Azasugar inhibitors as pharmacological chaperones for Krabbe disease

Krabbe disease is a devastating neurodegenerative disorder characterized by rapid demyelination of nerve fibers. This disease is caused by defects in the lysosomal enzyme β-galactocerebrosidase (GALC), which hydrolyzes the terminal galactose from glycosphingolipids. These lipids are essential components of eukaryotic cell membranes: substrates of GALC include galactocerebroside, the primary lipid component of myelin, and psychosine, a cytotoxic metabolite. Mutations of GALC that cause misfolding of the protein may be responsive to pharmacological chaperone therapy (PCT), whereby small molecules are used to stabilize these mutant proteins, thus correcting trafficking defects and increasing residual catabolic activity in cells. Here we describe a new approach for the synthesis of galacto-configured azasugars and the characterization of their interaction with GALC using biophysical, biochemical and crystallographic methods. We identify that the global stabilization of GALC conferred by azasugar derivatives, measured by fluorescence-based thermal shift assays, is directly related to their binding affinity, measured by enzyme inhibition. X-ray crystal structures of these molecules bound in the GALC active site reveal which residues participate in stabilizing interactions, show how potency is achieved and illustrate the penalties of aza/iminosugar ring distortion. The structure–activity relationships described here identify the key physical properties required of pharmacological chaperones for Krabbe disease and highlight the potential of azasugars as stabilizing agents for future enzyme replacement therapies. This work lays the foundation for new drug-based treatments of Krabbe disease.     

Rapid convergence of a Galerkin projection of the KdV equation

In this Note, it is shown that a Fourier Galerkin approximation of the Korteweg–de Vries equation with periodic boundary conditions converges exponentially fast if the initial data can be continued analytically to a strip about the real axis. To cite this article: H. Kalisch, C. R. Acad. Sci. Paris, Ser. I 341 (2005).     

On-line cysteine modification for protein analysis: new probes for electrochemical tagging nanospray mass spectrometry

A series of electrogenerated selective electrophiles based on substituted benzoquinones has been characterized as tags for l-cysteine and cysteine residues in proteins. The electrophiles are generated electrochemically from the corresponding hydroquinones. It is shown from mass spectrometry analysis that the electrogenerated benzoquinone can tag the biomolecules. The rate constants pertaining to the addition of l-cysteine onto the electrogenerated benzoquinones have been determined using electrochemical techniques. The substitution patterns have been unraveled leading to the assessment of site-specific rate constants. It is shown that the rate constants are primarily dependent on the electronic nature of the substituents as expressed by the Hammett substitution constant. The apparent tagging yields observed for l-cysteine in nanospray mass spectrometry experiments do not correspond to the yields expected from the electrochemical study, as the ionisation efficiencies are highly dependent on the tag. Finally, the on-line tagging has been tested using β-lactoglobulin A and myoglobin. Based on these results, it is concluded that the tagging reaction is selective towards cysteine when it takes place in the nanospray interface. The results show that the methodology presented can be used for a rapid characterization and identification of reactive sites in biomolecules.     

146Ce核的八级形变带和准γ带

通过测量²⁵²Cf自发裂变所产生的瞬发γ射线, 对¹⁴⁶Ce核的高自旋结构进行了重新研究, 结果更新了以前报道的能级纲图, 把八级形变集体带扩展到更高的自旋, 并且重新构建了可能的准γ带结构. 此外, 用反射不对称壳模型(RASM)对¹⁴⁶Ce核的八级形变带进行了计算, 低自旋处的计算结果与实验数据符合得很好.     

