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One way to test whether gene expression differences between species accumulate at a rate consistent with neutral expectation is to compare them to the expression differences observed for a class of genes that can reasonably be expected to not be the direct targets of positive or negative selection. Since expressed pseu... | 15138501_p9 | 15138501 | A Test for Neutrality | 4.184958 | biomedical | Study | [
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To test this, we considered the expression patterns in four regions of the brain in three humans and three chimpanzees using the Affymetrix U95 array set interrogating approximately 40,000 genes (Philipp Khaitovich, unpublished data). In order to identify all probe sets on these arrays that interrogate expressed pseudo... | 15138501_p10 | 15138501 | A Test for Neutrality | 4.17389 | biomedical | Study | [
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We compared the distributions of the squared differences between the mean expression levels of each gene in humans and in chimpanzees for the 23 pseudogenes and 12,647 intact genes for each of the four brain regions. In each case, only the genes detected in a given brain region were used for the calculation. In all fou... | 15138501_p11 | 15138501 | A Test for Neutrality | 4.11399 | biomedical | Study | [
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Thus, we failed to detect any significant excess of intact genes that diverged faster in expression than pseudogenes. This indicates that the fraction of gene expression differences between the species that are fixed by positive selection is small. Interestingly, there was also no detectable excess of intact genes that... | 15138501_p12 | 15138501 | A Test for Neutrality | 4.095333 | biomedical | Study | [
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The fact that the overall accumulation of expression differences conforms to a selectively neutral model does not mean, of course, that all expression differences between species are selectively neutral. As for nucleotide changes, some changes in gene expression will have had phenotypic consequences and some of these w... | 15138501_p13 | 15138501 | A Test for Positive Selection | 4.325393 | biomedical | Study | [
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Since we are unable to tease apart genetic and environmental contributions to expression diversity, we instead used pseudogenes to estimate the distribution of divergence to diversity ratios observed in the absence of selection and compared these ratios to intact genes. No significant difference was found (Kolmogorov-S... | 15138501_p14 | 15138501 | A Test for Positive Selection | 4.10301 | biomedical | Study | [
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Different anatomical brain structures appeared at different times during vertebrate evolution. These time points can be viewed as divergence times between brain regions extending millions of years back in the past . If gene expression changes between different brain regions have a large random component, gene expressio... | 15138501_p15 | 15138501 | Transcriptome Evolution among Brain Regions | 4.226161 | biomedical | Study | [
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If gene expression differences between the brain regions were largely adaptive, one would expect them to correlate with tissue function and not with evolutionary divergence time. Our data show that tissues that diverged recently have very similar gene expression profiles irrespective of the differences in function. For... | 15138501_p16 | 15138501 | Transcriptome Evolution among Brain Regions | 4.182488 | biomedical | Study | [
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A noteworthy finding is that the accumulation of expression differences between brain regions within a species is much slower than the accumulation of expression differences within a brain region between species. In fact, the expression differences that have accumulated among the primate species over 20 million years a... | 15138501_p17 | 15138501 | Transcriptome Evolution among Brain Regions | 4.245424 | biomedical | Study | [
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A possible alternative explanation for the correlation between differences in gene expression and evolutionary divergence time among brain regions could be that differences in gene expression do not correlate with evolutionary divergence time, but instead with divergence time during fetal development. Our observations ... | 15138501_p18 | 15138501 | Transcriptome Evolution among Brain Regions | 4.200582 | biomedical | Study | [
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We show that a neutral model of evolution can predict the main features of transcriptome evolution in the brains of primates and mice. A neutral model is also in agreement with published observations in Drosophila and fish . Although selective scenarios that explain some or even most of these observations can be found,... | 15138501_p19 | 15138501 | Conclusions | 4.247097 | biomedical | Study | [
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Finally, the finding that gene expression differences can be used as a molecular clock to date tissue divergences opens the prospect of reconstructing the evolutionary history of organs and tissues based on gene expression measurements in a single species. | 15138501_p20 | 15138501 | Conclusions | 3.890893 | biomedical | Study | [
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For the primate samples, approximately 200 mg of gray matter was collected from post mortem brain samples from prefrontal cortex region corresponding to Brodmann's area 9 in the left hemisphere from six male humans who were 45, 45, 63, 65, 70, and 70 years old; five male chimpanzees that were 7, 12, 12, 12, and approxi... | 15138501_p21 | 15138501 | Tissue samples and microarray data collection | 4.145786 | biomedical | Study | [
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For Affymetrix microarrays, labeling of 5 μg of the RNA, hybridization, staining, washing steps, and array scanning were carried out following Affymetrix protocols. Expression data were collected using Affymetrix HG U95Av2 arrays for the primate samples and Affymetrix MG U74Av2 arrays for the mice samples. The Affymetr... | 15138501_p22 | 15138501 | Tissue samples and microarray data collection | 3.998848 | biomedical | Study | [
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Arrays containing 51,000 cDNAs corresponding to approximately 40,000 UniGene clusters were manufactured in the laboratory of W.A. as described elsewhere . Labeling, hybridization, staining, washing, and array scanning were carried out as described by Cortes-Canteli et al. with slight modifications. All samples were hyb... | 15138501_p23 | 15138501 | Tissue samples and microarray data collection | 4.0308 | biomedical | Study | [
