Discovering patterns in drug-protein interactions based on their fingerprints

<p>Abstract</p> <p>Background</p> <p>The discovering of interesting patterns in drug-protein interaction data at molecular level can reveal hidden relationship among drugs and proteins and can therefore be of paramount importance for such application as drug design. To discover such patterns, we propose here a computational approach to analyze the molecular data of drugs and proteins that are known to have interactions with each other. Specifically, we propose to use a data mining technique called <it>Drug-Protein Interaction Analysis </it>(<it>D-PIA</it>) to determine if there are any commonalities in the fingerprints of the substructures of interacting drug and protein molecules and if so, whether or not any patterns can be generalized from them.</p> <p>Method</p> <p>Given a database of drug-protein interactions, <it>D-PIA </it>performs its tasks in several steps. First, for each drug in the database, the fingerprints of its molecular substructures are first obtained. Second, for each protein in the database, the fingerprints of its protein domains are obtained. Third, based on known interactions between drugs and proteins, an interdependency measure between the fingerprint of each drug substructure and protein domain is then computed. Fourth, based on the interdependency measure, drug substructures and protein domains that are significantly interdependent are identified. Fifth, the existence of interaction relationship between a previously unknown drug-protein pairs is then predicted based on their constituent substructures that are significantly interdependent.</p> <p>Results</p> <p>To evaluate the effectiveness of <it>D-PIA</it>, we have tested it with real drug-protein interaction data. <it>D-PIA </it>has been tested with real drug-protein interaction data including enzymes, ion channels, and protein-coupled receptors. Experimental results show that there are indeed patterns that one can discover in the interdependency relationship between drug substructures and protein domains of interacting drugs and proteins. Based on these relationships, a testing set of drug-protein data are used to see if <it>D-PIA </it>can correctly predict the existence of interaction between drug-protein pairs. The results show that the prediction accuracy can be very high. An AUC score of a ROC plot could reach as high as 75% which shows the effectiveness of this classifier.</p> <p>Conclusions</p> <p><it>D-PIA </it>has the advantage that it is able to perform its tasks effectively based on the fingerprints of drug and protein molecules without requiring any 3D information about their structures and <it>D-PIA </it>is therefore very fast to compute. <it>D-PIA </it>has been tested with real drug-protein interaction data and experimental results show that it can be very useful for predicting previously unknown drug-protein as well as protein-ligand interactions. It can also be used to tackle problems such as ligand specificity which is related directly and indirectly to drug design and discovery.</p

Efficacy of Single-Dose and Triple-Dose Albendazole and Mebendazole against Soil-Transmitted Helminths and Taenia spp.: A Randomized Controlled Trial

BACKGROUND: The control of soil-transmitted helminth (STH) infections currently relies on the large-scale administration of single-dose oral albendazole or mebendazole. However, these treatment regimens have limited efficacy against hookworm and Trichuris trichiura in terms of cure rates (CR), whereas fecal egg reduction rates (ERR) are generally high for all common STH species. We compared the efficacy of single-dose versus triple-dose treatment against hookworm and other STHs in a community-based randomized controlled trial in the People's Republic of China. METHODOLOGY/PRINCIPAL FINDINGS: The hookworm CR and fecal ERR were assessed in 314 individuals aged </=5 years who submitted two stool samples before and 3-4 weeks after administration of single-dose oral albendazole (400 mg) or mebendazole (500 mg) or triple-dose albendazole (3x400 mg over 3 consecutive days) or mebendazole (3x500 mg over 3 consecutive days). Efficacy against T. trichiura, Ascaris lumbricoides, and Taenia spp. was also assessed. ALBENDAZOLE CURED SIGNIFICANTLY MORE HOOKWORM INFECTIONS THAN MEBENDAZOLE IN BOTH TREATMENT REGIMENS (SINGLE DOSE: respective CRs 69% (95% confidence interval [CI]: 55-81%) and 29% (95% CI: 20-45%); triple dose: respective CRs 92% (95% CI: 81-98%) and 54% (95% CI: 46-71%)). ERRs followed the same pattern (single dose: 97% versus 84%; triple dose: 99.7% versus 96%). Triple-dose regimens outperformed single doses against T. trichiura; three doses of mebendazole - the most efficacious treatment tested - cured 71% (95% CI: 57-82%). Both single and triple doses of either drug were highly efficacious against A. lumbricoides (CR: 93-97%; ERR: all <99.9%). Triple dose regimens cured all Taenia spp. infections, whereas single dose applications cured only half of them. CONCLUSIONS/SIGNIFICANCE: Single-dose oral albendazole is more efficacious against hookworm than mebendazole. To achieve high CRs against both hookworm and T. trichiura, triple-dose regimens are warranted. CONCLUSIONS/SIGNIFICANCE: Single-dose oral albendazole is more efficacious against hookworm than mebendazole. To achieve high CRs against both hookworm and T. trichiura, triple-dose regimens are warranted. TRIAL REGISTRATION: www.controlled-trials.comISRCTN4737502

