Página 25 dos resultados de 6914 itens digitais encontrados em 0.016 segundos

‣ Comparison between apo and complexed structures of bothropstoxin-I reveals the role of Lys122 and Ca2+-binding loop region for the catalytically inactive Lys49-PLA(2)s

Fernandes, Carlos A. H.; Marchi-Salvador, Daniela P.; Salvador, Guilherme M.; Silva, Mabel C. O.; Costa, Tassia R.; Soares, Andreimar M.; Fontes, Marcos R. M.
Fonte: Academic Press Inc. Elsevier B.V. Publicador: Academic Press Inc. Elsevier B.V.
Tipo: Artigo de Revista Científica Formato: 31-43
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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); Phospholipases A(2) (Asp49-PLA(2)s) are enzymes responsible for cellular membrane disruption through Ca2+-dependent hydrolysis of phospholipids. A class of these proteins (Lys49-PLA(2)s) does not show catalytic activity but can exert a pronounced local myotoxic effect that is not neutralized by serum therapy. In this work, we present five structures of Lys49-PLA(2)s from snakes of the Bothrops genus in apo form, complexed with PEG molecules and chemically modified by p-bromofenacil bromide (BPB), a classic inhibitor of PLA(2). We present herein an extensive structural analysis including: (i) the function of hydrophobic long-chain molecules as Lys49-PLA(2)s inhibitors, (ii) the role of Lys122, previously indicated as being responsible for Lys49-PLA(2)s catalytic inactivity and, (iii) a structural comparison of the Ca2+-binding loop region between Lys49 and Asp49-PLA(2)s. The Lys122 analysis of 30 different monomers for apo and complexed Lys49-PLA(2)s structures shows that this residue is very flexible and may bind to different carboxyl groups giving stability to the crystal structures. The structural comparisons of the Ca2+-binding loop region between Lys49 and Asp49-PLA(2)s reveal the importance of the Tyr28 residue conservation in Asp49-PLA(2)s to the integrity of this loop. The Tyr28 residue stabilizes this region by an interaction with Gly35 residue. In Lys49-PLA(2)s and low-catalytic Asp49-PLA(2)s this interaction does not occur...

‣ Blast-wave absorption capacity of sandwich structures incorporating cellular materials; Capacidade de proteção contra ondas de choque de sistemas multi-camada incorporando materiais celulares

Martins, Joana de Sousa
Fonte: Universidade de Aveiro Publicador: Universidade de Aveiro
Tipo: Tese de Doutorado
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A incorporação de materiais absorsores de energia (AE) em sistemas de protecção é uma clara possibilidade de melhoraria do seu desempenho, devido à elevada relação entre a sua resistência e o seu peso, e a excelente capacidade para absorverem energia quando solicitados dinamicamente. As propriedades mecânicas da cortiça (e.g. a baixa densidade e a elevada rigidez e resistência específicas) sugerem que este material — assim como os seus derivados — podem apresentar propriedades excelentes quando aplicados como núcleos em sistemas AE do tipo estrutura sanduíche. Esta dissertação engloba trabalho experimental e numérico. O primeiro conjunto de testes experimentais consistiu na caracterização experimental dinâmica (ondas de choque de explosivos) do comportamento de dois micra aglomerados de cortiça (MAC), NL20 e TB40. Um pendulo balístico de 4 cabos foi usado para a medição do impulso transmitido a uma amostra de MAC impactada por uma onda de choque com origem na detonação de um explosivo energético. Foi registado o movimento do pêndulo e os valores de força resultantes. Um modelo numérico do problema recorrendo ao método dos elementos finitos (MEF) foi também desenvolvido, apresentando uma elevada correlação com a análise experimental...

