A machine learning approach for genome-wide prediction of morbid and druggable human genes based on systems-level data

Background: The genome-wide identification of both morbid genes, i.e., those genes whose mutations cause hereditary human diseases, and druggable genes, i.e., genes coding for proteins whose modulation by small molecules elicits phenotypic effects, requires experimental approaches that are time-consuming and laborious. Thus, a computational approach which could accurately predict such genes on a genome-wide scale would be invaluable for accelerating the pace of discovery of causal relationships between genes and diseases as well as the determination of druggability of gene products.Results: In this paper we propose a machine learning-based computational approach to predict morbid and druggable genes on a genome-wide scale. For this purpose, we constructed a decision tree-based meta-classifier and trained it on datasets containing, for each morbid and druggable gene, network topological features, tissue expression profile and subcellular localization data as learning attributes. This meta-classifier correctly recovered 65% of known morbid genes with a precision of 66% and correctly recovered 78% of known druggable genes with a precision of 75%. It was than used to assign morbidity and druggability scores to genes not known to be morbid and druggable and we showed a good match between these scores and literature data. Finally, we generated decision trees by training the J48 algorithm on the morbidity and druggability datasets to discover cellular rules for morbidity and druggability and, among the rules, we found that the number of regulating transcription factors and plasma membrane localization are the most important factors to morbidity and druggability, respectively.Conclusions: We were able to demonstrate that network topological features along with tissue expression profile and subcellular localization can reliably predict human morbid and druggable genes on a genome-wide scale. Moreover, by constructing decision trees based on these data, we could discover cellular rules governing morbidity and druggability.

Comparison of naturally acquired parasite burdens among Florida Native, Rambouillet and crossbreed ewes

The response to natural infection by gastrointestinal nematodes was evaluated in three groups of lambing mature ewes: 16 Florida Native; 21 Rambouillet; and 18 1/2 Florida Native x 1/2 Rambouillet (F1 generation). Fecal egg counts (FEC),packed cell volume (PCV) and plasma protein levels were determined periodically through a one-year period. The highest FEC was recorded in Rambouillet ewes, with most of the means higher than 1000 eggs per gram (EPG). Florida Native and Fl ewes showed similar trends in FEC, with most of the means below 500 EPG. The highest mean PCV values were recorded in Florida Native ewes, followed in decreasing order by Fl and Rambouillet ewes. Fl ewes showed the lowest plasma protein levels and Florida Natives the highest. Fecal cultures revealed the highest percentages of Haemonchus larvae in Rambouillet ewes (>64%) and the lowest percentages in Florida Native ewes. Florida Native and Fl ewes were more resistant to gastrointestinal nematode infections than were Rambouillet ewes. High negative correlation coefficients between FEC x PCV and FEC x plasma protein levels coincided with peaks in mean FEC of Rambouillet (May and July), Florida Native and Fl ewes (October). This study showed that crossbreeding Rambouillet and Florida Native sheep resulted in the production of Fl ewes resistant against gastrointestinal nematode infections. (C) 1999 Elsevier B.V. B.V. All rights reserved.

Nematode burdens and cellular responses in the abomasal mucosa and blood of Florida Native, Rambouillet and crossbreed lambs