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In order to exclude all oligonucleotide probes that did not match perfectly between humans and chimpanzees, we aligned all Affymetrix target sequences ( http://www.affymetrix.com/analysis/index.affx ) first to the human genome (build 33) and then to a draft version of the chimpanzee genome . Using BLAT , we matched chi... | 15138501_p24 | 15138501 | Masking of sequence differences between humans and chimpanzees | 4.138158 | biomedical | Study | [
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Affymetrix microarray image data were analyzed with Affymetrix Microarray Suite v5.0 using default parameters. Arrays were scaled to the same average intensity using all probes on the array. Detected genes were defined as those with a detection p -value less than or equal to 0.05. For calculation of the expression valu... | 15138501_p25 | 15138501 | Microarray data analysis | 4.208042 | biomedical | Study | [
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We measured the divergence between human and chimpanzee by looking at the squared difference between the mean expression values in humans and chimpanzees. This estimate of divergence includes the errors in our estimates of the two means, which is proportional to the variance in each of the species, and thus to the dive... | 15138501_p26 | 15138501 | Correlation significance test | 4.253573 | biomedical | Study | [
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We retrieved sequences of all pseudogenes as determined by Torrents et al. , Zhang et al. , and the VEGA project ( http://vega.sanger.ac.uk ). These sequences, as well as the Affymetrix target sequences, were mapped to the human genome (build 34) using BLAT , and the best hit was determined using the following paramete... | 15138501_p27 | 15138501 | Expressed pseudogenes | 4.211842 | biomedical | Study | [
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Biochemical studies performed in higher eukaryotes have shown that DNA replication initiates at specific sites, or within initiation zones, suggesting the involvement of particular DNA sequences called replicators . In contrast, functional studies, as well as studies of DNA replication performed in early embryos of var... | 15208711_p0 | 15208711 | Introduction | 4.18052 | biomedical | Study | [
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The presence of specific initiation sites and of initiation zones has also been proposed to explain the latent replication of the Epstein-Barr virus (EBV) genome in human cell lines. During latent replication, the EBV genome is maintained as a circular episome (∼175 kb in size), and the host cell provides both the repl... | 15208711_p1 | 15208711 | Introduction | 4.681689 | biomedical | Study | [
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We recently began to study the replication of individual EBV episomes using fluorescence microscopy . In a previous study, we collected various images of the Raji EBV genome . The analysis of those molecules demonstrated that the duplication of different EBV episomes begins at different initiation sites located within ... | 15208711_p2 | 15208711 | Introduction | 4.061748 | biomedical | Study | [
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In the present study, we performed an extensive analysis of the replication dynamics of the EBV genome in two human Burkitt's lymphoma cell lines (Raji and Mutu I). By utilizing a different procedure to stretch DNA molecules we were able to collect a large number of images of the EBV genome representative of different ... | 15208711_p3 | 15208711 | Introduction | 4.139605 | biomedical | Study | [
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These improvements allowed us to obtain important new results as well as to extend previous observations. Here we show that initiation events are not limited to a specific portion of the EBV genome (namely the initiation zone detected by 2D gel electrophoresis), but, unexpectedly, take place throughout the EBV genome. ... | 15208711_p4 | 15208711 | Introduction | 4.096342 | biomedical | Study | [
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Our new results also indicate that, in these two EBV strains, both the frequency and the order of activation of the initiation sites vary considerably throughout the viral genome. This variation involves initiation sites such as oriP, the sequence of which is highly conserved in the two EBV strains . Hence, the utiliza... | 15208711_p5 | 15208711 | Introduction | 4.21562 | biomedical | Study | [
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In order to study DNA replication, we used a procedure that we call single molecule analysis of replicated DNA (SMARD). This procedure labels the replicating DNA in a way that allows us to determine the position, the direction, and the density of the replication forks in a steady-state population of replicating molecul... | 15208711_p6 | 15208711 | Fluorescent Hybridization Immunostaining of Individual EBV Episomes Stretched on Microscope Slides | 4.1419 | biomedical | Study | [
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In our procedure, an asynchronous population of cells is sequentially labeled with 5′-iodo-2′-deoxyuridine (IdU) and 5′-chloro-2′-deoxyuridine (CldU) . The length of each labeling period is longer than the time required to completely replicate the EBV genome (3.5–4 h; see Materials and Methods ). This allows some of th... | 15208711_p7 | 15208711 | Fluorescent Hybridization Immunostaining of Individual EBV Episomes Stretched on Microscope Slides | 4.166544 | biomedical | Study | [
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In the experiments described in this study, agarose-embedded total DNA was prepared from cells labeled with halogenated nucleotides. The circular EBV episomes were converted to linear molecules by digestion with a restriction endonuclease (PacI or SwaI). After pulsed field gel electrophoresis, the EBV DNA was recovered... | 15208711_p8 | 15208711 | Fluorescent Hybridization Immunostaining of Individual EBV Episomes Stretched on Microscope Slides | 4.122641 | biomedical | Study | [
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In order to define precisely how the Raji EBV genome replicates, we recovered the images of 245 PacI-linearized EBV episomes that incorporated halogenated nucleotides along their entire length (112 fully stained in red, 84 fully stained in green, and 49 stained in both red and green). The results of this experiment are... | 15208711_p9 | 15208711 | The Raji EBV Genome Contains a Region That Usually Replicates First and a Region That Usually Replicates Last | 4.134166 | biomedical | Study | [
