918 resultados para global changes
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Malaria caused by several species of Plasmodium is major parasitic disease of humans, causing 1-3 million deaths worldwide annually. The widespread resistance of the human parasite to current drug therapies is of major concern making the identification of new drug targets urgent. While the parasite grows and multiplies inside the host erythrocyte it degrades the host cell hemoglobin and utilizes the released amino acids to synthesize its own proteins. The P. falciparum malarial M1 alanyl-aminopeptidase (PfA-M1) is an enzyme involved in the terminal stages of hemoglobin digestion and the generation of an amino acid pool within the parasite. The enzyme has been validated as a potential drug target since inhibitors of the enzyme block parasite growth in vitro and in vivo. In order to gain further understanding of this enzyme, molecular dynamics simulations using data from a recent crystal structure of PfA-M1 were performed. The results elucidate the pentahedral coordination of the catalytic Zn in these metallo-proteases and provide new insights into the roles of this cation and important active site residues in ligand binding and in the hydrolysis of the peptide bond. Based on the data, we propose a two-step catalytic mechanism, in which the conformation of the active site is altered between the Michaelis complex and the transition state. In addition, the simulations identify global changes in the protein in which conformational transitions in the catalytic domain are transmitted at the opening of the N-terminal 8 angstrom-long channel and at the opening of the 30 angstrom-long C-terminal internal chamber that facilitates entry of peptides to the active site and exit of released amino acids. The possible implications of these global changes with regard to enzyme function are discussed.
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<p>The relationship between changes in retinal vessel morphology and the onset and progression of diseases such as diabetes, hypertension and retinopathy of prematurity (ROP) has been the subject of several large scale clinical studies. However, the difficulty of quantifying changes in retinal vessels in a sufficiently fast, accurate and repeatable manner has restricted the application of the insights gleaned from these studies to clinical practice. This paper presents a novel algorithm for the efficient detection and measurement of retinal vessels, which is general enough that it can be applied to both low and high resolution fundus photographs and fluorescein angiograms upon the adjustment of only a few intuitive parameters. Firstly, we describe the simple vessel segmentation strategy, formulated in the language of wavelets, that is used for fast vessel detection. When validated using a publicly available database of retinal images, this segmentation achieves a true positive rate of 70.27%, false positive rate of 2.83%, and accuracy score of 0.9371. Vessel edges are then more precisely localised using image profiles computed perpendicularly across a spline fit of each detected vessel centreline, so that both local and global changes in vessel diameter can be readily quantified. Using a second image database, we show that the diameters output by our algorithm display good agreement with the manual measurements made by three independent observers. We conclude that the improved speed and generality offered by our algorithm are achieved without sacrificing accuracy. The algorithm is implemented in MATLAB along with a graphical user interface, and we have made the source code freely available.</p>
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Tese de doutoramento, Geologia (Geologia Econmica e do Ambiente), Universidade de Lisboa, Faculdade de Cincias, 2014
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We have used massively parallel signature sequencing (MPSS) to sample the transcriptomes of 32 normal human tissues to an unprecedented depth, thus documenting the patterns of expression of almost 20,000 genes with high sensitivity and specificity. The data confirm the widely held belief that differences in gene expression between cell and tissue types are largely determined by transcripts derived from a limited number of tissue-specific genes, rather than by combinations of more promiscuously expressed genes. Expression of a little more than half of all known human genes seems to account for both the common requirements and the specific functions of the tissues sampled. A classification of tissues based on patterns of gene expression largely reproduces classifications based on anatomical and biochemical properties. The unbiased sampling of the human transcriptome achieved by MPSS supports the idea that most human genes have been mapped, if not functionally characterized. This data set should prove useful for the identification of tissue-specific genes, for the study of global changes induced by pathological conditions, and for the definition of a minimal set of genes necessary for basic cell maintenance. The data are available on the Web at http://mpss.licr.org and http://sgb.lynxgen.com.
