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PubMed1991

Modular organization of actin crosslinking proteins.

A family of actin-crosslinking proteins share a conserved 125 residue sequence that lies within a 250 residue actin-binding domain. This domain is combined with spacer segments consisting of a variable number of repeated alpha-helical or beta-sheet motifs and other functional domains, which generate proteins that differ in their ability to form actin bundles or networks and to associate with the plasma membrane. These functional domains are not in other actin-crosslinking proteins, one of which is elongation factor 1a (EF-1a) suggesting there are several pathways for the evolution of actin-crosslinking function.

Actinin↗
PubMed2006

Affinity chromatography for purification of the modular protein growth factor receptor-bound protein 2 and development of a screening test for growth factor receptor-bound protein 2 Src homology 3 domain inhibitor using peroxidase-linked ligand.

Growth factor receptor-bound protein 2 (Grb2) is an adapter protein involved in the Ras-dependent signaling pathway that plays an important role in human cancers initiated by oncogenic receptors. Grb2 is constituted by one Src homology 2 domain surrounded by two SH3 domains, and the inhibition of the interactions produced by these domains could provide an antitumor approach. In evaluating chemical libraries, to search for potential Grb2 inhibitors, it was necessary to elaborate a rapid test for their screening. We have developed, first, a batch method based on the use of an affinity column bearing a Grb2-SH3 peptide ligand to isolate highly purified Grb2. We subsequently describe a very rapid 96-well screening of inhibitors based on a simple competition between purified Grb2 and a peroxidase-coupled proline-rich peptide.

Amino Acid Sequence↗
PubMed2005

Revision total knee arthroplasty with modular components inserted with metaphyseal cement and stems without cement.

The clinical and radiographic outcomes of 50 consecutive revision total knee arthroplasties in 47 patients, placed with metaphyseal cemented femoral and tibial components with press-fit cementless stems, were reviewed at 36-month average follow-up. Revision was performed for aseptic loosening (11/50), infection (17/50), periprosthetic fracture (8/50), component failure (6/50), instability (6/50), and malalignment (2/50). The press-fit cementless stems were 80 to 160 mm in length and tightly contacted the endosteum of the metadiaphyseal areas. Four (9%) knees were re-revised for infection, zero for aseptic loosening. The average modified Hospital for Special Surgery knee score improved from 49 to 87. One patient (2%) reported thigh pain, and 1 reported leg pain. Metaphyseal cemented revision total knee components with press-fit cementless femoral and tibial stems were not associated with significant thigh and leg pain.

Adult↗
PubMed2006

The role of modularity in primary total hip arthroplasty.

A combined series of 795 primary SROM (DePuy, Warsaw, Ind) stems have been reviewed. The mean follow-up is 11 years; 2 (0.25%) were revised for aseptic stem loosening. Two (0.25%) cases of osteolysis distal to the sleeve occurred, 1 of which was revised. The low incidence of distal osteolysis and aseptic loosening justifies the continued use of this stem in primary total hip arthroplasties.

Adult↗
PubMed2006

MTERF3, the most conserved member of the mTERF-family, is a modular factor involved in mitochondrial protein synthesis.

The MTERF-family is a wide family of proteins identified in Metazoa and plants which includes the known mitochondrial transcription termination factors. With the aim to shed light on the function of MTERF-family members in Drosophila, we performed the cloning and characterization of D-MTERF3, a component of the most conserved group of this family. D-MTERF3 is a mitochondrial protein of 323 amino acids. Sequence analysis in seven different organisms showed that the protein contains five conserved "mTERF-motifs", three of which include a leucine zipper-like domain. D-MTERF3 knock-down, obtained by RNAi in D.Mel-2 cells, did not affect mitochondrial replication and transcription. On the contrary, it decreased to a variable extent the rate of labelling of about half of the mitochondrial polypeptides, with ND1 being the most affected by D-MTERF3 depletion. These results indicate that D-MTERF3 is involved in mitochondrial translation. This role, likely based on protein-protein interactions, may be exerted either through a direct interaction with the translation machinery or by bridging the mitochondrial transcription and translation apparatus.

