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1.  Describing the Breakbone Fever: IDODEN, an Ontology for Dengue Fever 
PLoS Neglected Tropical Diseases  2015;9(2):e0003479.
Background
Ontologies represent powerful tools in information technology because they enhance interoperability and facilitate, among other things, the construction of optimized search engines. To address the need to expand the toolbox available for the control and prevention of vector-borne diseases we embarked on the construction of specific ontologies. We present here IDODEN, an ontology that describes dengue fever, one of the globally most important diseases that are transmitted by mosquitoes.
Methodology/Principal Findings
We constructed IDODEN using open source software, and modeled it on IDOMAL, the malaria ontology developed previously. IDODEN covers all aspects of dengue fever, such as disease biology, epidemiology and clinical features. Moreover, it covers all facets of dengue entomology. IDODEN, which is freely available, can now be used for the annotation of dengue-related data and, in addition to its use for modeling, it can be utilized for the construction of other dedicated IT tools such as decision support systems.
Conclusions/Significance
The availability of the dengue ontology will enable databases hosting dengue-associated data and decision-support systems for that disease to perform most efficiently and to link their own data to those stored in other independent repositories, in an architecture- and software-independent manner.
Author Summary
The need for the construction of a dengue ontology arose through the fact that the incidence of dengue fever is on the rise across the world; the number of cases may be three to four times higher than the 100 million estimated by the WHO and a vaccine is still not available in spite of the significant efforts undertaken. Thus, control of dengue fever still relies mostly on controlling its mosquito vectors. Large amounts of entomological, epidemiological and clinical data are generated; these need to be efficiently organized in order to further our comprehension of the disease and its control. IDODEN aims to cover the different aspects and intricacies of dengue fever and syndromes caused by dengue virus(es). It contains more than 5000 terms describing epidemiological data, vaccine development, clinical features, the disease course, and more. We show here that it can be a helpful tool for researchers and that, in addition to allowing sophisticated search strategies, it is also useful for tasks such as modeling.
doi:10.1371/journal.pntd.0003479
PMCID: PMC4315569  PMID: 25646954
2.  Male-specific phosphorylated SR proteins in adult flies of the Mediterranean Fruitfly Ceratitis capitata 
BMC Genetics  2014;15(Suppl 2):S6.
Alternative splicing is a widely used mechanism of gene regulation in sex determination pathways of Insects. In species from orders as distant as Diptera, Hymenoptera and Coleoptera, female differentiation relies on the activities of conserved splicing regulators, TRA and TRA-2, promoting female-specific expression of the global effector doublesex (dsx). Less understood is to what extent post-translational modifications of splicing regulators plays a role in this pathway. In Drosophila melanogaster phosphorylation of TRA, TRA-2 and the general RBP1 factor by the LAMMER kinase doa (darkener of apricot) is required for proper female sex determination. To explore whether this is a general feature of the pathway we examined sex-specific differences in phosphorylation levels of SR splicing factors in the dipteran species D. melanogaster, Ceratitis capitata (Medfly) and Musca domestica (Housefly). We found a distinct and reproducible pattern of male-specific phosphorylation on protein extracts enriched for SR proteins in C. capitata suggesting that differential phosphorylation may also contribute to the regulation of sex-specific splicing in the Medfly.
doi:10.1186/1471-2156-15-S2-S6
PMCID: PMC4255826  PMID: 25472723
3.  Non-coding RNA gene families in the genomes of anopheline mosquitoes 
BMC Genomics  2014;15(1):1038.
Background
Only a small fraction of the mosquito species of the genus Anopheles are able to transmit malaria, one of the biggest killer diseases of poverty, which is mostly prevalent in the tropics. This diversity has genetic, yet unknown, causes. In a further attempt to contribute to the elucidation of these variances, the international “Anopheles Genomes Cluster Consortium” project (a.k.a. “16 Anopheles genomes project”) was established, aiming at a comprehensive genomic analysis of several anopheline species, most of which are malaria vectors. In the frame of the international consortium carrying out this project our team studied the genes encoding families of non-coding RNAs (ncRNAs), concentrating on four classes: microRNA (miRNA), ribosomal RNA (rRNA), small nuclear RNA (snRNA), and in particular small nucleolar RNA (snoRNA) and, finally, transfer RNA (tRNA).
Results
Our analysis was carried out using, exclusively, computational approaches, and evaluating both the primary NGS reads as well as the respective genome assemblies produced by the consortium and stored in VectorBase; moreover, the results of RNAseq surveys in cases in which these were available and meaningful were also accessed in order to obtain supplementary data, as were “pre-genomic era” sequence data stored in nucleic acid databases. The investigation included the identification and analysis, in most species studied, of ncRNA genes belonging to several families, as well as the analysis of the evolutionary relations of some of those genes in cross-comparisons to other members of the genus Anopheles.