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The molecular events after spinal cord injury that lead to the establishment of a permissive environment and epimorphic regeneration remain unclear. Two molecular pathway regulators that may converge to create a spinal cord regeneration-permissive environment in the urodele are retinoic acid (RA) and microRNAs (miRNAs). Recent evidence suggests that RAR-mediated signaling is necessary for tail and caudal spinal cord regeneration in the adult newt. MicroRNAs are attractive candidates as mediators of retinoid signaling during regeneration, as their pleiotropic effects are vital in situations where global changes in gene expression are required. Thus, the overall aim of this thesis was to determine if miRNAs are involved in tail and caudal spinal cord regeneration in the adult newt, and if they act as regulators and/or effectors of retinoid signaling during this process. I have demonstrated here, for the first time, that multiple miRNAs are dysregulated in response to spinal cord injury in the adult newt, as well as in response to inhibition of retinoid signaling. Two of these miRNAs, miR-133a and miR-1, appear to target RAR2 transcripts both in vivo and in vitro. Inhibition of RA signaling via RAR with a selective antagonist, LE135, alters the pattern of expression of these miRNAs, which leads to an inhibition of tail regeneration. These data are indicative of a negative feed back loop, albeit potentially an indirect one. I also aimed to examine which miRNAs are affected by inhibiting RA synthesis during regeneration, and provided a long list of miRNAs that are dysregulated. These data provide the foundation for future studies on the putative roles of these miRNAs, as well as their function in retinoid signaling. Overall, these studies provide the first evidence for a role for miRNAs as mediators of retinoid signaling during caudal spinal cord regeneration in any system.
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Le centromre est le site chromosomal o le kinetochore se forme, afin dassurer une sgrgation fidles des chromosomes et ainsi maintenir la plodie approprie lors de la mitose. Lidentit du centromere est hrite par un mcanisme pigntique impliquant une variante de lhistone H3 nomme centromere protein-A (CENP-A), qui remplace lhistone H3 au niveau de la chromatine du centromre. Des erreurs de propagation de la chromatine du centromre peuvent mener des problmes de sgrgation des chromosomes, pouvant entraner laneuplodie, un phnomne frquemment observ dans le cancer. De plus, une expression non-rgule de CENP-A a aussi t rapporte dans diffrentes tumeurs humaines. Ainsi, plusieurs tudes ont cherches lucider la structure et le rle de la chromatine contenant CENP-A dans des cellules en prolifration. Toutefois, la nature molculaire de CENP-A en tant que marqueur pigntique ainsi que ces dynamiques l'extrieur du cycle cellulaire demeurent des sujets dbat. Dans cette thse, une nouvelle mthode de comptage de molcules uniques l'aide de la microscopie rflexion totale interne de la fluorescence (TIRF) sera dcrite, puis exploite afin d'lucider la composition molculaire des nuclosomes contenant CENP-A, extraits de cellules en prolifration. Nous dmontrons que les nuclosomes contenant CENP-A marquent les centromres humains de faon pigntique travers le cycle cellulaire. De plus, nos donnes dmontrent que la forme prnuclosomale de CENP-A, en association avec la protine chaperon HJURP existe sous forme de monomre et de dimre, ce qui reflte une tape intermdiaire de l'assemblage de nuclosomes contenant CENP-A. Ensuite, des analyses quantitatives de centromres lors de diffrenciation myognique, et dans diffrents tissus adultes rvlent des changements globaux qui maintiennent la marque pigntique dans une forme inactive suite la diffrentiation terminale. Ces changements incluent une rduction du nombre de points focaux de CENP-A, un rarrangement des points dans le noyau, ainsi qu'une rduction importante de la quantit de CENP-A. De plus, nous dmontrons que lorsqu'une ddiffrenciation cellulaire est induite puis le cycle cellulaire r-entam, le phnotype "diffrenci" dcrit ci-haut est rcupr, et les centromres reprennent leur phnotype "prolifratif". En somme, cet oeuvre dcrit la composition structurale sous-jacente l'identit pigntique des centromres de cellules humaines lors du cycle cellulaire, et met en lumire le rle de CENP-A l'extrieur du cycle cellulaire.
