Evaluation of algorithms used to order markers on genetic maps

When building genetic maps, it is necessary to choose from several marker ordering algorithms and criteria, and the choice is not always simple. In this study, we evaluate the efficiency of algorithms try (TRY), seriation (SER), rapid chain delineation (RCD), recombination counting and ordering (RECORD) and unidirectional growth (UG), as well as the criteria PARF (product of adjacent recombination fractions), SARF (sum of adjacent recombination fractions), SALOD (sum of adjacent LOD scores) and LHMC (likelihood through hidden Markov chains), used with the RIPPLE algorithm for error verification, in the construction of genetic linkage maps. A linkage map of a hypothetical diploid and monoecious plant species was simulated containing one linkage group and 21 markers with fixed distance of 3 cM between them. In all, 700 F(2) populations were randomly simulated with and 400 individuals with different combinations of dominant and co-dominant markers, as well as 10 and 20% of missing data. The simulations showed that, in the presence of co-dominant markers only, any combination of algorithm and criteria may be used, even for a reduced population size. In the case of a smaller proportion of dominant markers, any of the algorithms and criteria (except SALOD) investigated may be used. In the presence of high proportions of dominant markers and smaller samples (around 100), the probability of repulsion linkage increases between them and, in this case, use of the algorithms TRY and SER associated to RIPPLE with criterion LHMC would provide better results. Heredity (2009) 103, 494-502; doi:10.1038/hdy.2009.96; published online 29 July 2009

Plasmodium vivax recombinant vaccine candidate AMA-1 plays an important role in adaptive immune response eliciting differentiation of dendritic cells

The Apical Membrane Antigen-1 (AMA-1) is a well-characterized and functionally important merozoite protein and is currently considered a major candidate antigen for a malaria vaccine. Previously, we showed that AMA-1 has an influence on cellular immune responses of malaria-naive subjects, resulting in an alternative activation of monocyte-derived dendritic cells and induction of a pro-inflammatory response by stimulated PBMCs. Although there is evidence, from human and animal malaria model systems that cell-mediated immunity may contribute to both protection and pathogenesis, the knowledge on cellular immune responses in vivax malaria and the factors that may regulate this immunity are poorly understood. In the current work, we describe the maturation of monocyte-derived dendritic cells of P. vivax naturally infected individuals and the effect of P. vivax vaccine candidate Pv-AMA-1 on the immune responses of the same donors. We show that malaria-infected subjects present modulation of DC maturation, demonstrated by a significant decrease in expression of antigen-presenting molecules (CD1a, HLA-ABC and HLA-DR), accessory molecules (CD40, CD80 and CD86) and Fc gamma RI (CD64) receptor (P <= 0.05). Furthermore, Pv-AMA-1 elicits an upregulation of CD1a and HLA-DR molecules on the surface of monocyte-derived dendritic cells (P=0.0356 and P=0.0196, respectively), and it is presented by AMA-1-stimulated DCs. A significant pro-inflammatory response elicited by Pv-AMA-1-pulsed PBMCs is also demonstrated, as determined by significant production of TNF-alpha, IL-12p40 and IFN-gamma (P <= 0.05). Our results suggest that Pv-AMA-1 may partially revert DC down-modulation observed in infected subjects, and exert an important role in the initiation of pro-inflammatory immunity that might contribute substantially to protection. (c) 2009 Elsevier Ltd. All rights reserved.

Use of the q-Gaussian mutation in evolutionary algorithms

This paper proposes the use of the q-Gaussian mutation with self-adaptation of the shape of the mutation distribution in evolutionary algorithms. The shape of the q-Gaussian mutation distribution is controlled by a real parameter q. In the proposed method, the real parameter q of the q-Gaussian mutation is encoded in the chromosome of individuals and hence is allowed to evolve during the evolutionary process. In order to test the new mutation operator, evolution strategy and evolutionary programming algorithms with self-adapted q-Gaussian mutation generated from anisotropic and isotropic distributions are presented. The theoretical analysis of the q-Gaussian mutation is also provided. In the experimental study, the q-Gaussian mutation is compared to Gaussian and Cauchy mutations in the optimization of a set of test functions. Experimental results show the efficiency of the proposed method of self-adapting the mutation distribution in evolutionary algorithms.

