Molecular and phenotypic characterization of a mouse model of oculopharyngeal muscular dystrophy reveals severe muscular atrophy restricted to fast glycolytic fibres

Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by ptosis, dysphagia and proximal limb weakness. Autosomal-dominant OPMD is caused by a short (GCG)8–13 expansions within the first exon of the poly(A)-binding protein nuclear 1 gene (PABPN1), leading to an expanded polyalanine tract in the mutated protein. Expanded PABPN1 forms insoluble aggregates in the nuclei of skeletal muscle fibres. In order to gain insight into the different physiological processes affected in OPMD muscles, we have used a transgenic mouse model of OPMD (A17.1) and performed transcriptomic studies combined with a detailed phenotypic characterization of this model at three time points. The transcriptomic analysis revealed a massive gene deregulation in the A17.1 mice, among which we identified a significant deregulation of pathways associated with muscle atrophy. Using a mathematical model for progression, we have identified that one-third of the progressive genes were also associated with muscle atrophy. Functional and histological analysis of the skeletal muscle of this mouse model confirmed a severe and progressive muscular atrophy associated with a reduction in muscle strength. Moreover, muscle atrophy in the A17.1 mice was restricted to fast glycolytic fibres, containing a large number of intranuclear inclusions (INIs). The soleus muscle and, in particular, oxidative fibres were spared, even though they contained INIs albeit to a lesser degree. These results demonstrate a fibre-type specificity of muscle atrophy in this OPMD model. This study improves our understanding of the biological pathways modified in OPMD to identify potential biomarkers and new therapeutic targets.

A fast two-grid and finite section method for a class of integral equations on the real line with application to an acoustic scattering problem in the half-plane

We consider the numerical treatment of second kind integral equations on the real line of the form ∅(s) = ∫_(-∞)^(+∞)▒〖κ(s-t)z(t)ϕ(t)dt,s=R〗 (abbreviated ϕ= ψ+K_z ϕ) in which K ϵ L_1 (R), z ϵ L_∞ (R) and ψ ϵ BC(R), the space of bounded continuous functions on R, are assumed known and ϕ ϵ BC(R) is to be determined. We first derive sharp error estimates for the finite section approximation (reducing the range of integration to [-A, A]) via bounds on (1-K_z )^(-1)as an operator on spaces of weighted continuous functions. Numerical solution by a simple discrete collocation method on a uniform grid on R is then analysed: in the case when z is compactly supported this leads to a coefficient matrix which allows a rapid matrix-vector multiply via the FFT. To utilise this possibility we propose a modified two-grid iteration, a feature of which is that the coarse grid matrix is approximated by a banded matrix, and analyse convergence and computational cost. In cases where z is not compactly supported a combined finite section and two-grid algorithm can be applied and we extend the analysis to this case. As an application we consider acoustic scattering in the half-plane with a Robin or impedance boundary condition which we formulate as a boundary integral equation of the class studied. Our final result is that if z (related to the boundary impedance in the application) takes values in an appropriate compact subset Q of the complex plane, then the difference between ϕ(s)and its finite section approximation computed numerically using the iterative scheme proposed is ≤C_1 [kh log⁡〖(1⁄kh)+(1-Θ)^((-1)⁄2) (kA)^((-1)⁄2) 〗 ] in the interval [-ΘA,ΘA](Θ<1) for kh sufficiently small, where k is the wavenumber and h the grid spacing. Moreover this numerical approximation can be computed in ≤C_2 N log⁡N operations, where N = 2A/h is the number of degrees of freedom. The values of the constants C1 and C2 depend only on the set Q and not on the wavenumber k or the support of z.

Synthesis of novel hyperbranched polymers featuring oxazoline linear units and their application in fast-drying solvent-borne coating formulations

Novel acid-terminated hyperbranched polymers (HBPs) containing adipic acid and oxazoline monomers derived from oleic and linoleic acid have been synthesized via a bulk polymerization procedure. Branching was achieved as a consequence of an acid-catalyzed opening of the oxazoline ring to produce a trifunctional monomer in situ which delivered branching levels of >45% as determined by 1H and 13C NMR spectroscopy. The HBPs were soluble in common solvents, such as CHCl3, acetone, tetrahydrofuran, dimethylformamide, and dimethyl sulfoxide and were further functionalized by addition of citronellol to afford white-spirit soluble materials that could be used in coating formulations. During end group modification, a reduction in branching levels of the HBPs (down to 12–24%) was observed, predominantly on account of oxazoline ring reformation and trans-esterification processes under the reaction conditions used. In comparison to commercial alkyd resin paint coatings, formulations of the citronellol-functionalized hyperbranched materials blended with a commercial alkyd resin exhibited dramatic decreases of the blend viscosity when the HBP content was increased. The curing characteristics of the HBP/alkyd blend formulations were studied by dynamic mechanical analysis which revealed that the new coatings cured more quickly and produced tougher materials than otherwise identical coatings prepared from only the commercial alkyd resins.