Patterns and Risk Factors of Helminthiasis and Anemia in a Rural and a Peri-urban Community in Zanzibar, in the Context of Helminth Control Programs

In many parts of the developing world, parasitic worms and anemia are of considerable public health and economic importance. We studied the patterns and risk factors of parasitic worm infections in a rural and a peri-urban community on Zanzibar Island, Tanzania, in the context of national deworming programs. We invited 658 individuals aged between 5 and 100 years and examined their stool and urine for the presence of parasitic worm eggs. Additionally, we obtained a finger-prick blood sample to estimate the level of anemia and to assess for specific immune reactions against parasitic worm infections. We found that, despite large-scale deworming efforts in Zanzibar over the past 15 years, three-quarter of the rural participants and half of the peri-urban residents were infected with parasitic worms. Every second participant was anemic. Risk factors for a parasitic worm infection were age, sex, consumption of raw vegetables or salad, recent travel history, and socio-economic status. For a sustainable control of parasitic worm infections and prevention of anemia, access to safe and efficacious drugs, complemented with health education and improvements in water supply and adequate sanitation are necessary

Safety, Immunogenicity and Duration of Protection of the RTS,S/AS02D Malaria Vaccine: One Year Follow-Up of a Randomized Controlled Phase I/IIb Trial

The RTS,S/AS02(D) vaccine has been shown to have a promising safety profile, to be immunogenic and to confer protection against malaria in children and infants.We did a randomized, controlled, phase I/IIb trial of RTS,S/AS02(D) given at 10, 14 and 18 weeks of age staggered with routine immunization vaccines in 214 Mozambican infants. The study was double-blind until the young child completed 6 months of follow-up over which period vaccine efficacy against new Plasmodium falciparum infections was estimated at 65.9% (95% CI 42.6-79.8, p<0.0001). We now report safety, immunogenicity and estimated efficacy against clinical malaria up to 14 months after study start. Vaccine efficacy was assessed using Cox regression models. The frequency of serious adverse events was 32.7% in the RTS,S/AS02(D) and 31.8% in the control group. The geometric mean titers of anti-circumsporozoite antibodies declined from 199.9 to 7.3 EU/mL from one to 12 months post dose three of RTS,S/AS02(D), remaining 15-fold higher than in the control group. Vaccine efficacy against clinical malaria was 33% (95% CI: -4.3-56.9, p = 0.076) over 14 months of follow-up. The hazard rate of disease per 2-fold increase in anti-CS titters was reduced by 84% (95% CI 35.1-88.2, p = 0.003).The RTS,S/AS02(D) malaria vaccine administered to young infants has a good safety profile and remains efficacious over 14 months. A strong association between anti-CS antibodies and risk of clinical malaria has been described for the first time. The results also suggest a decrease of both anti-CS antibodies and vaccine efficacy over time.ClinicalTrials.gov NCT00197028

Molecular Epidemiology of Neisseria meningitidis Serogroup B in Brazil

Background: Neisseria meningitidis serogroup B has been predominant in Brazil, but no broadly effective vaccine is available to prevent endemic meningococcal disease. To understand genetic diversity among serogroup B strains in Brazil, we selected a nationally representative sample of clinical disease isolates from 2004, and a temporally representative sample for the state of São Paulo (1988-2006) for study (n = 372). Methods: We performed multi-locus sequence typing (MLST) and sequence analysis of five outer membrane protein (OMP) genes, including novel vaccine targets fHbp and nadA. Results: In 2004, strain B:4:P1.15,19 clonal complex ST-32/ET-5 (cc32) predominated throughout Brazil; regional variation in MLST sequence type (ST), fetA, and porB was significant but diversity was limited for nadA and fHbp. Between 1988 and 1996, the São Paulo isolates shifted from clonal complex ST-41/44/Lineage 3 (cc41/44) to cc32. OMP variation was associated with but not predicted by cc or ST. Overall, fHbp variant 1/subfamily B was present in 80% of isolates and showed little diversity. The majority of nadA were similar to reference allele 1. Conclusions: A predominant serogroup B lineage has circulated in Brazil for over a decade with significant regional and temporal diversity in ST, fetA, and porB, but not in nadA and fHbp