Most of the patients presenting myocardial infarction would not be eligible for intensive lipid-lowering based on clinical algorithms or plasma C-reactive protein

Objective: The study we assessed how often patients who are manifesting a myocardial infarction (MI) would not be considered candidates for intensive lipid-lowering therapy based on the current guidelines. Methods: In 355 consecutive patients manifesting ST elevation MI (STEMI), admission plasma C-reactive protein (CRP) was measured and Framingham risk score (FRS), PROCAM risk score, Reynolds risk score, ASSIGN risk score, QRISK, and SCORE algorithms were applied. Cardiac computed tomography and carotid ultrasound were performed to assess the coronary artery calcium score (CAC), carotid intima-media thickness (cIMT) and the presence of carotid plaques. Results: Less than 50% of STEMI patients would be identified as having high risk before the event by any of these algorithms. With the exception of FRS (9%), all other algorithms would assign low risk to about half of the enrolled patients. Plasma CRP was <1.0 mg/L in 70% and >2 mg/L in 14% of the patients. The average cIMT was 0.8 +/- 0.2 mm and only in 24% of patients was >= 1.0 mm. Carotid plaques were found in 74% of patients. CAC > 100 was found in 66% of patients. Adding CAC >100 plus the presence of carotid plaque, a high-risk condition would be identified in 100% of the patients using any of the above mentioned algorithms. Conclusion: More than half of patients manifesting STEMI would not be considered as candidates for intensive preventive therapy by the current clinical algorithms. The addition of anatomical parameters such as CAC and the presence of carotid plaques can substantially reduce the CVD risk underestimation. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

In situ apoptosis of adaptive immune cells and the cellular escape of rabies virus in CNS from patients with human rabies transmitted by Desmodus rotundus

The aim of the current study was to investigate the apoptosis of neurons, astrocytes and immune cells from human patients that were infected with rabies virus by vampire bats bite. Apoptotic neurons were identified by their morphology and immune cells were identified using double immunostaining. There were very few apoptotic neurons present in infected tissue samples, but there was an increase of apoptotic infiltrating CD4+ and TCD8+ adaptive immune cells in the rabies infected tissue. No apoptosis was present in NK, macrophage and astrocytes. The dissemination of the human rabies virus within an infected host may be mediated by viral escape of the virus from an infected cell and may involve an anti-apoptotic mechanism, which does not kill the neuron or pro-apoptosis of TCD4+ and TCD8+ lymphocytes and which allows for increased proliferation of the virus within the CNS by attenuation of the adaptive immune response. (C) 2011 Elsevier B.V. All rights reserved.

A description of adaptive and maladaptive behaviour in children and adolescents with Cri-du-chat syndrome

Background Psychological tests can be useful to record adaptive and maladaptive behaviours of children with intellectual disability. The objective of this study was to describe the adaptive and maladaptive behaviour of children and adolescents with Cri-du-chat syndrome. Methods The sample consisted of 10 children and adolescents with Cri-du-chat syndrome (mean chronological age = 11.3 years, mean mental age = 18 months). The developmental quotient was calculated through the Psychoeducational Profile - Revised. An observational protocol was used to record adaptive and maladaptive behaviours. Results The number of maladaptive behaviours observed was different among participants. However, all of them had high rates of adaptive behaviours, such as rule-following. Conclusions These results, though preliminary, justify that we continue to think about the need for psychoeducational interventions aimed at stimulating the repertoire of adaptive behaviours, in people with Cri-du-chat syndrome.

HLA-G polymorphisms in women with squamous intraepithelial lesions harboring human papillomavirus

Human papillomavirus (HPV) infection is etiologically associated with low-(LSIL) and high-grade squamous intraepithelial lesions (HSIL) and with cervical cancer. The progression or regression of the lesions may depend, among other factors, on the host heritable immune response. Because human leukocyte antigen (HLA)-G molecules are involved in the modulation of innate and adaptive immune responses, and because no previous studies have evaluated HLA-G polymorphism in patients with SIL, we conducted a study to assess the association between HLA-G polymorphisms and cervical lesions harboring HPV infection. Cervico-vaginal scrapings and blood samples were collected from 125 women with SIL (68 LSIL and 57 HSIL) and from 94 healthy women without HPV infection and cytological abnormalities. HPV type and HLA-G polymorphisms in exons 2, 3 and 8 (14 bp insertion/deletion) were evaluated by PCR methodology, and digested with restriction endonucleases. The Genepop software and the EM and PHASE algorithms were used for statistical analysis. A significant protective association was observed between the presence of the G*0103 allele and SIL and between the G0101/G0104 genotype and HSIL in the group of patients compared to control. The presence of the G0104/+14 bp and G0104/-14 bp haplotypes conferred susceptibility to SIL compared to control. In addition, patients possessing the G0104/+14 bp haplotype and harboring HPV-16 and -18 co-infections were particularly associated with HSIL. These findings suggest that HLA-G polymorphisms may be associated with HPV infection and SIL, consequently representing a profile of predisposition to cervical cancer. Modern Pathology (2009) 22, 1075-1082; doi: 10.1038/modpathol.2009.67; published online 1 May 2009

A Dynamical Modeling to Study the Adaptive Immune System and the Influence of Antibodies in the Immune Memory

Immunological systems have been an abundant inspiration to contemporary computer scientists. Problem solving strategies, stemming from known immune system phenomena, have been successfully applied to chall enging problems of modem computing. Simulation systems and mathematical modeling are also beginning use to answer more complex immunological questions as immune memory process and duration of vaccines, where the regulation mechanisms are not still known sufficiently (Lundegaard, Lund, Kesmir, Brunak, Nielsen, 2007). In this article we studied in machina a approach to simulate the process of antigenic mutation and its implications for the process of memory. Our results have suggested that the durability of the immune memory is affected by the process of antigenic mutation.and by populations of soluble antibodies in the blood. The results also strongly suggest that the decrease of the production of antibodies favors the global maintenance of immune memory.