Conclusions
Our study led to the identification of members of these gene families in the majority of twenty different anopheline taxa. A set of tools for the study of the evolution and molecular biology of important disease vectors has, thus, been obtained.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-1038) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2164-15-1038
PMCID: PMC4300560  PMID: 25432596
Anopheles; Genome evolution; microRNA; ncRNA; Ribosomal genes; Small nuclear RNA; Small nucleolar RNA; tRNA; Whole Genome Sequencing
4.  Genome-wide RIP-Chip analysis of translational repressor-bound mRNAs in the Plasmodium gametocyte 
Genome Biology  2014;15(11):493.
Background
Following fertilization, the early proteomes of metazoans are defined by the translation of stored but repressed transcripts; further embryonic development relies on de novo transcription of the zygotic genome. During sexual development of Plasmodium berghei, a rodent model for human malaria species including P. falciparum, the stability of repressed mRNAs requires the translational repressors DOZI and CITH. When these repressors are absent, Plasmodium zygote development and transmission to the mosquito vector is halted, as hundreds of transcripts become destabilized. However, which mRNAs are direct targets of these RNA binding proteins, and thus subject to translational repression, is unknown.
Results
We identify the maternal mRNA contribution to post-fertilization development of P. berghei using RNA immunoprecipitation and microarray analysis. We find that 731 mRNAs, approximately 50% of the transcriptome, are associated with DOZI and CITH, allowing zygote development to proceed in the absence of RNA polymerase II transcription. Using GFP-tagging, we validate the repression phenotype of selected genes and identify mRNAs relying on the 5′ untranslated region for translational control. Gene deletion reveals a novel protein located in the ookinete crystalloid with an essential function for sporozoite development.
Conclusions
Our study details for the first time the P. berghei maternal repressome. This mRNA population provides the developing ookinete with coding potential for key molecules required for life-cycle progression, and that are likely to be critical for the transmission of the malaria parasite from the rodent and the human host to the mosquito vector.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0493-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13059-014-0493-0
PMCID: PMC4234863  PMID: 25418785
5.  Asaia accelerates larval development of Anopheles gambiae 
Pathogens and Global Health  2013;107(6):305-311.
Arthropod borne diseases cause significant human morbidity and mortality and, therefore, efficient measures to control transmission of the disease agents would have great impact on human health. One strategy to achieve this goal is based on the manipulation of bacterial symbionts of vectors. Bacteria of the Gram-negative, acetic acid bacterium genus Asaia have been found to be stably associated with larvae and adults of the Southeast Asian malaria vector Anopheles stephensi, dominating the microbiota of the mosquito. We show here that after the infection of Anopheles gambiae larvae with Asaia the bacteria were stably associated with the mosquitoes, becoming part of the microflora of the midgut and remaining there for the duration of the life cycle. Moreover they were passed on to the next generation through vertical transmission. Additionally, we show that there is an increase in the developmental rate when additional bacteria are introduced into the organism which leads us to the conclusion that Asaia plays a yet undetermined crucial role during the larval stages. Our microarray analysis showed that the larval genes that are mostly affected are involved in cuticle formation, and include mainly members of the CPR gene family.
doi:10.1179/2047773213Y.0000000106
PMCID: PMC4001610  PMID: 24091152
Asaia; Anopheles gambiae; Larval development; Cuticle proteins; Paratransgenesis; Symbiont
6.  IDOMAL: the malaria ontology revisited 
Background
With about half a billion cases, of which nearly one million fatal ones, malaria constitutes one of the major infectious diseases worldwide. A recently revived effort to eliminate the disease also focuses on IT resources for its efficient control, which prominently includes the control of the mosquito vectors that transmit the Plasmodium pathogens. As part of this effort, IDOMAL has been developed and it is continually being updated.
Findings
In addition to the improvement of IDOMAL’s structure and the correction of some inaccuracies, there were some major subdomain additions such as a section on natural products and remedies, and the import, from other, higher order ontologies, of several terms, which were merged with IDOMAL terms. Effort was put on rendering IDOMAL fully compatible as an extension of IDO, the Infectious Disease Ontology. The reason for the difficulties in fully reaching that target were the inherent differences between vector-borne diseases and “classical” infectious diseases, which make it necessary to specifically adjust the ontology’s architecture in order to comprise vectors and their populations.
Conclusions
In addition to a higher coverage of domain-specific terms and optimizing its usage by databases and decision-support systems, the new version of IDOMAL described here allows for more cross-talk between it and other ontologies, and in particular IDO. The malaria ontology is available for downloading at the OBO Foundry (http://www.obofoundry.org/cgi-bin/detail.cgi?id=malaria_ontology) and the NCBO BioPortal (http://bioportal.bioontology.org/ontologies/1311).
doi:10.1186/2041-1480-4-16
PMCID: PMC3848731  PMID: 24034841
Malaria; Vector borne disease; IDO; Remedies; Ontology
7.  The Ontology for Parasite Lifecycle (OPL): towards a consistent vocabulary of lifecycle stages in parasitic organisms 
Background
Genome sequencing of many eukaryotic pathogens and the volume of data available on public resources have created a clear requirement for a consistent vocabulary to describe the range of developmental forms of parasites. Consistent labeling of experimental data and external data, in databases and the literature, is essential for integration, cross database comparison, and knowledge discovery. The primary objective of this work was to develop a dynamic and controlled vocabulary that can be used for various parasites. The paper describes the Ontology for Parasite Lifecycle (OPL) and discusses its application in parasite research.
