Highly efficient synthesis of the tricyclic core of Taxol by cascade metathesis

An efficient enantioselective synthesis of the ABC tricyclic core of the anticancer drug Taxol is reported. The key step of this synthesis is a cascade metathesis reaction, which leads in one operation to the required tricycle if appropriate fine-tuning of the dienyne precursor is performed

Shell structure underlying the evolution of quadrupole collectivity in S-38 and S-40 probed by transient-field g-factor measurements on fast radioactive beams

The shell structure underlying shape changes in neutron-rich nuclei between N=20 and N=28 has been investigated by a novel application of the transient field technique to measure the first-excited state g factors in S-38 and S-40 produced as fast radioactive beams. Details of the new methodology are presented. In both S-38 and S-40 there is a fine balance between the proton and neutron contributions to the magnetic moments. Shell model calculations which describe the level schemes and quadrupole properties of these nuclei also give a satisfactory explanation of the g factors. In S-38 the g factor is extremely sensitive to the occupation of the neutron p3/2 orbit above the N=28 shell gap as occupation of this orbit strongly affects the proton configuration. The g factor of deformed S-40 does not resemble that of a conventional collective nucleus because spin contributions are more important than usual.Comment: 10 pages, 36 figures, accepted for publication in Physical Review

Angular Correlations in Internal Pair Conversion of Aligned Heavy Nuclei

We calculate the spatial correlation of electrons and positrons emitted by internal pair conversion of Coulomb excited nuclei in heavy ion collisions. The alignment or polarization of the nucleus results in an anisotropic emission of the electron-positron pairs which is closely related to the anisotropic emission of $\gamma$-rays. However, the angular correlation in the case of internal pair conversion exhibits diverse patterns. This might be relevant when investigating atomic processes in heavy-ion collisions performed at the Coulomb barrier.Comment: 27 pages + 6 eps figures, uses revtex.sty and epsf.sty, tar-compressed and uuencoded with uufile

Magnetic Moment of the Fragmentation Aligned 61Fe(9/2)+ Isomer

We report on the g factor measurement of the isomer in $^{61}Fe$ ($E^{*}=861 keV$). The isomer was produced and spin-aligned via a projectile-fragmentation reaction at intermediate energy, the Time Dependent Perturbed Angular Distribution (TDPAD) method being used for the measurement of the g factor. For the first time, due to significant improvements of the experimental technique, an appreciable residual alignment of the isomer has been observed, allowing a precise determination of its g factor: $g=-0.229(2)$. Comparison of the experimental g factor with shell-model and mean field calculations confirms the $9/2^+$ spin and parity assignments and suggests the onset of deformation due to the intrusion of Nilsson orbitals emerging from the $\nu g_{9/2}$.Comment: 4 figures. Submitted to Phys. Rev. Let

Development of a macromolecular prodrug for the treatment of inflammatory arthritis: mechanisms involved in arthrotropism and sustained therapeutic efficacy

INTRODUCTION: The purpose of the present manuscript is to test the hypothesis that arthrotropic localization and synovial cell internalization account for the unique capacity of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-dexamethasone conjugate (P-Dex, a macromolecular prodrug of dexamethasone) to induce sustained amelioration of joint inflammation and inhibition of tissue damage in an animal model of inflammatory arthritis. METHODS: Rats with adjuvant-induced arthritis (AA) were treated with P-Dex, free dexamethasone, saline or HPMA homopolymer. To define the biodistribution of P-Dex, conjugates with different imaging labels were given to AA rats and analyzed. Isolated joint tissues were evaluated by fluorescence-activated cell sorting (FACS) and immunohistochemical staining. Cellular uptake of P-Dex and its effects on apoptosis and production of proinflammatory cytokines were examined using human monocyte-macrophages and fibroblasts. RESULTS: A single systemic administration of P-Dex completely suppressed AA for \u3e20 days. Magnetic resonance imaging demonstrated higher HPMA copolymer influx into the inflamed joints than the normal joints. Immunohistochemistry and FACS analyses of arthritic joints revealed extensive uptake of the polymer conjugate by synovial fibroblasts and myeloid lineage cells. The capacity of P-Dex to suppress inflammation was confirmed in monocyte-macrophage cultures in which P-Dex treatment resulted in suppression of lipopolysaccharide-induced IL-6 and TNFα release. Similarly, TNFα-induced expression of matrix metalloproteinases (MMP1 and MMP3) in synovial fibroblasts from a rheumatoid arthritis patient was suppressed by P-Dex. P-Dex showed no detectable effect on monocyte apoptosis. CONCLUSIONS: P-Dex provides superior and sustained amelioration of AA compared with an equivalent dose of free dexamethasone. The arthrotropism and local retention of P-Dex is attributed to the enhanced vascular permeability in arthritic joints and the internalization of P-Dex by synovial cells. The uptake and processing of P-Dex by macrophages and fibroblasts, and downregulation of proinflammatory mediators, provides an explanation for the sustained anti-inflammatory efficacy of P-Dex in this model of inflammatory arthritis

Development of a macromolecular prodrug for the treatment of inflammatory arthritis: mechanisms involved in arthrotropism and sustained therapeutic efficacy.

