Molecular basis for the lack of enantioselectivity of human 3-phosphoglycerate kinase.

Non-natural L-nucleoside analogues are increasingly used as therapeutic agents to treat cancer and viral infections. To be active, L-nucleosides need to be phosphorylated to their respective triphosphate metabolites. This stepwise phosphorylation relies on human enzymes capable of processing L-nucleoside enantiomers. We used crystallographic analysis to reveal the molecular basis for the low enantioselectivity and the broad specificity of human 3-phosphoglycerate kinase (hPGK), an enzyme responsible for the last step of phosphorylation of many nucleotide derivatives. Based on structures of hPGK in the absence of nucleotides, and bound to L and d forms of MgADP and MgCDP, we show that a non-specific hydrophobic clamp to the nucleotide base, as well as a water-filled cavity behind it, allows high flexibility in the interaction between PGK and the bases. This, combined with the dispensability of hydrogen bonds to the sugar moiety, and ionic interactions with the phosphate groups, results in the positioning of different nucleotides so to expose their diphosphate group in a position competent for catalysis. Since the third phosphorylation step is often rate limiting, our results are expected to alleviate in silico tailoring of L-type prodrugs to assure their efficient metabolic processing.

Spread of infectious chronic bee paralysis virus by honeybee (Apis mellifera L.) feces.

Knowledge of the spreading mechanism of honeybee pathogens within the hive is crucial to our understanding of bee disease dynamics. The aim of this study was to assess the presence of infectious chronic bee paralysis virus (CBPV) in bee excreta and evaluate its possible role as an indirect route of infection. Samples of paralyzed bees were (i) produced by experimental inoculation with purified virus and (ii) collected from hives exhibiting chronic paralysis. CBPV in bee heads or feces (crude or absorbed onto paper) was detected by reverse transcription-PCR. CBPV infectivity was assessed by intrathoracic inoculation of bees with virus extracted from feces and by placement of naive bees in cages previously occupied by contaminated individuals. CBPV RNA was systematically detected in the feces of naturally and experimentally infected bees and on the paper sheets that had been used to cover the floors of units containing bees artificially infected with CBPV or the floor of one naturally infected colony. Both intrathoracic inoculation of bees with virus extracted from feces and placement of bees in contaminated cages provoked overt disease in naive bees, thereby proving that the excreted virus was infectious and that this indirect route of infection could lead to overt chronic paralysis. This is the first experimental confirmation that infectious CBPV particles excreted in the feces of infected bees can infect naive bees and provoke overt disease by mere confinement of naive bees in a soiled environment.

Thirteen-velocity three-dimensional lattice Boltzmann model.

A thirteen-velocity three-dimensional lattice Boltzmann model on a cubic grid is presented. The transport coefficients derived from the standard Chapman-Enskog expansion are given together with the conditions for isotropy and Galilean invariance. The different invariants of the model are discussed. The results of measurements of drag and torque on a free falling sphere in a cylinder are in good agreement with solutions of the Navier-Stokes equation. Comparison of the time evolution of a freely decaying Taylor-Green vortex computed by fast Fourier transform and by the present model is presented.

Infant apnea and gastroesophageal reflux.

The value of a combination of ultrasound studies and barium swallow examination in the analysis of temporal relationships between apnea and reflux is demonstrated. The two techniques allow acute apneic spells induced by gastroesophageal reflux to be documented and underlying specific digestive tract disorders demonstrated. The high incidence of digestive tract disorders in this area has been identified.

Ultrasound of the gastroesophageal junction.

In 560 endoscopy examinations performed on infants with severe vomiting, no esophagitis was found without endoscopic herniation of the gastroesophageal junction. The length of the abdominal esophagus therefore appears fundamental in reflux studies. Sonography is one of few techniques able to define the abdominal esophagus in vivo, both in terms of its anatomy and as a functional structure. Accurate assessment of the sonographic canal requires careful measurement under strictly defined clinical conditions. Using such criteria, ultrasound has a better sensitivity than barium studies in detecting small herniations. In addition to the important length measurements of the abdominal esophagus, other morphological and functional data can also be acquired by ultrasound.

Theory of the lattice boltzmann method: dispersion, dissipation, isotropy, galilean invariance, and stability

The generalized hydrodynamics (the wave vector dependence of the transport coefficients) of a generalized lattice Boltzmann equation (LBE) is studied in detail. The generalized lattice Boltzmann equation is constructed in moment space rather than in discrete velocity space. The generalized hydrodynamics of the model is obtained by solving the dispersion equation of the linearized LBE either analytically by using perturbation technique or numerically. The proposed LBE model has a maximum number of adjustable parameters for the given set of discrete velocities. Generalized hydrodynamics characterizes dispersion, dissipation (hyperviscosities), anisotropy, and lack of Galilean invariance of the model, and can be applied to select the values of the adjustable parameters that optimize the properties of the model. The proposed generalized hydrodynamic analysis also provides some insights into stability and proper initial conditions for LBE simulations. The stability properties of some two-dimensional LBE models are analyzed and compared with each other in the parameter space of the mean streaming velocity and the viscous relaxation time. The procedure described in this work can be applied to analyze other LBE models. As examples, LBE models with various interpolation schemes are analyzed. Numerical results on shear flow with an initially discontinuous velocity profile (shock) with or without a constant streaming velocity are shown to demonstrate the dispersion effects in the LBE model; the results compare favorably with our theoretical analysis. We also show that whereas linear analysis of the LBE evolution operator is equivalent to Chapman-Enskog analysis in the long-wavelength limit (wave vector k=0), it can also provide results for large values of k. Such results are important for the stability and other hydrodynamic properties of the LBE method and cannot be obtained through Chapman-Enskog analysis.