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However, the progression of DNA replication throughout the EBV genome is better described by the replication profile of the molecules analyzed . This profile was obtained by dividing the map of the episomes into intervals of 5 kb (horizontal axis) and then indicating the percentage of molecules stained in red within ea... | 15208711_p10 | 15208711 | The Raji EBV Genome Contains a Region That Usually Replicates First and a Region That Usually Replicates Last | 4.12683 | biomedical | Study | [
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The RRF contains the initiation sites most frequently utilized to begin the duplication of the Raji EBV episomes. More than 80% of the molecules analyzed were stained in red throughout intervals 1–7 and 31–35 . In the molecules representing early stages of episomal duplication , initiation events took place either with... | 15208711_p11 | 15208711 | The Raji EBV Genome Contains a Region That Usually Replicates First and a Region That Usually Replicates Last | 4.258297 | biomedical | Study | [
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The RRL appears in the replication profile of the Raji EBV episomes as a large valley . The bottom of the valley spans about 40 kb (intervals 11–18), and its flat appearance indicates that throughout this region the episomes terminate their duplication with similar probability. Note, however, that termination events ca... | 15208711_p12 | 15208711 | The Raji EBV Genome Contains a Region That Usually Replicates First and a Region That Usually Replicates Last | 4.231851 | biomedical | Study | [
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The presence of RRF and RRL was confirmed by a second SMARD experiment in which we digested the EBV episomes with SwaI. This enzyme cleaves twice in the viral genome, producing fragments of 105 and 70 kb. The larger fragment was expected to contain most of the RRF (now located near the center of DNA molecules), and a s... | 15208711_p13 | 15208711 | The Raji EBV Genome Contains a Region That Usually Replicates First and a Region That Usually Replicates Last | 4.174006 | biomedical | Study | [
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The movement of the replication forks throughout the EBV genome is described by the profiles of replication fork abundance . These profiles were obtained by dividing the map of the EBV genome into intervals of 5 kb (horizontal axis) and then indicating the percentage of molecules containing red-to-green transitions wit... | 15208711_p14 | 15208711 | Replication Forks Move Without Significant Pausing throughout the Raji EBV Genome with the Exception of the Genomic Region near oriP | 4.246817 | biomedical | Study | [
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From the profiles of replication fork abundance we can also determine the prevalent direction of the replication forks throughout specific portions of the EBV genome. For example, throughout most of the RRL, replication forks move in both directions at similar frequencies . The bidirectional movement of the replication... | 15208711_p15 | 15208711 | Replication Forks Move Without Significant Pausing throughout the Raji EBV Genome with the Exception of the Genomic Region near oriP | 4.139754 | biomedical | Study | [
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Within the rest of the EBV genome, however, the movement of the replication forks is mostly unidirectional . For example, replication forks move mainly rightward from interval 11 throughout oriP and beyond . This direction bias is compatible with a previous 2D gel analysis of the oriP region in Raji cells and is not af... | 15208711_p16 | 15208711 | Replication Forks Move Without Significant Pausing throughout the Raji EBV Genome with the Exception of the Genomic Region near oriP | 4.256543 | biomedical | Study | [
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Early studies performed by electron microscopy identified Raji EBV episomes with multiple replication bubbles but could not identify the position of these initiation events . In order to detect the presence of these events and to determine their location we analyzed the immunostaining patterns of the DNA molecules desc... | 15208711_p17 | 15208711 | Active Initiation Sites Are Not Limited to the RRF | 4.450789 | biomedical | Study | [
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In the previous sections we showed that different portions of the EBV genome are not equivalent with respect to when and where DNA replication begins and how DNA replication progresses. Here we wanted to determine the quantitative aspects of DNA replication in different portions of the EBV genome. The data obtained by ... | 15208711_p18 | 15208711 | DNA Replication Proceeds at Different Speeds throughout Different Portions of the Raji EBV Genome | 4.136368 | biomedical | Study | [
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We calculated the value of Sd for each portion of the Raji EBV genome, depicted with double-headed arrows in Figure 5 (segments A–K; Td is reported in Table 1 ). The results obtained from the PacI and the SwaI experiments were analyzed independently but show remarkable similarities . Therefore, the quantitative analysi... | 15208711_p19 | 15208711 | DNA Replication Proceeds at Different Speeds throughout Different Portions of the Raji EBV Genome | 3.821609 | biomedical | Study | [
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We found that different portions of the EBV genome replicate at different speeds, with values that range from a minimum of 0.3 kb/min to a maximum of 3.5–4.7 kb/min (segment I ). More details are provided later in the text. However, it is important to note that the highest Sd values were detected within the central por... | 15208711_p20 | 15208711 | DNA Replication Proceeds at Different Speeds throughout Different Portions of the Raji EBV Genome | 4.089117 | biomedical | Study | [
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0.00021320537780411541,
0.00005165399852558039
] | en | 0.999998 |
Three lines of evidence indicate that multiple initiation events take place within the Raji RRF. Two lines of evidence are discussed in this section (the presence of multiple red patches in the immunostaining patterns of some EBV episomes and the detection of termination events by 2D gel analysis); the third is discuss... | 15208711_p21 | 15208711 | Multiple Initiation Events Can Take Place on the Same Raji EBV Episome within the RRF | 3.843614 | biomedical | Study | [
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] | [
0.9890778660774231,
0.0075904252007603645,
0.003142311703413725,
0.00018934674153570086
] | en | 0.999999 |