Generation of nonvernal-obligate, faster-cycling Noccaea caerulescens lines through fast neutron mutagenesis

Noccaea caerulescens (formerly Thlaspi caerulescens) is a widely studied metal hyperaccumulator. However, molecular genetic studies are challenging in this species because of its vernal-obligate biennial life cycle of 7-9 months. Here, we describe the development of genetically stable, faster cycling lines of N. caerulescens which are nonvernal-obligate. A total of 5500 M(0) seeds from Saint Laurent Le Minier (France) were subjected to fast neutron mutagenesis. Following vernalization of young plants, 79 of plants survived to maturity. In all, 80 000 M(2) lines were screened for flowering in the absence of vernalization. Floral initials were observed in 35 lines, with nine flowering in < 12 wk. Two lines (A2 and A7) were selfed to the M(4) generation. Floral initials were observed 66 and 87 d after sowing (DAS) in A2 and A7, respectively. Silicle development occurred for all A2 and for most A7 at 92 and 123 DAS, respectively. Floral or silicle development was not observed in wild-type (WT) plants. Leaf zinc (Zn) concentration was similar in WT, A2 and A7 lines. These lines should facilitate future genetic studies of this remarkable species. Seed is publicly available through the European Arabidopsis Stock Centre (NASC).

A fast algorithm for sparse probability density function construction

A new sparse kernel density estimator is introduced. Our main contribution is to develop a recursive algorithm for the selection of significant kernels one at time using the minimum integrated square error (MISE) criterion for both kernel selection. The proposed approach is simple to implement and the associated computational cost is very low. Numerical examples are employed to demonstrate that the proposed approach is effective in constructing sparse kernel density estimators with competitive accuracy to existing kernel density estimators.

Flow synthesis using gaseous ammonia in a Teflon AF-2400 tube-in-tube reactor: Paal–Knorr pyrrole formation and gas concentration measurement by inline flow titration

Using a simple and accessible Teflon AF-2400 based tube-intube reactor, a series of pyrroles were synthesised in flow using the Paal–Knorr reaction of 1,4-diketones with gaseous ammonia. An inline flow titration technique allowed measurement of the ammonia concentration and its relationship to residence time and temperature.

Continuous-flow processing of gaseous ammonia using a Teflon AF-2400 tube-in-tube reactor: synthesis of thioureas and in-line titrations

A simple tube-in-tube reactor based on the gas-permeable membrane Teflon AF-2400 was used in the continuous flow reaction of gaseous ammonia with isothiocyanates and one isocyanate. A colourimetric in-line titration technique is also reported as a simple method to quantify the amount of ammonia taken up by the solvent in the system.

Fast identification algorithms for Gaussian process model

A class identification algorithms is introduced for Gaussian process(GP)models.The fundamental approach is to propose a new kernel function which leads to a covariance matrix with low rank,a property that is consequently exploited for computational efficiency for both model parameter estimation and model predictions.The objective of either maximizing the marginal likelihood or the Kullback–Leibler (K–L) divergence between the estimated output probability density function(pdf)and the true pdf has been used as respective cost functions.For each cost function,an efficient coordinate descent algorithm is proposed to estimate the kernel parameters using a one dimensional derivative free search, and noise variance using a fast gradient descent algorithm. Numerical examples are included to demonstrate the effectiveness of the new identification approaches.

A phosphoramidite-based [FeFe]H2ase functional mimic displaying fast electrocatalytic proton reduction

A phosphoramidite modified [FeFe]H2ase mimic is studied as a model for photodriven production of H2. On cathodic activation, the pyridyl–phosphoramidite complex exhibits a strongly enhanced rate of proton reduction over the previously reported pyridylphosphine model at the same overpotential. Analysis of the cyclic voltammograms shows an apparent H2 evolution rate strongly influenced by the presence of both side-bound pyridyl and phosphorous-bound dimethylamino moieties at the phosphoramidite ligands. This difference is ascribed to the basic amines acting as proton relays.

Tagged phosphine reagents to assist reaction work-up by phase-switched scavenging using a modular flow reactor

The use of three orthogonally tagged phosphine reagents to assist chemical work-up via phase-switch scavenging in conjunction with a modular flow reactor is described. These techniques (acidic, basic and Click chemistry) are used to prepare various amides and tri-substituted guanidines from in situ generated iminophosphoranes.

[3 + 2] Cycloaddition of acetylenes with azides to give 1,4-disubstituted 1,2,3-triazoles in a modular flow reactor

The cycloaddition of acetylenes with azides to give the corresponding 1,4-disubstituted 1,2,3-triazoles is reported using immobilised reagents and scavengers in pre-packed glass tubes in a modular flow reactor.

A modular flow reactor for performing Curtius rearrangements as a continuous flow process

The use of a mesofluidic flow reactor is described for performing Curtius rearrangement reactions of carboxylic acids in the presence of diphenylphosphoryl azide and trapping of the intermediate isocyanates with various nucleophiles.

A flow reactor process for the synthesis of peptides utilizing immobilized reagents, scavengers and catch and release protocols

A general flow process for the multi-step assembly of peptides has been developed and this procedure has been used to successfully construct a series of Boc, Cbz and Fmoc N-protected dipeptides in excellent yields and purities, including an extension of the method to enable the preparation of a tripeptide derivative.