From SNPs to pathways: integration of functional effect of sequence variations on models of cell signalling pathways

Background: Single nucleotide polymorphisms (SNPs) are the most frequent type of sequence variation between individuals, and represent a promising tool for finding genetic determinants of complex diseases and understanding the differences in drug response. In this regard, it is of particular interest to study the effect of non-synonymous SNPs in the context of biological networks such as cell signalling pathways. UniProt provides curated information about the functional and phenotypic effects of sequence variation, including SNPs, as well as on mutations of protein sequences. However, no strategy has been developed to integrate this information with biological networks, with the ultimate goal of studying the impact of the functional effect of SNPs in the structure and dynamics of biological networks. Results: First, we identified the different challenges posed by the integration of the phenotypic effect of sequence variants and mutations with biological networks. Second, we developed a strategy for the combination of data extracted from public resources, such as UniProt, NCBI dbSNP, Reactome and BioModels. We generated attribute files containing phenotypic and genotypic annotations to the nodes of biological networks, which can be imported into network visualization tools such as Cytoscape. These resources allow the mapping and visualization of mutations and natural variations of human proteins and their phenotypic effect on biological networks (e.g. signalling pathways, protein-protein interaction networks, dynamic models). Finally, an example on the use of the sequence variation data in the dynamics of a network model is presented. Conclusion: In this paper we present a general strategy for the integration of pathway and sequence variation data for visualization, analysis and modelling purposes, including the study of the functional impact of protein sequence variations on the dynamics of signalling pathways. This is of particular interest when the SNP or mutation is known to be associated to disease. We expect that this approach will help in the study of the functional impact of disease-associated SNPs on the behaviour of cell signalling pathways, which ultimately will lead to a better understanding of the mechanisms underlying complex diseases.

In vitro effect of malachite green on Candida albicans involves multiple pathways and transcriptional regulators UPC2 and STP2.

In this study, we show that a chemical dye, malachite green (MG), which is commonly used in the fish industry as an antifungal, antiparasitic, and antibacterial agent, could effectively kill Candida albicans and non-C. albicans species. We have demonstrated that Candida cells are susceptible to MG at a very low concentration (MIC that reduces growth by 50% [MIC(50)], 100 ng ml(-1)) and that the effect of MG is independent of known antifungal targets, such as ergosterol metabolism and major drug efflux pump proteins. Transcriptional profiling in response to MG treatment of C. albicans cells revealed that of a total of 207 responsive genes, 167 genes involved in oxidative stress, virulence, carbohydrate metabolism, heat shock, amino acid metabolism, etc., were upregulated, while 37 genes involved in iron acquisition, filamentous growth, mitochondrial respiration, etc., were downregulated. We confirmed experimentally that Candida cells exposed to MG resort to a fermentative mode of metabolism, perhaps due to defective respiration. In addition, we showed that MG triggers depletion of intracellular iron pools and enhances reactive oxygen species (ROS) levels. These effects could be reversed by the addition of iron or antioxidants, respectively. We provided evidence that the antifungal effect of MG is exerted through the transcription regulators UPC2 (regulating ergosterol biosynthesis and azole resistance) and STP2 (regulating amino acid permease genes). Taken together, our transcriptome, genetic, and biochemical results allowed us to decipher the multiple mechanisms by which MG exerts its anti-Candida effects, leading to a metabolic shift toward fermentation, increased generation of ROS, labile iron deprivation, and cell necrosis.

Little effect of seasonal constraints on population genetic structure in eusocial paper wasps.

Climate has long been suggested to affect population genetic structures of eusocial insect societies. For instance, Hamilton [Journal of Theoretical Biology7 (1964) 17] discusses whether temperate and tropical eusocial insects may show differences in population-level genetic structure and viscosity, and how this might relate to differences in the degree of synchrony in their life cycles or modes of nest founding. Despite the importance of Hamilton's 1964 papers, this specific idea has not been tested in actual populations of wasps, probably due to the paucity of studies on tropical species. Here, we compare colony and population genetic structures in two species of primitively eusocial paper wasps with contrasting ecologies: the tropical species Polistes canadensis and the temperate species P. dominulus. Our results provide important clarifications of Hamilton's discussion. Specifically, we show that the genetic structures of the temperate and tropical species were very similar, indicating that seasonality does not greatly affect population viscosity or inbreeding. For both species, the high genetic differentiation between nests suggests strong selection at the nest level to live with relatives, whereas low population viscosity and low genetic differentiation between nest aggregations might reflect balancing selection to disperse, avoiding competition with relatives. Overall, our study suggests no prevalence of seasonal constraints of the life cycle in affecting the population genetic structure of eusocial paper wasps. These conclusions are likely to apply also to other primitively eusocial insects, such as halictine bees. They also highlight how selection for a kin structure that promotes altruism can override potential effects of ecology in eusocial insects.

