Since the death of his mother, John lives a wandering life. He runs away from his home and loiters about the streets of Lucknow, where his father, an English.
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From Wikipedia, the free encyclopedia. Wikimedia Commons has media related to People of Madrid. The main article for this category is List of people from Madrid. Subcategories This category has the following 4 subcategories, out of 4 total. Pages in category "People from Madrid" The following pages are in this category, out of approximately total. I Amalia de Isaura. Retrieved from " https: Madrid People by city in the Community of Madrid. Spain joined the European Union, experiencing a renaissance and steady economic growth 3.
Madrid [videos] Madrid Spanish: Celtic castro in Galicia. Toledo , capital of the Visigothic Kingdom. Reccared I and bishops. Council III of Toledo , Codex Vigilanus , fol. Javier Cacho born 19 December is a Spanish writer, scientist, physicist and disseminator. Javier Cacho and prof.
Javier Cacho Gomez 1. The Fallen Angel detail. Francisco Camilo — was a Spanish painter, the son of an Italian immigrant who had settled in Madrid. San Juan Bautista en Orla de Flores private collection. Juan Caramuel y Lobkowitz. Hatching table printed by Lobkowitz in Francisco de Borja y Aragon.
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Urban walking Exclusive essay by David Sedaris. This picture signalled an end to segregation in the US south Why has so little changed? In , Dorothy Counts endured a taunting mob to integrate a North Carolina school. Sixty-one years later, her work is being undone. In afterword to her book What Happened, Clinton accuses Trump of undermining democracy and positioning himself as a tyrant. Monday's best photos A love ceremony and giant land art. Beckham returned to London fashion week to celebrate her 10th anniversary. Denis Thorpe A view from the north.
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Coca-Cola considers cannabis-infused range. A Positive selected sites identified by the site models M2a and M8 vs M1 and M7 respectively, for all E2 gene sequences included in the study. All the sites were denoted in the ribbon structure and highlighted in pink on the protein surface. B — I Positive selected sites identified by the branches-site models A1 vs A for the three subgenotypes of CSFV under the influence of positive selection action. The sites detected under positive selection pressure by the branches-site model were denoted on the ribbon structure and colored on the surface CSFV-subgenotype 1.
Hence, significant site-specific changes altered the selective constraints of CSFV subgenotypes, leading to subgroup-specific functional evolution after diversification of these subgenotypes. In addition, the critical amino acid residues responsible for functional divergence were identified by a combination of suitable cut-off values derived from the Qk and false discovery rate FDR , which provides more statistical evaluations for predicted sites. To analyse the possible role of these amino acid changes among the different clusters, the sites identified were mapped on the E2 protein structure together with the CSFV-tree representations Fig.
Mapping of functional divergence sites on the three dimensional structure of the E2 for the different subgenotypes of CSFV. Functional divergent selected sites were denoted in pink on the protein surface. The subgenotype involved in the funcional divergence type I were represented. The cluster was collapsed for simplification purposes. The sequence IDs belonging to each cluster involved in functional divergence episode were also denoted.
The procrustean superimposition plot of axes one and two, corresponding to patristic distances of species belonging to Pestivirus genus and their mammalian hosts, suggested four groups of host-parasite associations Supplementary Fig.
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The bar plots of squared residuals using patristic distances Fig. The remaining relationships, including the one between CSFV and Sus scrofa , rejected the coevolutionary hypothesis. The reconciliation of the Pestivirus tree with the host tree revealed that a maximum of two cospeciation events might have occurred in their evolution Supplementary Fig. This reconciliation also contained six host switches and seven failures in diverge duplications Supplementary Fig.
The total cost for this reconciliation was Based on both analyses PACo and Jane analyses , the reconciliation among the different Pestivirus and their respective host was reconstructed. To test for consistency between the divergence times of each pestivirus species with those of their hosts, the tMRCA values for a range of ruminant Pestivirus and CSFV were estimated Fig. Virus-host evolutionary association in the Pestivirus genus.
A Contributions of individual host-parasite links to the Procrustean fit: Asterisks identify links significantly supported. The median squared residual value is shown dashed line. B Tanglegram indicating the associations between each pestivirus and its reservoir host. The numbers at the nodes indicate the divergence time for that node, as estimated using the BEAST softaware packge. Red lines represent host-parasite associations observed which were significantly supported by PACo and blue lines the unsupported links. Ovis aries , Bibi: Bison bison , Ranta: Rangifer tarandus , Suss: Sus scrofa , Cahi: Capra hircus , Bost: Bos Taurus , Capc: Capreolus capreolus , Cere: Cervus elaphus , Girc: Giraffa Camelopardalis , Anta: Despite recent progress in the understanding of CSF and its causal agent CSFV, this viral disease remains a major challenge for the scientific community 2.
