Lamin-Related Congenital Muscular Dystrophy Alters Mechanical Signaling and Skeletal Muscle Growth

Laminopathies are a clinically heterogeneous group of disorders caused by mutations in the LMNA gene, which encodes the nuclear envelope proteins lamins A and C. The most frequent diseases associated with LMNA mutations are characterized by skeletal and cardiac involvement, and include autosomal dominant Emery–Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy type 1B, and LMNA-related congenital muscular dystrophy (LMNA-CMD). Although the exact pathophysiological mechanisms responsible for LMNA-CMD are not yet understood, severe contracture and muscle atrophy suggest that mutations may impair skeletal muscle growth. Using human muscle stem cells (MuSCs) carrying LMNA-CMD mutations, we observe impaired myogenic fusion with disorganized cadherin/β catenin adhesion complexes. We show that skeletal muscle from Lmna-CMD mice is unable to hypertrophy in response to functional overload, due to defective fusion of activated MuSCs, defective protein synthesis and defective remodeling of the neuromuscular junction. Moreover, stretched myotubes and overloaded muscle fibers with LMNA-CMD mutations display aberrant mechanical regulation of the yes-associated protein (YAP). We also observe defects in MuSC activation and YAP signaling in muscle biopsies from LMNA-CMD patients. These phenotypes are not recapitulated in closely related but less severe EDMD models. In conclusion, combining studies in vitro, in vivo, and patient samples, we find that LMNA-CMD mutations interfere with mechanosignaling pathways in skeletal muscle, implicating A-type lamins in the regulation of skeletal muscle growth.     

Synthesis of Spiro[piperidine‐3,3′‐oxindoles] via Gold(I)‐Catalyzed Dearomatization of N‐Propargyl‐ and N‐Homoallenyl‐2‐bromotryptamines

N‐Propargyl‐ and N‐homoallenyl‐2‐bromo‐β‐tryptamines undergo gold(I)‐catalyzed dearomatizing cyclizations to afford 2‐bromospiroindolenines that are in situ hydrolyzed to furnish spirooxindoles in a one‐pot process. Tryptophane derivatives (R²=CO₂Et) led upon cyclization to chiral spirooxindoles in excellent diastereoselectivities.

     

Destabilizing interactions between the partners of a bifunctional fusion protein

Hybrid MalE–GVP is a bifunctional protein in vitro sinceit binds maltose as protein MalE of Escherichia coli and sinceit is dimeric and specifically binds single-stranded DNA asprotein GVP of phage M13. The oxidation rate of a unique cysteineresidue was used to compare the stabilities of GVP in its freeand hybrid forms, under conditions where MalE was either foldedor unfolded by a denaturing agent. The results showed that boththe covalent link and tertiary non-covalent interactions betweenMalE and GVP destabilized GVP in MalE–GVP. To test whetherGVP had identical structures in its free and hybrid forms, mutationswere used as local conformational probes. The effects of thesemutations on the capabilities of MalE–GVP to dimerizeand to bind single-stranded DNA were assayed in vitro. Theywere compatible with the effects of the same mutations on theglobal activity of free GVP in vivo and with the effects thatcould be predicted from the known data on free GVP, in particularits crystal structure. Thus, one partner of a hybrid proteincan be destabilized by the other partner while maintaining itsstructural and functional characteristics.     

A code tagging approach to software product line development

Software product line engineering seeks to systematise reuse when developing families of similar software systems so as to minimise development time, cost and defects. To realise variability at the code level, product line methods classically advocate usage of inheritance, components, frameworks, aspects or generative techniques. However, these might require unaffordable paradigm shifts for developers if the software was not thought at the outset as a product line. Furthermore, these techniques can be conflicting with a company’s coding practices or external regulations. These concerns were the motivation for the industry–university collaboration described in this paper in which we developed a minimally intrusive coding technique based on tags. The approach was complemented with traceability from code to feature diagrams which were exploited for automated configuration. It is supported by a toolchain and is now in use in the partner company for the development of flight-grade satellite communication software libraries.     