Effect of mating history on gender preference in the hermaphroditic snail physa acuta

Several internally fertilizing hermaphroditic animals can only perform one sexual role at a time. In such species, two individuals that engage in a copulation may have different interests in acting as male or female. A gender choice must be made which, if both individuals have the same preference, may give rise to a severe sexual conflict. Here we tested the hypothesis that gender choice could be influenced by mating history, using the freshwater snail, Physa acuta. We recorded the copulatory behaviour of 240 pairs composed of a focal individual and a partner, each either short- or long-isolated. We found that the time to the first copulation was unaffected by isolation status, suggesting that first contacts in this species are random processes. In contrast, the duration of copulations and the frequency of rejection behaviours suggested that individual gender preference switches from male biased to female biased as isolation increases. In addition, snails rejected copulations more frequently when presented to a partner with the same isolation status. Reciprocity, measured as the rate of gender swapping between the first and second copulations, was high irrespective of gender status. We suggest possible evolutionary causes for this gender preference switch and discuss its potential importance in natural population as well as its consequences for the maintenance of hermaphroditism

Effect of obesity onset on pendular energy transduction at spontaneous walking speed: Prader-Willi versus nonsyndromal obese individuals.

OBJECTIVE: To compare the mechanical external work (Wext ) and pendular energy transduction (Rstep ) at spontaneous walking speed (Ss ) in individuals with Prader-Willi syndrome (PWS) versus subjects with nonsyndromal obesity (OB) to investigate whether the early onset of obesity allows PWS subjects to adopt energy conserving gait mechanics. DESIGN AND METHODS: Wext and Rstep were computed using kinematic data acquired by an optoelectronic system and compared in 15 PWS (BMI = 39.5 ± 1.8 kg m(-2) ; 26.7 ± 1.5 year) and 15 OB (BMI = 39.3 ± 1.0 kg m(-2) ; 28.7 ± 1.9 year) adults matched for gender, age and BMI and walking at Ss . RESULTS: Ss was significantly lower in PWS (0.98 ± 0.03 m s(-1) ) than in OB (1.20 ± 0.02 m s(-1) ; P < 0.001). There were no significant differences in Wext per kilogram between groups (PWS: 0.37 ± 0.04 J kg(-1) m(-1) ; OB: 0.40 ± 0.05 J kg(-1) m(-1) ; P = 0.66) and in Rstep (PWS: 69.9 ± 2.9%; OB: 67.7 ± 2.4%; P = 0.56). However, Rstep normalized to Froude number (Rstep /Fr) was significantly greater in PWS (6.0 ± 0.6) than in OB (3.8 ± 0.2; P = 0.001). Moreover, Rstep /Fr was inversely correlated with age of obesity onset (r = -0.49; P = 0.006) and positively correlated with obesity duration (r = 0.38; P = 0.036). CONCLUSION: Individuals with PWS seem to alter their gait to improve pendular energy transduction as a result of precocious and chronic adaptation to loading.

Predicted effect of climate change on the invasibility and distribution of the Western corn root-worm

1 Insect pests, biological invasions and climate change are considered to representmajor threats to biodiversity, ecosystem functioning, agriculture and forestry.Deriving hypothesis of contemporary and/or future potential distributions of insectpests and invasive species is becoming an important tool for predicting the spatialstructure of potential threats.2 The western corn rootworm (WCR) Diabrotica virgifera virgifera LeConte is apest of maize in North America that has invaded Europe in recent years, resultingin economic costs in terms of maize yields in both continents. The present studyaimed to estimate the dynamics of potential areas of invasion by the WCR under aclimate change scenario in the Northern Hemisphere. The areas at risk under thisscenario were assessed by comparing, using complementary approaches, the spatialprojections of current and future areas of climatic favourability of the WCR. Spatialhypothesis were generated with respect to the presence records in the native rangeof the WCR and physiological thresholds from previous empirical studies.3 We used a previously developed protocol specifically designed to estimatethe climatic favourability of the WCR. We selected the most biologicallyrelevant climatic predictors and then used multidimensional envelope (MDE) andMahalanobis distances (MD) approaches to derive potential distributions for currentand future climatic conditions.4 The results obtained showed a northward advancement of the upper physiologicallimit as a result of climate change, which might increase the strength of outbreaksat higher latitudes. In addition, both MDE and MD outputs predict the stability ofclimatic favourability for the WCR in the core of the already invaded area in Europe,which suggests that this zone would continue to experience damage from this pestin Europe.

