Unifying a Geometric Framework of Evolutionary Algorithms and Elementary Landscapes Theory

Evolutionary algorithms (EAs) are randomised general-purpose strategies, inspired by natural evolution, often used for finding (near) optimal solutions to problems in combinatorial optimisation. Over the last 50 years, many theoretical approaches in evolutionary computation have been developed to analyse the performance of EAs, design EAs or measure problem difficulty via fitness landscape analysis. An open challenge is to formally explain why a general class of EAs perform better, or worse, than others on a class of combinatorial problems across representations. However, the lack of a general unified theory of EAs and fitness landscapes, across problems and representations, makes it harder to characterise pairs of general classes of EAs and combinatorial problems where good performance can be guaranteed provably. This thesis explores a unification between a geometric framework of EAs and elementary landscapes theory, not tied to a specific representation nor problem, with complementary strengths in the analysis of population-based EAs and combinatorial landscapes. This unification organises around three essential aspects: search space structure induced by crossovers, search behaviour of population-based EAs and structure of fitness landscapes. First, this thesis builds a crossover classification to systematically compare crossovers in the geometric framework and elementary landscapes theory, revealing a shared general subclass of crossovers: geometric recombination P-structures, which covers well-known crossovers. The crossover classification is then extended to a general framework for axiomatically analysing the population behaviour induced by crossover classes on associated EAs. This shows the shared general class of all EAs using geometric recombination P-structures, but no mutation, always do the same abstract form of convex evolutionary search. Finally, this thesis characterises a class of globally convex combinatorial landscapes shared by the geometric framework and elementary landscapes theory: abstract convex elementary landscapes. It is formally explained why geometric recombination P-structure EAs expectedly can outperform random search on abstract convex elementary landscapes related to low-order graph Laplacian eigenvalues. Altogether, this thesis paves a way towards a general unified theory of EAs and combinatorial fitness landscapes

Effects of Methotrexate on IL-6alphar, VCAM-1 and NF Kappa B Expression in a Rat Model of Metabolic Syndrome

Background: In this study, we used Methotrexate (Mtx) to examine the role of immunomodulation on the activation of IL-6 and VCAM-1, which could generate a microenvironment that supports cardiovascular remodelling.Methods: Male WKY and SHR rats were separated into five groups: Control, FFR: WKY rats receiving a 10% (w/v) fructose solution during all 12 weeks, SHR, FFHR: SHR receiving a 10% (w/v) fructose solution during all 12 weeks and FFHR+Mtx (0,3 mg/kg intraperitoneal one injection per day week for 6 weeks) (n = 8 per group). Metabolic variables and systolic blood pressure were measured. Cardiac and vascular remodelling was also evaluated. To assess this, IL-6R and VCAM-1 immunostaining techniques were used.Results: The FFHR experimental model developed metabolic syndrome, vascular and cardiac remodelling, and vascular inflammation because of increased expression of IL-6 and VCAM-1. Chronic treatment with Mtx completely or partiality reversed the variables studied.Conclusions: The results demonstrated an impact on immunomodulation after mtx treatment, which included a reduction in vascular inflammation and a favourable reduction in metabolic and structural parameters.Fil: Renna, Nicolas Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaFil: Ramirez, Jésica M.. Universidad Nacional de Cuyo. Instituto de Genética; ArgentinaFil: García, Rodrigo Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaFil: Diez, Emiliano Raúl. Universidad Nacional de Cuyo. Instituto de Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Miatello, Roberto Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Instituto de Genética; Argentin

Effects of slowed gastrointestinal motility on levodopa pharmacokinetics

P. 67-72Autonomic disorders are often seen in Parkinson's disease, with disturbances of the gastrointestinal tract occurring most frequently. These disorders, mainly a delay in gastric emptying and slowed gastrointestinal motility, can modify the pharmacokinetics and effectiveness of drugs used to treat Parkinson's disease and administered orally. In this study, we evaluated in a rabbit model the pharmacokinetics of levodopa (administered with carbidopa) in the context of gastrointestinal motility slowed by the administration of an anticholinergic drug. Levodopa+carbidopa (20:5 mg/kg) and the anticholinergic biperiden (100 μg/kg) were orally administered to rabbits over one of two time periods (7 or 14 days) to verify the stabilization of levodopa concentrations. The values of the area under the curve (AUC) and Cmax were higher on the final day of treatment with an increase in AUC of 25% on day 7 and 33.4% on day 14; for Cmax, the increase was 15% on day 7 and 12.8% on day 14. The values of AUC and Cmax were lower than those obtained when levodopa was administered to rabbits with normal gastrointestinal motility. The values obtained for Cmin (baseline sample obtained before administration) also increased with treatment duration (24% and 47.4% on days 7 and 14, respectively). These values were higher than those obtained in the absence of anticholinergic administration. We conclude that, under our experimental conditions of slowed gastrointestinal motility, levodopa absorption diminishes, and final concentrations and Cmin are higher than under conditions of normal motility.S