The first line of evidence is provided by the immunostaining pattern of the EBV molecules. Although discontinuities in the immunostaining make it difficult to detect multiple initiation events when the distance between converging forks is 5 kb or less, the replication patterns of some of the molecules are compatible wi... | 15208711_p22 | 15208711 | Multiple Initiation Events Can Take Place on the Same Raji EBV Episome within the RRF | 4.369236 | biomedical | Study | [
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] | [
0.9991496801376343,
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0.0003729081654455513,
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] | en | 0.999996 |
A second line of evidence is provided by the structure of the replication intermediates examined by 2D gel electrophoresis in exponentially growing Raji cells ( see Materials and Methods ). We analyzed nine restriction fragments, indicated in Figure 3 A as gray bars (a–i). We also reexamined the hybridization patterns ... | 15208711_p23 | 15208711 | Multiple Initiation Events Can Take Place on the Same Raji EBV Episome within the RRF | 4.292602 | biomedical | Study | [
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0.00008370095019927248
] | en | 0.999999 |
Previous observations have suggested that some initiation sites (such as oriP) are used at a different frequency in different EBV strains . However, it was not known whether these changes were the result of modifications in the activity of individual initiation sites or involved multiple initiation sites throughout the... | 15208711_p24 | 15208711 | In Mutu I Cells, the Order of Activation of the Initiation Sites Varies Throughout the Viral Genome | 4.060429 | biomedical | Study | [
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0.0002116139221470803,
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] | en | 0.999996 |
The most striking differences in the replication of the two EBV strains were found in the order of activation of the initiation sites. In Raji episomes, primary initiation events are restricted to an 80-kb region approximately corresponding to the RRF . In contrast, in Mutu I episomes primary initiation events occur at... | 15208711_p25 | 15208711 | In Mutu I Cells, the Order of Activation of the Initiation Sites Varies Throughout the Viral Genome | 4.393945 | biomedical | Study | [
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] | en | 0.999997 |
Modifications in the activity of individual initiation sites (such as oriP) could potentially explain the different location of the RRF in Raji and Mutu I episomes. However, the following considerations indicate that this is not the case. Initiation events occurring at oriP take place in the vicinity of the dyad symmet... | 15208711_p26 | 15208711 | The RRFs Are Produced by Clusters of Initiation Sites Frequently Activated at the Beginning of the Duplication of the Episomes | 4.488549 | biomedical | Study | [
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] | [
0.9984851479530334,
0.0008581013535149395,
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0.00014541455311700702
] | en | 0.999998 |
Similar conclusions apply to the RRF of the Raji EBV genome (∼80 kb in size), in which primary initiation events were detected at various locations . This could explain why only weak bubble arcs were detected by 2D gel electrophoresis throughout the RRF, even though the duplication of the episomes usually begins within... | 15208711_p27 | 15208711 | The RRFs Are Produced by Clusters of Initiation Sites Frequently Activated at the Beginning of the Duplication of the Episomes | 4.279161 | biomedical | Study | [
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] | [
0.9989103078842163,
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0.00043046934297308326,
0.00008752290887059644
] | en | 0.999997 |
In the previous sections we have shown that the order of activation of the initiation sites in Raji and Mutu I EBV episomes is not conserved. Here, we wanted to determine whether the quantitative aspects of DNA replication were also different. SMARD was used to calculate Sd for each portion of the Mutu I EBV genome, de... | 15208711_p28 | 15208711 | The Duplication Speed of Various Portions of the EBV Genome Is Different in Raji and Mutu I EBV Episomes | 4.1578 | biomedical | Study | [
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] | [
0.9994563460350037,
0.0001996109203901142,
0.00027964546461589634,
0.00006437687261495739
] | en | 0.999998 |
We also noticed that similar portions of the EBV genome have different Sd values in the two viral strains. Segments A′–G′ divide the Mutu I EBV genome in seven parts of identical size . These segments encompass portions of the EBV genome similar to segments A–G in the Raji genome . However, the values of Sd differ sign... | 15208711_p29 | 15208711 | The Duplication Speed of Various Portions of the EBV Genome Is Different in Raji and Mutu I EBV Episomes | 4.259351 | biomedical | Study | [
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] | [
0.9993545413017273,
0.00025652023032307625,
0.0003139288164675236,
0.00007498265040339902
] | en | 0.999996 |
Previous observations have suggested that in mammalian cells the speed of the replication forks can vary . Here, we wanted to determine if some of the differences detected in the replication of Raji and Mutu I episomes could be ascribed to modifications in the rate of progression of the replication forks as proposed fo... | 15208711_p30 | 15208711 | Replication Forks Progress at Similar Rates Across Different Portions of the EBV Genome and in Different EBV Strains | 4.095655 | biomedical | Study | [
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] | [
0.999479353427887,
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] | en | 0.999998 |
In Raji episomes, we found that the average speed of the replication forks was about 1.0 kb/min throughout both segment H and segment J ; these segments are replicated by forks moving predominantly in one direction . Interestingly, a similar value (1.1 kb/min) was found for two different portions of the Mutu I EBV geno... | 15208711_p31 | 15208711 | Replication Forks Progress at Similar Rates Across Different Portions of the EBV Genome and in Different EBV Strains | 4.182025 | biomedical | Study | [
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] | [
0.9993104934692383,
0.0003729649761226028,
0.00024941947776824236,
0.00006712406320730224
] | en | 0.999999 |
Studies performed in different systems have suggested that transcription could interfere with the progression of the replication forks . In the Raji EBV genome, segments J and H are located within the long transcription unit of the EBNA genes . Throughout segment J, replication forks progress in the same direction of t... | 15208711_p32 | 15208711 | Replication Forks Progress at Similar Rates Across Different Portions of the EBV Genome and in Different EBV Strains | 4.220762 | biomedical | Study | [