Effect of an ectoparasite on lay date, nest-site choice, desertion, and hatching success in the great tit (Parus major)

Ectoparasites are common in most bird species, but experimental evidence of their effects on life-history traits is scarce. We investigated experimentally the effects of the hematophagous hen flea (Ceratophyllus gallinae) on timing of reproduction, nest-site choice, nest desertion, clutch size, and hatching success in the great tit (Parus major). When great tits were offered a choice on their territory between an infested and a parasite-free nest-box, they chose the one without parasites. When there was no choice, the great tits in a territory containing an infested nest-box delayed laying the clutch by 11 days as compared with the birds that were offered a parasite-free nesting opportunity. The finding that there was no difference in phenotypic traits related to dominance between the birds nesting in infested boxes and birds nesting in parasite-free boxes suggests that the delay is not imposed by social dominance. Nest desertion between laying and shortly after hatching was significandy higher in infested nests. There was no difference between infested and parasite-free nests in clutch size, but hatching success and hence brood size at hatching were significantly smaller in infested nests. Nest-box studies of great tits have been seminal in the development of evolutionary, ecological, and behavioral theory, but recently a polemic has arisen in the literature about the validity of the conclusions drawn from nest-box studies where the naturally occurring, detrimental ectoparasites are eliminated by the routine removal of old nests between breeding seasons. Our study suggests that this criticism is valid and that the evaluation of the effects of ectoparasites may improve our understanding of behavioral traits, life-history traits, or population dynamics

Let's (not) talk about sex: The effect of information provision on gender differences in performance under competition

We study how gender differences in performance under competition areaffected by the provision of information regarding rival s gender and/ordifferences in relative ability. In a laboratory experiment, we use two tasks thatdiffer regarding perceptions about which gender outperforms the other. Weobserve women s underperformance only under two conditions: 1) tasks areperceived as favoring men and 2) rivals gender is explicitly mentioned. Thisresult can be explained by stereotype-threat being reinforced when explicitlymentioning gender in tasks in which women already consider they are inferior.Omitting information about gender is a safe alternative to avoid women sunderperformance in competition.

The Effect of Teacher Expectations on Student Achievement: Does The Pygmalion Effect Hold True for Cape Verde?

The present study is about the relationship between teacher expectations and student achievement. Do teachers have the power to influence student achievement? This is the question at hand. Are students under the influence of their teachers in regards to how they perceive themselves as achievers and ultimately how well they perform? What are the other factors that come into play when assessing student’s academic achievement? In light of the literature written on this topic, the two most prevalent theories are (1) Pygmalion in the Class and (2) The Sustaining Effect. These theories show a direct and determinant relationship between teacher expectations and student achievement. The main objective of this study was to investigate if in Cape Verde, teachers follow the same trend. Responses to teacher and student surveys carried out at Domingos Ramos High School gave revealing insights into how Capeverdean teachers view their students and the role the teachers themselves play in supporting the studen’s academic performance. Is the teacher’s expectation of their students the last word? In general, teachers do have a powerful influence on their students for good or for bad, but the key questions are: (1) are they aware of this power and (2) how well do they manage it? This paper includes an in-depth discussion on the different factors that influence student achievement and research carried out at an urban secondary school which characterizes how teachers and students view their roles in the student’s academic success. Recommendations are also provided to assist teachers in managing their expectations to maximize their role as a positive contributor to the success of their students.

The effect of unemployment spells on subsequent wages in Spain

In our analysis we try and recover the wage loss from unemploymentin Spain and see how it is affected by previous unemploymentexperience, unemployment duration, eligibility for unemploymentbenefits, and previous wages. We also study its variations acrossgroups. Our main conclusion is that while there is some evidencethat labour market rigidities tend to lower it, the wage loss ofdisplaced workers is remarkably high: more than 30%, that is,twice the equivalent figure for the US and France. Wages in Spainsuffer from a serious mismeasurement problems that we do our best tocontrol, so that our results are less robust than the ones thatwould be obtained with better data sets. However, they indicate a large level of wage flexibility in Spain.

The effect of intergroup competition on group coordination: An experimental study

We report an experiment on the effect of intergroup competition on group coordination in the minimal-effort game (Van Huyck et al., 1990). The competition was between two 7-person groups. Each player in each group independently chose an integer from 1 to 7. The group with the higher minimum won the competition and each of its members was paid according to the game s original payoff matrix. Members of the losing group were paid nothing. In case of a tie, each player was paid half the payoff in the original matrix. This treatment was contrasted with two control treatments where each of the two groups played an independent coordination game, either with or without information about the minimum chosen by the outgroup. Although the intergroup competition does not change the set of strict equilibria, we found that it improved collective rationality by moving group members in the direction of higher-payoff equilibria. Merely providing group members with information about the minimal-effort level in the other group was not sufficient to generate this effect.