This experiment was carried out to compare the worm burden and cellular responses in the abomasal mucosa and blood of Florida Native and Rambouillet lambs and also in animals produced by crosses of these two breeds (generations F1 and F2). Animals were exposed to infection by gastrointestinal nematodes on three different occasions. The first infection was natural, occurring while they were suckling lambs. After weaning, they were kept indoors for 53 days and then were allowed to graze a contaminated pasture for 50 days for a second natural infection. The third infection was an artificial challenge with 6000 Haemonchus contortus infective larvae. The highest mean fecal egg counts (FEC) values were found in Rambouillet lambs followed in decreasing order by F1, F2 and Florida Native lambs. Throughout the trial, most of the high mean packed cell volumes and plasma protein levels were recorded in the F2 lambs; in contrast, most of the low values were found in the Rambouillet lambs. During the natural infection period, the highest percentages of larvae in the fecal cultures of the lambs were Haemonchus. However, high percentages of Trichostrongylus larvae were found particularly in Florida Native lambs. The mean number of blood eosinophils increased after the artificial challenge, reached a peak 21 days after infection and then declined. The highest and lowest blood eosinophil means were recorded in F2 and Florida Native lambs, respectively. The H. contortus burden was significantly higher in Rambouillet and in F1 lambs than in Florida Native and F2 lambs (p < 0.05), while no significant differences were recorded among eosinophil, mast cell and globule leucocyte counts in the abomasal mucosa (p > 0.05). The highest correlation coefficient recorded at the end of this study was between FEC and worm burden (r = 0.7). These two parameters showed a moderate negative correlation with PCV, plasma protein and mast cell counts in the abomasal mucosa. The results obtained in this study indicate that crossbreeding Florida Native and Rambouillet sheep can be a rapid way to combine and improve the characteristics of these two breeds. The parasitological results were promising. however, more studies will be necessary to verify the impact of crossbreeding in other traits. (C) 1999 Elsevier B.V. B.V. All rights reserved.

Resistance of Santa Ines, Suffolk and Ile de France sheep to naturally acquired gastrointestinal nematode infections

A study was conducted to assess the breed resistance against nematode infections in Santa Ines, Ile de France and Suffolk male lambs over a 9-month period in São Paulo state, Brazil. Lambs were born during the winter (year 2000) and were weaned at 2 months of age. The animals were then housed and treated with anthelmintics to eliminate natural infections by gastrointestinal nematodes. In late October 2000, lambs were placed in a paddock, where they stayed until August of the following year. Fecal and blood samples were taken from each animal every 2 weeks. on the same day, a pasture sample was collected to determine the number of infective larvae on the herbage. To prevent deaths, individual treatment with anthelmintics was provided to lambs with fecal egg counts (FEC) higher than 4000 eggs per gram (EPG) or with a packed cell volume (PCV) lower than 21%. In August 2001, all animals were slaughtered and the worms present in samples of the gastrointestinal contents were identified and counted. Most of the Suffolk and Ile de France sheep received three to six anthelmintic treatments over a period of 7 months, while most of the Santa Ines were not treated. Reductions in PCV and plasma protein values associated with high FEC and worm burdens were recorded, particularly, in Suffolk and Ile de France lambs. Haemonchus contortus and Oesophagostomum columbianum burdens and number of nodular lesions caused in the large intestine by O. columbianum larvae were significantly lower in Santa Ines sheep. All three breeds showed similar Trichostrongylus colubriformis worm burdens. The relative resistance of Santa Ines young male sheep was superior to that of Suffolk and Ile de France sheep. (C) 2004 Elsevier B.V. All rights reserved.

PRODUCTION of FREE RADICALS and CATALASE ACTIVITY DURING ACUTE EXERCISE TRAINING IN YOUNG MEN

Reactive oxygen species (ROS) are constantly produced by cells that promote cellular oxidative damage and are neutralized by an antioxidant system including superoxide dismutase, glutathione, peroxidase and catalase. Male volunteers were exercised for 20 minutes, three days (60, 70 and 80% of maximum heart rate). Catalase activity and plasma malondialdehyde concentration were measured. The mean age of the volunteers was 25 +/- 7 years, with body mass index 2 of 24.03 +/- 4.32 kg/m(2). Acute exercise training produced an increase of malondialdehyde concentration that was exercise intensity-dependent in young volunteers. However, catalase activity shows a great variability at baseline and the percentual of reduction was exercise intensity-independent in this particular population. Therefore, our study shows that acute cycling exercise promotes an increase of oxidative stress that was exercise intensity-dependent in young volunteers. Furthermore, the antioxidant system measured by catalase activity was effective to counterbalance the ROS production showing a saturation behavior at an intensity of 70% of maximum heart rate.

