Effect of immune pressure on hepatitis C virus evolution: insights from a single-source outbreak

The host's immune response to hepatitis C virus (HCV) can result in the selection of characteristic mutations (adaptations) that enable the virus to escape this response. The ability of the virus to mutate at these sites is dependent on the incoming virus, the fitness cost incurred by the mutation, and the benefit to the virus in escaping the response. Studies examining viral adaptation in chronic HCV infection have shown that these characteristic immune escape mutations can be observed at the population level as human leukocyte antigen (HLA)-specific viral polymorphisms. We examined 63 individuals with chronic HCV infection who were infected from a single HCV genotype 1b source. Our aim was to determine the extent to which the host's immune pressure affects HCV diversity and the ways in which the sequence of the incoming virus, including preexisting escape mutations, can influence subsequent mutations in recipients and infection outcomes. Conclusion: HCV sequences from these individuals revealed 29 significant associations between specific HLA types within the new hosts and variations within their viruses, which likely represent new viral adaptations. These associations did not overlap with previously reported adaptations for genotypes 1a and 3a and possibly reflected a combination of constraint due to the incoming virus and genetic distance between the strains. However, these sites accounted for only a portion of the sites in which viral diversity was observed in the new hosts. Furthermore, preexisting viral adaptations in the incoming (source) virus likely influenced the outcomes in the new hosts.

Wolf habitat selection at the territory level : seasonal and interannual variation and influence on reproductive success

Habitat selection has been one of the main research topics in ecology for decades. Nevertheless, many aspects of habitat selection still need to be explored. In particular, previous studies have overlooked the importance of temporal variation in habitat selection and the value of including data on reproductive success in order to describe the best quality habitat for a species. We used data collected from radiocollared wolves in Yellowstone National Park (USA), between 1996 and 2008, to describe wolf habitat selection. In particular, we aimed to identify i) seasonal differences in wolf habitat selection, ii) factors influencing interannual variation in habitat selection, and iii) the effect of habitat selection on wolf reproductive success. We used probability density functions to describe wolf habitat use and habitat coverages to represent the habitat available to wolves. We used regression analysis to connect habitat use with habitat characteristics and habitat selection with reproductive success. Our most relevant result was discovering strong interannual variability in wolf habitat selection. This variability was in part explained by pack identity and differences in litter size and leadership of a pack between two years (summer) and in pack size and precipitation (winter). We also detected some seasonal differences. Wolves selected open habitats, intermediate elevations, intermediate distances from roads, and avoided steep slopes in late winter. They selected areas close to roads and avoided steep slopes in summer. In early winter, wolves selected wetlands, herbaceous and shrub vegetation types, and areas at intermediate elevation and distance from roads. Surprisingly, the habitat characteristics selected by wolves were not useful in predicting reproductive success. We hypothesize that interannual variability in wolf habitat selection may be too strong to detect effects on reproductive success. Moreover, prey availability and competitor pressure may also have an influence on wolf reproductive success, which we did not assess. This project demonstrated how important temporal variation is in shaping patterns of habitat selection. We still believe in the value of running long-term studies, but the effect of temporal variation should always be taken into account.

A quantitative analysis of microcirculation in sore-prone pressure areas on conventional and pressure relief hospital mattresses using laser Doppler flowmetry and tissue spectrophotometry

BACKGROUND Pressure ulcers are associated with severe impairment for the patients and high economic load. With this study we wanted to gain more insight to the skin perfusion dynamics due to external loading. Furthermore, we evaluated the effect of different types of pressure relief mattresses. METHODS A total of 25 healthy volunteers were enrolled in the study. Perfusion dynamics of the sacral and the heel area were assessed using the O2C-device, which combines a laser light, to determine blood flow, and white light to determine the relative amount of hemoglobin. Three mattresses were evaluated compared to a hard surface: a standard hospital foam mattress bed, a visco-elastic foam mattress, and an air-fluidized bed. RESULTS In the heel area, only the air-fluidized bed was able to maintain the blood circulation (mean blood flow of 13.6 ± 6 versus 3.9 ± 3 AU and mean relative amount of hemoglobin of 44.0 ± 14 versus 32.7 ± 12 AU.) In the sacral area, all used mattresses revealed an improvement of blood circulation compared to the hard surface. CONCLUSION The results of this study form a more precise pattern of perfusion changes due to external loading on various pressure relief mattresses. This knowledge may reduce the incidence of pressure ulcers and may be an influencing factor in pressure relief mattress selection.