Integrating T-cell epitope annotations with sequence and structural information using DAS

Immunoinformatics is an emerging new field that benefits from computational analyses and tools that facilitate the understanding of the immune system. A large number of immunoinformatics resources such as immune-related databases and analysis software are available through the World Wide Web for the benefit of the research community. However, immunoinformatics developments have sometimes remained isolated from mainstream bioinformatics. Therefore, there is clearly a need for integration, which will empower the exchange of data and annotations within the scientific community in a quick and efficient fashion. Here, we have chosen the Distributed Annotation System (DAS), for integrating in house annotations on experimental and predicted HLA I-restriction elements of CD8 T-cell epitopes with sequence and structural information

Hypoglycemic and hypolipidemic potential of a high fiber diet in healthy versus diabetic rabbits

P. 960568 - 960575The aim of this study was to investigate potential hypoglycaemic and hypolipidemic effects of Plantago ovata husk included in the diet, in healthy and diabetic rabbits. We also examined the effects of this fiber in other biochemical parameters. Two groups of 18 rabbits were used.The first group was fed with standard chow and the second with chow supplemented with Plantago ovata husk (3.5mg/kg/day). On day 14 diabetes mellitus was induced by the intravenous administration of alloxan (80mg/kg). After an oral glucose load (3 g), glucose, insulin, and other biochemical parameters were determined on day 14 (healthy rabbits) and on day 28 (diabetic rabbits). In healthy rabbits, fiber did not modify glucose or insulin levels but decreased significantly total cholesterol, LDL-cholesterol, atherogenic index, and glycosylated hemoglobin. In diabetic rabbits, fiber was more beneficial in mild diabetics than in severe diabetics with significant decreases in glucose levels and increases in insulin concentrations. In these animals fiber caused an important reduction in cholesterol, indicating a beneficial effect of Plantago ovata husk in diabetic rabbits. Although further studies in patients are necessary, we think that Plantago ovata husk offers interesting perspectives to be administered to patients with diabetes mellitus.S

Taxonomic review of selected invertebrate groups collected during the Campaigns of the Prince Albert I of Monaco in the Azorean waters.

In the late 19th and early 20th centuries Prince Albert I of Monaco promoted 13 cruises that sampled the Azorean waters. During those cruises a total of 2624 nominal marine species were reported in the area. This work assembles the biological data provided by these expeditions to the Azores in a geo-referenced database. Faunal lists for seven invertebrate groups (Echiura, Sipuncula, Cephalopoda, Annelida, Brachiopoda, Chaetognatha and Echinodermata) are compiled. The checklist includes 331 nominal species, of which 310 are valid names: 1 echiurid; 11 sipunculids; 32 cephalopods; 130 annelids; 4 brachiopods; 14 chaetognaths; and 118 echinoderms. Eighteen percent are synonyms, 29% of the species were allocated to a different genus, 2.8% were misspellings and corrections due to gender or concordance rules, 0.8% were specific epithets allocated to sub-specific level or vice-versa, the rest were validated directly (without any modification in their nomenclature)

Parasitostatic effect of maslinic acid. I. Growth arrest of Plasmodium falciparum intraerythrocytic stages

<p>Abstract</p> <p>Background</p> <p>Natural products have played an important role as leads for the development of new drugs against malaria. Recent studies have shown that maslinic acid (MA), a natural triterpene obtained from olive pomace, which displays multiple biological and antimicrobial activities, also exerts inhibitory effects on the development of some Apicomplexan, including <it>Eimeria, Toxoplasma </it>and <it>Neospora</it>. To ascertain if MA displays anti-malarial activity, the main objective of this study was to asses the effect of MA on <it>Plasmodium falciparum</it>-infected erythrocytes <it>in vitro</it>.</p> <p>Methods</p> <p>Synchronized <it>P. falciparum</it>-infected erythrocyte cultures were incubated under different conditions with MA, and compared to chloroquine and atovaquone treated cultures. The effects on parasite growth were determined by monitoring the parasitaemia and the accumulation of the different infective stages visualized in thin blood smears.</p> <p>Results</p> <p>MA inhibits the growth of <it>P. falciparum </it>Dd2 and 3D7 strains in infected erythrocytes in, dose-dependent manner, leading to the accumulation of immature forms at IC₅₀concentrations, while higher doses produced non-viable parasite cells. MA-treated infected-erythrocyte cultures were compared to those treated with chloroquine or atovaquone, showing significant differences in the pattern of accumulation of parasitic stages. Transient MA treatment at different parasite stages showed that the compound targeted intra-erythrocytic processes from early-ring to schizont stage. These results indicate that MA has a parasitostatic effect, which does not inactivate permanently <it>P. falciparum</it>, as the removal of the compound allowed the infection to continue</p> <p>Conclusions</p> <p>MA displays anti-malarial activity at multiple intraerythrocytic stages of the parasite and, depending on the dose and incubation time, behaves as a plasmodial parasitostatic compound. This novel parasitostatic effect appears to be unrelated to previous mechanisms proposed for current anti-malarial drugs, and may be relevant to uncover new prospective plasmodial targets and opens novel possibilities of therapies associated to host immune response.</p