Amino Acid Sequence↗
PubMed2007

The reach-to-grasp-food task for rats: a rare case of modularity in animal behavior?

Humans and non-human animals make use of sensory hierarchies in "selecting" strategies for solving many cognitive and behavioral tasks. Often, if a preferred type of sensory information is unavailable or is not useful for solving a given task, the animal can switch to a lower-priority strategy, making use of a different class of sensory information. In the case of rats performing a classic reach-to-grasp-food task, however, prior studies indicate that the reaching maneuver may be a fixed action pattern that is guided exclusively by the food's odor plume until the point of contact with the food morsel [Whishaw IQ, Tomie JA. Olfaction directs skilled forelimb reaching in the rat. Behav Brain Res 1989;32(1):11-21; Metz GA, Whishaw IQ. Skilled reaching an action pattern: stability in rat (Rattus norvegicus) grasping movements as a function of changing food pellet size. Behav Brain Res 2000;116(2):111-22; Whishaw IQ. Did a change in sensory control of skilled movements stimulate the evolution of the primate frontal cortex? Behav Brain Res 2003;146(1/2):31-41]. We sought to confirm and extend these findings in several ways. In Experiment 1, using a GO/NO-GO variant of the classic task, we demonstrated that rats used the GO target's odor both to trigger and guide their reaches. In Experiment 2, we showed that rats deprived of (a) vision, (b) object-recognizing rostral whiskers and forearm sinus hairs, or (c) both, displayed no deficits in triggering and guiding their reaches. Finally, in a third experiment in which the GO target's location varied randomly across trials and only olfactory cues were available, we demonstrated that rats could determine the spatial endpoint of their reach without any loss of accuracy. Combined with results from a prior study in which bulbectomized rats never developed a new, successful reaching strategy despite extensive post-operative training [Whishaw IQ, Tomie JA. Olfaction directs skilled forelimb reaching in the rat. Behav Brain Res 1989;32(1):11-21], these results indicate that rats do not have a sensory hierarchy for solving the reach-to-grasp-food task, but rather, are guided by olfaction alone until their paw contacts the food morsel.

Animals↗
PubMed2006

Modulation of protein delivery from modular polymer scaffolds.

Growth factors are increasingly employed to promote tissue regeneration with various biomaterial scaffolds. In vitro release kinetics of protein growth factors from tissue engineering scaffolds are often investigated in aqueous environment, which is significantly different from in vivo environment. This study investigates the release of model proteins with net-positive (histone) and net-negative charge (bovine serum albumin, BSA) from various scaffolding surfaces and from encapsulated microspheres in the presence of ions, proteins, and cells. The release kinetics of proteins in media with varying concentrations of ions (NaCl) suggests stronger electrostatic interaction between the positively charged histone with the negatively charged substrates. While both proteins released slowly from hydrophobic PCL surfaces, plasma etching resulted in rapid release of BSA, but not histone. Interestingly, although negatively charged BSA released readily from negatively charged collagen (col), BSA released slowly from col-coated PCL scaffolds. Such electrostatic interaction effects were abolished in the presence of serum proteins and cells as evidenced by the rapid release of proteins from col-coated scaffolds. To achieve sustained release in the complex environment of serum proteins and cells, the model proteins were encapsulated into poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres, which were embedded within col-coated PCL scaffolds. Protein release from microspheres was modulated by changing the lactide-to-glycolide ratio of PLGA polymer. BSA adsorbed to col released faster than histone encapsulated in microspheres in the presence of serum and cells. Collectively, the data suggest that growth factor release is highly influenced by scaffold surface and the presence of ions, proteins, and cells in the media. Strategies to deliver multiple growth factors and studies which investigate their release should consider these important variables.