Patterns of positive selection in seven ant genomes

The evolution of ants is marked by remarkable adaptations that allowed the development of very complex social systems. To identify how ant-specific adaptations are associated with patterns of molecular evolution, we searched for signs of positive selection on amino-acid changes in proteins. We identified 24 functional categories of genes which were enriched for positively selected genes in the ant lineage. We also reanalyzed genome-wide datasets in bees and flies with the same methodology, to check whether positive selection was specific to ants or also present in other insects. Notably, genes implicated in immunity were enriched for positively selected genes in the three lineages, ruling out the hypothesis that the evolution of hygienic behaviors in social insects caused a major relaxation of selective pressure on immune genes. Our scan also indicated that genes implicated in neurogenesis and olfaction started to undergo increased positive selection before the evolution of sociality in Hymenoptera. Finally, the comparison between these three lineages allowed us to pinpoint molecular evolution patterns that were specific to the ant lineage. In particular, there was ant-specific recurrent positive selection on genes with mitochondrial functions, suggesting that mitochondrial activity was improved during the evolution of this lineage. This might have been an important step toward the evolution of extreme lifespan that is a hallmark of ants.

INCREASED EXPRESSION OF ONE OF TWO ADENOSINE DEAMINASE ALLELES IN A HUMAN CHORIOCARCINOMA CELL LINE FOLLOWING SELECTION WITH ADENINE NUCLEOSIDES

The human choriocarcinoma cell line JEG-3 is heterozygous at the adenosine deaminase (ADA) gene locus. Both allelic genes are under strong but incomplete repression causing a very low level expression of the gene locus. Because cytotoxic adenosine analogues such as 9-(beta)-D arabinofuranosyladenine (ara-A) and 9-(beta)-D xylofuranosyladenine (xyl-A) can be specifically detoxified by the action of ADA, these analogues were used to select for JEG-3 derived cells which had increased ADA expression. When JEG-3 cells were subjected to a multi-step, successively increasing dosage of either ara-A or xyl-A, resistant cells with increased ADA expression were generated. This increased ADA expression in the resistant cells was unstable, so that when the selective pressure was removed, cellular ADA expression would decrease. Subclone analysis of xyl-A resistant cells revealed that compared to parental JEG-3 cells, individual resistant cells had either elevated ADA levels or decreased adenosine kinase (ADK) levels or both. This altered ADA and ADK expression in the resistant cells were found to be independent events. Because of high endogenous tissue conversion factor (TCF) expression in the JEG-3 cells, the allelic nature of the increased ADA expression in most of the resistant cells could not be determined. However, several resistant subcloned cells were found to have lost TCF expression. These TCF('-) cells expressed only the ADA*2 allelic gene product. Cell fusion experiments demonstrated that the ADA*1 allelic gene was intact and functional in the A3-1A7 cell line. Chromosomal analysis of the A3-1A7 cells showed that they had no double-minutes or homogeneously staining chromosomal regions, although a pair of new chromosomes were found in these cells. Segregation analysis of the hybrid cells indicated that an ADA*2 allelic gene was probably located on this new chromosome. The analysis of the A3-1A7 cell line suggested that the expression of only ADA 2 in these cells was the result of possibly a cis-deregulation of the ADA gene locus or more probably an amplification of the ADA*2 allelic gene. Two effective positive selection systems for ADA('+) cells were also developed and tested. These selection systems should eventually lead to the isolation of the ADA gene.^

MARITAL STATUS AND CARDIOVASCULAR RISK (SERUM, CHOLESTEROL, CIGARETTE, SMOKING, BLOOD, PRESSURE, SYSTOLIC)

There were three purposes of this study. The first was to describe the association between stable marital status and serum cholesterol, systolic blood pressure and cigarette smoking. The second purpose was to determine whether individuals who were married at one point and became widowed or divorced/separated had higher serum cholesterol, higher systolic blood pressure or were more likely to smoke prior to the change in marital status compared with individuals who did not change marital status. The third purpose was to determine whether the changes in marital status described above were related to increases in serum cholesterol or in cigarette smoking behavior. The rationale for the study was to determine whether previously reported associations between marital status categories and cardiovascular mortality may be mediated through higher values of risk correlates for cardiovascular disease among unmarried individuals.^ The study group selected for this dissertation was a sample from the Hypertension Detection and Follow-up Program (HDFP) population. The HDFP population was aged 30-69 years at the initial visit and included blacks and whites, males and females. The population was followed five years after the initial visit and periodic measurements of serum cholesterol, blood pressure and cigarette smoking behavior were obtained.^ Serum cholesterol was not associated with stable marital status category or with marital status prior to change. Changes in serum cholesterol were associated with marital status categories after change but the serum cholesterol values deceased rather than increased. Married individuals were shown to have higher serum cholesterol values compared with unmarried. Selection of the HDFP population may have influenced an ability to detect a significant association between marital status and serum cholesterol but it is doubtful that use of a general population would alter the direction of the association.^ Systolic blood pressure was significantly higher at the initial visit among unmarried white males and females compared with their married counterparts. No association between systolic blood pressure was found among black males or females. Those individuals who were married at the initial visit who experienced a change in marital status were found to have higher systolic blood pressure prior to the change in marital status. . . . (Author's abstract exceeds stipulated maximum length. Discontinued here with permission of author.) UMI ^