‣ Human RNA-specific adenosine deaminase ADAR1 transcripts possess alternative exon 1 structures that initiate from different promoters, one constitutively active and the other interferon inducible

George, Cyril X.; Samuel, Charles E.
Fonte: The National Academy of Sciences Publicador: The National Academy of Sciences
Tipo: Artigo de Revista Científica
Publicado em 13/04/1999 Português
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RNA-specific adenosine deaminase (ADAR1) catalyzes the deamination of adenosine to inosine in viral and cellular RNAs. Two size forms of the ADAR1 editing enzyme are known, an IFN-inducible ≈150-kDa protein and a constitutively expressed N-terminally truncated ≈110-kDa protein. We have now identified alternative exon 1 structures of human ADAR1 transcripts that initiate from unique promoters, one constitutively expressed and the other IFN inducible. Cloning and sequence analyses of 5′-rapid amplification of cDNA ends (RACE) cDNAs from human placenta established a linkage between exon 2 of ADAR1 and two alternative exon 1 structures, designated herein as exon 1A and exon 1B. Analysis of RNA isolated from untreated and IFN-treated human amnion cells demonstrated that exon 1B–exon 2 transcripts were synthesized in the absence of IFN and were not significantly altered in amount by IFN treatment. By contrast, exon 1A–exon 2 transcripts were IFN inducible. Transient transfection analysis with reporter constructs led to the identification of two functional promoters, designated PC and PI. Exon 1B transcripts were initiated from the PC promoter whose activity in transient transfection reporter assays was not increased by IFN treatment. The 107-nt exon 1B mapped 14.5 kb upstream of exon 2. The 201-nt exon 1A that mapped 5.4 kb upstream of exon 2 was initiated from the interferon-inducible PI promoter. These results suggest that two promoters...

‣ Investigation of the subcellular architecture of L7 neurons of Aplysia californica using magnetic resonance microscopy (MRM) at 7.8 microns

Lee, Choong H.; Flint, Jeremy J.; Hansen, Brian; Blackband, Stephen J.
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Publicado em 10/06/2015 Português
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Magnetic resonance microscopy (MRM) is a non-invasive diagnostic tool which is well-suited to directly resolve cellular structures in ex vivo and in vitro tissues without use of exogenous contrast agents. Recent advances in its capability to visualize mammalian cellular structure in intact tissues have reinvigorated analytical interest in aquatic cell models whose previous findings warrant up-to-date validation of subcellular components. Even if the sensitivity of MRM is less than other microscopic technologies, its strength lies in that it relies on the same image contrast mechanisms as clinical MRI which make it a unique tool for improving our ability to interpret human diagnostic imaging through high resolution studies of well-controlled biological model systems. Here, we investigate the subcellular MR signal characteristics of isolated cells of Aplysia californica at an in-plane resolution of 7.8 μm. In addition, direct correlation and positive identification of subcellular architecture in the cells is achieved through well-established histology. We hope this methodology will serve as the groundwork for studying pathophysiological changes through perturbation studies and allow for development of disease-specific cellular modeling tools. Such an approach promises to reveal the MR contrast changes underlying cellular mechanisms in various human diseases...

‣ Synthesis of New Styrylquinoline Cellular Dyes, Fluorescent Properties, Cellular Localization and Cytotoxic Behavior

Rams-Baron, Marzena; Dulski, Mateusz; Mrozek-Wilczkiewicz, Anna; Korzec, Mateusz; Cieslik, Wioleta; Spaczyńska, Ewelina; Bartczak, Piotr; Ratuszna, Alicja; Polanski, Jaroslaw; Musiol, Robert
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 26/06/2015 Português
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New styrylquinoline derivatives with their photophysical constants are described. The synthesis was achieved via Sonogashira coupling using the newly developed heterogeneous nano-Pd/Cu catalyst system, which provides an efficient synthesis of high purity products. The compounds were tested in preliminary fluorescent microscopy studies to in order to identify their preferable cellular localization, which appeared to be in the lipid cellular organelles. The spectroscopic properties of the compounds were measured and theoretical TD-DFT calculations were performed. A biological analysis of the quinolines that were tested consisted of cytotoxicity assays against normal human fibroblasts and colon adenocarcinoma cells. All of the compounds that were studied appeared to be safe and indifferent to cells in a high concentration range. The presented results suggest that the quinoline compounds that were investigated in this study may be valuable structures for development as fluorescent dyes that could have biological applications.