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] | [
0.9991783499717712,
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] | en | 0.999999 |
Variation in the utilization of the initiation sites and similarity in the speed of the replication forks suggest that the former should have a stronger influence on the duplication speed of a genomic segment. If we assume that the speed of the replication forks is constant throughout the EBV genome (except for the reg... | 15208711_p33 | 15208711 | The Duplication Speed of a Genomic Segment Reflects the Average Number of Replication Forks Involved in Its Replication | 4.540548 | biomedical | Study | [
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0.9985764026641846,
0.00046504789497703314,
0.0007558928919024765,
0.00020261640020180494
] | en | 0.999996 |
In this study, we determined how DNA replication initiates and progresses in EBV episomes latently replicating in two human Burkitt's lymphoma cell lines (Raji and Mutu I). Previous experiments had suggested that some variability in the utilization of oriP might exist among different EBV strains . Here, however, we fou... | 15208711_p34 | 15208711 | Conserved and Nonconserved Features in the Latent Replication of Different EBV Strains | 4.306999 | biomedical | Study | [
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] | [
0.9991400241851807,
0.00020337250316515565,
0.0005488715250976384,
0.00010776955605251715
] | en | 0.999999 |
The EBV episomes replicating in these two cell lines have a similar size and genomic organization. However, the number of internal repeats 1 (also called Bam HI W) is reduced by one unit in the Mutu I strain (not shown), while the Raji EBV genome contains two short deletions . In principle, these differences could affe... | 15208711_p35 | 15208711 | Conserved and Nonconserved Features in the Latent Replication of Different EBV Strains | 4.417957 | biomedical | Study | [
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] | [
0.9988963603973389,
0.0003666313423309475,
0.0006223262753337622,
0.00011465133866295218
] | en | 0.999998 |
This study also revealed modifications in the pausing of the replication forks in the oriP region. Accumulation of replication forks is clearly present in both EBV strains within this genomic region. However, only 25% of replicating Mutu I episomes contain replication forks at this location , compared with 43% of Raji ... | 15208711_p36 | 15208711 | Conserved and Nonconserved Features in the Latent Replication of Different EBV Strains | 4.186725 | biomedical | Study | [
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] | [
0.9993652701377869,
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0.00007925460522528738
] | en | 0.999998 |
We also found that some features of the episomal duplication do not vary. In both Raji and Mutu I cells, replication forks move freely throughout the EBV genome , and their progression rate appears to be constant. This indicates that modifications in the speed of the replication forks do not contribute significantly to... | 15208711_p37 | 15208711 | Conserved and Nonconserved Features in the Latent Replication of Different EBV Strains | 4.160759 | biomedical | Study | [
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] | [
0.9993903636932373,
0.00020281251636333764,
0.000341813632985577,
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] | en | 0.999998 |
Another common feature between Raji and Mutu I cells is the presence of a genomic region that usually replicates first during the duplication of each episome. The position of this RRF differs in the two EBV strains. However, the direction of movement of the replication forks throughout the RRFs is similar. For example,... | 15208711_p38 | 15208711 | Conserved and Nonconserved Features in the Latent Replication of Different EBV Strains | 4.260644 | biomedical | Study | [
0.9994792342185974,
0.0002637277648318559,
0.0002570903452578932
] | [
0.9990739822387695,
0.0004941380466334522,
0.00035893896711058915,
0.00007283405284397304
] | en | 0.999997 |
Even if the EBV episomes utilize the same replication machinery (provided by the host cell), several aspects of their duplication are not conserved between Raji and Mutu I. In mammalian cells, prereplication complexes are believed to form at the end of mitosis, when general transcription is shut off . However, the sele... | 15208711_p39 | 15208711 | Utilization of Initiation Sites is Regulated at the Level of Genomic Regions Rather Than at the Level of Individual Initiation Sites | 4.214394 | biomedical | Study | [
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] | [
0.9993228912353516,
0.00026719580637291074,
0.000339202000759542,
0.00007080943032633513
] | en | 0.999996 |
One of the questions we tried to answer is whether initiation of DNA replication is regulated at the level of individual initiation sites. Clues to a possible regulatory mechanism can be found in the replication profiles of the EBV episomes. The RRFs are localized in specific portions of the EBV genome that differ in t... | 15208711_p40 | 15208711 | Utilization of Initiation Sites is Regulated at the Level of Genomic Regions Rather Than at the Level of Individual Initiation Sites | 4.226023 | biomedical | Study | [
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] | [
0.9992493987083435,
0.0003345009172335267,
0.00035196729004383087,
0.00006406671309377998
] | en | 0.999997 |
Recent findings have shown that histone acetylation can influence the timing of replication origin firing in yeast . In this study we found that even if initiation events were detected at many locations within the MutuI episomes, primary initiation events occurred predominantly within the RRFs. Modifications in chromat... | 15208711_p41 | 15208711 | Utilization of Initiation Sites is Regulated at the Level of Genomic Regions Rather Than at the Level of Individual Initiation Sites | 4.164083 | biomedical | Study | [
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] | [
0.999384880065918,
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0.0002626106725074351,
0.00006696606578771025
] | en | 0.999995 |
In addition to changes in the order of activation of the initiation sites, other mechanisms could influence their utilization by affecting their frequency of activation. We noticed that in Raji episomes the frequency of initiation events across the RRL appears to be reduced compared to that of the RRF. This difference ... | 15208711_p42 | 15208711 | Utilization of Initiation Sites is Regulated at the Level of Genomic Regions Rather Than at the Level of Individual Initiation Sites | 4.519415 | biomedical | Study | [
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] | [
0.9986901879310608,