Cytokine Signatures of Innate and Adaptive Immunity in 17DD Yellow Fever Vaccinated Children and Its Association With the Level of Neutralizing Antibody

Background. The live attenuated yellow fever (YF) vaccines have been available for decades and are considered highly effective and one of the safest vaccines worldwide. Methods. The impact of YF-17DD-antigens recall on cytokine profiles of YF-17DD-vaccinated children were characterized using short-term cultures of whole blood samples and single-cell flow cytometry. This study enrolled seroconverters and nonseroconverters after primovaccination (PV-PRNT(+) and PV-PRNT(-)), seroconverters after revaccination (RV-PRNT(+)), and unvaccinated volunteers (UV-PRNT(-)). Results. The analysis demonstrated in the PV-PRNT(+) group a balanced involvement of pro-inflammatory/regulatory adaptive immunity with a prominent participation of innate immunity pro-inflammatory events (IL-12(+) and TNF-alpha(+) NEU and MON). Using the PV-PRNT(+) cytokine signature as a reference profile, PV-PRNT(+) presented a striking lack of innate immunity proinflammatory response along with an increased adaptive regulatory profile (IL-4(+) CD4(+) T cells and IL-10(+) and IL-5(+) CD8(+) T cells). Conversely, the RV-PRNT(+) shifted the overall cytokine signatures toward an innate immunity pro-inflammatory profile and restored the adaptive regulatory response. Conclusions. The data demonstrated that the overall cytokine signature was associated with the levels of PRNT antibodies with a balanced innate/adaptive immunity with proinflammatory/regulatory profile as the hallmark of PV-PRNT(MEDIUM+), whereas a polarized regulatory response was observed in PV-PRNT(-) and a prominent proinflammatory signature was the characteristic of PV-PRNT(HIGH+).

A FOSSIL BULGE GLOBULAR CLUSTER REVEALED BY VERY LARGE TELESCOPE MULTI-CONJUGATE ADAPTIVE OPTICS

The globular cluster HP 1 is projected on the bulge, very close to the Galactic center. The Multi-Conjugate Adaptive Optics Demonstrator on the Very Large Telescope allowed us to acquire high-resolution deep images that, combined with first epoch New Technology Telescope data, enabled us to derive accurate proper motions. The cluster and bulge fields` stellar contents were disentangled through this process and produced an unprecedented definition in color-magnitude diagrams of this cluster. The metallicity of [Fe/H] approximate to -1.0 from previous spectroscopic analysis is confirmed, which together with an extended blue horizontal branch imply an age older than the halo average. Orbit reconstruction results suggest that HP 1 is spatially confined within the bulge.

Multi-Conjugate Adaptive Optics VLT imaging of the distant old open cluster FSR 1415

We employ the recently installed near-infrared Multi-Conjugate Adaptive Optics demonstrator (MAD) to determine the basic properties of a newly identified, old and distant, Galactic open cluster (FSR 1415). The MAD facility remarkably approaches the diffraction limit, reaching a resolution of 0.07 arcsec (in K), that is also uniform in a field of similar to 1.8 arcmin in diameter. The MAD facility provides photometry that is 50 per cent complete at K similar to 19. This corresponds to about 2.5 mag below the cluster main-sequence turn-off. This high-quality data set allows us to derive an accurate heliocentric distance of 8.6 kpc, a metallicity close to solar and an age of similar to 2.5 Gyr. On the other hand, the deepness of the data allows us to reconstruct (completeness-corrected) mass functions (MFs) indicating a relatively massive cluster, with a flat core MF. The Very Large Telescope/MAD capabilities will therefore provide fundamental data for identifying/analysing other faint and distant open clusters in the Galaxy III and IV quadrants.