‣ Matrix Rigidity Regulates Cancer Cell Growth by Modulating Cellular Metabolism and Protein Synthesis

Tilghman, Robert W.; Blais, Edik M.; Cowan, Catharine R.; Sherman, Nicholas E.; Grigera, Pablo R.; Jeffery, Erin D.; Fox, Jay W.; Blackman, Brett R.; Papin, Jason A.; Tschumperlin, Daniel J.; Parsons, J. Thomas
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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Background: Tumor cells in vivo encounter diverse types of microenvironments both at the site of the primary tumor and at sites of distant metastases. Understanding how the various mechanical properties of these microenvironments affect the biology of tumor cells during disease progression is critical in identifying molecular targets for cancer therapy. Methodology/Principal Findings: This study uses flexible polyacrylamide gels as substrates for cell growth in conjunction with a novel proteomic approach to identify the properties of rigidity-dependent cancer cell lines that contribute to their differential growth on soft and rigid substrates. Compared to cells growing on more rigid/stiff substrates (>10,000 Pa), cells on soft substrates (150–300 Pa) exhibited a longer cell cycle, due predominantly to an extension of the G1 phase of the cell cycle, and were metabolically less active, showing decreased levels of intracellular ATP and a marked reduction in protein synthesis. Using stable isotope labeling of amino acids in culture (SILAC) and mass spectrometry, we measured the rates of protein synthesis of over 1200 cellular proteins under growth conditions on soft and rigid/stiff substrates. We identified cellular proteins whose syntheses were either preferentially inhibited or preserved on soft matrices. The former category included proteins that regulate cytoskeletal structures (e.g....

‣ Quantitative analysis of subcellular biomechanics and mechanotransduction

Lammerding, Jan, 1974-
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 2 v. (283 leaves); 15809434 bytes; 15847632 bytes; application/pdf; application/pdf
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Biological cells such as endothelial or muscle cells respond to mechanical stimulation with activation of specific intracellular and extracellular signaling pathways and cytoskeletal remodeling, a process termed mechanotransduction. Intracellular mechanosensors are thought to be activated by conformational changes induced by local cellular deformations. Since these mechanosensors have been speculated to be located in several cellular domains including the cell membrane, the cytoskeleton, and the nucleus, it is necessary to achieve a detailed understanding of subcellular mechanics. In this work, we present novel methods to independently quantify cytoskeletal displacements, mechanical coupling between the cytoskeleton and the extracellular matrix, and nuclear mechanics based on high resolution tracking of cellular structures and receptor bound magnetic beads in response to applied strain or microscopic forces. These methods were applied to study the effects of several human disease associated mutations on subcellular mechanics and to examine the interaction between known protein function and specific changes in cellular mechanical properties and mechanotransduction pathways. Initial experiments were targeted to the role of membrane adhesion receptors. Experiments with cells expressing a mutant form of the integrin-associated molecule tetraspanin CD151 revealed that CD151 plays a key role in selectively strengthening α6βl integrin-mediated adhesion to laminin-1. We then studied cytoplasmic behavior using cells from mice with an αB-Crystallin mutation (R120G) that causes desmin-related myopathy. These studies showed impaired passive cytoskeletal mechanics in adult mouse cardiac myocytes. Finally...

‣ Biomechanics of the single chondrocyte and its developing extracellular matrix

Ofek, Gidon
Fonte: Universidade Rice Publicador: Universidade Rice
Tipo: Thesis; Text Formato: application/pdf
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Degradation of articular cartilage results in poor joint movement and afflicts millions of patients each year. Since this tissue is incapable of self-repair, developing new approaches to treat injured cartilage would be a tremendous boon to patient quality of life, as well as have important economic ramifications. To address this debilitating condition, this thesis investigated the biomechanical nature of single chondrocytes and studied their emergent biophysical environment. Detailed insight into the role of intracellular structures on chondrocyte mechanical characteristics is a vital first step in understanding the etiology of cartilage degradation and identifying potential treatments. This thesis demonstrated that actin, intermediate filaments, and microtubules each play a unique function in cellular compressive stiffness, Poisson's ratio and its strain dependence, as well as recovery behavior in response to a range of applied strains. The in situ stiffness of the nucleus was found to be minimally greater than that of the cytoplasm, countering current theories in chondrocyte biomechanics and identifying a potential new avenue for mechanotransduction. A videocapture method was also developed to examine the response of single chondrocytes to direct shear...

