956 resultados para Network Modelling
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Projecte de recerca elaborat a partir duna estada a la University of British Columbia, Canad, entre 2010 i 2012 La malaltia d'Alzheimer (MA) representa avui la forma ms comuna de demncia en la poblaci envellida. Malgrat fa 100 anys que va ser descoberta, encara avui no existeix cap tractament preventiu i/o curatiu ni cap agent de diagnstic que permeti valorar quantitativament l'evoluci d'aquesta malaltia. L'objectiu en el que s'emmarca aquest treball s contribuir a aportar solucions al problema de la manca d'agents teraputics i de diagnosi, unvocs i rigorosos, per a la MA. Des del camp de la qumica bioinorgnica s fcil fixar-se en l'excessiva concentraci d'ions Zn(II) i Cu(II) en els cervells de malalts de MA, plantejar-se la seva utilitzaci com a dianes teraputica i, en conseqncia, cercar agents quelants que evitin la formaci de plaques senils o contribueixin a la seva dissoluci. Si b aquest va ser el punt de partida daquest projecte, els mltiples factors implicats en la patognesi de la MA fan que el clssic paradigma d una molcula, una diana limiti la capacitat de la molcula de combatre aquesta malaltia tan complexa. Per tant, un esfor considerable sha dedicat al disseny dagentsmultifuncionals que combatin els mltiples factors que caracteritzen el desenvolupament de la MA. En el present treball shan dissenyat agents multifuncionals inspirats en dos esquelets moleculars ben establers i coneguts en el camp de la qumica medicinal: la tioflavina-T (ThT) i la deferiprona (DFP). La utilitzaci de tcniques in silico que inclouen clculs farmacocintics i modelatge molecular ha estat un procs cabdal per a lavaluaci dels millors candidats en base als segents requeriments: (a) compliment de determinades propietats farmacocintiques que estableixin el seu possible s com a frmac (b) hidrofobicitat adequada per travessar la BBB i (c) interacci amb el pptid Aen soluci.
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PURPOSE: The aim of this study was to assess the outcome of patients with primary spinal myxopapillary ependymoma (MPE). MATERIALS AND METHODS: Data from a series of 85 (35 females, 50 males) patients with spinal MPE were collected in this retrospective multicenter study. Thirty-eight (45%) underwent surgery only and 47 (55%) received postoperative radiotherapy (RT). Median administered radiation dose was 50.4 Gy (range, 22.2-59.4). Median follow-up of the surviving patients was 60.0 months (range, 0.2-316.6). RESULTS: The 5-year progression-free survival (PFS) was 50.4% and 74.8% for surgery only and surgery with postoperative low- (<50.4 Gy) or high-dose (>or=50.4 Gy) RT, respectively. Treatment failure was observed in 24 (28%) patients. Fifteen patients presented treatment failure at the primary site only, whereas 2 and 1 patients presented with brain and distant spinal failure only. Three and 2 patients with local failure presented with concomitant spinal distant seeding and brain failure, respectively. One patient failed simultaneously in the brain and spine. Age greater than 36 years (p = 0.01), absence of neurologic symptoms at diagnosis (p = 0.01), tumor size >or=25 mm (p = 0.04), and postoperative high-dose RT (p = 0.05) were variables predictive of improved PFS on univariate analysis. In multivariate analysis, only postoperative high-dose RT was independent predictors of PFS (p = 0.04). CONCLUSIONS: The observed pattern of failure was mainly local, but one fifth of the patients presented with a concomitant spinal or brain component. Postoperative high-dose RT appears to significantly reduce the rate of tumor progression.