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The resurgence of the enteric pathogen Vibrio cholerae, the causative organism of epidemic cholera, remains a major health problem in many developing countries like India. The southern Indian state of Kerala is endemic to cholera. The outbreaks of cholera follow a seasonal pattern in regions of endemicity. Marine aquaculture settings and mangrove environments of Kerala serve as reservoirs for V. cholerae. The non-O1/non-O139 environmental isolates of V. cholerae with incomplete virulence casette are to be dealt with caution as they constitute a major reservoir of diverse virulence genes in the marine environment and play a crucial role in pathogenicity and horizontal gene transfer. The genes coding cholera toxin are borne on, and can be infectiously transmitted by CTX, a filamentous lysogenic vibriophages. Temperate phages can provide crucial virulence and fitness factors affecting cell metabolism, bacterial adhesion, colonization, immunity, antibiotic resistance and serum resistance. The present study was an attempt to screen the marine environments like aquafarms and mangroves of coastal areas of Alappuzha and Cochin, Kerala for the presence of lysogenic V. cholerae, to study their pathogenicity and also gene transfer potential. Phenotypic and molecular methods were used for identification of isolates as V. cholerae. The thirty one isolates which were Gram negative, oxidase positive, fermentative, with or without gas production on MOF media and which showed yellow coloured colonies on TCBS (Thiosulfate Citrate Bile salt Sucrose) agar were segregated as vibrios. Twenty two environmental V. cholerae strains of both O1 and non- O1/non-O139 serogroups on induction with mitomycin C showed the presence of lysogenic phages. They produced characteristic turbid plaques in double agar overlay assay using the indicator strain V. cholerae El Tor MAK 757. PCR based molecular typing with primers targeting specific conserved sequences in the bacterial genome, demonstrated genetic diversity among these lysogen containing non-O1 V. cholerae . Polymerase chain reaction was also employed as a rapid screening method to verify the presence of 9 virulence genes namely, ctxA, ctxB, ace, hlyA, toxR, zot,tcpA, ninT and nanH, using gene specific primers. The presence of tcpA gene in ALPVC3 was alarming, as it indicates the possibility of an epidemic by accepting the cholera. Differential induction studies used ALPVC3, ALPVC11, ALPVC12 and EKM14, underlining the possibility of prophage induction in natural ecosystems, due to abiotic factors like antibiotics, pollutants, temperature and UV. The efficiency of induction of prophages varied considerably in response to the different induction agents. The growth curve of lysogenic V. cholerae used in the study drastically varied in the presence of strong prophage inducers like antibiotics and UV. Bacterial cell lysis was directly proportional to increase in phage number due to induction. Morphological characterization of vibriophages by Transmission Electron Microscopy revealed hexagonal heads for all the four phages. Vibriophage ALPVC3 exhibited isometric and contractile tails characteristic of family Myoviridae, while phages ALPVC11 and ALPVC12 demonstrated the typical hexagonal head and non-contractile tail of family Siphoviridae. EKM14, the podophage was distinguished by short non-contractile tail and icosahedral head. This work demonstrated that environmental parameters can influence the viability and cell adsorption rates of V. cholerae phages. Adsorption studies showed 100% adsorption of ALPVC3 ALPVC11, ALPVC12 and EKM14 after 25, 30, 40 and 35 minutes respectively. Exposure to high temperatures ranging from 50C to 100C drastically reduced phage viability. The optimum concentration of NaCl required for survival of vibriophages except EKM14 was 0.5 M and that for EKM14 was 1M NaCl. Survival of phage particles was maximum at pH 7-8. V. cholerae is assumed to have existed long before their human host and so the pathogenic clones may have evolved from aquatic forms which later colonized the human intestine by progressive acquisition of genes. This is supported by the fact that the vast majority of V. cholerae strains are still part of the natural aquatic environment. CTX has played a critical role in the evolution of the pathogenicity of V. cholerae as it can transmit the ctxAB gene. The unusual transformation of V. cholerae strains associated with epidemics and the emergence of V. cholera O139 demonstrates the evolutionary success of the organism in attaining greater fitness. Genetic changes in pathogenic V. cholerae constitute a natural process for developing immunity within an endemically infected population. The alternative hosts and lysogenic environmental V. cholerae strains may potentially act as cofactors in promoting cholera phage blooms within aquatic environments, thereby influencing transmission of phage sensitive, pathogenic V. cholerae strains by aquatic vehicles. Differential induction of the phages is a clear indication of the impact of environmental pollution and global changes on phage induction. The development of molecular biology techniques offered an accessible gateway for investigating the molecular events leading to genetic diversity in the marine environment. Using nucleic acids as targets, the methods of fingerprinting like ERIC PCR and BOX PCR, revealed that the marine environment harbours potentially pathogenic group of bacteria with genetic diversity. The distribution of virulence associated genes in the environmental isolates of V. cholerae provides tangible material for further investigation. Nucleotide and protein sequence analysis alongwith protein structure prediction aids in better understanding of the variation inalleles of same gene in different ecological niche and its impact on the protein structure for attaining greater fitness of pathogens. The evidences of the co-evolution of virulence genes in toxigenic V. cholerae O1 from different lineages of environmental non-O1 strains is alarming. Transduction studies would indicate that the phenomenon of acquisition of these virulence genes by lateral gene transfer, although rare, is not quite uncommon amongst non-O1/non-O139 V. cholerae and it has a key role in diversification. All these considerations justify the need for an integrated approach towards the development of an effective surveillance system to monitor evolution of V. cholerae strains with epidemic potential. Results presented in this study, if considered together with the mechanism proposed as above, would strongly suggest that the bacteriophage also intervenes as a variable in shaping the cholera bacterium, which cannot be ignored and hinting at imminent future epidemics.