‣ Safety evaluation of a sinus surfactant in an explant-based cytotoxicity assay

Tan, N.C.W.; Cooksley, C.M.; Paramasivan, S.; Vreugde, S.; Wormald, P.J.
Fonte: Wiley Publicador: Wiley
Tipo: Artigo de Revista Científica
Publicado em //2014 Português
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Objectives/Hypothesis:Biofilms are associated with clinical relapse following surgery for chronic rhinosinusitis. Encased bacteria are protected from innate immunity and antimicrobial therapy. Surfactants can disperse the biofilm into its planktonic phenotype so that traditional treatments may be effective. The aim of this study was to assess a surfactant for its cytotoxicity profile. Study Design In vitro explant-based cytotoxicity study. Methods:Sinonasal mucosa harvested from patients undergoing sinus surgery was tested using an air-liquid interface explant system. Surfactant at 1×, 2×, and 3× manufacturer's recommended concentrations were compared to control (saline) and Zinc Sulphate (ZnSO4), a known cytotoxic agent. Culture supernatant was analyzed for lactate dehydrogenase (LDH) as a marker of cellular toxicity. After 7 days, specimens were imaged using structured histopathology and scanning electron microscopy. Results:Application of surfactant at 1× concentration did not elicit an elevation in LDH, whereas ZnSO4 caused a significant rise 1 day after application. Specimens tested with a 2× and 3× surfactant demonstrated LDH rises 4 days and 2 days after application, respectively. Mucosa tested with the 1× surfactant and control demonstrated intact cellular structures on histopathology and preserved cilial ultrastructure on SEM. In ZnSO4-treated specimens...

‣ Dégradation des membres de la famille du LDLR par la convertase PCSK9 : troisième locus de l'hypercholestérolémie familiale

Poirier, Steve
Fonte: Université de Montréal Publicador: Université de Montréal
Tipo: Thèse ou Mémoire numérique / Electronic Thesis or Dissertation
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Les maladies cardiovasculaires (MCV) sont les principales causes de mortalité et de morbidité à travers le monde. En Amérique du Nord, on estime à 90 millions le nombre d’individus ayant une ou plusieurs MCV, à près de 1 million le nombre de décès reliés par année et à 525 milliards de dollars les coûts directs et indirects en 2010. En collaboration avec l’équipe du Dre. Boileau, notre laboratoire a récemment identifié, le troisième locus impliqué dans l’hypercholestérolémie familiale. Une étude publiée dans le New Engl J Med a révélé que l’absence de la convertase PCSK9 réduit de 88% le risque de MCV, corrélé à une forte réduction du taux de cholestérol plasmatique (LDL-C). Il fut démontré que PCSK9 lie directement le récepteur aux lipoprotéines de faible densité (LDLR) et, par un mécanisme méconnu, favorise sa dégradation dans les endosomes/lysosomes provoquant ainsi une accumulation des particules LDL-C dans le plasma. Dans cet ouvrage, nous nous sommes intéressés à trois aspects bien distincts : [1] Quels sont les cibles de PCSK9 ? [2] Quelle voie du trafic cellulaire est impliquée dans la dégradation du LDLR par PCSK9 ? [3] Comment peut-on inhiber la fonction de PCSK9 ? [1] Nous avons démontré que PCSK9 induit la dégradation du LDLR de même que les récepteurs ApoER2 et VLDLR. Ces deux membres de la famille du LDLR (fortes homologies) sont impliqués notamment dans le métabolisme des lipides et de la mise en place de structures neuronales. De plus...

‣ Multi-Scale Imaging and Informatics Pipeline for In Situ Pluripotent Stem Cell Analysis

Gorman, Bryan R.; Lu, Junjie; Baccei, Anna; Lowry, Nathan C.; Purvis, Jeremy E.; Mangoubi, Rami S.; Lerou, Paul H.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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Human pluripotent stem (hPS) cells are a potential source of cells for medical therapy and an ideal system to study fate decisions in early development. However, hPS cells cultured in vitro exhibit a high degree of heterogeneity, presenting an obstacle to clinical translation. hPS cells grow in spatially patterned colony structures, necessitating quantitative single-cell image analysis. We offer a tool for analyzing the spatial population context of hPS cells that integrates automated fluorescent microscopy with an analysis pipeline. It enables high-throughput detection of colonies at low resolution, with single-cellular and sub-cellular analysis at high resolutions, generating seamless in situ maps of single-cellular data organized by colony. We demonstrate the tool's utility by analyzing inter- and intra-colony heterogeneity of hPS cell cycle regulation and pluripotency marker expression. We measured the heterogeneity within individual colonies by analyzing cell cycle as a function of distance. Cells loosely associated with the outside of the colony are more likely to be in G1, reflecting a less pluripotent state, while cells within the first pluripotent layer are more likely to be in G2, possibly reflecting a G2/M block. Our multi-scale analysis tool groups colony regions into density classes...