INTRODUCTION: The purpose of the present manuscript is to test the hypothesis that arthrotropic localization and synovial cell internalization account for the unique capacity of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-dexamethasone conjugate (P-Dex, a macromolecular prodrug of dexamethasone) to induce sustained amelioration of joint inflammation and inhibition of tissue damage in an animal model of inflammatory arthritis. METHODS: Rats with adjuvant-induced arthritis (AA) were treated with P-Dex, free dexamethasone, saline or HPMA homopolymer. To define the biodistribution of P-Dex, conjugates with different imaging labels were given to AA rats and analyzed. Isolated joint tissues were evaluated by fluorescence-activated cell sorting (FACS) and immunohistochemical staining. Cellular uptake of P-Dex and its effects on apoptosis and production of proinflammatory cytokines were examined using human monocyte-macrophages and fibroblasts. RESULTS: A single systemic administration of P-Dex completely suppressed AA for \u3e20 days. Magnetic resonance imaging demonstrated higher HPMA copolymer influx into the inflamed joints than the normal joints. Immunohistochemistry and FACS analyses of arthritic joints revealed extensive uptake of the polymer conjugate by synovial fibroblasts and myeloid lineage cells. The capacity of P-Dex to suppress inflammation was confirmed in monocyte-macrophage cultures in which P-Dex treatment resulted in suppression of lipopolysaccharide-induced IL-6 and TNFα release. Similarly, TNFα-induced expression of matrix metalloproteinases (MMP1 and MMP3) in synovial fibroblasts from a rheumatoid arthritis patient was suppressed by P-Dex. P-Dex showed no detectable effect on monocyte apoptosis. CONCLUSIONS: P-Dex provides superior and sustained amelioration of AA compared with an equivalent dose of free dexamethasone. The arthrotropism and local retention of P-Dex is attributed to the enhanced vascular permeability in arthritic joints and the internalization of P-Dex by synovial cells. The uptake and processing of P-Dex by macrophages and fibroblasts, and downregulation of proinflammatory mediators, provides an explanation for the sustained anti-inflammatory efficacy of P-Dex in this model of inflammatory arthritis

alpha-particle production in the scattering of 6He by 208Pb at energies around the Coulomb barrier

New experimental data from the scattering of 6He+208Pb at energies around and below the Coulomb barrier are presented. The yield of breakup products coming from projectile fragmentation is dominated by a strong group of $\alpha$ particles. The energy and angular distributions of this group have been analyzed and compared with theoretical calculations. This analysis indicates that the $\alpha$ particles emitted at backward angles in this reaction are mainly due to two-neutron transfer to weakly bound states of the final nucleus.Comment: 20 pages, 5 figures. Nuclear Physics A792 (2007) 2-1

CIB2 Interacts with TMC1 and TMC2 and is Essential for Mechanotransduction in Auditory Hair Cells

Inner ear hair cells detect sound through deflection of stereocilia, the microvilli-like projections that are arranged in rows of graded heights. Calcium and integrin-binding protein 2 is essential for hearing and localizes to stereocilia, but its exact function is unknown. Here, we have characterized two mutant mouse lines, one lacking calcium and integrin-binding protein 2 and one carrying a human deafness-related Cib2 mutation, and show that both are deaf and exhibit no mechanotransduction in auditory hair cells, despite the presence of tip links that gate the mechanotransducer channels. In addition, mechanotransducing shorter row stereocilia overgrow in hair cell bundles of both Cib2 mutants. Furthermore, we report that calcium and integrin-binding protein 2 binds to the components of the hair cell mechanotransduction complex, TMC1 and TMC2, and these interactions are disrupted by deafness-causing Cib2 mutations. We conclude that calcium and integrin-binding protein 2 is required for normal operation of the mechanotransducer channels and is involved in limiting the growth of transducing stereocilia

Breakup branches of Borromean beryllium-9

The breakup reaction 9Be(4He, 3α)n was measured using an array of four double-sided silicon strip detectors at beam energies of 22 and 26 MeV. Excited states in 9Be up to 12 MeV were populated and reconstructed through the measurement of the charged reaction products. It is proposed that limits on the spins and parities of the states can be derived from the way that they decay. Various breakup paths for excited states in 9Be have been explored including the 8Be(g.s.) + n, 8Be(2+) + n and 5He(g.s.) + 4He channels. By imposing the condition that the breakup proceeded via the 8Be ground state, clean excitation spectra for 9Be were reconstructed. The remaining two breakup channels were found to possess strongly-overlapping kinematic signatures and more sophisticated methods (referenced) are required to completely disentangle these other possibilities. Emphasis is placed on the development of the experimental analysis and the usefulness of Monte-Carlo simulations for this purpose