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O trabalho cooperativo nas comunidades escolares apresenta inmeras vantagens ao nvel do desenvolvimento dos alunos, dos professores e da prpria escola. No entanto, continuam a existir vrias lacunas neste tipo de actividades e, especificando Portugal, existem muitos trabalhos de tipo diagnstico, que no chegam para implantar cultura de cooperao. Quando falamos da implementao da cooperao nas escolas, temos de atender, obrigatoriamente, cultura de escola vivenciada nas mesmas e liderana, pois influenciam a cooperao. Este trabalho tem como finalidade verificar at que ponto existe trabalho cooperativo entre professores e perceber como se desenvolve a cultura de cooperao entre professores nos diferentes grupos de rea disciplinar duma mesma escola. Para verificar este objectivo, participaram 13 responsveis dos diferentes grupos de reas Disciplinares de uma escola secundria da zona do Estoril. Estes foram inquiridos atravs da aplicao de um questionrio adaptado, daquele que foi validado e utilizado por Bolam et al (2005), e atravs de uma entrevista semi-estruturada, para anlise da percepo que os mesmos tm sobre a cooperao e a cultura vivenciada dentro dos seus Grupos de rea Disciplinar. No geral, verificou-se que, relativamente cooperao e cultura cooperativa de grupo, os Departamentos de rea Curricular no diferem significativamente entre si, no existindo um grande sentido de cooperao. De acordo com as percepes dos inquiridos, verificou-se que existe uma fraca participao dos professores em aces cooperativas focalizadas no desenvolvimento profissional docente e focalizadas no desenvolvimento da cultura cooperativa ou atravs das precrias condies ou prticas extrnsecas a este desenvolvimento. Analisando a globalidade das mudanas verificadas nos ltimos dois anos, constatou-se que os Grupos de rea Disciplinar esto a viver um momento de estagnao na maioria das questes inquiridas. Averiguou-se, tambm, que a no/fraca liderana por parte dos responsveis de grupo de rea disciplinar, resulta numa fraca participao dos professores em questes cooperativas. Atravs deste estudo, pode-se concluir que existe uma fraca cooperao entre os professores do mesmo Grupo de rea Disciplinar desta escola. Conclui-se tambm que a escola atravessa um momento de estagnao, no existindo um real desenvolvimento da cultura cooperativa na escola.
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El artculo se refiere a los cambios globales que se han dado en el sistema internacional cuyo resultado ha sido el debilitamiento de la gobernanza global. En esta lgica, el autor argumenta que las relaciones de poder han provocado un cambio en los conceptos tradicionales de las Ciencias Sociales y las Relaciones Internacionales, especialmente los relacionados al tiempo y espacio que en la actualidad son globales y simultneos. Finalmente concluye que varias tendencias afectarn a Amrica Latina y a la Unin Europea en cuanto a la globalizacin, la paz, el afianzamiento del sistema democrtico, la diplomacia de cumbres, la cooperacin y al poder como elemento cambiante.