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Des del segon quart del s. I aC i, especialment, durant el regnat dAugust, es va desenvolupar a lantiga provncia Tarraconensis un sistema productiu centrat en lexplotaci agrria vitivincola amb una finalitat clarament comercial. La majoria dassentament vitivincoles es troben emplaats al litoral catal, associats de vegades a figlinae que fabricaven les mfores per al transport i comer de lexcedent vincola. No obstant, a lrea del Valls Occidental i del Baix Llobregat es troben una srie de villes vinculades a la producci de vi i a la fabricaci dmfores que han proporcionat restes molt significatives sobre la contribuci daquesta zona a lexpansi econmica de la provncia. La caracteritzaci arqueolgica i arqueomtrica dun gran nombre dmfores procedents de diversos tallers cermics situats al Valls Occidental i al Baix Llobregat, utilitzant diverses tcniques danlisi qumica, mineralgica i petrogrfica, ha portat a establir quins tipus dmfores es van fabricar a cada taller i de quina manera. Shan identificat alguns dels processos tecnolgics de la cadena operativa: la selecci i processat de les matries primeres per conformar la pasta procedents, generalment, de lrea on es troba cada centre de producci, el modelatge, lassecat i la cocci de les peces. En alguns dels casos analitzats, sha identificat quins tipus de contenidors van ser importants a lestabliment i la seva provinena. La integraci daquests resultats en la base de dades analtica que disposa lERAAUB ha perms avaluar el grau destandarditzaci dels processos tecnolgics en aquesta rea. La contrastaci final amb les dades histriques i arqueolgiques contribueix al coneixement arqueolgic de les mfores vinries de la Tarraconensis i, a travs delles, al coneixement de les societats que les van fabricar, comercialitzar i utilitzar.
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Aim We investigated the late Quaternary history of two closely related and partly sympatric species of Primula from the south-western European Alps, P. latifolia Lapeyr. and P. marginata Curtis, by combining phylogeographical and palaeodistribution modelling approaches. In particular, we were interested in whether the two approaches were congruent and identified the same glacial refugia. Location South-western European Alps. Methods For the phylogeographical analysis we included 353 individuals from 28 populations of P. marginata and 172 individuals from 15 populations of P. latifolia and used amplified fragment length polymorphisms (AFLPs). For palaeodistribution modelling, species distribution models (SDMs) were based on extant species occurrences and then projected to climate models (CCSM, MIROC) of the Last Glacial Maximum (LGM), approximately 21 ka. Results The locations of the modelled LGM refugia were confirmed by various indices of genetic variation. The refugia of the two species were largely geographically isolated, overlapping only 6% to 11% of the species' total LGM distribution. This overlap decreased when the position of the glacial ice sheet and the differential elevational and edaphic distributions of the two species were considered. Main conclusions The combination of phylogeography and palaeodistribution modelling proved useful in locating putative glacial refugia of two alpine species of Primula. The phylogeographical data allowed us to identify those parts of the modelled LGM refugial area that were likely source areas for recolonization. The use of SDMs predicted LGM refugial areas substantially larger and geographically more divergent than could have been predicted by phylogeographical data alone
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Iowa DOT savings through use of Iowa Communcations Network (ICN) videoconferencing
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Modern urban lifestyle encourages the prolongation of wakefulness, leaving less and less time for sleep. Although the exact functions of sleep remain one of the biggest mysteries in neuroscience, the society is well aware of the negative consequences of sleep loss on human physical and mental health and performance. Enhancing sleep's recuperative functions might allow shortening sleep duration while preserving the beneficial effects of sleep. During sleep, brain activity oscillates across a continuum of frequencies. Individual oscillations have been suggested to underlie distinct functions for sleep and cognition. Gaining control about individual oscillations might allow boosting their specific functions. Sleep spindles are 11 - 15 Hz oscillations characteristic for light non-rapid-eye-movement sleep (NREMS) and have been proposed to play a role in memory consolidation and sleep protection against environmental