Heparin and Heparan Sulfate: Analyzing Structure and Microheterogeneity [chapter]

available in PMC 2013 August 28The structural microheterogeneity of heparin and heparan sulfate is one of the major reasons for the multifunctionality exhibited by this class of molecules. In a physiological context, these molecules primarily exert their effects extracellularly by mediating key processes of cellular cross-talk and signaling leading to the modulation of a number of different biological activities including development, cell proliferation, and inflammation. This structural diversity is biosynthetically imprinted in a nontemplate-driven manner and may also be dynamically remodeled as cellular function changes. Understanding the structural information encoded in these molecules forms the basis for attempting to understand the complex biology they mediate. This chapter provides an overview of the origin of the structural microheterogeneity observed in heparin and heparan sulfate, and the orthogonal analytical methodologies that are required to help decipher this information

GNAO1 encephalopathy: broadening the phenotype and evaluating treatment and outcome

OBJECTIVE: To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1-related disease. METHODS: We reviewed clinical information, video recordings, and neuroimaging of a newly identified cohort of 7 patients with de novo missense and splice site GNAO1 mutations, detected by next-generation sequencing techniques. RESULTS: Patients first presented in early childhood (median age of presentation 10 months, range 0-48 months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder phenotype, featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention, although tetrabenazine was effective in partially controlling dyskinesia for 2/7 patients. Emergency deep brain stimulation (DBS) was life saving in 1 patient, resulting in immediate clinical benefit with complete cessation of violent hyperkinetic movements. Five patients had well-controlled epilepsy and 1 had drug-resistant seizures. Structural brain abnormalities, including mild cerebral atrophy and corpus callosum dysgenesis, were evident in 5 patients. One patient had a diffuse astrocytoma (WHO grade II), surgically removed at age 16. CONCLUSIONS: Our findings support the causative role of GNAO1 mutations in an expanded spectrum of early-onset epilepsy and movement disorders, frequently exacerbated by specific triggers and at times associated with self-injurious behavior. Tetrabenazine and DBS were the most useful treatments for dyskinesia

Description of diffusive and propagative behavior on fractals

The known properties of diffusion on fractals are reviewed in order to give a general outlook of these dynamic processes. After that, we propose a description developed in the context of the intrinsic metric of fractals, which leads us to a differential equation able to describe diffusion in real fractals in the asymptotic regime. We show that our approach has a stronger physical justification than previous works on this field. The most important result we present is the introduction of a dependence on time and space for the conductivity in fractals, which is deduced by scaling arguments and supported by computer simulations. Finally, the diffusion equation is used to introduce the possibility of reaction-diffusion processes on fractals and analyze their properties. Specifically, an analytic expression for the speed of the corresponding travelling fronts, which can be of great interest for application purposes, is derived

COST292 experimental framework for TRECVID 2008

In this paper, we give an overview of the four tasks submitted to TRECVID 2008 by COST292. The high-level feature extraction framework comprises four systems. The first system transforms a set of low-level descriptors into the semantic space using Latent Semantic Analysis and utilises neural networks for feature detection. The second system uses a multi-modal classifier based on SVMs and several descriptors. The third system uses three image classifiers based on ant colony optimisation, particle swarm optimisation and a multi-objective learning algorithm. The fourth system uses a Gaussian model for singing detection and a person detection algorithm. The search task is based on an interactive retrieval application combining retrieval functionalities in various modalities with a user interface supporting automatic and interactive search over all queries submitted. The rushes task submission is based on a spectral clustering approach for removing similar scenes based on eigenvalues of frame similarity matrix and and a redundancy removal strategy which depends on semantic features extraction such as camera motion and faces. Finally, the submission to the copy detection task is conducted by two different systems. The first system consists of a video module and an audio module. The second system is based on mid-level features that are related to the temporal structure of videos

Trends in Metal Oxide Stability for Nanorods, Nanotubes, and Surfaces

The formation energies of nanostructures play an important role in determining their properties, including the catalytic activity. For the case of 15 different rutile and 8 different perovskite metal oxides, we find that the density functional theory (DFT) calculated formation energies of (2,2) nanorods, (3,3) nanotubes, and the (110) and (100) surfaces may be described semi-quantitatively by the fraction of metal--oxygen bonds broken and the bonding band centers in the bulk metal oxide