A seasonally dependent change in the distribution and physiological condition of Caiman crocodilus yacare in the Paraguay River Basin

The distribution and physiological condition of 116 Caiman crocodilus yacare was assessed over one year in the Southern Pantanal. Body mass and intermediary plasma metabolites were measured at three different time periods, representing large differences in the abundance of surface water. During the wet season the study site was completely submerged under water and C. c. yacare were distributed evenly throughout. High levels of [glucose] and [triglyceride] in the plasma indicated regular feeding. As the dry season progressed C. c. yacare became increasingly crowded around the remaining ponds. They showed a reduction in plasma [glucose] and [triglyceride], and an increase in plasma [beta-hydroxy-butyrate], signifying that they were feeding less and utilising fat reserves. At this sampling period, similar to 40% of the male C. c. yacare that were > 10 years old inhabited dry grassland and did not have access to water. These animals were significantly lighter than males of a similar length that had immediate water access, and plasma [uric acid] indicated that they had not fed for a long time and were metabolising tissue proteins. Essentially, the adult male C. c. yacare that inhabited dry grassland were in a state of energy deficiency. This was so severe in some animals that recovery seemed unlikely. The study suggests that fluctuations in the abundance of surface ground water may influence the size and structure of the C. c. yacare population in the Pantanal.

Optical and Structural Properties of Zein-Xanthan Gum Biofilms

Structural and optical characteristics of zein-based films produced with different xanthan gum concentrations have been studied in this work. Scanning electronic microscopy (SEM) and optical microscopy (OM) were performed to identify if the incorporation of the material into the matrix film, formed a homogeneous structure, as well as to characterize its constituents as the colour and shape. SEM showed a homogeneous matrix for the control (0% xanthan) with good lipid distribution. However, when the samples were investigated by OM, lipids globules in the control biofilm appeared larger and more dispersed in the matrix than the others samples. Transparency/opacity test measurements by UV-VIS analysis indicated that the addition of xanthan to the film matrix lowered significantly its transparency properties Overall, the addition of xanthan gum favoured lipid dispersion in the matrix, making biomaterials more homogeneous, although with less transparency.

Effect of Static and Cyclic Loading on Ceramic Laminate Veneers Adhered to Teeth with and Without Aged Composite Restorations

Purpose: Existing composite restorations on teeth are often remade prior to the cementation of fixed dental prostheses. The aim of this study was to evaluate the effect of static and cyclic loading on ceramic laminate veneers adhered to aged resin composite restorations.Materials and Methods: Eighty sound maxillary incisors were collected and randomly divided into four groups: group 1: control group, no restorations; group 2: two Class III restorations; group 3: two Class IV restorations; group 4: complete composite substrate. Standard composite restorations were made using a microhybrid resin composite (Anterior Shine). Restored teeth were subjected to thermocycling (6000 cycles). Window preparations were made on the labial surface of the teeth for ceramic laminate fabrication (Empress II). Teeth were conditioned using an etch-and-rinse system. Existing composite restorations representing the aged composites were silica coated (CoJet) and silanized (ESPE-Sil). Ceramic laminates were cemented using a bis-GMA-based cement (Variolink Veneer). The specimens were randomly divided into two groups and were subjected to either static (groups 1a, 2a, 3a, 4a) or cyclic loading (groups 1b, 2b, 3b, 4b). Failure type and location after loading were classified. Data were analyzed using one-way ANOVA and Tukey's test.Results: Significantly higher fracture strength was obtained in group 4 (330 +/- 81 N) compared to the controls in group 1 (179 +/- 120 N) (one-way ANOVA, p < 0.05). Group lb survived a lower mean number of cyclic loads (672,820 cycles) than teeth of groups 2b to 4b (846x10(3) to 873x10(3) cycles). Failure type evaluation after the fracture test showed predominantly adhesive failures between dentin and cement, but after cyclic loading, more cohesive fractures in the ceramic were seen.Conclusion: Ceramic laminate veneers bonded to conditioned aged composite restorations provided favorable results. Surface conditioning of existing restorations may eliminate the necessity of removing aged composite restorations.