Effect of solvent nature on spin exchange in rigid nitroxide biradicals

Intramolecular electron spin exchange as a function of temperature and solvent viscosity and polarity has been studied by X-band electron paramagnetic resonance (EPR) spectroscopy in two rigid nitroxide biradicals existing in one spatial conformation only. Temperature variations of the isotropic hyperfine splitting constanta and exchange integral value |J/a| were measured from EPR spectra and subsequently analyzed. The interaction of polar solvent molecules with >N-O fragments of nitroxide groups led to a slight decrease of the |J/a| value with the increase of temperatureT. In contrast, the interaction of polar solvent molecules with functional groups inside the bridge resulted in a noticeable increase of |J/a| vs.T. In the last case, a coverse relationship between the values of |J/a| and the hyperfine splitting constanta has been observed for solvents with different polarity.     

Bimodal fission in binary and ternary spontaneous fission of 252Cf

The hot bimodal fission of ²⁵²Cf is reexamined with new high-statistics data. We constructed a γ-γ-γ coincidence cube for binary fission and LCP-gated γ-γ matrix for ternary fission. By identifying the secondary fission fragments from their γ-ray transitions, we measured the yields for various fission splits. The normal neutron yield distribution is found to be Gaussian for Xe-Ru. However, the binary fission split of Ba-Mo is found to exhibit a bimodal neutron distribution with the “hot mode” corresponding to ≈3.1% of the total yield. In α ternary fission, the first measurements of yields for specific fission splits are presented. The Te-α-Ru and Xe-α-Mo neutron yields fit well with a single mode, but the Ba-α-Zr split shows evidence for an enhanced hot mode with an intensity of ≈13.8% of the normal mode. The text was submitted by the authors in English.     

Evolution in complex systems

What features characterize complex system dynamics? Power laws and scale invariance of fluctuations are often taken as the hallmarks of complexity, drawing on analogies with equilibrium critical phenomena. Here we argue that slow, directed dynamics, during which the system's properties change significantly, is fundamental. The underlying dynamics is related to a slow, decelerating but spasmodic release of an intrinsic strain or tension. Time series of a number of appropriate observables can be analyzed to confirm this effect. The strain arises from local frustration. As the strain is released through “quakes,” some system variable undergoes record statistics with accompanying log‐Poisson statistics for the quake event times. We demonstrate these phenomena via two very different systems: a model of magnetic relaxation in type II superconductors and the Tangled Nature model of evolutionary ecology and show how quantitative indications of aging can be found. © 2004 Wiley Periodicals, Inc. Complexity 10: 49–56, 2004     

Solutions of the WDVV Equations and Integrable Hierarchies of KP Type

We show that reductions of KP hierarchies related to the loop algebra of SL_n with homogeneous gradation give solutions of the Darboux-Egoroff system of PDE's. Using explicit dressing matrices of the Riemann-Hilbert problem generalized to include a set of commuting additional symmetries, we construct solutions of the Witten– Dijkgraaf–E. Verlinde–H. Verlinde equations.     

Advancing Mathematical Activity: A Practice-Oriented View of Advanced Mathematical Thinking

The purpose of this article is to contribute to the dialogue about the notion of advanced mathematical thinking by offering an alternative characterization for this idea, namely advancing mathematical activity. We use the term advancing (versus advanced) because we emphasize the progression and evolution of students' reasoning in relation to their previous activity. We also use the term activity, rather than thinking. This shift in language reflects our characterization of progression in mathematical thinking as acts of participation in a variety of different socially or culturally situated mathematical practices. For these practices, we emphasize the changing nature of students' mathematical activity and frame the process of progression in terms of multiple layers of horizontal and vertical mathematizing.     

On the torsion of Jacobians of principal modular curves of level 3<Superscript><Emphasis Type="Italic">n</Emphasis></Superscript>

We demonstrate that the 3-power torsion points of the Jacobians of the principal modular curves X(3ⁿ) are fixed by the kernel of the canonical outer Galois representation of the pro-3 fundamental group of the projective line minus three points. The proof proceeds by demonstrating the curves in question satisfy a two-part criterion given by Anderson and Ihara. Two proofs of the second part of the criterion are provided; the first relies on a theorem of Shimura, while the second uses the moduli interpretation. Received: 30 September 2005