EFFECT OF AN INNOVATIVE ISOLATION SYSTEM ON THE SEISMIC RESPONSE OF CULTURAL HERITAGE BUILDING CONTENTS

An experimental study was conducted at the University of Pavia and at the EUCENTRE Foundation (Pavia, Italy) to assess the effectiveness of an innovative seismic isolation device at protecting cultural heritage building contents. The recently patented isolator, named “Kinematic Steel Joint (KSJ)”, is based on a multiple articulated quadrilateral mechanism and is entirely made of steel components obtained by simply cutting, folding, and pinning metal sheets, eventually employing stainless steel to limit corrosion issues. The trajectory imposed by the KSJ isolator to the supported mass combines horizontal with increasing vertical displacements, resulting in a pendulum-type motion with self-centering behavior. The friction developing within the pinned joints can be exploited to grant energy dissipation capacity to the device. The KSJ isolator can be manufactured with different sizes, payloads, and displacement ranges. In fact, seismic isolation can be applied at a global building level as an integrated system or as a retrofit solution in new or existing construction, respectively, or at a local scale as a passive protection technique for non-structural components. Despite their undeniable effectiveness in reducing the seismic accelerations transmitted to the isolated structure and to its content, currently available isolation devices may add significantly to the construction cost of buildings, and may require particular maintenance to preserve a stable performance over time. The proposed KSJ solution will allow for a reduction in manufacturing and maintenance burdens compared to established technologies. This paper discusses the main results of a shake-table test conducted at the EUCENTRE Foundation laboratories on an assembly with four prototypes of the KSJ device. The experimental setup included a 19-t rigid mass supported by the isolators, simulating the building superstructure, and four marble blocks installed above the rigid mass, representing non-structural rocking components such as parapets, pinnacles, statues, or other architectural ornaments. Moreover, a museum showcase with a small-scale replica of Michelangelo’s David was mounted above the rigid block, while two clay vases completed the setup, to encompass additional cultural heritage features. Accelerometers and potentiometers were deployed at several locations to monitor the kinematic response of the individual isolators, as well as their effect on the dynamic response of the rigid mass and of the different non-structural elements. The experiment was conducted first with the KSJ devices allowed to displace freely, then after fastening the rigid mass to the shake-table through post-tensioning rods, following the same incremental dynamic test sequence. This allowed comparing the response of the non-structural components with and without seismic isolation, to better understand the effect of the proposed isolation devices on the overall test assembly and on each sub-component

Computational modelling of the LCAT::rHDL complex and bases of LCAT pharmacological activation

LCAT is a liver-secreted protein that circulates in plasma reversibly bound to lipoproteins, where its main function is to catalyze cholesterol esterification, transferring an acyl chain from phosphatidylcholine to free cholesterol, thus playing a crucial role in HDL maturation and reverse cholesterol transfer. Loss of function mutations in the LCAT gene may lead to LCAT deficiencies, rare monogenic disorders of lipid metabolism with important clinical consequences, for which no definite cure is available. Despite the effectiveness of recombinant enzyme replacement therapy, the viability of a small molecule-based approach to treat LCAT deficiencies would provide superior advantages to patients in terms of an improved quality of life and lower social costs. Preliminary results show that small molecules (SM) with allosteric activating mechanism may operate LCAT mutants in vitro, thus, the aim of this project is to rationalize the in-silico design of LCAT activators that could partially restore enzyme activity in carriers of defective LCAT. We took advantage of recently published crystallographic data of LCAT and apo-AI structures and assembled the LCAT::rHDL supramolecular complex with a chimeric model of a reconstituted HDL (rHDL); using molecular dynamics, stochastic sampling, protein::protein docking and other bioinformatics tools, we provided a data-driven general model of LCAT activation by apo-AI and a study of the dynamic behavior of LCAT subdomains critical to catalytic site accessibility and interaction with HDLs. Models were validated in light of recently published cryo-EM, HDX and XL- MS data, shedding light on the interactions between LCAT and rHDLs. We then used the generated architecture to provide a mechanistic explanation of the activity loss in LCAT mutants and to understand how novel activators can restore their functionality. We analyzed the binding mode and the affinity of two published LCAT activators, and rationalized their mechanism of action, laying the foundations for the rational drug design of SM activators