Influence of support on catalytic behavior of nickel catalysts in the steam reforming of ethanol for hydrogen production

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Burnt sugarcane harvesting: Particulate matter exposure and the effects on lung function, oxidative stress, and urinary 1-hydroxypyrene

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Evaluation of the haematological parameters in Piaractus mesopotamicus Holmberg (Osteichthyes, Characidae) with Argulus sp. (Crustacea, Branchiura) infestation and treatment with organophosphate

Haematological parameters as erythrocytes, leukocytes and plasma glucose in Piaractus mesopotamicus Holmberg, 1887 were analyzed. Fish were parasitized with Argulus sp. (Crustacea, Branchiura) and treated with 0.4 mg of thriclorphon 500/L water. The effects of parasitism and the action of the treatment were evaluated. Parasitized fish showed greater number of monocytes (P>0.05) and special granulocitic cells (P<0.01) in the peripheric blood than the unparasitized (control) fish. Parasitized fish showed lower number of thrombocytes (P>0.05). Organophosphate treatment presented significantly reduction (P>0.05) in red blood cells (RBC) and hemoglobin.

Endocrine profiles and ovulation rate of cows superovulated with FSH following passive immunization against steroid free-bovine follicular fluid

Dez vacas multíparas, secas, foram distribuídas aleatoriamente em dois grupos de cinco animais cada. Nos dias 8 a 12 do diestro, o primeiro grupo recebeu 100 ml de anti-soro contra líquido folicular livre de esteróides (anti-LFb) produzido em ovelhas ovariectomizadas. O segundo grupo (controle) recebeu 100 ml de soro de ovelhas não-imunizadas. Seis horas após a aplicação, os dois grupos foram superovulados com FSH (18 NIH-FSH-S1 unidades) e LH (0,29 NIH-LH-S1 unidades) administrados em quantidades decrescentes durante quatro dias. Na manhã do terceiro dia, foi administrada uma dose luteolítica de cloprostenol. Duas inseminações foram realizadas 48 e 60 horas após. Os embriões foram recuperados pelo método cervical 7 dias após a primeira inseminação. Amostras de sangue foram coletadas durante todo o período experimental para determinar, por radioimunoensaio, as concentrações plasmáticas de FSH, LH e progesterona. Todas as vacas do grupo imunizado e 3 do grupo controle apresentaram mais de 2 CL. Não existiu diferença significativa (P>0,05) na taxa de ovulação entre os grupos imunizado e controle (14,4 e 9,9, respectivamente). O número de embriões recuperado não foi significativamente diferente (P>0,05) entre os grupos, embora o grupo imunizado tenha apresentado maior número de embriões transferíveis (3,4 ± 1,0 versus 0,8 ± 0,4, P<0,05). As concentrações de gonadotrofinas plasmáticas não foram correlacionadas com a taxa de ovulação ou com o número de embriões recuperados. As concentrações de progesterona plasmática foram positivamente correlacionadas (r = 0,88, P<0,01) com a taxa de ovulação. Os resultados sugerem que o anti-LFb, aplicado antes da superovulação, não reduz a variabilidade da resposta ovariana.

Interaction between vitamin K nutriture and bacterial overgrowth in hypochlorhydria induced by omeprazole

Subjects taking a hydrogen pump blocking agent (omeprazole) develop bacterial overgrowth of the small intestine. We tested the hypothesis that this bacterial overgrowth produces menaquinones, which would meet the Vitamin requirement in situations of vitamin K deficiency. In a crossover-type design, 13 healthy Volunteers eating a phylloquinone-restricted diet for 35 d were randomly assigned to take omeprazole during the first period of study or starting on day 15 until the end of the study. Coagulation times, serum osteocalcin [total osteocalcin and undercarboxylated osteocalcin (ucOC)], plasma phylloquinone, urinary gamma-carboxyglutamic acid, and plasma undercarboxylated prothrombin (PIVKA-II) were measured. Plasma phylloquinone concentrations declined 82% with dietary phylloquinone restriction (P < 0.05) and were not significantly different in the period when the diet was combined with omeprazole treatment (P > 0.05), the mean value for PIVKA-II during the phylloquinone-restricted diet significantly increased 5.7-fold from baseline (P < 0.05); however, the combination of omeprazole treatment and the phylloquinone-restricted diet significantly reduced PIVKA-II values by 21% (P < 0.05) compared with the diet period alone. There were no alterations in total or percentage ucOC concentrations during the phylloquinone-restricted diet or during the period of diet plus omeprazole treatment. Our data support the hypothesis that bacterial overgrowth results in the synthesis and absorption of menaquinones. These menaquinones contribute to vitamin K nutriture during dietary phylloquinone restriction, but not enough to restore normal vitamin K status.