0.0003988878452219069,
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0.00016298123227898031
] | en | 0.999998 |
In this study, we have shown that initiation events are not confined to a specific portion of the episomes, suggesting that DNA sequences capable of functioning as initiation sites must be rather common. This can explain why, under various experimental conditions, individual initiation sites do not appear to play an es... | 15208711_p43 | 15208711 | Initiation Sites Are Redundant Elements of the EBV Genome | 4.183215 | biomedical | Study | [
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] | [
0.99937504529953,
0.00023921526735648513,
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0.00007717328844591975
] | en | 0.999998 |
Large deletions are also well tolerated , even when they encompass portions of the EBV genome known to contain multiple initiation sites (such as the Raji RRF). One of the deleted EBV genomes shown in Figure 7 was recently analyzed to detect binding sites for ORC and MCM proteins. Significant binding of these proteins ... | 15208711_p44 | 15208711 | Initiation Sites Are Redundant Elements of the EBV Genome | 4.41186 | biomedical | Study | [
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] | [
0.999052107334137,
0.00038927971036173403,
0.0004489587736316025,
0.00010962576925521716
] | en | 0.999999 |
Initiation site oriP is the best characterized initiation site of the EBV genome. Initiation of DNA replication has been detected at this site in every EBV strain analyzed to date by 2D gel electrophoresis. However, the frequency of the initiation events at oriP varies in different EBV strains, and it is particularly l... | 15208711_p45 | 15208711 | Role of oriP in the Replication of EBV Episomes | 4.365325 | biomedical | Study | [
0.999519944190979,
0.0002604879264254123,
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] | [
0.998678982257843,
0.0004710270732175559,
0.0007537456694990396,
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] | en | 0.999998 |
In our current study we show that primary initiation events are frequently detected by SMARD near oriP in Mutu I but not in Raji episomes. This could be explained, in part, by the decreased frequency of utilization of this site in the Raji strains. However, this is unlikely to be the only reason. Even infrequent primar... | 15208711_p46 | 15208711 | Role of oriP in the Replication of EBV Episomes | 4.361882 | biomedical | Study | [
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] | [
0.9992524981498718,
0.0002957235847134143,
0.0003500382590573281,
0.00010163599654333666
] | en | 0.999997 |
Various groups have suggested that different cellular proteins could participate in regulating the activity of oriP . However, it is currently not clear why, in Raji episomes, oriP is not among the preferred initiation sites. Interestingly, it has been reported that oriP is more extensively methylated in Raji than in o... | 15208711_p47 | 15208711 | Role of oriP in the Replication of EBV Episomes | 4.255044 | biomedical | Study | [
0.9995354413986206,
0.00023756817972753197,
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] | [
0.9980315566062927,
0.0004215511726215482,
0.0014638772699981928,
0.00008307661482831463
] | en | 0.999999 |
In this study we have shown that, while the basic features of DNA replication are conserved (i.e., the progression of the replication forks), the activity of the initiation sites (order and frequency of activation) varies significantly in different EBV strains and across different portions of the EBV genome. Importantl... | 15208711_p48 | 15208711 | Conclusions—Flexible Utilization of Initiation Sites in Higher Eukaryotes | 4.355237 | biomedical | Study | [
0.9994169473648071,
0.00038112697075121105,
0.0002019316452788189
] | [
0.9986547231674194,
0.0003215069300495088,
0.0009113333653658628,
0.0001124524642364122
] | en | 0.999998 |
Raji cells were grown in exponential phase , keeping the cell density between 3 × 10 5 and 8 × 10 5 cells/ml. The experiments presented in this manuscript were performed at approximately 5 × 10 5 Raji cells/ml, using two labeling periods (240 min each) with 25 μM IdU (first label) and 25 μM CldU (second label). IdU was... | 15208711_p49 | 15208711 | Cell cultures, EBV strains, and double-labeling of replicating DNA | 4.085213 | biomedical | Study | [
0.9995619654655457,
0.0002256150619359687,
0.00021245692914817482
] | [
0.9983966946601868,
0.0012417292455211282,
0.0002890364557970315,
0.0000724713972886093
] | en | 0.999994 |
Early passages of the Mutu I cells were provided by Alan B. Rickinson and grown for only seven additional passages (keeping the cell density between 4 × 10 5 and 8 × 10 5 cells/ml) before the replicating DNA was labeled. The conditions used for growth and labeling were the same as those used for Raji cells, with the ex... | 15208711_p50 | 15208711 | Cell cultures, EBV strains, and double-labeling of replicating DNA | 4.143893 | biomedical | Study | [
0.9994799494743347,
0.00023855095787439495,
0.00028159661451354623
] | [
0.9988898634910583,
0.0007830847753211856,
0.0002509618934709579,
0.00007610908505739644
] | en | 0.999997 |
Only ten EBV genes (out of about 100) can be expressed during latency . In EBV-associated diseases, where the viral genome is maintained as a circular episome, the phenotype of the infected cell influences the viral patterns of expression . Three different latent transcription patterns have been described : type I (onl... | 15208711_p51 | 15208711 | Cell cultures, EBV strains, and double-labeling of replicating DNA | 4.26985 | biomedical | Study | [
0.9995526671409607,
0.0001957994099939242,
0.00025150328292511404
] | [
0.9990724325180054,
0.00040533492574468255,
0.00046066194772720337,
0.00006151866546133533
] | en | 0.999996 |
In order to collect a sufficient number of images of the EBV genome, the population of replicated episomes needed to be enriched by a partial purification using pulsed field gel electrophoresis. However, starting from the limited amount of DNA that can be purified from a pulsed field gel, we could not stretch a suffici... | 15208711_p52 | 15208711 | Improved method to stretch a large number of EBV molecules on individual slides | 4.19122 | biomedical | Study | [
0.9995181560516357,
0.0002581393637228757,
0.0002237235603388399
] | [
0.9993126392364502,
0.00035803928039968014,
0.00026235266705043614,
0.00006704129191348329
] | en | 0.999998 |
Hybridization was performed as previously described using probes prepared by nick translation in the presence of biotin-16-dUTP (Roche, Basel, Switzerland). The probes used in this study, pSalF, p107.5, and pWW (provided by John L. Yates), were detected using a modification of the DIRVISH procedure . Briefly, five laye... | 15208711_p53 | 15208711 | Hybridization, probe detection, and immunostaining of the individual DNA molecules stretched on microscope slides | 4.139997 | biomedical | Study | [
