Spirodiepoxides in total synthesis: epoxomicin

The first use of the spirodiepoxide functional group in total synthesis, a study culminating in an efficient synthesis of the potent proteasome inhibitor epoxomicin, is described. Spirodiepoxides derived from allenes by oxidation are shown to give syn disubstituted ketones and their derivatives, including ortho ester, oxazoline, azido epoxide, as well as sulfonamide-, amide-, and azide-containing hydroxy ketones.     

Energy loss of fast quarks in nuclei

We report an analysis of the nuclear dependence of the yield of Drell-Yan dimuons from the 800 GeV/c proton bombardment of 2H, C, Ca, Fe, and W targets. Employing a new formulation of the Drell-Yan process in the rest frame of the nucleus, this analysis examines the effect of initial-state energy loss and shadowing on the nuclear-dependence ratios versus the incident proton's momentum fraction and dimuon effective mass. The resulting energy loss per unit path length is -dE/dz = 2.32+/-0.52+/-0.5 GeV/fm. This is the first observation of a nonzero energy loss of partons traveling in a nuclear environment.     

Investigating the vortex melting phenomenon in BSCCO crystals using magneto-optical imaging technique

Using a novel differential magneto-optical imaging technique we investigate the phenomenon of vortex lattice melting in crystals of Bi₂Sr₂CaCu₂O₈ (BSCCO). The images of melting reveal complex patterns in the formation and evolution of the vortex solid-liquid interface with varying field (H)/temperature (T). We believe that the complex melting patterns are due to a random distribution of material disorder/inhomogeneities across the sample, which create fluctuations in the local melting temperature or field value. To study the fluctuations in the local melting temperature/field, we have constructed maps of the melting landscape T _m(H, r), viz., the melting temperature (T _m) at a given location (r) in the sample at a given field (H). A study of these melting landscapes reveals an unexpected feature: the melting landscape is not fixed, but changes rather dramatically with varying field and temperature along the melting line. It is concluded that the changes in both the scale and shape of the landscape result from the competing contributions of different types of quenched disorder which have opposite effects on the local melting transition.     

Energy dependence of multiplicity in proton-nucleus collisions and models of multiparticle production

This is a continuation of our earlier investigation (Gurtuet al 1974Phys. Lett. 50 B 391) on multiparticle production in proton-nucleus collisions based on an exposure of emulsion stack to 200 GeV/c beam at the NAL. It is found that the ratioR _em = 〈n _s〉/〈n _ch〉, where 〈n _ch〉 is the charged particle multiplicity in pp-collisions, increases slowly from about 1 at 10 GeV/c to 1·6 at 68 GeV/c and attains a constant value of 1·71 ± 0·04 in the region 200 to 8000 GeV/c. Furthermore,R _em = 1·71 implies an effectiveA-dependence ofR _A =A ^0.18,i.e., a very weak dependence. Predictions ofR _em on various models are discussed and compared with the emulsion data. Data seem to favour models of hadron-nucleon collisions in which production of particles takes place through adouble step mechanism,e.g., diffractive excitation, hydrodynamical and energy flux cascade as opposed to models which envisage instantaneous production.     

Tri-partite complex for axonal transport drug delivery achieves pharmacological effect

Background

Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System) neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior.

Results

We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle.

Conclusion

Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal transport holds great promise. The data shown here provide a basic framework for the intraneural pharmacology of this tripartite complex. The pharmacologically efficacious drug delivery demonstrated here verify the fundamental feasibility of using axonal transport for targeted drug delivery.     

Polarized proton inelastic scattering from 40Ca and 48Ca at 500 MeV

Differential cross sections and analyzing powers for inelastic scattering of 500 MeV polarized protons to several low-lying states in ⁴⁰Ca and ⁴⁸Ca are presented. Phenomenological optical potentials (including density squared terms) have been determined and the data have been analyzed to obtain mass deformation parameters. It is expected that these data will be useful in further testing the recently developed relativistic impulse approximation formalisms and in studying the need for medium modification of the interaction.     

Comparison between fixed and Gaussian steplength in Monte Carlo simulations for diffusion processes

We analyze the different degrees of accuracy of two Monte Carlo methods for the simulation of one-dimensional diffusion processes with homogeneous or spatial dependent diffusion coefficient that we assume correctly described by a differential equation. The methods analyzed correspond to fixed and Gaussian steplengths. For a homogeneous diffusion coefficient it is known that the Gaussian steplength generates exact results at fixed time steps Δt. For spatial dependent diffusion coefficients the symmetric character of the Gaussian distribution introduces an error that increases with time. As an example, we consider a diffusion coefficient with constant gradient and show that the error is not present for fixed steplength with appropriate asymmetric jump probabilities.