‣ The hierarchical structure and mechanics of plant materials

Gibson, Lorna J.
Fonte: The Royal Society Publicador: The Royal Society
Tipo: Artigo de Revista Científica
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The cell walls in plants are made up of just four basic building blocks: cellulose (the main structural fibre of the plant kingdom) hemicellulose, lignin and pectin. Although the microstructure of plant cell walls varies in different types of plants, broadly speaking, cellulose fibres reinforce a matrix of hemicellulose and either pectin or lignin. The cellular structure of plants varies too, from the largely honeycomb-like cells of wood to the closed-cell, liquid-filled foam-like parenchyma cells of apples and potatoes and to composites of these two cellular structures, as in arborescent palm stems. The arrangement of the four basic building blocks in plant cell walls and the variations in cellular structure give rise to a remarkably wide range of mechanical properties: Young's modulus varies from 0.3 MPa in parenchyma to 30 GPa in the densest palm, while the compressive strength varies from 0.3 MPa in parenchyma to over 300 MPa in dense palm. The moduli and compressive strength of plant materials span this entire range. This study reviews the composition and microstructure of the cell wall as well as the cellular structure in three plant materials (wood, parenchyma and arborescent palm stems) to explain the wide range in mechanical properties in plants as well as their remarkable mechanical efficiency.

‣ Soil restoration with organic amendments: linking cellular functionality and ecosystem processes

Bastida, F.; Selevsek, N.; Torres, I. F.; Hernández, T.; García, C.
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Publicado em 27/10/2015 Português
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A hot topic in recent decades, the application of organic amendments to arid-degraded soils has been shown to benefit microbially-mediated processes. However, despite the importance of soils for global sustainability, a gap has not been addressed yet in soil science: is there any connection between ecosystem-community processes, cellular functionality, and microbial lifestyles (i.e. oligotrophy-copiotrophy) in restored soils? Together with classical ecosystem indicators (fatty-acids, extracellular-enzyme activities, basal respiration), state-of-the-art metaproteomics was applied to fill this gap in a model-restoration experiment initiated 10-years ago by the addition of sewage-sludge and compost. Organic amendment strongly impacted ecosystem processes. Furthermore, the type of material used induced differences in the cellular functionalities through variations in the percentages of proteins involved in translation, transcription, energy production and C-fixation. We conclude that the long-term impact of organic restoration goes beyond ecosystem processes and affects cellular functionalities and phyla-lifestyles coupled with differences in microbial-community structures.

‣ Relating Chemical Structure to Cellular Response: An Integrative Analysis of Gene Expression, Bioactivity, and Structural Data Across 11,000 Compounds

Chen, B; Greenside, P; Paik, H; Sirota, M; Hadley, D; Butte, AJ
Fonte: John Wiley & Sons, Ltd Publicador: John Wiley & Sons, Ltd
Tipo: Artigo de Revista Científica
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A central premise in systems pharmacology is that structurally similar compounds have similar cellular responses; however, this principle often does not hold. One of the most widely used measures of cellular response is gene expression. By integrating gene expression data from Library of Integrated Network-based Cellular Signatures (LINCS) with chemical structure and bioactivity data from PubChem, we performed a large-scale correlation analysis of chemical structures and gene expression profiles of over 11,000 compounds taking into account confounding factors such as biological conditions (e.g., cell line, dose) and bioactivities. We found that structurally similar compounds do indeed yield similar gene expression profiles. There is an ∼20% chance that two structurally similar compounds (Tanimoto Coefficient ≥ 0.85) share significantly similar gene expression profiles. Regardless of structural similarity, two compounds tend to share similar gene expression profiles in a cell line when they are administrated at a higher dose or when the cell line is sensitive to both compounds.