In our opinion, it is imperative to gain deep insight into three relevant topics: Using state-of-the-art methodologies including phylogenetic inference, homology modelling, phylodynamic and host-virus reconciliation reconstructions, the current study was focused on deciphering the origin, genetic variability and evolutionary process of CSFV. In a first approach, the reliability of the most commonly used phylogenetic markers to perform molecular epidemiology studies of CSFV 4 was evaluated.
Hence, finding a highly reliable phylogenetic marker that is capable of reproducing the same phylogenetic information as the complete genome is an essential task. From the phylogenetic marker assessment, the complete E2 gene was found to be the best phylogenetic marker. This result was supported by different parameters previously described in Alfonso-Morales et al. Previous studies have observed that, with regards to the saturation of substitutions, if a dataset is saturated, phylogenetic reconstruction may be misleading due to the homoplasious signal Of all phylogenetic markers evaluated, only the region proposed by Paton et al.
The power of a dataset is another critical factor to guarantee a reliable phylogenetic design. Phylogenetic noise from the fast-evolving sites can mislead phylogenetic inference. Identification of optimal levels of noise exclusion reduces the number of topologies that are not significantly worse than the optimal tree. This allows for a more robust inference of phylogeny and stronger conclusions about evolutionary character However, the lowest phylogenetic noise was shown by the E2-complete marker, with the same value as the complete CSFV genome.
This strongly supports the use of the E2 complete region as phylogenetic marker. High consistency between specific regions and their whole genome in phylogenetic relationships can be considered as a good signature of a phylogenetic marker However, the best possible phylogenetic estimation can come from using robust inference methods allied with accurate evolutionary models and proper statistical support.
A commonly used method for assessing the robustness of a tree is the non-parametric bootstrapping. Nevertheless, bootstrap values are more suitable for examining small parts of the tree one or two key branches rather than the whole tree Meanwhile, non-parametric bootstrap tests based on likelihood ratio tests LRTs , such as the Shimodaira and Hasegawa test, provide a straightforward means to decide which topologies best fit the data under analysis.
These type of tests consider all possible topologies and make the proper allowances for their comparison with the ML topology derived from the same data In this study, all parameters assessed and both statistical support analyses parametric and non-parametric strongly supported the E2-complete marker as the best phylogenetic marker for CSFV, capable of reproducing the same phylogenetic information as the complete viral genome. In addition, the node of the phylogenetic tree where the subgenotypes 2. This analysis clearly demonstrated that subgenotypes 2.
As proposed in the current study, we established a reliable cut-off for classification of CSFV, based on two methods widely accepted by ICTV and the scientific community with the aim to avoid further misclassifications of this viral agent. The first evidence of a swine illness resembling CSF was described in U. S during the s. However, at that time, the illness was not considered a significant problem.
Losses were generally confined to a single animal at a time, with a first outbreak of the condition attributed to CSF in Ohio in Only 10 outbreaks in 10 different states were reported through correspondents from to However, in the U. By , the disease had been reported in 35 states, from Maine to Texas to California It later spread to Denmark and Germany in The results obtained in the current study coincide with the historical reports of CSF outbreaks.
The previous estimation of CSFV emergence framed it approximately Several factors could bias this result, including the genomic region used to estimate the tMRCA, the number of sequences and the reliability of the phylogenetic methods accomplished A critical analysis can show that Kwon et al.
CSFV appears to exhibit significant heterogeneity in the rates of evolutionary changes among genotypes. All of the evolutionary changes were within the evolutionary rate of RNA viruses 35 , The differences found in the evolution of the three CSFV-genotypes could be a consequence of the diverse times of emergence.
However, the fact that the disease remains endemic in some countries leads to the preservation of its genetic diversity. This genotype has been found mainly in Europe, Asia and Africa 4. Therefore, the high genetic diversity found in the BSP analysis could be the consequence of the endemic situation related to this genotype.
The sudden loss of diversity, a population bottleneck that occurred between —, seems to be related to the stamping-out policy applied in Europe during the devastating CSF epidemic of — that affected Germany, the Netherlands, Italy, Spain and Belgium, caused by a virus strain of CSFV-G2 On the other hand, the endemic circulation of CSFV-G2 in pigs in areas of China 4 and India 4 , as well as in wild boar in Europe, can contribute to the maintenance of genetic diversity in this genotype.
However, no further information about the following years is available for this lineage. Another aspect addressed in the current study was the action of the evolutionary forces that lead to the genetic variability and the evolution of CSFV. Previous studies have shown this selective force acting on different sites of the E2-glycoprotein of CSFV 14 , 17 , 18 , Four of them 34, 36, 49, 72 have been previously linked to a decrease in the virulence of the field strains and promotion of viral escape from the host immune response 14 , 17 , Nonetheless, the biological significance of these sites needs to be further characterized.
In this antigenic domain, no previous reports have described the action of this evolutionary force.
However, Leifer et al. This change demonstrated by the parental strains, which evolved after subsequent passages under selective antibody pressure, could result in a small fitness advantage The biological evidence showed by Leifer et al. However, to define the functional importance of the remaining sites, additional studies will be required. Studies focused on sites , , , , and which were found together on the same protein surface, will be particularly important since these sites may potentially create an undescribed epitope Fig.