Factorial structure and reliability of a perceived influence on selection of a specialized plan of studies, IPEP, in secondary school students of Chillan, Chile

To evaluate these factors, the scale of perceived influences on the election of a specialized plan of studies, IPEP, was built and in this study its factorial structure and reliability were evaluated. The instrument was applied to 115 students, chosen by quote sampling. They were students of a subsidized private secondary school from the city of Chillan, Chile. An exploratory factorial analysis identified eight factors in the scale IPEP: Academic projection, Personal development, Maintenance of the social environment, Academic requirements, Satisfaction of others' expectations, Vocational information, Image of the plan and Family pressure. The results present an initial factorial structure, that empirically and theoretically adequate, whose factors were reliable and conceptually useful. These factors distinguish psychogenic and sociogenic aspects of the vocational process, and allow to initiate diagnostic and investigative actions in relation to this early vocational election that is established in secondary schools of the Chilean educational system

Factorial structure and reliability of a perceived influence on selection of a specialized plan of studies, IPEP, in secondary school students of Chillan, Chile

To evaluate these factors, the scale of perceived influences on the election of a specialized plan of studies, IPEP, was built and in this study its factorial structure and reliability were evaluated. The instrument was applied to 115 students, chosen by quote sampling. They were students of a subsidized private secondary school from the city of Chillan, Chile. An exploratory factorial analysis identified eight factors in the scale IPEP: Academic projection, Personal development, Maintenance of the social environment, Academic requirements, Satisfaction of others' expectations, Vocational information, Image of the plan and Family pressure. The results present an initial factorial structure, that empirically and theoretically adequate, whose factors were reliable and conceptually useful. These factors distinguish psychogenic and sociogenic aspects of the vocational process, and allow to initiate diagnostic and investigative actions in relation to this early vocational election that is established in secondary schools of the Chilean educational system

Factorial structure and reliability of a perceived influence on selection of a specialized plan of studies, IPEP, in secondary school students of Chillan, Chile

To evaluate these factors, the scale of perceived influences on the election of a specialized plan of studies, IPEP, was built and in this study its factorial structure and reliability were evaluated. The instrument was applied to 115 students, chosen by quote sampling. They were students of a subsidized private secondary school from the city of Chillan, Chile. An exploratory factorial analysis identified eight factors in the scale IPEP: Academic projection, Personal development, Maintenance of the social environment, Academic requirements, Satisfaction of others' expectations, Vocational information, Image of the plan and Family pressure. The results present an initial factorial structure, that empirically and theoretically adequate, whose factors were reliable and conceptually useful. These factors distinguish psychogenic and sociogenic aspects of the vocational process, and allow to initiate diagnostic and investigative actions in relation to this early vocational election that is established in secondary schools of the Chilean educational system

Gene expression changes in the coccolithophore Emiliania huxleyi after 500 generations of selection to ocean acidification

Coccolithophores are unicellular marine algae that produce biogenic calcite scales and substantially contribute to marine primary production and carbon export to the deep ocean. Ongoing ocean acidification particularly impairs calcifying organisms, mostly resulting in decreased growth and calcification. Recent studies revealed that the immediate physiological response in the coccolithophore Emiliania huxleyi to ocean acidification may be partially compensated by evolutionary adaptation, yet the underlying molecular mechanisms are currently unknown. Here, we report on the expression levels of 10 candidate genes putatively relevant to pH regulation, carbon transport, calcification and photosynthesis in E. huxleyi populations short-term exposed to ocean acidification conditions after acclimation (physiological response) and after 500 generations of high CO2 adaptation (adaptive response). The physiological response revealed downregulation of candidate genes, well reflecting the concomitant decrease of growth and calcification. In the adaptive response, putative pH regulation and carbon transport genes were up-regulated, matching partial restoration of growth and calcification in high CO2-adapted populations. Adaptation to ocean acidification in E. huxleyi likely involved improved cellular pH regulation, presumably indirectly affecting calcification. Adaptive evolution may thus have the potential to partially restore cellular pH regulatory capacity and thereby mitigate adverse effects of ocean acidification.

Corporate social responsibility in portfolio selection: A "goal games" against nature approach

Nowadays, there is an uprising social pressure on big companies to incorporate into their decision-making process elements of the so-called social responsibility. Among the many implications of this fact, one relevant one is the need to include this new element in classic portfolio selection models. This paper meets this challenge by formulating a model that combines goal programming with "goal games" against nature in a scenario where the social responsibility is defined through the introduction of a battery of sustainability indicators amalgamated into a synthetic index. In this way, we have obtained an efficient model that only implies solving a small number of linear programming problems. The proposed approach has been tested and illustrated by using a case study related to the selection of securities in international markets.