Variety matters: adaptive genetic diversity and parasite load in two mouse opossums from the Brazilian Atlantic forest

The adaptive potential of a species to a changing environment and in disease defence is primarily based on genetic variation. Immune genes, such as genes of the major histocompatibility complex (MHC), may thereby be of particular importance. In marsupials, however, there is very little knowledge about natural levels and functional importance of MHC polymorphism, despite their key role in the mammalian evolution. In a previous study, we discovered remarkable differences in the MHC class II diversity between two species of mouse opossums (Gracilinanus microtarsus, Marmosops incanus) from the Brazilian Atlantic forest, which is one of the most endangered hotspots for biodiversity conservation. Since the main forces in generating MHC diversity are assumed to be pathogens, we investigated in this study gastrointestinal parasite burden and functional associations between the individual MHC constitution and parasite load. We tested two contrasting scenarios, which might explain differences in MHC diversity between species. We predicted that a species with low MHC diversity would either be under relaxed selection pressure by low parasite diversity (`Evolutionary equilibrium` scenario), or there was a recent loss in MHC diversity leading to a lack of resistance alleles and increased parasite burden (`Unbalanced situation` scenario). In both species it became apparent that the MHC class II is functionally important in defence against gastrointestinal helminths, which was shown here for the first time in marsupials. On the population level, parasite diversity did not markedly differ between the two host species. However, we did observe considerable differences in the individual parasite load (parasite prevalence and infection intensity): while M. incanus revealed low MHC DAB diversity and high parasite load, G. microtarsus showed a tenfold higher population wide MHC DAB diversity and lower parasite burden. These results support the second scenario of an unbalanced situation.

MyD88 Signaling Is Required for Efficient Innate and Adaptive Immune Responses to Paracoccidioides brasiliensis Infection

The mechanisms that govern the initial interaction between Paracoccidioides brasiliensis, a primary dimorphic fungal pathogen, and cells of the innate immunity need to be clarified. Our previous studies showed that Toll-like receptor 2 (TLR2) and TLR4 regulate the initial interaction of fungal cells with macrophages and the pattern of adaptive immunity that further develops. The aim of the present investigation was to assess the role of MyD88, an adaptor molecule used by TLRs to activate genes of the inflammatory response in pulmonary paracoccidioidomycosis. Studies were performed with normal and MyD88(-/-) C57BL/6 mice intratracheally infected with P. brasiliensis yeast cells. MyD88(-/-) macrophages displayed impaired interaction with fungal yeast cells and produced low levels of IL-12, MCP-1, and nitric oxide, thus allowing increased fungal growth. Compared with wild-type (WT) mice, MyD88(-/-) mice developed a more severe infection of the lungs and had marked dissemination of fungal cells to the liver and spleen. MyD88(-/-) mice presented low levels of Th1, Th2, and Th17 cytokines, suppressed lymphoproliferation, and impaired influx of inflammatory cells to the lungs, and this group of cells comprised lower numbers of neutrophils, activated macrophages, and T cells. Nonorganized, coalescent granulomas, which contained high numbers of fungal cells, characterized the severe lesions of MyD88(-/-) mice; the lesions replaced extensive areas of several organs. Therefore, MyD88(-/-) mice were unable to control fungal growth and showed a significantly decreased survival time. In conclusion, our findings demonstrate that MyD88 signaling is important in the activation of fungicidal mechanisms and the induction of protective innate and adaptive immune responses against P. brasiliensis.

Investigation of a new GRASP-based clustering algorithm applied to biological data

A large amount of biological data has been produced in the last years. Important knowledge can be extracted from these data by the use of data analysis techniques. Clustering plays an important role in data analysis, by organizing similar objects from a dataset into meaningful groups. Several clustering algorithms have been proposed in the literature. However, each algorithm has its bias, being more adequate for particular datasets. This paper presents a mathematical formulation to support the creation of consistent clusters for biological data. Moreover. it shows a clustering algorithm to solve this formulation that uses GRASP (Greedy Randomized Adaptive Search Procedure). We compared the proposed algorithm with three known other algorithms. The proposed algorithm presented the best clustering results confirmed statistically. (C) 2009 Elsevier Ltd. All rights reserved.

A hybrid approach to learn with imbalanced classes using evolutionary algorithms

There is an increasing interest in the application of Evolutionary Algorithms (EAs) to induce classification rules. This hybrid approach can benefit areas where classical methods for rule induction have not been very successful. One example is the induction of classification rules in imbalanced domains. Imbalanced data occur when one or more classes heavily outnumber other classes. Frequently, classical machine learning (ML) classifiers are not able to learn in the presence of imbalanced data sets, inducing classification models that always predict the most numerous classes. In this work, we propose a novel hybrid approach to deal with this problem. We create several balanced data sets with all minority class cases and a random sample of majority class cases. These balanced data sets are fed to classical ML systems that produce rule sets. The rule sets are combined creating a pool of rules and an EA is used to build a classifier from this pool of rules. This hybrid approach has some advantages over undersampling, since it reduces the amount of discarded information, and some advantages over oversampling, since it avoids overfitting. The proposed approach was experimentally analysed and the experimental results show an improvement in the classification performance measured as the area under the receiver operating characteristics (ROC) curve.