Grid-Controlled Lightpaths for High Performance Grid Applications

Grid applications call for high performance networking support. One attractive solution is to deploy Grids over optical networks. However, resource management in optical domains is traditionally very rigid and cannot successfully meet the requirements of Grid applications, such as flexible provisioning and configuration. In this paper, we present a customizable resource management solution for optical networks where users can create lightpaths on demand and manage their own network resources. Thanks to a Grid-centric system architecture, lightpath resources can be shared among users and easily integrated with data and computation Grids.     

Binding of the tautomeric forms of isoniazid-NAD adducts to the active site of the Mycobacterium tuberculosis enoyl-ACP reductase (InhA): a theoretical approach

The front-line antituberculosis drug isoniazid (INH) inhibits InhA, the NADH-dependent fatty acid biosynthesis enoyl ACP-reductase from Mycobacterium tuberculosis, via formation of covalent adducts with NAD (INH-NAD adducts). While ring tautomers were found the main species formed in solution, only the 4S chain INH-NAD tautomer was evidenced in the crystallized InhA:INH-NAD complex. In this study we attempted to explore the modes of interaction and energy binding of the different isomers placed in the active site of InhA with the help of various molecular modelling techniques. Ligand and enzyme models were generated with the help of the Vega ZZ program package. Resulting ligands were then docked into the InhA active site individually using computational automated docking package AUTODOCK 3.0.5. The more relevant docked conformations were then used to compute the interaction energy between the ligands and the InhA cavity. The AM1 Hamiltonian and the QM/MM ONIOM methodologies were used and the results compared. The various tautomers were found docked in almost the same place where INH-NAD was present as predicted by earlier X-ray crystallographic studies. However, some changes of ligand conformation and of the interactions ligand-protein were evidenced. The lower binding energy was observed for the 4S chain adduct that probably represents the effective active form of the INH-NAD adducts, as compared to the 4R epimer. The two 4S,7R and 4R,7S ring tautomers show intermediate and similar binding energies contrasting with their different experimental inhibitory potency on InhA. As a possible explanation based on calculated conformations, we formulated the hypothesis of an initial binding of the two ring tautomers to InhA followed by opening of only the ring hemiamidal 4S,7R tautomer (possibly catalyzed by Tyr158 phenolate basic group) to give the 4S chain INH-NAD tight-binding inhibitor. The predictions of ligand-protein interactions at the molecular level can be of primary importance in elucidating the mechanisms of action of isoniazid and InhA-related resistances, in identifying the effective mycobactericidal entities and, in further step, in the design of a new generation of antitubercular drugs.     

Variational implicit surface meshing

In this paper, we propose a new algorithm to mesh implicit surfaces which produces meshes both with a good triangle aspect ratio as well as a good approximation quality. The number of vertices of the output mesh is defined by the end-user. For this goal, we perform a two-stage processing: an initialization step followed by an iterative optimization step. The initialization step consists in capturing the surface topology and allocating the vertex budget. The optimization algorithm is based on a variational vertices relaxation and triangulation update. In addition a gradation parameter can be defined to adapt the mesh sampling to the curvature of the implicit surface. We demonstrate the efficiency of the approach on synthetic models as well as real-world acquired data, and provide comparisons with previous approaches.     

Multi-heuristic scheduling: three approaches to tune compromises

Most of the available industrial schedulers are based on a simulation approach using dispatching rules. These rules are often dedicated to the satisfaction of a single performance criterion, and are used whatever the characteristics of the workshop or of the set of jobs. An approach which allows one to bring in compromises between rules is set out in this paper. These compromises can be parametered in accordance with the objectives of the workshop and the characteristics of the jobs in order to introduce some reactivity in the decision system. Three ways to set up the parameters are compared: experimental design, fuzzy expert system and neural network. The method allowing one to define compromises can be implemented on each scheduler that uses a simulation approach. Tests have been made with an industrial scheduler called SIPAPLUS, the results of which are developed in this paper.