Rapid decline of fitness in panmictic populations of Drosophila melanogaster maintained under relaxed natural selection

The parameters of the spontaneous deleterious mutation process remain poorly known, despite their importance. Here, we report the results of a mutation accumulation experiment performed on panmictic populations of Drosophila melanogaster without any genetic manipulations. Two experimental populations were kept for 30 generations under relaxed natural selection. Each generation, 100 pairs were formed randomly, and every fecund pair contributed a son and a daughter to the next generation. Comparison with two controls, one cryopreserved and the other kept as the experimental populations but with long generation time, showed that the number of surviving offspring per female declined by 0.2% and 2.0% per generation under benign and harsh, competitive conditions, respectively. Thus, the mutational pressure on fitness may be strong and depends critically on the conditions under which fitness is assayed.

Positive Darwinian selection drives the evolution of several female reproductive proteins in mammals

Rapid evolution driven by positive Darwinian selection is a recurrent theme in male reproductive protein evolution. In contrast, positive selection has never been demonstrated for female reproductive proteins. Here, we perform phylogeny-based tests on three female mammalian fertilization proteins and demonstrate positive selection promoting their divergence. Two of these female fertilization proteins, the zona pellucida glycoproteins ZP2 and ZP3, are part of the mammalian egg coat. Several sites identified in ZP3 as likely to be under positive selection are located in a region previously demonstrated to be involved in species-specific sperm-egg interaction, suggesting the selective pressure is related to male-female interaction. The results provide long-sought evidence for two evolutionary hypotheses: sperm competition and sexual conflict.

Rapid, local adaptation of zooplankton behavior to changes in predation pressure in the absence of neutral genetic changes

Organisms producing resting stages provide unique opportunities for reconstructing the genetic history of natural populations. Diapausing seeds and eggs often are preserved in large numbers, representing entire populations captured in an evolutionary inert state for decades and even centuries. Starting from a natural resting egg bank of the waterflea Daphnia, we compare the evolutionary rates of change in an adaptive quantitative trait with those in selectively neutral DNA markers, thus effectively testing whether the observed genetic changes in the quantitative trait are driven by natural selection. The population studied experienced variable and well documented levels of fish predation over the past 30 years and shows correlated genetic changes in phototactic behavior, a predator-avoidance trait that is related to diel vertical migration. The changes mainly involve an increased plasticity response upon exposure to predator kairomone, the direction of the changes being in agreement with the hypothesis of adaptive evolution. Genetic differentiation through time was an order of magnitude higher for the studied behavioral trait than for neutral markers (DNA microsatellites), providing strong evidence that natural selection was the driving force behind the observed, rapid, evolutionary changes.

Selective pressure of a quinoxaline nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) on HIV-1 replication results in the emergence of nucleoside RT-inhibitor-specific (RT Leu-74-->Val or Ile and Val-75-->Leu or Ile) HIV-1 mutants.

The quinoxaline nonnucleoside RT inhibitor (NNRTI) (S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3,4- dihydroquinoxaline-2(1H)-thione (HBY 097) was used to select for drug-resistant HIV-1 variants in vitro. The viruses first developed mutations affecting the NNRTI-binding pocket, and five of six strains displayed the RT G190-->E substitution, which is characteristic for HIV-1 resistance against quinoxalines. In one variant, a new mutant (G190-->Q) most likely evolved from preexisting G190-->E mutants. The negative charge introduced by the G190-->E substitution was maintained at that site of the pocket by simultaneous selection for V179-->D together with G190-->Q. After continued exposure to the drug, mutations at positions so far known to be specific for resistance against nucleoside RT inhibitors (NRTIs) (L74-->V/I and V75-->L/I) were consistently detected in all cultures. The inhibitory activities of the cellular conversion product of 2',3'-dideoxyinosine (ddI, didanosine), 2',3'-dideoxyadenosine (ddA) and of 2',3'-didehydro-3'-deoxythymidine (d4T, stavudine) against these late-passage viruses were shown to be enhanced with the L74-->V/I RT mutant virus as compared with the wild-type (wt) HIV-1MN isolate. Clonal analysis proved linkage of the codon 74 and codon 75 mutations to the NNRTI-specific mutations in all RT gene fragments. The nonnucleoside- and nucleoside-resistance mutation sites are separated by approximately 35 A. We propose that the two sites "communicate" through the template-primer which is situated in the DNA-binding cleft between these two sites. Quinoxalines cause high selective pressure on HIV-1 replication in vitro; however, the implication of these findings for the treatment of HIV-1 infection has yet to be determined.