Midazolam and ketamine induction before halothane anaesthesia in ponies: cardiorespiratory, endocrine and metabolic changes

Six Welsh gelding ponies were premedicated with 0.03 mg/kg of acepromazine intravenously (i.v.) prior to induction of anaesthesia with midazolam at 0.2 mg/kg and ketamine at 2 mg/kg i.v.. Anaesthesia was maintained for 2 h using 1.2% halothane concentration in oxygen. Heart rate, electrocardiograph (EGG), arterial blood pressure, respiratory rate, blood gases, temperature, haematocrit, plasma arginine vasopressin (AVP), dynorphin, beta-endorphin, adrenocorticotropic hormone (ACTH), cortisol, dopamine, noradrenaline, adrenaline, glucose and lactate concentrations were measured before and after premedication, immediately after induction, every 20 min during anaesthesia, and at 20 and 120 min after disconnection. Induction was rapid, excitement-free and good muscle relaxation was observed. There were no changes in heart and respiratory rates, Decrease in temperature, hyperoxia and respiratory acidosis developed during anaesthesia and slight hypotension was observed (minimum value 76 +/- 10 mm Hg at 40 mins), No changes were observed in dynorphin, beta-endorphin, ACTH, catecholamines and glucose, Plasma cortisol concentration increased from 220 +/- 17 basal to 354 +/- 22 nmol/L at 120 min during anaesthesia; plasma AVP concentration increased from 3 +/- 1 basal to 346 +/- 64 pmol/L at 100 min during anaesthesia and plasma lactate concentration increased from 1.22 +/- 0.08 basal to 1.76 +/- 0.13 mmol/L at 80 min during anaesthesia, Recovery was rapid and uneventful with ponies taking 46 +/- 6 min to stand. When midazolam/ketamine was compared with thiopentone or detomidine/ketamine for induction before halothane anaesthesia using an otherwise similar protocol in the same ponies, it caused slightly more respiratory depression, but less hypotension. Additionally, midazolam reduced the hormonal stress response commonly observed during halothane anaesthesia and appears to have a good potential for use in horses.

Comparative susceptibility and pathogeny of Nelore and Holstein-Friesian calves to the experimental infection of Haemonchus placei (Place, 1893)

Two groups of Holstein-Friesian and Nelore calves, five animals each, about nine months old, received, by oral route, 1,000 infective larvae (L-3) per kg of body weight of Haemonchus placei. Blood samples were collected by venipuncture, at weekly intervals, from one week before, to eight weeks after infection. Hematological studies comprised the hematocrit, differential leukocyte counts, hemoglobin, fibrinogen and plasma protein determinations. Parasitological examinations covered weekly fecal egg counts (EPG) and worm burden counts at necropsy. Samples of the abomasal mucosa were submitted to gross examination and histopathological studies. Both groups had increasing EPG after the fifth week, with Holstein calves showing higher counts than the Nelore. Holstein calves had anemia and hipoproteinemia from the third week post-infection to the end of the experiment, whereas Nelore calves showed no significant differences in those, parameters. Holstein calves had significantly larger worm counts than the Nelore. The gross and histopathological lesions in the abomasum at necropsy were very similar, although macroscopically they look more apparent in the Holstein group. These results showed that Holstein calves are more susceptible to the infection and pathogenic effects of H. placei than Nelore calves.