On the carboxyl-terminal half of the E2 protein, 13 sites influenced by the positive selection pressure were determined. From these sites, the position has been previously described under positive selection pressure 18 , 41 and has been linked to the attenuation of highly virulent CSFV-strains The residue was determined by Hu et al.
In our study, in addition to these two previously described sites, the positions , , , , , , , , , , and were determined as positively selected. Thus, the novel residues detected under positive selection pressure on the carboxyl terminal domain could play a role in the early replication stages or in tropism of CSFV. Nevertheless, further studies to verify their potential biological functions will need to be accomplished.
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From the branches-site model, only the CSFV-subgenotype 1. Several factors could have conditioned this event in the CSFV evolutionary pattern. Since then, controls policies have been put in place that include a vaccination campaigns using first a crystal violet vaccine and later a locally produced modified live vaccine containing a lapinized CSFV Chinese strain 3. During the establishment and improvement of the Cuban pig industry, three relevant swine importations took place: The fact that these movements of pigs to Cuba were from countries with a CSF- free status combined with the fact that Cuba is an island suggests that spatial segregation is responsible for the viral population in this country.
Thus, these studies also support the premise of segregation for the Cuban CSF-viral population. Another aspect to consider is that the Cuban viral population has been under continuous pressure exerted by the vaccine. This event has also been linked to a potential adaptive advantage for viral field strains. The resulting viral progeny has shown to cause less severe clinical signs in the animals affected 14 , 48 , which has been associated with persistent infection 49 and a decrease in the virulence of the circulating strains 15 , 16 , Thus, both spatial segregation and the selection pressure exerted by the vaccine seem to drive the evolutionary pattern of CSFV-subgenotype 1.
Our results also showed that the protein E2 suffered functional divergence during the evolutionary process and diversification of CSFV. The residues found under Type-I of functional divergence play different roles in the viral pathogenesis such as antigenicity and viral entry and attachment Therefore, changes in these positions might be associated with functional adaptiveness of E2, promoting a change in the viral tropism, rate of infectivity, or escape from the host immune system response.
The positions found were linked to functional domains playing a role blocking the activation of the innate immune system, as well as in the viral attachment and entry into host cells However, taking into account that the action of positive selection pressure on the E2 protein has been previously described 14 , 17 , 18 , 40 , it is highly probable that those mutations fixed by positive selection can promote new functions for this viral protein. The differences in results obtained in the current study and the results described by Li et al.
The evidence of recent positive selection on CSFV alternatively suggests that this viral agent has recently emerged in pigs. To our knowledge this is the first report approaching a cophylogenetic analysis for CSFV. In fact, Geoghegan et al.
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Considering that CSFV is an RNA virus with high rates of evolutionary change, this characteristic could confer more rapid adaptation to new environments, which, coupled with the frequency of exposure to new hosts, could facilitate host-switching. Our results indicated that CSFV emerged due to a switch of Tunisian sheep virus TSV from the host Ovis aries to the new host, Sus scrofa , in an event that occurred around years ago.
From the analysis performed, this event could have taken place around A historical review of the origin and development of the Animal Industry of the United States described the importation of the first Tunis sheep as a gift from the Bey of Tunis to Judge Richard Peters of Pennsylvania around Judge Peters, who was a practical farmer and the founder and first president of the Philadelphia Agricultural Society 51 , spread the Tunis sheep breed using native ewe, and their popularity continued to grow until approximately when they were one of the predominant breeds in this country As a characteristic of this period, mixed-farms allowed this new introduced specie to interact with the native pigs.
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Hence, these two different hosts, habiting the same geographic region, increased their interactions, facilitating the cross-species transmission of TSV, which could have resulted in the emergence of CSFV. The results obtained here using cophylogenetic analysis and a time-calibrated phylogenomic approach are in concordance with the historical, geographical and epidemiolocal evidence regarding the emergence of CSFV.
Our study provides novel and significant insights into the origin, diversification and evolutionary process of CSFV. The E2-complete marker was selected as the best phylogenetic marker for CSFV capable of reproducing the same phylogenetic and evolutionary information as the complete viral genome. By using this molecular marker, a reliable cut-off to establish an accurate classification of CSFV at genotype and subgenotypes levels was determined.
Based on tMRCA reconstruction and cophylogenetic analysis it was proposed that CSFV emerged approximately years ago as result of the Tunisian Sheep Virus host-jumping from its natural host to swine. CSFV emergence was followed by a genetic expansion in three main lineages due to the action of the positive selection pressure and the functional divergence as the main natural forces driving the genetic diversity and the evolution of the virus.
In addition, in our study, a structural 3D model for the main viral immunogenic protein E2 was obtained, which allowed us to map those residues involved in different process of the viral infection, antigenicity, pathogenesis and other unidentified functions. This model could also be useful to identify novel epitope targets for new vaccine candidates or new diagnostic assays in the future.