Animals↗
PubMed2005

Improved recycling of livestock slurries on maize by means of a modular tanker and spreader.

Slurry spreading represents a critical component of the waste management strategy since it influences the nutrients' availability for the crops. The Italian Regulation in force sets severe limits to the slurry application to land. These limits--and the necessity to optimise the slurry fertilising value--require to operate with the correct application rate and with a sufficient spreading uniformity. An innovative slurry spreader able to optimise the reuse of this by-product as an agronomic resource whilst respecting the national regulation has been tested under practical conditions. The agronomic trials showed that the controlled recycling--performed with the innovative slurry spreader--gave no statistically different grain yields from those obtained with the chemical fertilisation. The ammonia emissions recorded after the slurry injection were the 16% of those recorded after the band application.

Agriculture↗
PubMed2005

Towards building the silicon cell: a modular approach.

Systems Biology aims to understand quantitatively how properties of biological systems can be understood as functions of the characteristics of, and interactions between their macromolecular components. Whereas, traditional biochemistry focused on isolation and characterization of cellular components, the challenge for Systems Biology lies in integration of this knowledge and the knowledge about molecular interactions. Computer models play an important role in this integration. We here discuss an approach with which we aim to link kinetic models on small parts of metabolism together, so as to form detailed kinetic models of larger chunks of metabolism, and ultimately of the entire living cell. Specifically, we will discuss techniques that can be used to model a sub-network in isolation of a larger network of which it is a part, while still maintaining the dynamics of the larger complete network. We will start by outlining the JWS online system, the silicon cell project, and the type of models we propose. JWS online is a model repository, which can be used for the storage, simulation and analysis of kinetic models. We advocate to integrate a top-down approach, where measurements on the complete system are used to derive fluxes in a detailed structural model, with a bottom-up approach, consisting of the integration of molecular mechanism-based detailed kinetic models into the structural model.

Animals↗
PubMed2005

Modular polyketide synthases: Investigating intermodular communication using 6 deoxyerythronolide B synthase module 2.

A novel variant of 6-deoxyerythronolide B synthase (DEBS) module 2 was constructed to explore the balance between protein-protein-mediated intermodular channeling and intrinsic substrate specificity within DEBS. This construct, termed (N3)Mod2+TE, was co-incubated with a complementary, donor form of the same module, (N5)Mod2(C2), as well as with a mutant of (N5)Mod2(C2) with an inactive ketosynthase domain, in order to determine the extent of intermediate channeling versus substrate diffusion into the downstream module.

Chemistry, Pharmaceutical↗
PubMed2005

Mapping enzymatic functionalities of mannuronan C-5 epimerases and their modular units by dynamic force spectroscopy.

Alginates are (1-->4)-linked structural copolyuronans consisting of beta-D-mannuronic acid (M) and its C-5 epimer alpha-L-guluronic acid (G). The residue sequence variation is introduced in a unique postpolymerisation step catalysed by a family of C-5 epimerases named AlgE enzymes. The seven known AlgE's are composed of two modules, designated A and R, present in different number. The molecular details of the structure-function relationship of these seven epimerases, introducing specific residue sequences, are not understood. In this study, single-molecular pair interactions between alginate and AlgE enzymes were investigated using dynamic force spectroscopy. The AlgE enzymes AlgE4 and AlgE6, the recombinant construct PKA1 composed of A- and R-modules from various AlgE's, as well as separate R- and A-modules were studied. The strength of the protein-mannuronan interaction, when applying a loading rate of 0.6 nN/s, varied from 73 pN (AlgE4) to 144 pN (A-module). The determined potential width, that is, the distance from the activation barrier to the bound substrate molecule, was 0.23 nm for AlgE4, 0.19 nm for AlgE6 and 0.1 nm for the A-module. No attraction was observed between the R-module and the substrate. The observations indicate that the A-module contains the substrate binding site and that the R-module modulates the enzyme-substrate binding strength. The observed AlgE4-polymer residence times, two orders of magnitude longer than expected from kcat reported for AlgE4, not observed for PKA1, led us to propose a processive mode of action of AlgE4.

