Building siRNAs with Cubes: Synthesis and Evaluation of Cubane-Modified siRNAs

Cubane molecules hold great potential for medicinal chemistry applications due to their inherent stability and low toxicity. In this study, we report the synthesis of a cubane derivative phosphoramidite for the incorporation of cubane into small interfering RNAs (siRNAs). Synthetic siRNAs rely on chemical modifications to improve their pharmacokinetic profiles. However, they are still able to mediate sequence-specific gene silencing via the endogenous RNA interference pathway. We designed a library of siRNAs bearing cubane at different positions within the sense and antisense strands. All siRNAs showed excellent gene-silencing activity, with IC₅₀ values ranging from 45.4 to 305 pM. Incorporating the cubane modification in both the sense and antisense strand led to viable duplexes with good biological activity. To the best of our knowledge, this is the first report of siRNAs bearing a cubane derivative within the backbone.     

A new class of phosphotransferases phosphorylated on an aspartate residue in an amino-terminal DXDX(T/V) motif

When incubated with their substrates, human phosphomannomutase and L-3-phosphoserine phosphatase are known to form phosphoenzymes with chemical characteristics of an acyl-phosphate. The phosphorylated residue in phosphomannomutase has now been identified by mass spectrometry after reduction of the phosphoenzyme with tritiated borohydride and trypsin digestion. It is the first aspartate in a conserved DVDGT motif. Replacement of either aspartate of this motif by asparagine or glutamate resulted in complete inactivation of the enzyme. The same mutations performed in the DXDST motif of L-3-phosphoserine phosphatase also resulted in complete inactivation of the enzyme, except for the replacement of the second aspartate by glutamate, which reduced the activity by only about 40%. This suggests that the first aspartate of the motif is also the phosphorylated residue in L-3-phosphoserine phosphatase. Data banks contained seven other phosphomutases or phosphatases sharing a similar, totally conserved DXDX(T/V) motif at their amino terminus. One of these (beta-phosphoglucomutase) is shown to form a phosphoenzyme with the characteristics of an acyl-phosphate. In conclusion, phosphomannomutase and L-3-phosphoserine phosphatase belong to a new phosphotransferase family with an amino-terminal DXDX(T/V) motif that serves as an intermediate phosphoryl acceptor.     

Early Stages of Crystallite Growth of ZnO Obtained from an Oxalate Precursor

A detailed analysis of the microstructure of zinc oxide produced by thermal decomposition of zinc oxalate at temperatures in the range 328° to 650°C is described. Parameters describing the breadth and shape of X-ray diffraction line profiles were obtained by means of pattern decomposition, and a method based on the Voigt function was used to obtain information on the temperature dependence of the microstructure. It was found that the crystallites are prismatic, the dimensions increasing significantly with formation temperature, and that each contains one stacking fault, on average. The results of size determinations are in broad agreement with TEM and SEM measurements. The specific surface area of the crystallites, obtained by the BET method, is compared with the results of X-ray diffraction line-profile analysis, leading to a determination of the variation of "packing factor" with temperature. Results suggest a homogeneous crystallite growth in the initial sintering of the loosely packed zinc oxide powder.     

Towards formalising AADL in Proof Assistants

This paper presents first steps towards a formalisation of the Architecture Analysis and Design Language, mainly concentrating on a representation of its data model. For this, we contrast two approaches: one set-based (using the B modelling framework) and one in a higher-order logic (using the Isabelle proof assistant). We illustrate a transformation on a simplified part of the AADL metamodel concerning flows.     

DCT-based complexity regularization for EM tomographic reconstruction.

This paper introduces a simple algorithm for tomographic reconstruction based on the use of a complexity regularization term. The regularization is formulated in the discrete cosine transform (DCT) domain by promoting a low-noise reconstruction having a high sparsity in the frequency domain. The resulting algorithm simply alternates between a maximum-likelihood (ML) expectation-maximization (EM) update and a decreasing sparsity constraint in the DCT domain. Applications to SPECT reconstruction and comparisons with a classical estimator using the best available regularization terms are given in order to illustrate the potential of our reconstruction technique.     

Étude des architectures de processeurs parallèles pour le traitement de l’image

The interest for computervision has led to the proliferation of image processors during the past 25 years. Their study is a challenge, complicating needlessly the access to the domain. This article attempts to solve the problem by presenting a structured analysis of the principal realisations to get a clear understanding of the situation. Then, it becomes clear that most processors are derived from a few basic architectures. An analysis of the trend of developments is presented along with suggestions for futur research.     

A generic architecture for VPN configuration management

This paper describes the specification of a management architecture allowing virtual private network (VPN) customers to dynamically modify the configuration of their VPN. The specification has been structured according to the ODP viewpoints. A special emphasis has been laid on how changes in the logical VPN configuration affect or are reflected in the underlying physical networks. As a result, an informational and a computational VPN configuration management architecture have been developed illustrating how processing and data can be distributed between the different layers and domains composing the architecture.     

A High Temperature Micropower Capacitive Pressure Sensor Interface Circuit

A pressure sensor interface circuit featuring micropower consumptionis presented. The sensitivity to leakage currents has been reduced, allowingoperation at high temperature. Special attention has been paid to minimisealiasing in the sampled interface. An optimal combination of contradictoryrequirements on power consumption, temperature range and sampling speed wasobtained by a very careful system design and optimisation. The circuitconverts a sensor capacitance variation of ±5pF into an 11 bit outputword at a 2Hz rate. This resolution is guaranteed in the –40°C to100°C temperature range. It may slowly decay above 100°C but ensuresat least 5 bit at 130°C. The power consumption at room temperature issmaller than 2µA from a 2.4V to 4V battery.     

Synthesis of glycopeptides from type II collagen-incorporating galactosylated hydroxylysine mimetics and their use in studying the fine specificity of arthritogenic T cells

Five analogues of the bovine type II collagen (bCII) immunodominant glycopeptide [beta-D-Gal-(5R)-5-Hyl264]CII(256-270) (1) carrying diverse modifications at the critical hydroxylysine (Hyl) 264 side chain were designed and synthesised, to explore the fine specificity of bCII-reactive T cells involved in the initiation and/or regulation of collagen-induced arthritis (CIA), a mouse model for rheumatoid arthritis (RA). Beta-D-galactosyl-(5R)-5-hydroxy-L-lysine (19) and corresponding mimetics (22-25), conveniently protected for solid-phase synthesis, were all obtained by a divergent route involving enantiopure 5-hydroxylated 6-oxo-1,2-piperidinedicarboxylates as the key intermediates. All three bCII-specific T hybridomas used, as well as a recurrent pathogenic CD4+ T-cell clone isolated from bCII-immunised DBA/1 mice, recognised the galactosylated form 1 of the immunodominant bCII (256-270) epitope. These cells were extremely sensitive to changes at the epsilon-amino group of Hyl264, but differed in their pattern of recognition of analogues with a Hyl264 side chain modified at C-5 (i.e. inversion of stereochemistry, methylation). These data further document the importance of collagen post-translational modifications in autoimmunity and in the CIA model in particular, and provide a new insight into the molecular interaction between glycopeptide 1 and the TCR of pathogenic T cells.     

Influence of Stoichiometry on the Electrical and Mechanical Behavior of Yttrium Oxide Ceramics

Because of their method of preparation, ceramics contain point defects, the concentration of which may vary from the center to the boundary of the grains, which may change the bulk properties of the material. The electronic structure of the oxygen-related defects has been studied by electron spectroscopy in yttria ceramics submitted to various heating conditions under controlled atmospheres. The differences in the mechanical and electrical behaviors are observed to correlate with the defect content.