Practical Syntheses of Functionalized 1-Oxo-L,2,3,4-Tetrahydro-β-carboline-3-carboxylic Acid Esters

Three methods have been proposed for the preparation of functionalized 1-oxo-1,2,3,4-tetrahydro-β-carboline-3 carboxylates (3) from which the “acylazide formation-Curtius rearrangement-acid catalyzed ring closure” sequence starling from hemi-ester hemi-acids (8) seemed to be quite general.     

Bioconjugatable Azo‐Based Dark‐Quencher Dyes: Synthesis and Application to Protease‐Activatable Far‐Red Fluorescent Probes

We describe the efficient synthesis and one‐step derivatization of novel, nonfluorescent azo dyes based on the Black Hole Quencher‐3 (BHQ‐3) scaffold. These dyes were equipped with various reactive and/or bioconjugatable groups (azido, α‐iodoacetyl, ketone, terminal alkyne, vicinal diol). The azido derivative was found to be highly reactive in the context of copper‐catalyzed azide–alkyne cycloaddition (CuAAC) reactions and allowed easy synthetic access to the first water‐soluble (sulfonated derivative) and aldehyde‐modified BHQ‐3 dyes, the direct preparation of which failed by means of conventional azo‐coupling reactions. The aldehyde‐ and α‐iodoacetyl‐containing fluorescence quenchers were readily conjugated to aminooxy‐ and cysteine‐containing peptides by the formation of a stable oxime or thioether linkage, respectively. Further fluorescent labeling of the resultant peptide conjugates with red‐ or far‐red‐emitting rhodamine or cyanine dyes through sequential and/or one‐pot bioconjugations, led to novel Förster resonance energy transfer (FRET) based probes suitable for the in vivo detection and imaging of urokinase plasminogen activator, a key protease in cancer invasion and metastasis.     

On the vanishing of some non-semisimple orbital integrals

We prove the vanishing of the (possibly twisted) orbital integrals of certain functions on real Lie groups at non-semisimple elliptic elements. This applies to Euler–Poincaré functions and makes some results of [7] (Chenevier and Clozel, 2009) unconditional.     

Universal scaling in transient creep

We present experimental evidence that pressure solution creep does not establish a steady-state interface microstructure as previously thought. Conversely, pressure solution controlled strain and the characteristic length scale of interface microstructures grow as the cubic root of time. Transient creep with the same scaling is known in metallurgy (Andrade creep). The apparent universal scaling of pressure solution transient creep is explained using an analogy with spinodal dewetting.     

Design and synthesis of an alpha,alpha-difluorophosphinate hapten for antibody-catalyzed hydrolysis of organophosphorus nerve agents

In a new approach to the safe neutralization of organophosphorus chemical weapons, we designed a hapten to elicit catalytic antibodies with phosphatase activity. Here we report the synthesis of this alpha,alpha-difluorophosphinate hapten 6. Various methods for the introduction of the key alpha,alpha-difluoromethyl feature into the phosphinate hapten are discussed. The best results were obtained with the electrophilic gem-difluorinating agent N-fluorobenzenesulfonimide.     

Neutron scattering study of the 1-D short range and 3-D long range magnetic order in TMNB

Quasielastic neutron scattering experiments on TMNB show for T > 2.8 K a diffraction pattern characteristic for a 1-D ferromagnet with an exchange energy along the chain J/k_B ? 10 K. For T < T_N =2.7 K the 3-D magnetic ordering was found to be of a simple antiferromagnetic type. A lattice distortion was observed as well below 200 K.     

AnomalousZ′ effects in the WW channel at NLC

We consider the virtual signals of aZ′ of very general type in the processe ⁺ e ^?→W ⁺ W ^? at a future linear collider (NLC). We show that possible deviations from the SM predictions in this channel are related to similar deviations in the purely leptonic one in a way that is only characteristic of thisZ′ model, and not in general of possible competitor models with anomalous gauge couplings.     

Critical behaviour of two slightly uniaxial ferromagnets: Evidence for crossover with anisotropy

The critical exponents β, γ, δ and the scaling function of ferromagnetic Cu(NH₄)₂Br₄, 2H₂O and CuRb₂Br₄, 2H₂O have been determined. The experimental scaling function is close to the theoretical one of three-dimensional Heisenberg model and the scaling laws are approximately fullfilled. The measured susceptibilities agree well with theoretical results for slightly anisotropic Heisenberg ferromagnet. The predicted cross-over effect, well observed on the perpendicular susceptibility, allows to explain the low experimental value of γ.     

Helicity conservation in gauge boson scattering at high energy

We remark that the high energy gauge boson scattering processes involving two-body initial and final states satisfy certain selection rules described as helicity conservation of the gauge boson amplitudes (GBHC). These rules are valid at the Born level, as well as at the level of the leading and subleading 1-loop logarithmic corrections, in both the standard model and the minimal supersymmetric standard model (MSSM). A "fermionic equivalence" theorem is also proved, which suggests that GBHC is valid at all orders in the MSSM at sufficiently high energies, where the mass suppressed contributions are neglected.     

<Emphasis Type="Italic">parkin</Emphasis> counteracts symptoms in a <Emphasis Type="Italic">Drosophila</Emphasis> model of Parkinson's disease

Background

Parkinson's disease, a prevalent neurodegenerative disease, is characterized by the reduction of dopaminergic neurons resulting in the loss of motor control, resting tremor, the formation of neuronal inclusions and ultimately premature death. Two inherited forms of PD have been linked to mutations in the α-synuclein and parkin genes. The parkin protein functions as an ubiquitin ligase targeting specific proteins for degradation. Expression of human α-synuclein in Drosophila neurons recapitulates the loss of motor control, the development of neuronal inclusions, degeneration of dopaminergic neurons and the ommatidial array to provide an excellent genetic model of PD.

Results

To investigate the role of parkin, we have generated transgenic Drosophila that conditionally express parkin under the control of the yeast UAS enhancer. While expression of parkin has little consequence, co-expression of parkin with α-synuclein in the dopaminergic neurons suppresses the α-synuclein-induced premature loss of climbing ability. In addition directed expression of parkin in the eye counteracts the α-synuclein-induced degeneration of the ommatidial array. These results show that parkin suppresses the PD-like symptoms observed in the α-synuclein-dependent Drosophila model of PD.

Conclusion

The highly conserved parkin E3 ubiquitin ligase can suppress the damaging effects of human α-synuclein. These results are consistent with a role for parkin in targeting α-synuclein to the proteasome. If this relationship is conserved in humans, this suggests that up-regulation of parkin should suppress α-synucleinopathic PD. The development of therapies that regulate parkin activity may be crucial in the treatment of PD.