Effect of genetic convergence on phylogenetic inference.

Phylogenetic reconstructions are a major component of many studies in evolutionary biology, but their accuracy can be reduced under certain conditions. Recent studies showed that the convergent evolution of some phenotypes resulted from recurrent amino acid substitutions in genes belonging to distant lineages. It has been suggested that these convergent substitutions could bias phylogenetic reconstruction toward grouping convergent phenotypes together, but such an effect has never been appropriately tested. We used computer simulations to determine the effect of convergent substitutions on the accuracy of phylogenetic inference. We show that, in some realistic conditions, even a relatively small proportion of convergent codons can strongly bias phylogenetic reconstruction, especially when amino acid sequences are used as characters. The strength of this bias does not depend on the reconstruction method but varies as a function of how much divergence had occurred among the lineages prior to any episodes of convergent substitutions. While the occurrence of this bias is difficult to predict, the risk of spurious groupings is strongly decreased by considering only 3rd codon positions, which are less subject to selection, as long as saturation problems are not present. Therefore, we recommend that, whenever possible, topologies obtained with amino acid sequences and 3rd codon positions be compared to identify potential phylogenetic biases and avoid evolutionarily misleading conclusions.

The effect of divorce laws on divorce rates in Europe

This paper analyzes a panel of 18 European countries spanning from 1950 to 2003 toexamine the extent to which the legal reforms leading to easier divorce that took placeduring the second half of the 20th century have contributed to the increase in divorce rates across Europe. We use a quasi-experimental set-up and exploit the different timing of the reforms in divorce laws across countries. We account for unobserved country-specificfactors by introducing country fixed effects, and we include country-specific trends tocontrol for time-varying factors at the country level that may be correlated with divorcerates and divorce laws, such as changing social norms or slow moving demographictrends. We find that the reforms were followed by significant increases in divorce rates.Overall, we estimate that the introduction of no-fault, unilateral divorce increased thedivorce rate by about 1, a sizeable effect given the average rate of 4.2 divorces per 1,000married people in 2002.

Effect of irrigation water on the incidence of Salmonella spp. on lettuces produced by urban agriculture and sold on the markets in Dakar, Senegal

The aim of our survey was to assess the effect of irrigation water of the microbiological quality on the production chain of lettuce in the Dakar area. Microbiological analysis showed that 35% of irrigation water was contaminated by Salmonella spp. between the two water-types used for irrigation (groundwater and wastewater), no significant difference (p>0.05) in their degree of contamination was found. The incidence of different types of irrigation water on the contamination rate of lettuces from the farm (Pikine and Patte d'Oie) was not different either (p>0.05). However, the contamination rate of lettuce from markets of Dalifort and Grand-Yoff that were supplied by the area of Patte d'Oie was greater than those of Sham and Zinc supplied by Pikine (p<0.05). Comparison of serotypes of Salmonella isolated from irrigation water and lettuce showed that irrigation water may affect the microbiological quality of lettuce. Manures, frequently used as organic amendment in cultivating lettuce are another potential source of contamination. These results showed that lettuce may constitute effective vectors for the transmission of pathogens to consumers. Extensive treatment of the used wastewater and/or composting of manure could considerably reduce these risks.

The effect of vaccines based on ovalbumin coupled to gas-filled microbubbles for reducing infection by ovalbumin-expressing Listeria monocytogenes.

Gas-filled microbubbles (MB) are a very promising alternative to the currently evaluated lipid- or polymer-based particulate Ag delivery systems. We recently demonstrated the ability of MB to deliver associated Ag to DC, to activate them and thereby induce both humoral and cellular immune responses. We now extended the characterization of MB as antigen-delivery system by appraising the efficiency of MB-associated ovalbumin (OVA-MB) at protecting mice against pathogen infection. Ultrasound-mediated imaging demonstrated that the administration of OVA via MB generates a depot at the injection site that lasts for several hours. We found that OVA-MB injected subcutaneously is far more effective at inducing specific Ab and T cell immunity than immunization with free OVA. Moreover, a covalent link between MB and OVA causes a stronger bias towards a Th1-type of immune response than adsorption of the Ag or its covalent link to liposomes of the same lipid composition. Finally, vaccination of mice with OVA-MB partially protects against a systemic infection with OVA-expressing Listeria monocytogenes. The vaccine induces specific effector CD8 T cell responses capable of decreasing more than 100 fold the bacterial load. MB thus represent a potent Ag delivery system for vaccination against intracellular infectious agents.