Haemoglobin interference and increased sensitivity of fluorimetric assays for quantification of low-parasitaemia Plasmodium infected erythrocytes

<p>Abstract</p> <p>Background</p> <p>Improvements on malarial diagnostic methods are currently needed for the correct detection in low-density <it>Plasmodium falciparum </it>infections. Microfluorimetric DNA-based assays have been previously used for evaluation of anti-malarial drug efficacy on <it>Plasmodium </it>infected erythrocytes. Several factors affecting the sensitivity of these methods have been evaluated, and tested for the detection and quantification of the parasite in low parasitaemia conditions.</p> <p>Methods</p> <p>Parasitaemia was assessed by measuring SYBRGreen I^®(SGI) and PicoGreen^®(PG) fluorescence of <it>P. falciparum </it>Dd2 cultures on human red blood cells. Different modifications of standard methods were tested to improve the detection sensitivity. Calculation of IC₅₀for chloroquine was used to validate the method.</p> <p>Results</p> <p>Removal of haemoglobin from infected red-blood cells culture (IRBC) increased considerably the fluorescent signal obtained from both SGI and PG. Detergents used for cell lysis also showed to have an effect on the fluorescent signal. Upon depletion of haemoglobin and detergents the fluorescence emission of SGI and PG increased, respectively, 10- and 60-fold, extending notably the dynamic range of the assay. Under these conditions, a 20-fold higher PG vs. SGI fluorescent signal was observed. The estimated limits of detection and quantification for the PG haemoglobin/detergent-depleted method were 0.2% and 0.7% parasitaemia, respectively, which allow the detection of ~10 parasites per microliter. The method was validated on whole blood-infected samples, displaying similar results as those obtained using IRBC. Removal of white-blood cells prior to the assay allowed to increase the accuracy of the measurement, by reducing the relative uncertainty at the limit of detection from 0.5 to 0.1.</p> <p>Conclusion</p> <p>The use of PG microassays on detergent-free, haemoglobin-depleted samples appears as the best choice both for the detection of <it>Plasmodium </it>in low-density infections and anti-malarial drugs tests.</p

Parasitostatic effect of maslinic acid. II. Survival increase and immune protection in lethal Plasmodium yoelii-infected mice

<p>Abstract</p> <p>Background</p> <p>The anti-malarial activity of maslinic acid (MA), a natural triterpene which has been previously shown to exert a parasitostatic action on <it>Plasmodium falciparum </it>cultures, was analysed <it>in vivo </it>by using the <it>Plasmodium yoelii </it>17XL murine model.</p> <p>Methods</p> <p>ICR mice were infected with <it>P. yoelii </it>and treated with a single dose of MA by a intraperitoneal injection of MA (40 mg kg^-1day^-1) followed by identical dose administration for the following three days. Parasitaemia and accumulation of intraerythrocytic stages was monitored microscopically. To assess protective immunity, cured mice were challenged with the same dose of parasites 40 days after recovery from the primary infection and parasitaemia was further monitored for 30 days. Humoral response was tested by ELISA and visualization of specific anti-<it>P. yoelii </it>antibodies was performed by Western-blotting.</p> <p>Results</p> <p>ICR mice treated with MA increased the survival rate from 20% to 80%, showing an arrest of parasite maturation from day 3 to 7 after infection and leading to synchronization of the intraerythrocytic cycle and accumulation of schizonts by day 6, proving that MA also behaves as a parasitostatic agent <it>in vivo</it>. Mice which survived the primary infection displayed lower rates of parasitic growth, showing a decline of parasitaemia after day 15, and complete clearance at day 20. These mice remained immunoprotected, showing not malaria symptoms or detectable parasitaemia after rechallenge with the same lethal strain. The analysis of specific antibodies against <it>P. yoelii</it>, present in mice which survived the infection, showed a significant increase in the number and intensity of immunoreactive proteins, suggesting that the protected mice may trigger a strong humoral response.</p> <p>Conclusion</p> <p>The survival increase observed in MA-treated mice can be explained considering that the parasitostatic effect exerted by this compound during the first days of infection increases the chances to develop effective innate and/or acquired immune responses. MA may represent a new class of anti-malarial compounds which, as a consequence of its parasitostatic action, favours the development of more effective sterilizing immune responses.</p