Urban malaria and associated risk factors in Jimma town, south-west Ethiopia

<p>Abstract</p> <p>Background</p> <p>Malaria kills millions around the world. Until recently it was believed to be a disease of rural areas, since the <it>Anopheles </it>mosquito, which transmits <it>Plasmodium </it>species breeds in rural areas. Urban malaria is emerging as a potential, but "avertable" crisis, in Africa. In view of the rapidly growing number of small and medium-sized towns in Ethiopia there is a pressing need to improve the understanding of the epidemiology of malaria. Therefore, the aim of this study was to determine malaria prevalence and associated risk factors in Jimma town.</p> <p>Methods</p> <p>A cross-sectional study was carried out in Jimma town from April 1 to May 28, 2010. 804 study participants were included from 291 households for microscopic examination of malaria parasites. Socio-demography data and risk factors were collected using structured questionnaires. Logistic regression analysis was done using SPSS 15.0 statistical software.</p> <p>Results</p> <p>From a total of 804 study participants in current survey only 42 (5.2%) were positive for malaria parasites. <it>Plasmodium vivax, Plasmodium falciparum </it>and mixed infection accounted 71.4%, 26.2% and 2.4%, respectively. Higher malaria prevalence rate was observed among under-five children (11%). Those who do not use insecticide-treated bed nets (ITN) were more likely to be infected with malaria (OR = 13.6; 95% CI 4.9-37.2, p < 0.001) compared with those who use the ITN. Living in areas where stagnant water existed (OR = 2.1; 95% CI 1.00-4.2, p = 0.047) and its distance of existence <1 km from the house(OR = 2.1; 95% CI 2.0-15.8, p = 0.001) were more likely to be infected with malaria parasite compared with those who live away from stagnant at a distance greater than 1 km.</p> <p>Conclusion</p> <p>Malaria is a major health problem with <it>P. vivax </it>becoming a predominant species in the town. The prevalence was strongly associated with proximity of residence to potential mosquito breeding sites. Malaria is affecting significant proportions of the urban settlers and human activities nevertheless play an important role in bringing the mosquito breeding sites closer to residences.</p

A Research Agenda for Helminth Diseases of Humans: Intervention for Control and Elimination

Recognising the burden helminth infections impose on human populations, and particularly the poor, major intervention programmes have been launched to control onchocerciasis, lymphatic filariasis, soil-transmitted helminthiases, schistosomiasis, and cysticercosis. The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. A summary of current helminth control initiatives is presented and available tools are described. Most of these programmes are highly dependent on mass drug administration (MDA) of anthelmintic drugs (donated or available at low cost) and require annual or biannual treatment of large numbers of at-risk populations, over prolonged periods of time. The continuation of prolonged MDA with a limited number of anthelmintics greatly increases the probability that drug resistance will develop, which would raise serious problems for continuation of control and the achievement of elimination. Most initiatives have focussed on a single type of helminth infection, but recognition of co-endemicity and polyparasitism is leading to more integration of control. An understanding of the implications of control integration for implementation, treatment coverage, combination of pharmaceuticals, and monitoring is needed. To achieve the goals of morbidity reduction or elimination of infection, novel tools need to be developed, including more efficacious drugs, vaccines, and/or antivectorial agents, new diagnostics for infection and assessment of drug efficacy, and markers for possible anthelmintic resistance. In addition, there is a need for the development of new formulations of some existing anthelmintics (e.g., paediatric formulations). To achieve ultimate elimination of helminth parasites, treatments for the above mentioned helminthiases, and for taeniasis and food-borne trematodiases, will need to be integrated with monitoring, education, sanitation, access to health services, and where appropriate, vector control or reduction of the parasite reservoir in alternative hosts. Based on an analysis of current knowledge gaps and identification of priorities, a research and development agenda for intervention tools considered necessary for control and elimination of human helminthiases is presented, and the challenges to be confronted are discussed

