dynamics, solvation, and moreover both the interactions of these ions with each other in the crystal and in solution and the interactions of ions with other molecules. At present, the best force fields for biomolecules employ a simple additive, nonpolarizable, and pairwise potential for atomic interaction. In this work, we describe our efforts to build better models of the monovalent ions within the pairwise Coulombic and 6-12 Lennard-Jones framework, where the models are tuned to balance crystal and solution properties in Ewald simulations with specific choices of well-known water models. Although it has been clearly demonstrated that truly accurate treatments of ions will require inclusion of nonadditivity and polarizability (particularly with the anions) and ultimately even a quantum mechanical treatment, our goal was to simply push the limits of the additive treatments to see if a balanced model could be created. The applied methodology is general and can be extended to other ions and to polarizable force-field models. Our starting point centered on observations from long simulations of biomolecules in salt solution with the AMBER force fields where salt crystals formed well below their solubility limit. The likely cause of the artifact in the AMBER parameters relates to the naive mixing of the Smith and Dang chloride parameters with AMBER-adapted Åqvist cation parameters. To provide a more appropriate balance, we reoptimized the parameters of the Lennard-Jones potential for the ions and specific choices of water models. To validate and optimize the parameters, we calculated hydration free energies of the solvated ions and also lattice energies (LE) and lattice constants (LC) of alkali halide salt crystals. This is the first effort that systematically scans across the Lennard-Jones space (well depth and radius) while balancing ion properties like LE and LC across all pair combinations of the alkali ions and halide ions. The optimization across the entire monovalent series avoids systematic deviations. The ion parameters developed, optimized, and characterized were targeted for use with some of the most commonly used rigid and nonpolarizable water models, specifically TIP3P, TIP4PEW, and SPC/E. In addition to well reproducing the solution and crystal properties, the new ion parameters well reproduce binding energies of the ions to water and the radii of the first hydration shells

Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens

he antibiotic target. One class of such proteins are the antibiotic resistance (ARE) ATP-binding cassette (ABC) proteins of the F-subtype (ARE-ABCFs), which are widely distributed throughout Gram-positive bacteria and bind the ribosome to alleviate translational inhibition from antibiotics that target the large ribosomal subunit. Here, we present single-particle cryo-EM structures of ARE-ABCF-ribosome complexes from three Gram-positive pathogens: Enterococcus faecalis LsaA, Staphylococcus haemolyticus VgaALC and Listeria monocytogenes VgaL. Supported by extensive mutagenesis analysis, these structures enable a general model for antibiotic resistance mediated by these ARE-ABCFs to be proposed. In this model, ABCF binding to the antibiotic-stalled ribosome mediates antibiotic release via mechanistically diverse long-range conformational relays that converge on a few conserved ribosomal RNA nucleotides located at the peptidyltransferase center. These insights are important for the future development of antibiotics that overcome such target protection resistance mechanisms