‣ Microfluidic hydrodynamic cellular patterning for systematic formation of co-culture spheroids

Torisawa, Yu-suke; Mosadegh, Bobak; Luker, Gary D.; Morell, Maria; O'Shea, K. Sue; Takayama, Shuichi
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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This paper describes a microfluidic method to form co-culture spheroids of various geometries and compositions in order to manipulate cell–cell interaction dynamics. The cellular patterning is performed in a two-layered microfluidic device that sandwiches a semi-porous membrane so that flow occurs from the top channel through the membrane to the bottom channel. Arbitrary cellular arrangements are enabled by regulating the geometric features of the bottom channel so that as culture media drains, the flow hydrodynamically focuses (aggregates) cells onto the membrane only over the regions of the bottom channel. Furthermore, when the top channel has multiple inlets, cells can be seeded in adjacent laminar streams, allowing different cell types to be patterned simultaneously in well defined spatial arrangements. Interestingly, the initial cell positioning of certain cell types can result in two juxtaposed non-concentric “Janus” spheroids, rather than homogeneous mixtures or layered shell structures. Therefore, the initial position of cells prior to aggregation can influence the final configuration within a co-culture spheroid. When Janus spheroids were constructed from mouse embryonic stem (mES) cells and hepatocytes, the mES cells differentiated in a spatially distinct pattern dictated by the position of the hepatocytes. This contrasts with uniform mES differentiation observed when co-culture spheroids are formed by the conventional method of randomly mixing the two cell types. This cellular patterning method opens new possibilities for understanding and manipulating interactions between different cell types in 3D.

‣ CORSEN, a new software dedicated to microscope-based 3D distance measurements: mRNA–mitochondria distance, from single-cell to population analyses

Jourdren, Laurent; Delaveau, Thierry; Marquenet, Emelie; Jacq, Claude; Garcia, Mathilde
Fonte: Cold Spring Harbor Laboratory Press Publicador: Cold Spring Harbor Laboratory Press
Tipo: Artigo de Revista Científica
Publicado em /07/2010 Português
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Recent improvements in microscopy technology allow detection of single molecules of RNA, but tools for large-scale automatic analyses of particle distributions are lacking. An increasing number of imaging studies emphasize the importance of mRNA localization in the definition of cell territory or the biogenesis of cell compartments. CORSEN is a new tool dedicated to three-dimensional (3D) distance measurements from imaging experiments especially developed to access the minimal distance between RNA molecules and cellular compartment markers. CORSEN includes a 3D segmentation algorithm allowing the extraction and the characterization of the cellular objects to be processed—surface determination, aggregate decomposition—for minimal distance calculations. CORSEN's main contribution lies in exploratory statistical analysis, cell population characterization, and high-throughput assays that are made possible by the implementation of a batch process analysis. We highlighted CORSEN's utility for the study of relative positions of mRNA molecules and mitochondria: CORSEN clearly discriminates mRNA localized to the vicinity of mitochondria from those that are translated on free cytoplasmic polysomes. Moreover, it quantifies the cell-to-cell variations of mRNA localization and emphasizes the necessity for statistical approaches. This method can be extended to assess the evolution of the distance between specific mRNAs and other cellular structures in different cellular contexts. CORSEN was designed for the biologist community with the concern to provide an easy-to-use and highly flexible tool that can be applied for diverse distance quantification issues.

‣ Protein-protein interaction networks identify targets which rescue the MPP+ cellular model of Parkinson’s disease

Keane, Harriet; Ryan, Brent J.; Jackson, Brendan; Whitmore, Alan; Wade-Martins, Richard
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Publicado em 26/11/2015 Português
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Neurodegenerative diseases are complex multifactorial disorders characterised by the interplay of many dysregulated physiological processes. As an exemplar, Parkinson’s disease (PD) involves multiple perturbed cellular functions, including mitochondrial dysfunction and autophagic dysregulation in preferentially-sensitive dopamine neurons, a selective pathophysiology recapitulated in vitro using the neurotoxin MPP+. Here we explore a network science approach for the selection of therapeutic protein targets in the cellular MPP+ model. We hypothesised that analysis of protein-protein interaction networks modelling MPP+ toxicity could identify proteins critical for mediating MPP+ toxicity. Analysis of protein-protein interaction networks constructed to model the interplay of mitochondrial dysfunction and autophagic dysregulation (key aspects of MPP+ toxicity) enabled us to identify four proteins predicted to be key for MPP+ toxicity (P62, GABARAP, GBRL1 and GBRL2). Combined, but not individual, knockdown of these proteins increased cellular susceptibility to MPP+ toxicity. Conversely, combined, but not individual, over-expression of the network targets provided rescue of MPP+ toxicity associated with the formation of autophagosome-like structures. We also found that modulation of two distinct proteins in the protein-protein interaction network was necessary and sufficient to mitigate neurotoxicity. Together...