Technician components and requirements model for the formation and management of cooperation networks among civil construction companies

A indústria da Construção Civil possui um modo de operação semelhante ao das organizações virtuais, mas de forma não estruturada, deixando de proporcionar vantagens competitivas. Para tanto, o artigo propõe um Modelo de Requisitos e Componentes Técnicos, baseado na metodologia EKD (Enterprise Knwoledge Development), para auxiliar a formação e gerência de redes entre empresas da construção civil. Para a elaboração do modelo proposto, foi conduzida uma análise dos projetos internacionais mais relevantes no setor da construção além de estudo de casos contendo sete obras a fim de detectar seus objetivos e pontos falhos a serem reestruturados e adaptados para a indústria da construção civil brasileira. Não obstante, o modelo proposto baseou-se em uma adaptação das melhores práticas de uma arquitetura de referência para redes. Como resultado, a proposição viabiliza uma visão clara dos requisitos necessários, explora a necessidade de intensa comunicação e troca de informações, além de contribuir com pesquisas futuras no que tange a um futuro desenvolvimento de sistema de informação direcionado para este segmento econômico.The operational method of civil construction can be analyzed by the outlook of virtual organizations, however not yet structuralized, hence not providing competitive advantages. Thus, this article considers a Technical Components and Requirements Model, based on EKD methodology (Enterprise Knowledge Development), to assist in the formation and management of networks in civil construction companies. For the elaboration of the considered model, an analysis of the most important international construction projects was conducted, in addition to a case study from seven construction projects in order to detect their goals and defective points, to then be reorganized and adapted to the Brazilian civil construction industry. Moreover, the considered model was also based on an adaptation of reference architecture for civil construction networks. As a result, the proposal makes possible, to the stakeholders, a clear view of the necessary requirements, exploring the necessity of intense communication and exchange of information, besides contributing to future research works regarding a future development of an information system directed for this economic segment

In silico investigations of N-glycosylation role in modulating IgG1 conformational behavior and Fc effector functions

Currently, monoclonal antibodies (mAbs) are the most used biopharmaceuticals for human therapy. One of the key aspects in their development is the control of effector functions mediated by the interaction between fragment crystallizable (Fc) and Fcγ receptors, that is a secondary mechanism of action of biotherapeutics. N-glycosylation at Fc portion can regulate these mechanisms and many experimental evidences suggest that modifications of glycosydic chains can affect the antibody binding to FcγRIIIa, consequently impacting the immune response. In this work, we try to elucidate via in silico procedures the structural role exhibited by glycans, particularly fucose, that can potentially affect the receptor recognition. By using adalimumab, a marketed IgG1, as general template, after rebuilding its three-dimensional (3D) structure through homology modeling approaches, we carried out molecular dynamics simulations of three species: aglycosylated, afucosylated and fucosylated antibody, alone and in complex with FcγRIIIa. Trajectory analyses showed different dynamical behaviors among antibodies, highlighting that sugars can influence the overall 3D structure of the molecule and the orientation of Fragment antigen binding (Fab) domains. Moreover, oppositely to what happens in the fucosylated complex, in absence of fucose Fab arms can participate to the receptor recognition and many antibody residues considered critical for the complex formation by mutagenesis studies were found to interact with FcγRIIIa. Our study suggests a putative structural mechanism by which the fucose introduces conformational constraints in the whole antibody and not only in the Fc domain, preventing a conformation suitable for the interaction with the receptor. As secondary evidence, we observed a high flexibility of the antibodies that is translated in an asymmetric behavior of Fab portions shown by all the simulated biopolymers, suggesting a new molecular aspect that may be deeply investigated. In conclusion, these findings can help understand the contribution of sugars on the structural architecture of mAbs, paving the way to novel strategies of pharmaceutical development