0.9995792508125305,
0.0002144201862392947,
0.00020633747044485062
] | [
0.9992944002151489,
0.00039870120235718787,
0.0002431892353342846,
0.00006368605681927875
] | en | 0.999996 |
Immunostaining to detect IdU and CldU was performed simultaneously with the detection of the biotinylated DNA probes. Mouse anti-IdU (Becton-Dickinson, Palo Alto, California, United States) and rat anti-CldU (Accurate Chemical, Westbury, New York, United States) were used as primary antibodies (monoclonal), while Alexa... | 15208711_p54 | 15208711 | Hybridization, probe detection, and immunostaining of the individual DNA molecules stretched on microscope slides | 4.151271 | biomedical | Study | [
0.9995286464691162,
0.00026031810557469726,
0.00021102986647747457
] | [
0.9993206262588501,
0.0003300317330285907,
0.0002866531431209296,
0.00006277674401644617
] | en | 0.999996 |
Studies performed by fiber autoradiography have previously shown that the results obtained using DNA fibers (such as the average size of the replicons) are significantly affected by the length of the labeling period utilized to label the replicating DNA . In these studies bias could also be introduced during the collec... | 15208711_p55 | 15208711 | Advantages in the labeling scheme utilized for SMARD and internal controls | 4.105308 | biomedical | Study | [
0.9996092915534973,
0.00015138222079258412,
0.00023936420620884746
] | [
0.9910171031951904,
0.0011206648778170347,
0.007767651695758104,
0.00009460138971917331
] | en | 0.999998 |
These problems are completely eliminated by the labeling scheme that characterizes SMARD . For our experiments we utilized exponentially growing cells and labeling periods that are longer than the time required to fully replicate the genomic region of interest. In practice, since the replication of a specific genomic r... | 15208711_p56 | 15208711 | Advantages in the labeling scheme utilized for SMARD and internal controls | 4.108617 | biomedical | Study | [
0.999530553817749,
0.00021848476899322122,
0.0002508999896235764
] | [
0.9989379048347473,
0.0006857814732939005,
0.00031592900631949306,
0.00006034943362465128
] | en | 0.999996 |
Using long labeling periods, and limiting our analysis to the molecules entirely substituted with the halogenated nucleotides, also provides multiple internal controls. These controls cannot be performed when short labeling periods are used. Since the molecules are immunostained throughout their length, their images ca... | 15208711_p57 | 15208711 | Advantages in the labeling scheme utilized for SMARD and internal controls | 4.27791 | biomedical | Study | [
0.9994475245475769,
0.0003422444860916585,
0.00021021875727456063
] | [
0.9985697269439697,
0.0005833758041262627,
0.0007617164519615471,
0.0000851894510560669
] | en | 0.999998 |
The procedures for the enrichment of replication intermediates, 2D gel electrophoresis, and Southern analysis were essentially as described previously . Preparations of replication intermediates from Raji cells were digested with different restriction enzymes depending on the fragment analyzed: EcoRI/DraI for fragments... | 15208711_p58 | 15208711 | Analysis of the replication intermediates by 2D gel electrophoresis at neutral pH | 4.124649 | biomedical | Study | [
0.9995237588882446,
0.00023560297267977148,
0.00024069011851679534
] | [
0.998988926410675,
0.000540647772140801,
0.0004101474187336862,
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Genetic variation in pathogen virulence (harm to the host) has been found whenever it has been looked for. A considerable body of theory, based on the transmission consequences of virulence, has been developed to predict how natural selection will act on this genetic variation and how it will shape virulence levels in ... | 15221031_p0 | 15221031 | Introduction | 4.234485 | biomedical | Study | [
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As well as altering between-host selection pressures on virulence, host immunity can alter the nature of inhost selection. Different directions of virulence evolution are expected depending on the details of inhost competition among parasites . Unfortunately, these details are not well understood for any pathogen . The... | 15221031_p1 | 15221031 | Introduction | 4.372326 | biomedical | Study | [
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One barrier to testing theoretical models of virulence evolution is that the models typically predict the outcome at evolutionary and epidemiological equilibrium. New equi-libria may or may not take a long time to reach, but will in any case depend on the dynamics of the host population and the environmental conditions... | 15221031_p2 | 15221031 | Introduction | 3.983006 | biomedical | Study | [
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In this study, we begin the empirical effort to determine the likely direction of immune-mediated virulence evolution by performing experimental evolution of the rodent malaria parasite, Plasmodium chabaudi , in laboratory mice. We evolved multiple lines of P. chabaudi in immunized and naïve mice by repeated serial pas... | 15221031_p3 | 15221031 | Introduction | 4.111251 | biomedical | Study | [
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We found that both the I-lines and N-lines evolved to become more virulent than their ancestral populations, but the I-lines became even more virulent than the N-lines . This higher virulence was manifest in both naïve and immunized mice. When the lines were transmitted through mosquitoes, there was generally a reducti... | 15221031_p4 | 15221031 | Results/Discussion | 3.983609 | biomedical | Study | [
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The results suggest that immune selection on blood-stage parasites is more efficient at selecting virulent variants than is selection in naïve mice. Response to selection is a function of the amount of variation in the population and the proportion of the population that survives to produce offspring, i.e., the selecti... | 15221031_p5 | 15221031 | Immunity Selects for Higher Virulence | 4.193689 | biomedical | Study | [
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But why would selection favor more virulent parasites? Our previous studies have consistently shown that peak parasite densities in the acute phase are positively correlated to the level of virulence that they generate . We therefore expected to find that the higher virulence in I-lines was accompanied by higher parasi... | 15221031_p6 | 15221031 | Immunity Selects for Higher Virulence | 4.273593 | biomedical | Study | [