‣ Frame Structure Design and Analysis for Millimeter Wave Cellular Systems

Dutta, Sourjya; Mezzavilla, Marco; Ford, Russell; Zhang, Menglei; Rangan, Sundeep; Zorzi, Michele
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Publicado em 17/12/2015 Português
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Millimeter-wave (mmWave) frequencies between 30 and 300 GHz have attracted considerable attention for fifth generation (5G) cellular communication as they offer orders of magnitude greater bandwidth than current cellular systems. However, the MAC layer may need to be significantly redesigned to support the highly directional transmissions, very low latencies and high peak rates inherent in mmWave communication. This paper analyzes two aspects of the mmWave MAC design.Firstly, this paper analyzes radio frame design options for a mmWave cellular airlink under the assumption of an LTE-like OFDM frame structure. Simple analytic formulae are derived to estimate the utilization as a function of key parameters such as the control periodicity, number of users, and channel and traffic statistics. It is found that certain flexible frame structures can offer dramatically improved utilization under various assumptions on the traffic pattern. Secondly, the beamforming choices are analyzed based on the control channel overhead that the link incurs. Analytical expressions for the overhead due to the physical layer control messages are derived as a function of control periodicity, signal-to-noise ratio, antenna gains and the frame design choice. It is shown that fully digital beamforming architectures offer significantly lower overhead compared to analog and hybrid beamforming under equivalent power budgets.

‣ Optimizing the bulk modulus of cellular networks

Durand, Marc
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Publicado em 05/04/2005 Português
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We present an alternative derivation of upper-bounds for the bulk modulus of both two-dimensional and three-dimensional cellular materials. For two-dimensional materials, we recover exactly the expression of the Hashin-Shtrikman (HS) upper-bound in the low-density limit, while for three-dimensional materials we even improve the HS bound. Furthermore, we establish necessary and sufficient conditions on the cellular structure for maximizing the bulk modulus, for a given solid volume fraction. These conditions are found to be exactly those under which the electrical (or thermal) conductivity of the material reaches its maximal value as well. These results provide a set of straightforward criteria allowing to address the design of optimized cellular materials, and shed light on recent studies of structures with both maximal bulk modulus and maximal conductivity. Finally, we discuss the compatibility of the criteria presented here with the geometrical constraints caused by minimization of surface energy in a real foam.

‣ A new computational model for multi-cellular biological systems

Jennings, Joel Nicholas
Fonte: University of Cambridge; Department of Physiology, Development and Neuroscience Publicador: University of Cambridge; Department of Physiology, Development and Neuroscience
Tipo: Thesis; doctoral; PhD
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The early development of an animal results from a highly complex sequence of interactions within and between cells to transform a fertilised egg into a functional embryo. A major challenge in the field of morphogenesis is explaining how coordinated cell shape change, growth and movement create the structures that we are familiar with, and what drives the processes that pattern and control this behaviour. Embryos are complicated mechanical systems for which we have a wealth of morphological data about the shapes and movements of cells but it is diffcult to understand how these movements emerge as a result of force-generating mechanisms within the embryo. A new, force-based modelling technique designed to test hypotheses about dynamic processes within an embryo is presented. The model focusses on how the mechanical properties of a cell and inter-cellular forces affect the movements we see within a tissue. It is designed to probe the relationships between cellular and tissue behaviours; such as how forces propagate through a system or the response of a tissue to applied forces. The novel features of the model are discussed along with analysis of tissue and cellular behaviours for different idealised systems, describing how the parameters of the model affect experimental observables. The model is applied to two real world systems. Firstly examining the role of boundary conditions on the patterning seen in the formation of the zebrafish forebrain neural plate. Secondly...