The design, synthesis and evaluation of high affinity macrocyclic carbohydrate inhibitors

Carbohydrate-protein interactions have been investigated for a model system of a monoclonal antibody, SYA/J6, which binds a trisaccharide epitope of the O-polysaccharide of the Shigella flexneri variant Y lipopolysaccharide. The thermodynamics of binding for the methyl glycoside of the native trisaccharide epitope, Rha-Rha-GlcNAc () to SYA/J6 over a range of temperatures exhibits strong, linear enthalpy-entropy compensation and a negative heat capacity change (DeltaC(p)=-152 cal mol(-1) degree(-1)). At 293 K the free energy of association is the sum of favourable enthalpy and entropy contributions (DeltaH=-3.9 kcal mol(-1) and -TDeltaS=-2.9 kcal mol(-1)). Crystal structures for SYA/J6 Fab detailed the position of the native trisaccharide epitope, Rha-Rha-GlcNAc, and facilitated a strategy to design a tighter binding, low molecular weight ligand. This involved pre-organization of the native trisaccharide in its bound conformation by addition of intramolecular constraints (a beta-alanyl or glycinyl tether). ELISA measurements indicated that the glycinyl tethered trisaccharide was not an optimal candidate for further analysis, while microcalorimetry provided data showing that the beta-alanyl tethered trisaccharide displayed a 15-fold increase in affinity for SYA/J6. Tethering resulted in a favourable entropic contribution to binding, relative to the native trisaccharide (-TDeltaDeltaS=-1.2 kcal mol(-1)). Potential energy and dynamics calculations using the AMBER Plus force fields indicated that trisaccharide adopted a rigid conformation similar to that of the bound conformation of the native trisaccharide epitope. While this strategy resulted in modest free energy gains by minimizing losses due to conformational entropy, thermodynamic data are consistent with significant contributions from solvent reorganization.     

Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.     

Investigation of the low lying levels in9B

The reaction¹⁰B(³He, α)⁹B(p)⁸Be(g.s.) has been studied using a 1.8 MeV³He⁺ beam. Coincidence spectra were measured at θ_α=?150? and θ_α=22.5?, 30?, 37.5?, 45?, 52.5?, 60? and 67.5? for the indentification of the levels in⁹B which decay by proton emission. Possible new excited levels in⁹B were observed at (1.9±0.1), (2.1±0.1), (2.6±0.1) and (3.1±0.1) MeV.     

Statistics of Fourier modes of velocity and vorticity in turbulent flows: intermittency and long-range correlations

We perform a statistical analysis of experimental fully developed turbulence longitudinal velocity data in the Fourier space. We address the controversial issue of statistical intermittency of spatial Fourier modes by acting on the finite spectral resolution. We derive a link between velocity structure functions and the flatness of Fourier modes thanks to cascade models. Similar statistical behaviors are recovered in the analysis of spatial Fourier modes of vorticity obtained in an acoustic scattering experiment. We conclude that vorticity is long-range correlated and found more intermittent than longitudinal velocity.     

Vectorial Approach to Fast Correlation Attacks

A new, vectorial approach to fast correlation attacks on binary memoryless combiners is proposed. Instead of individual input sequences or their linear combinations, the new attack is targeting subsets of input sequences as a whole thus exploiting the full correlation between the chosen subset and the output sequence. In particular, the set of all the input sequences can be chosen as the target. The attack is based on a novel iterative probabilistic algorithm which is also applicable to general memoryless combiners over finite fields or finite rings. To illustrate the effectiveness of the introduced approach, experimental results obtained for random balanced combining functions are presentedMost of this work was done while he was with Rome CryptoDesign Center, Gemplus, Italy     

On the Motion of a Dynamic System with Minimal Dissipation

The motion of a holonomic scleronomic non-conservative mechanicalsystem with minimal dissipation is considered. As applicationsof the theory several problems are studied in detail.     

Fusion around the barrier for 7Li+12C

Fusion cross-sections for the ⁷Li + ¹²C reaction have been measured at energies above the Coulomb barrier by the direct detection of evaporation residues. The heavy evaporation residues with energies below 3 MeV could not be separated out from the α-particles in the spectrum and hence their contribution was estimated using statistical model calculations. The present work indicates that suppression of fusion cross-sections due to the breakup of ⁷Li may not be significant for ⁷Li + ¹²C reaction at energies around the barrier.     

Correlation Analysis of the Alternating Step Generator

The alternating step generator is a well-known keystream generator consisting of two stop/go clocked LFSRs, LFSR₁ and LFSR₂, whose clocks are controlled by another LFSR, LFSR₃, which is clocked regularly. A probabilistic analysis of this generator is conducted which shows that the posterior probabilites of individual bits of the first derivatives of the regularly clocked LFSR₁ and LFSR₂ sequences, when conditioned on a given segment of the first derivative of the keystream sequence, can be computed efficiently in a number of probabilistic models of interest. The expected values of these probabilities, for a random keystream sequence, are derived by an approximate theoretical analysis and are also verified by systematic computer experiments. It is pointed out that these posterior probabilities can be enhanced in a resynchronization scenario and thus used for a low-complexity fast correlation attack on the two LFSRs. More generally, it is argued that even without resynchronization these probabilities may be significantly different from one half for fast correlation attacks based on iterative decoding algorithms to be successful, although with incresead complexity. A related method for computing the posterior probabilities of individual bits of the LFSR₃ sequence, when conditioned on both the keystream sequence and the LFSR₁ and LFSR₂ sequences, is also developed. As these posterior probabilities are much more different from one half, they can be used for a low-complexity fast correlation attack on LFSR₃, provided that the initial states of LFSR₁ and LFSR₂ are previously reconstructed.