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There were positive relationships between virulence and lifetime transmission potential across all the lines , consistent with our previous studies , but the differences between the I-lines and N-lines were not statistically significant ( p > 0.05). Gametocyte densities are a good predictor of transmission probability ... | 15221031_p7 | 15221031 | Immunity Selects for Higher Virulence | 4.105534 | biomedical | Study | [
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Malaria parasites, like many microbes , are remarkable in their ability to rapidly adapt to changes in their host environment, and some of this is known to be due to phenotypic switching mechanisms in virulence-related phenotypes such as binding to host cells , red cell surface antigen expression , and red cell invasio... | 15221031_p8 | 15221031 | The Effects of Mosquito Transmission | 4.24454 | biomedical | Study | [
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We observed a general reduction in virulence across all lines following mosquito transmission , particularly when measured in immunized mice, and particularly in lines that had been selected under immune pressure, i.e., the I-lines, and in the CW-A ancestral line, which had been serially passaged on day 12 postinfectio... | 15221031_p9 | 15221031 | The Effects of Mosquito Transmission | 4.164851 | biomedical | Study | [
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The mechanistic basis for the reduction in virulence following mosquito transmission remains to be determined. We offer the following speculations. It may be that the virulence reductions we and others have observed are due to stochastic loss of virulent variants during the population bottlenecking that occurs during m... | 15221031_p10 | 15221031 | The Effects of Mosquito Transmission | 4.587007 | biomedical | Study | [
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Any of these mechanisms could explain the loss of virulence during mosquito transmission, but none are sufficient to explain why the I-lines were more virulent than the N-lines in naïve mice both before and after mosquito transmission. Thus, more than one distinct underlying mechanism probably explains the virulence di... | 15221031_p11 | 15221031 | The Effects of Mosquito Transmission | 4.153528 | biomedical | Study | [
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To what extent do our observations accord with previous work on serial passage of malaria in immune-modified environments? Results from other studies are difficult to interpret as none maintained control lines for selection (i.e., lines that were passaged in the nonmanipulated immune environment), most had no replicati... | 15221031_p12 | 15221031 | Other Serial Passage Studies in Malaria | 4.360569 | biomedical | Study | [
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However, the second form of immune selection—passage of acute-phase parasites from hosts injected with antiserum at the beginning of the infection—yielded parasites with lower virulence to naïve mice than their ancestors in one study , although it had no impact on virulence in two other studies . The third type of immu... | 15221031_p13 | 15221031 | Other Serial Passage Studies in Malaria | 4.251507 | biomedical | Study | [
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Our data demonstrate that host immunity can increase the potency of inhost selection for higher virulence in malaria. Whether our results generalize to other immunization protocols, parasite clones, parasite species, host genotypes, repeated mosquito passage, and so on requires extensive further experimentation. But, c... | 15221031_p14 | 15221031 | Conclusion | 4.138462 | biomedical | Study | [
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Starting from two separate ancestral lines derived from clone CW (see below), five parasite lines (“sublines”) from each ancestral line were repeatedly passaged in mice (female C57Bl/6J, 7–10 wk old) that were naïve to malaria infection (N-lines), and five from each ancestral line were passaged in immunized mice (I-lin... | 15221031_p15 | 15221031 | Selection phase. | 4.113912 | biomedical | Study | [
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Immunization was by infection with 10 4 parasites of a different clone (denoted ER), followed by drug cure with 10 mg/kg of mefloquine for 4 d starting on day 5 PI. Naïve mice were injected with parasite-free media but were not drug treated. Re-infection took place on average 3 wk after the end of drug treatment (range... | 15221031_p16 | 15221031 | Selection phase. | 4.115658 | biomedical | Study | [
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The serial passage experiments in this study were replicated using two different starting populations (ancestral lines)—one avirulent (CW-0) and one virulent (CW-A). CW-0 had been cloned by serial dilution from an isolate obtained from its natural host, the thicket rat, Thamnomys rutilans, and then blood passaged every... | 15221031_p17 | 15221031 | Selection phase. | 4.091252 | biomedical | Study | [
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All the lines, including the ancestral lines, were transmitted once through Anopheles stephensi mosquitoes by allowing 50–100 mosquitoes aged 2–5 d to take a blood meal for 20–30 min on an anaesthetized gametocytemic mouse that had been inoculated 6–10 d previously, i.e., prior to the peak of infection. Then, 11–12 d l... | 15221031_p18 | 15221031 | Selection phase. | 4.14347 | biomedical | Study | [
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After 18 passages, the pretransmission lines were evaluated in two replicate experimental blocks in naïve (generations 19 and 21) and immunized mice (generations 20 and 22). Ancestral lines were only evaluated in generations 21 and 22. This set of trials was denoted the “pretransmission experiments.” In a separate set ... | 15221031_p19 | 15221031 | Evaluation phase. | 4.123895 | biomedical | Study | [
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Statistical analyses were performed separately for the pretransmission and posttransmission experiments as these were carried out at different times. The virulence measure used for the final analysis was minimum red blood cell density, though other measures of virulence were also analyzed (unpublished data). Since sele... | 15221031_p20 | 15221031 | Analysis. | 4.184043 | biomedical | Study | [
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There is now compelling evidence that a subset of T-cells with regulatory activity suppresses T-cell activation in both mice and humans . Regulatory T-cells (Treg cells) have been shown to inhibit various autoimmune and allergic diseases , mediate transplantation and self-tolerance , and block the activation and prolif... | 15252446_p0 | 15252446 | Introduction | 4.02304 | biomedical | Review | [
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