Measurement of Total and Unbound Mycophenolic Acid and Its Glucuronide by LC Coupled with MS. Application to a Pharmacokinetic Study of Mycophenolate Mofetil in Patients with Autoimmune Diseases

Liquid chromatography coupled with mass spectrometry for the determination of total and unbound mycophenolic acid and its major metabolite in human plasma has been developed. Sample preparations were based on a fully automated solid-phase extraction process and ultrafiltration. Mass spectrometric data were acquired in a single-ion monitoring method. The analytes and nevirapine (internal standard) were well separated in an isocratic mode over 8 min. Validation study exhibited excellent linearity, with intra- and inter-day precision and accuracy of less than 12%. The assay was successfully applied to the pharmacokinetic study of mycophenolic acid in patients with autoimmune diseases.     

Selecting hidden Markov model state number with cross-validated likelihood

The problem of estimating the number of hidden states in a hidden Markov model is considered. Emphasis is placed on cross-validated likelihood criteria. Using cross-validation to assess the number of hidden states allows to circumvent the well-documented technical difficulties of the order identification problem in mixture models. Moreover, in a predictive perspective, it does not require that the sampling distribution belongs to one of the models in competition. However, computing cross-validated likelihood for hidden Markov models for which only one training sample is available, involves difficulties since the data are not independent. Two approaches are proposed to compute cross-validated likelihood for a hidden Markov model. The first one consists of using a deterministic half-sampling procedure, and the second one consists of an adaptation of the EM algorithm for hidden Markov models, to take into account randomly missing values induced by cross-validation. Numerical experiments on both simulated and real data sets compare different versions of cross-validated likelihood criterion and penalised likelihood criteria, including BIC and a penalised marginal likelihood criterion. Those numerical experiments highlight a promising behaviour of the deterministic half-sampling criterion.     

New studies on scattering properties of different kinds of soot and carbon-black

New polarization and brightness curves as a function of scattering angle are studied at λ=632.8 and 543.5 nm using PROGRA2 instruments (Propriétés Optiques des Grains Astronomiques et Atmosphériques) for four different kinds of soot and for two samples of carbon-black levitating in the cloud. The soot samples are also studied on the deposited surface. Two of the soot samples are issued from incomplete combustion of Toluene liquid solvent under two different combustion conditions. Two others are issued from a solid polymer. Polymethyl Methacrylate or PMMA under two different combustion conditions. These new studies are done using new more sensitive cameras than previous ones, allowing darker agglomerates to be detected.     

On the linear decoration of intuitionistic derivations

Summary We define an optimal proof-by-proof embedding of intuitionistic sequent calculus into linear logic and analyse the (purely logical) linearity information thus obtained. CNRS URA 753 Supported by the Netherlands Organization for Scientific Research (NWO)     

Solvability of Minimal Graph Equation Under Pointwise Pinching Condition for Sectional Curvatures

We study the asymptotic Dirichlet problem for the minimal graph equation on a Cartan–Hadamard manifold M whose radial sectional curvatures outside a compact set satisfy an upper bound

$$\begin{aligned} K(P)\le - \frac{\phi (\phi -1)}{r(x)^2} \end{aligned}$$

and a pointwise pinching condition

$$\begin{aligned} |K(P) |\le C_K|K(P') | \end{aligned}$$

for some constants \(\phi >1\) and \(C_K\ge 1\), where P and \(P'\) are any 2-dimensional subspaces of \(T_xM\) containing the (radial) vector \(\nabla r(x)\) and \(r(x)=d(o,x)\) is the distance to a fixed point \(o\in M\). We solve the asymptotic Dirichlet problem with any continuous boundary data for dimensions \(n=\dim M>4/\phi +1\).

     

A Grobman–Hartman Theorem for Control Systems

We consider the problem of locally linearizing a control system via topological transformations. According to [2,3], there is no naive generalization of the classical Grobman–Hartman theorem for ODEs to control systems: a generic control system, when viewed as a set of under-determined differential equations parametrized by the control, cannot be linearized using pointwise transformations on the state and the control values. However, if we allow the transformations to depend on the control at a functional level (open loop transformations), we are able to prove a version of the Grobman–Hartman theorem for control systems.     

Nonribosomal peptide synthesis in animals: the cyclodipeptide synthase of Nematostella

Cyclodipeptide synthases (CDPSs) are small enzymes structurally related to class-I aminoacyl-tRNA synthetases (aaRSs). They divert aminoacylated tRNAs from their canonical role in ribosomal protein synthesis, for cyclodipeptide formation. All the CDPSs experimentally characterized to date are?bacterial. We show here that a predicted CDPS from the sea anemone Nematostella vectensis is an active CDPS catalyzing the formation of various cyclodipeptides, preferentially containing tryptophan. Our findings demonstrate that eukaryotes encode active CDPSs and suggest that all CDPSs have?a similar aminoacyl-tRNA synthetase-like architecture and ping-pong mechanism. They also raise questions about the biological roles of the cyclodipeptides produced in bacteria and eukaryotes.     

Synthesis and luminescence properties of new red-shifted absorption lanthanide(III) chelates suitable for peptide and protein labelling

The synthesis and photo-physical properties of an original bis-pyridinylpyrazine chromophore efficiently sensitising europium(III) and samarium(III) are described. The corresponding lanthanide(III) complexes display in aqueous solutions a maximum excitation wavelength which is significantly red-shifted compared to the usual terpyridine-based chelates, and a valuable luminescence brightness above 2,000 dm(3) mol(-1) cm(-1) at 345 nm was obtained with a europium(III) derivative. Further functionalisation with three different bioconjugatable handles was also investigated and their ability to efficiently label a model hexapeptide was evaluated and compared. Finally, the best bioconjugatable europium(III) chelate was used in representative labelling experiments involving monoclonal antibodies and the luminescence features of the corresponding bioconjugates remained satisfactory.