stimuli. The reticular thalamic nucleus (nRt) has been identified as the major pacemaker of spindles. Intrinsic oscillatory burst discharge in nRt neurons, arising from the interplay of low-threshold (T-type) Ca2+ channels (T channels) and small conductance type 2 (SK2) K+ channels (SK2 channels), underlies this pacemaking function. In the present work we investigated the impact of altered nRt bursting on spindle generation during sleep by studying mutant mice for SK2 channels and for CaV3.3 channels, a subtype of T channels. Using in vitro electrophysiology I showed that nRt bursting was abolished in CaV3.3 knock out (CaV3.3 KO) mice. In contrast, in SK2 channel over-expressing (SK2-OE) nRt cells, intrinsic repetitive bursting was prolonged. Compared to wildtype (WT) littermates, altered nRt burst discharge lead to weakened thalamic network oscillations in vitro in CaV3.3 KO mice, while oscillatory activity was prolonged in SK2-OE mice. Sleep electroencephalographic recordings in CaV3.3 KO and SK2-OE mice revealed that reduced or potentiated nRt bursting respectively weakened or prolonged sleep spindle activity at the NREMS - REMS transition. Furthermore, SK2-OE mice showed more consolidated NREMS and increased arousal thresholds, two correlates of good sleep quality. This thesis work suggests that CaV3.3 and SK2 channels may be targeted in order to modulate sleep spindle activity. Furthermore, it proposes a novel function for spindles in NREMS consolidation. Finally, it provides evidence that sleep quality may be improved by promoting spindle activity, thereby supporting the hypothesis that sleep quality can be enhanced by modulating oscillatory activity in the brain. Le style de vie moderne favorise la prolongation de l'veil, laissant de moins en moins de temps pour le sommeil. Mme si le rle exact du sommeil reste un des plus grands mystres des neurosciences, la socit est bien consciente des consquences ngatives que provoque un manque de sommeil, la fois sur le plan de la sant physique et mentale ainsi qu'au niveau des performances cognitives. Augmenter les fonctions rcupratrices du sommeil pourrait permettre de raccourcir la dure du sommeil tout en en conservant les effets bnfiques. Durant le sommeil, on observe des oscillations travers un continuum de frquences. Il a t propos que chaque oscillation pourrait tre l'origine de fonctions spcifiques pour le sommeil et la cognition. Pouvoir de contrler les oscillations individuelles permettrait d'augmenter leurs fonctions respectives. Les fuseaux sont des oscillations de 11 15 Hz caractristiques du sommeil ondes lentes lger et il a t suggr qu'elles jouent un rle majeur pour la consolidation de la mmoire ainsi que dans la protection du sommeil contre les stimuli environnementaux. Le nucleus rticulaire du thalamus (nRt) a t identifi en tant que gnrateur de rythme des fuseaux. Les bouffes oscillatoires intrinsques des neurones du nRt, provenant de l'interaction de canaux calciques bas seuil de type T (canaux T) et de canaux potassiques faible conductance de type 2 (canaux SK2), sont l'origine de la fonction de gnrateur de rythme. Dans ce travail, j'ai tudi l'impact de la modulation de bouffes de nRT sur la gnration des fuseaux pendant le sommeil en investiguant des souris gntiquement modifies pour les canaux SK2 et les canaux CaV3.3, un sous-type de canaux T. En utilisant l'lectrophysiologie in vitro j'ai dmontr que les bouffes du nRT taient abolies dans les souris knock-out du type CaV3.3 (CaV3.3 KO). D'autre part, dans les cellules nRT sur-exprimant les canaux SK2 (SK2-OE), les bouffes oscillatoires intrinsques taient prolonges. Par rapport aux souris wild type, les souris CaV3.3 KO ont montr un affaiblissement des oscillations thalamiques en rponse un changement des bouffes de nRT, alors que l'activit oscillatoire tait prolonge dans les souris SK2-OE. Des enregistrements EEG du sommeil dans des souris de type CaV3.3 KO et SK2-OE ont rvl qu'une rduction ou augmentation des bouffes nRT ont respectivement affaibli ou prolong l'activit des fuseaux durant les transitions du sommeil ondes lentes au sommeil paradoxal. De plus, les souris SK2-OE ont montr des signes de consolidation du sommeil ondes lentes et un seuil augment pour le rveil, deux mesures qui corrlent avec une bonne qualit du sommeil. Le travail de cette thse propose que les canaux CaV3.3 et SK2 pourrait tre cibls pour moduler l'activit des fuseaux. De plus, je propose une fonction nouvelle pour les fuseaux dans la consolidation du sommeil ondes lentes. Finalement je suggre que la qualit du sommeil peut tre amliore en promouvant l'activit des fuseaux, soutenant ainsi l'ide que la qualit du sommeil peut tre amliore en modulant l'activit oscillatoire dans le cerveau.