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Empirical Constraints on Future Sea Level Rise; Bern, Switzerland, 2529 August 2008; Eustatic sea level (ESL) rise during the 21st century is perhaps the greatest threat from climate change, but its magnitude is contested. Geological records identify examples of nonlinear ice sheet response to climate forcing, suggesting a strategy for refining estimates of 21st-century sea level change. In August 2008, Past Global Changes (PAGES), International Marine Past Global Change Study (IMAGES), and the University of Bern cosponsored a workshop to address this possibility. The workshop highlighted several ways that paleoceanography studies can place limits on future sea level rise, and these are enlarged upon here.
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In the last decade, a vast number of land surface schemes has been designed for use in global climate models, atmospheric weather prediction, mesoscale numerical models, ecological models, and models of global changes. Since land surface schemes are designed for different purposes they have various levels of complexity in the treatment of bare soil processes, vegetation, and soil water movement. This paper is a contribution to a little group of papers dealing with intercomparison of differently designed and oriented land surface schemes. For that purpose we have chosen three schemes for classification: i) global climate models, BATS (Dickinson et al., 1986; Dickinson et al., 1992); ii) mesoscale and ecological models, LEAF (Lee, 1992) and iii) mesoscale models, LAPS (Mihailovi, 1996; Mihailovi and Kallos, 1997; Mihailovi et al., 1999) according to the Shao et al. (1995) classification. These schemes were compared using surface fluxes and leaf temperature outputs obtained by time integrations of data sets derived from the micrometeorological measurements above a maize field at an experimental site in De Sinderhoeve (The Netherlands) for 18 August, 8 September, and 4 October 1988. Finally, comparison of the schemes was supported applying a simple statistical analysis on the surface flux outputs.
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In the last decade, a vast number of land surface schemes has been designed for use in global climate models, atmospheric weather prediction, mesoscale numerical models, ecological models, and models of global changes. Since land surface schemes are designed for different purposes they have various levels of complexity in the treatment of bare soil processes, vegetation, and soil water movement. This paper is a contribution to a little group of papers dealing with intercomparison of differently designed and oriented land surface schemes. For that purpose we have chosen three schemes for classification: i) global climate models, BATS (Dickinson et al., 1986; Dickinson et al., 1992); ii) mesoscale and ecological models, LEAF (Lee, 1992) and iii) mesoscale models, LAPS (Mihailovi, 1996; Mihailovi and Kallos, 1997; Mihailovi et al., 1999) according to the Shao et al. (1995) classification. These schemes were compared using surface fluxes and leaf temperature outputs obtained by time integrations of data sets derived from the micrometeorological measurements above a maize field at an experimental site in De Sinderhoeve (The Netherlands) for 18 August, 8 September, and 4 October 1988. Finally, comparison of the schemes was supported applying a simple statistical analysis on the surface flux outputs.
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Interpretation of ice-core records is currently limited by paucity of modelling at adequate temporal and spatial resolutions. Several key questions relate to mechanisms of polar amplification and inter-hemispheric coupling on glacial/interglacial timescales. Here, we present the first results from a large set of global oceanatmosphere climate model snap-shot simulations covering the last 120000 years using the Hadley Centre climate model (HadCM3) at up to 1 kyr temporal resolution. Two sets of simulations were performed in order to examine the roles of orbit and greenhouse gases versus ice-sheet forcing of orbital-scale climate change. A series of idealised Heinrich events were also simulated, but no changes to aerosols or vegetation were prescribed. This paper focuses on high latitudes and inter-hemispheric linkages. The simulations reproduce polar temperature trends well compared to ice-core reconstructions, although the magnitude is underestimated. Polar amplification varies with obliquity, but this variability is dampened by including variations in land ice coverage, while the overall amplification factor increases. The relatively constant amplification of Antarctic temperatures (with ice-sheet forcing included) suggests it is possible to use Antarctic temperature reconstructions to estimate global changes (which are roughly half the magnitude). Atlantic Ocean overturning circulation varies considerably only with the introduction of Northern Hemisphere ice sheets, but only weakens in the North Atlantic in the deep glacial, when oceansea-ice feedbacks result in the movement of the region of deep convection to lower latitudes and with the introduction of freshwater to the surface North Atlantic in order to simulate Heinrich events.