Asymptomatic Carriage of Plasmodium in Urban Dakar: The Risk of Malaria Should Not Be Underestimated

Introduction: The objective of this study was to measure the rate of asymptomatic carriage of plasmodium in the Dakar region two years after the implementation of new strategies in clinical malaria management. Methodology: Between October and December 2008, 2952 households selected in 50 sites of Dakar area, were visited for interviews and blood sampling. Giemsa-stained thick blood smears (TBS) were performed for microscopy in asymptomatic adult women and children aged 2 to 10 years. To ensure the quality of the microscopy, we performed a polymerase chai

Sensitivity of Anopheles gambiae population dynamics to meteo-hydrological variability: a mechanistic approach

<p>Abstract</p> <p>Background</p> <p>Mechanistic models play an important role in many biological disciplines, and they can effectively contribute to evaluate the spatial-temporal evolution of mosquito populations, in the light of the increasing knowledge of the crucial driving role on vector dynamics played by meteo-climatic features as well as other physical-biological characteristics of the landscape.</p> <p>Methods</p> <p>In malaria eco-epidemiology landscape components (atmosphere, water bodies, land use) interact with the epidemiological system (interacting populations of vector, human, and parasite). In the background of the eco-epidemiological approach, a mosquito population model is here proposed to evaluate the sensitivity of <it>An. gambiae </it>s.s. population to some peculiar thermal-pluviometric scenarios. The scenarios are obtained perturbing meteorological time series data referred to four Kenyan sites (Nairobi, Nyabondo, Kibwesi, and Malindi) representing four different eco-epidemiological settings.</p> <p>Results</p> <p>Simulations highlight a strong dependence of mosquito population abundance on temperature variation with well-defined site-specific patterns. The upper extreme of thermal perturbation interval (+ 3°C) gives rise to an increase in adult population abundance at Nairobi (+111%) and Nyabondo (+61%), and a decrease at Kibwezi (-2%) and Malindi (-36%). At the lower extreme perturbation (-3°C) is observed a reduction in both immature and adult mosquito population in three sites (Nairobi -74%, Nyabondo -66%, Kibwezi -39%), and an increase in Malindi (+11%). A coherent non-linear pattern of population variation emerges. The maximum rate of variation is +30% population abundance for +1°C of temperature change, but also almost null and negative values are obtained. Mosquitoes are less sensitive to rainfall and both adults and immature populations display a positive quasi-linear response pattern to rainfall variation.</p> <p>Conclusions</p> <p>The non-linear temperature-dependent response is in agreement with the non-linear patterns of temperature-response of the basic bio-demographic processes. This non-linearity makes the hypothesized biological amplification of temperature effects valid only for a limited range of temperatures. As a consequence, no simple extrapolations can be done linking temperature rise with increase in mosquito distribution and abundance, and projections of <it>An. gambiae </it>s.s. populations should be produced only in the light of the local meteo-climatic features as well as other physical and biological characteristics of the landscape.</p

Development of environmental tools for anopheline larval control

<p>Abstract</p> <p>Background</p> <p>Malaria mosquitoes spend a considerable part of their life in the aquatic stage, rendering them vulnerable to interventions directed to aquatic habitats. Recent successes of mosquito larval control have been reported using environmental and biological tools. Here, we report the effects of shading by plants and biological control agents on the development and survival of anopheline and culicine mosquito larvae in man-made natural habitats in western Kenya. Trials consisted of environmental manipulation using locally available plants, the introduction of predatory fish and/or the use of <it>Bacillus thuringiensis </it>var. <it>israelensis </it>(<it>Bti</it>) in various combinations.</p> <p>Results</p> <p>Man-made habitats provided with shade from different crop species produced significantly fewer larvae than those without shade especially for the malaria vector <it>Anopheles gambiae</it>. Larval control of the African malaria mosquito <it>An. gambiae </it>and other mosquito species was effective in habitats where both predatory fish and <it>Bti </it>were applied, than where the two biological control agents were administered independently.</p> <p>Conclusion</p> <p>We conclude that integration of environmental management techniques using shade-providing plants and predatory fish and/or <it>Bti </it>are effective and sustainable tools for the control of malaria and other mosquito-borne disease vectors.</p