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Rsum Le cancer du sein est le cancer le plus commun chez les femmes et est responsable de presque 30% de tous les nouveaux cas de cancer en Europe. On estime le nombre de dcs lis au cancer du sein en Europe est plus de 130.000 par an. Ces chiffres expliquent l'impact social considrable de cette maladie. Les objectifs de cette thse taient: (1) d'identifier les prdispositions et les mcanismes biologiques responsables de l'tablissement des sous-types spcifiques de cancer du sein; (2) les valider dans un modle n vivo "humain-dans-souris"; et (3) de dvelopper des traitements spcifiques chaque sous-type de cancer du sein identifis. Le premier objectif a t atteint par l'intermdiaire de l'analyse des donnes d'expression de gnes des tumeurs, produite dans notre laboratoire. Les donnes obtenues par puces ADN ont t produites partir de 49 biopsies des tumeurs du sein provenant des patientes participant dans l'essai clinique EORTC 10994/BIG00-01. Les donnes taient trs riches en information et m'ont permis de valider des donnes prcdentes des autres tudes d'expression des gnes dans des tumeurs du sein. De plus, cette analyse m'a permis d'identifier un nouveau sous-type biologique de cancer du sein. Dans la premire partie de la thse, je dcris I identification des tumeurs apocrines du sein par l'analyse des puces ADN et les implications potentielles de cette dcouverte pour les applications cliniques. Le deuxime objectif a t atteint par l'tablissement d'un modle de cancer du sein humain, bas sur des cellules pithliales mammaires humaines primaires (HMECs) drives de rductions mammaires. J'ai choisi d'adapter un systme de culture des cellules en suspension bas sur des mammosphres prcdemment dcrit et pat dcid d'exprimer des gnes en utilisant des lentivirus. Dans la deuxime partie de ma thse je dcris l'tablissement d'un systme de culture cellulaire qui permet la transformation quantitative des HMECs. Par la suite, j'ai tabli un modle de xnogreffe dans les souris immunodficientes NOD/SCID, qui permet de modliser la maladie humaine chez la souris. Dans la troisime partie de ma thse je dcris et je discute les rsultats que j'ai obtenus en tablissant un modle estrogne-dpendant de cancer du sein par transformation quantitative des HMECs avec des gnes dfinis, identifis par analyse de donnes d'expression des gnes dans le cancer du sein. Les cellules transformes dans notre modle taient estrogne-dpendantes pour la croissance, diplodes et gntiquement normales mme aprs la culture cellulaire in vitro prolonge. Les cellules formaient des tumeurs dans notre modle de xnogreffe et constituaient des mtastases pritonales dissmines et du foie. Afin d'atteindre le troisime objectif de ma thse, j'ai dfini et examin des stratgies de traitement qui permettent rduire les tumeurs et les mtastases. J'ai produit un modle de cancer du sein gntiquement dfini et positif pour le rcepteur de l'estrogne qui permet de modliser le cancer du sein estrogne-dpendant humain chez la souris. Ce modle permet l'tude des mcanismes impliqus dans la formation des tumeurs et des mtastases. Abstract Breast cancer is the most common cancer in women and accounts for nearly 30% of all new cancer cases in Europe. The number of deaths from breast cancer in Europe is estimated to be over 130,000 each year, implying the social impact of the disease. The goals of this thesis were first, to identify biological features and mechanisms --responsible for the establishment of specific breast cancer subtypes, second to validate them in a human-in-mouse in vivo model and third to develop specific treatments for identified breast cancer subtypes. The first objective was achieved via the analysis of tumour gene expression data produced in our lab. The microarray data were generated from 49 breast tumour biopsies that were collected from patients enrolled in the clinical trial EORTC 10994/BIG00-01. The data set was very rich in information and allowed me to validate data of previous breast cancer gene expression studies and to identify biological features of a novel breast cancer subtype. In the first part of the thesis I focus on the identification of molecular apacrine breast tumours by microarray analysis and the potential imptcation of this finding for the clinics. The second objective was attained by the production of a human breast cancer model system based on primary human mammary epithelial cells {HMECs) derived from reduction mammoplasties. I have chosen to adopt a previously described