Alginates↗
PubMed2005

A modular design for the clathrin- and actin-mediated endocytosis machinery.

Endocytosis depends on an extensive network of interacting proteins that execute a series of distinct subprocesses. Previously, we used live-cell imaging of six budding-yeast proteins to define a pathway for association of receptors, adaptors, and actin during endocytic internalization. Here, we analyzed the effects of 61 deletion mutants on the dynamics of this pathway, revealing functions for 15 proteins, and we analyzed the dynamics of 8 of these proteins. Our studies provide evidence for four protein modules that cooperate to drive coat formation, membrane invagination, actin-meshwork assembly, and vesicle scission during clathrin/actin-mediated endocytosis. We found that clathrin facilitates the initiation of endocytic-site assembly but is not needed for membrane invagination or vesicle formation. Finally, we present evidence that the actin-meshwork assembly that drives membrane invagination is nucleated proximally to the plasma membrane, opposite to the orientation observed for previously studied actin-assembly-driven motility processes.

Actin Capping Proteins↗
PubMed2004

The modular approach to ligand discovery.

Identifying specific protein-ligand interactions is a long-standing problem in drug discovery and chemical biology, which is only exacerbated by the abundance of uncharacterized proteins revealed by genomics. Last month in Chemistry Biology, Sem et al. described a powerful technique for rapidly screening protein families for ligands.

Drug Evaluation, Preclinical↗
PubMed2006

Activating hybrid modular interfaces in synthetic polyketide synthases by cassette replacement of ketosynthase domains.

Unnatural combinations of polyketide synthase modules often fail to make a polyketide product. The causes of these failures are likely complex and are not yet amenable to rational correction. One possible explanation is the inability of the ketosynthase (KS) domain to extend the ketide donated to it by the upstream module. We therefore addressed the problem by exchanging KS domains of the acceptor module in a combinatorial fashion and coexpressing these chimeric modules with ketide-donor modules that naturally interact with the transplanted KS. This approach was remarkably successful in activating previously unproductive bimodular combinations, and the results augur well for the ongoing development of molecular tools to design and produce novel polyketides.

Ligases↗
PubMed2006

A modular and evolutive component oriented software architecture for patient modeling.

This paper deals with the design aspect of a software aiming at modeling the anatomical and pathological structures of patients from medical images, for diagnosis purposes. In terms of functionalities, it allows to combine image processing algorithms, and to visualize and manipulate 3D models and images. The proposed software uses specific extensible and reusable components and a system managing their combination, thanks to a formal XML-based description of their interfaces. This architecture facilitates the dynamic integration of new functionalities, in particular in terms of image processing algorithms. We describe the structural and behavioral aspects of the proposed reusable component-based architecture. We also discuss the potential of this work for developing other softwares in the field of computer aided surgery.

Computer Simulation↗
PubMed2005

Protein targeting: entropy, energetics and modular machines.

New light is being shed on the mechanism of protein import into mitochondria. The inner membrane translocase can switch between modes of translocation, and assists what might be an entropic device to drive the initial entry of substrate proteins across the outer membrane.

Entropy↗
PubMed2005

Integrin-linked kinase and its partners: a modular platform regulating cell-matrix adhesion dynamics and cytoskeletal organization.

Integrin-linked kinase (ILK) represents a key component of integrin signaling complexes that functions in concert with multiple binding partners to transmit cues from the extracellular matrix environment to the actin cytoskeleton. Both gain- and loss-of-function approaches to study ILK have confirmed the essential role of this protein in regulating cell-matrix adhesion dynamics and cytoskeletal organization.

Actin Cytoskeleton↗