suspension culture system based on mammospheres and expressed selected target genes using lentiviral expression constructs. In the second part of my thesis I mainly focus on the establishment of a cell culture system allowing for quantitative transformation of HMECs. I then established a xenograft model in immunodeficient NOD/SCID mice, allowing to model human disease in a mouse. In the third part of my thesis I describe and discuss the results that I obtained while establishing an oestrogen-dependent model of breast cancer by quantitative transformation of HMECs with defined genes identified after breast cancer gene expression data analysis. The transformed cells in our model are oestrogen-dependent for growth; remain diploid and genetically normal even after prolonged cell culture in vitro. The cells farm tumours and form disseminated peritoneal and liver metastases in our xenograft model. Along the lines of the third objective of my thesis I defined and tested treatment schemes allowing reducing tumours and metastases. I have generated a genetically defined model of oestrogen receptor alpha positive human breast cancer that allows to model human oestrogen-dependent breast cancer in a mouse and enables the study of mechanisms involved in tumorigenesis and metastasis.
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Cancer genomes frequently contain somatic copy number alterations (SCNA) that can significantly perturb the expression level of affected genes and thus disrupt pathways controlling normal growth. In melanoma, many studies have focussed on the copy number and gene expression levels of the BRAF, PTEN and MITF genes, but little has been done to identify new genes using these parameters at the genome-wide scale. Using karyotyping, SNP and CGH arrays, and RNA-seq, we have identified SCNA affecting gene expression ('SCNA-genes') in seven human metastatic melanoma cell lines. We showed that the combination of these techniques is useful to identify candidate genes potentially involved in tumorigenesis. Since few of these alterations were recurrent across our samples, we used a protein network-guided approach to determine whether any pathways were enriched in SCNA-genes in one or more samples. From this unbiased genome-wide analysis, we identified 28 significantly enriched pathway modules. Comparison with two large, independent melanoma SCNA datasets showed less than 10% overlap at the individual gene level, but network-guided analysis revealed 66% shared pathways, including all but three of the pathways identified in our data. Frequently altered pathways included WNT, cadherin signalling, angiogenesis and melanogenesis. Additionally, our results emphasize the potential of the EPHA3 and FRS2 gene products, involved in angiogenesis and migration, as possible therapeutic targets in melanoma. Our study demonstrates the utility of network-guided approaches, for both large and small datasets, to identify pathways recurrently perturbed in cancer.
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Biochemical systems are commonly modelled by systems of ordinary differential equations (ODEs). A particular class of such models called S-systems have recently gained popularity in biochemical system modelling. The parameters of an S-system are usually estimated from time-course profiles. However, finding these estimates is a difficult computational problem. Moreover, although several methods have been recently proposed to solve this problem for ideal profiles, relatively little progress has been reported for noisy profiles. We describe a special feature of a Newton-flow optimisation problem associated with S-system parameter estimation. This enables us to significantly reduce the search space, and also lends itself to parameter estimation for noisy data. We illustrate the applicability of our method by applying it to noisy time-course data synthetically produced from previously published 4- and 30-dimensional S-systems. In addition, we propose an extension of our method that allows the detection of network topologies for small S-systems. We introduce a new method for estimating S-system parameters from time-course profiles. We show that the performance of this method compares favorably with competing methods for ideal profiles, and that it also allows the determination of parameters for noisy profiles.
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This is the Annual Report for Fiscal Year 2004 (July 1, 2003-June 30, 2004) for the Iowa Communications Network.
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For self-pollinating plants to reproduce, male and female organ development must be coordinated as flowers mature. The Arabidopsis transcription factors AUXIN RESPONSE FACTOR 6 (ARF6) and ARF8 regulate this complex process by promoting petal expansion, stamen filament elongation, anther dehiscence, and gynoecium maturation, thereby ensuring that pollen released from the anthers is deposited on the stigma of a receptive gynoecium. ARF6 and ARF8 induce jasmonate production, which in turn triggers expression of MYB21 and MYB24, encoding R2R3 MYB transcription factors that promote petal and stamen growth. To understand the dynamics of this flower maturation regulatory network, we have characterized morphological, chemical, and global gene expression phenotypes of arf, myb, and jasmonate pathway mutant flowers. We found that MYB21 and MYB24 promoted not only petal and stamen development but also gynoecium growth. As well as regulating reproductive competence, both the ARF and MYB factors promoted nectary development or function and volatile sesquiterpene production, which may attract insect pollinators and/or repel pathogens. Mutants lacking jasmonate synthesis or response had decreased MYB21 expression and stamen and petal growth at the stage when flowers normally open, but had increased MYB21 expression in petals of older flowers, resulting in renewed and persistent petal expansion at later stages. Both auxin response and jasmonate synthesis promoted positive feedbacks that may ensure rapid petal and stamen growth as flowers open. MYB21 also fed back negatively on expression of jasmonate biosynthesis pathway genes to decrease flower jasmonate level, which correlated with termination of growth after flowers have opened. These dynamic feedbacks may promote timely, coordinated, and transient growth of flower organs.
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State Agency Audit Report
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Background: Single nucleotide polymorphisms (SNPs) are the most frequent type of sequence variation between individuals, and represent a promising tool for finding genetic determinants of complex diseases and understanding the differences in drug response. In this regard, it is of particular interest to study the effect of non-synonymous SNPs in the context of biological networks such as cell signalling pathways. UniProt provides curated information about the functional and phenotypic effects of sequence variation, including SNPs, as well as on mutations of protein sequences. However, no strategy has been developed to integrate this information with biological networks, with the ultimate goal of studying the impact of the functional effect of SNPs in the structure and dynamics of biological networks. Results: First, we identified the different challenges posed by the integration of the phenotypic effect of sequence variants and mutations with biological networks. Second, we developed a strategy for the combination of data extracted from public resources, such as UniProt, NCBI dbSNP, Reactome and BioModels. We generated attribute files containing phenotypic and genotypic annotations to the nodes of biological networks, which can be imported into network visualization tools such as Cytoscape. These resources allow the mapping and visualization of mutations and natural variations of human proteins and their phenotypic effect on biological networks (e.g. signalling pathways, protein-protein interaction networks, dynamic models). Finally, an example on the use of the sequence variation data in the dynamics of a network model is presented. Conclusion: In this paper we present a general strategy for the integration of pathway and sequence variation data for visualization, analysis and modelling purposes, including the study of the functional impact of protein sequence variations on the dynamics of signalling pathways. This is of particular interest when the SNP or mutation is known to be associated to disease. We expect that this approach will help in the study of the functional impact of disease-associated SNPs on the behaviour of cell signalling pathways, which ultimately will lead to a better understanding of the mechanisms underlying complex diseases.
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It is well known that multiple-input multiple-output (MIMO) techniques can bring numerous benefits, such as higher spectral efficiency, to point-to-point wireless links. More recently, there has been interest in extending MIMO concepts tomultiuser wireless systems. Our focus in this paper is on network MIMO, a family of techniques whereby each end user in a wireless access network is served through several access points within its range of influence. By tightly coordinating the transmission and reception of signals at multiple access points, network MIMO can transcend the limits on spectral efficiency imposed by cochannel interference. Taking prior information-theoretic analyses of networkMIMO to the next level, we quantify the spectral efficiency gains obtainable under realistic propagation and operational conditions in a typical indoor deployment. Our study relies on detailed simulations and, for specificity, is conducted largely within the physical-layer framework of the IEEE 802.16e Mobile WiMAX system. Furthermore,to facilitate the coordination between access points, we assume that a high-capacity local area network, such as Gigabit Ethernet,connects all the access points. Our results confirm that network MIMO stands to provide a multiple-fold increase in spectralefficiency under these conditions.