Results
The OPL is based on the Basic Formal Ontology (BFO) and follows the rules set by the OBO Foundry consortium. The first version of the OPL models complex life cycle stage details of a range of parasites, such as Trypanosoma sp., Leishmaniasp., Plasmodium sp., and Shicstosoma sp. In addition, the ontology also models necessary contextual details, such as host information, vector information, and anatomical locations. OPL is primarily designed to serve as a reference ontology for parasite life cycle stages that can be used for database annotation purposes and in the lab for data integration or information retrieval as exemplified in the application section below.
Conclusion
OPL is freely available at http://purl.obolibrary.org/obo/opl.owl and has been submitted to the BioPortal site of NCBO and to the OBO Foundry. We believe that database and phenotype annotations using OPL will help run fundamental queries on databases to know more about gene functions and to find intervention targets for various parasites. The OPL is under continuous development and new parasites and/or terms are being added.
doi:10.1186/2041-1480-3-5
PMCID: PMC3488002  PMID: 22621763
8.  A set of ontologies to drive tools for the control of vector-borne diseases 
We are developing a set of ontologies dealing with vector-borne diseases as well as the arthropod vectors that transmit them. After building ontologies for mosquito and tick anatomy we continued this project with an ontology of insecticide resistance followed by a series of ontologies that describe malaria as well as physiological processes of mosquitoes that are relevant to, and involved in, disease transmission. These will later be expanded to encompass other vector-borne diseases as well as non-mosquito vectors. The aim of the whole undertaking, which is worked out in the frame of the international IDO (Infectious Disease Ontology) project, is to provide the community with a set of ontological tools that can be used both in the development of specific databases and, most importantly, in the construction of decision support systems (DSS) to control these diseases.
doi:10.1016/j.jbi.2010.03.012
PMCID: PMC2953594  PMID: 20363364
anatomy; database; decision support system; insecticide resistance; malaria; mosquito; tick; transmission; arthropod vector
9.  Daily Newspaper View of Dengue Fever Epidemic, Athens, Greece, 1927–1931 
Emerging Infectious Diseases  2012;18(1):78-82.
Controversy remains about possible dengue hemorrhagic fever during the epidemic.
During the late summers of 1927 and 1928, a biphasic dengue epidemic affected the Athens, Greece, metropolitan area; >90% of the population became sick, and >1,000 persons (1,553 in the entire country) died. This epidemic was the most recent and most serious dengue fever epidemic in Europe. Review of all articles published by one of the most influential Greek daily newspapers (I Kathimerini) during the epidemic and the years that followed it did not shed light on the controversy about whether the high number of deaths resulted from dengue hemorrhagic fever after sequential infections with dengue virus types 1 and 2 or to a particularly virulent type 1 virus. Nevertheless, study of the old reports is crucial considering the relatively recent introduction of Aedes albopictus mosquitoes and the frequent warnings of a possible reemergence of dengue fever in Europe.
doi:10.3201/eid1801.110191
PMCID: PMC3310089  PMID: 22257469
Aedes aegypti; dengue virus; dengue hemorrhagic fever; viruses; epidemic; vector-borne infections; newspaper; Greece
10.  VectorBase: improvements to a bioinformatics resource for invertebrate vector genomics 
Nucleic Acids Research  2011;40(Database issue):D729-D734.
VectorBase (http://www.vectorbase.org) is a NIAID-supported bioinformatics resource for invertebrate vectors of human pathogens. It hosts data for nine genomes: mosquitoes (three Anopheles gambiae genomes, Aedes aegypti and Culex quinquefasciatus), tick (Ixodes scapularis), body louse (Pediculus humanus), kissing bug (Rhodnius prolixus) and tsetse fly (Glossina morsitans). Hosted data range from genomic features and expression data to population genetics and ontologies. We describe improvements and integration of new data that expand our taxonomic coverage. Releases are bi-monthly and include the delivery of preliminary data for emerging genomes. Frequent updates of the genome browser provide VectorBase users with increasing options for visualizing their own high-throughput data. One major development is a new population biology resource for storing genomic variations, insecticide resistance data and their associated metadata. It takes advantage of improved ontologies and controlled vocabularies. Combined, these new features ensure timely release of multiple types of data in the public domain while helping overcome the bottlenecks of bioinformatics and annotation by engaging with our user community.
doi:10.1093/nar/gkr1089
PMCID: PMC3245112  PMID: 22135296
11.  IDOMAL: an ontology for malaria 
Malaria Journal  2010;9:230.
Background
Ontologies are rapidly becoming a necessity for the design of efficient information technology tools, especially databases, because they permit the organization of stored data using logical rules and defined terms that are understood by both humans and machines. This has as consequence both an enhanced usage and interoperability of databases and related resources. It is hoped that IDOMAL, the ontology of malaria will prove a valuable instrument when implemented in both malaria research and control measures.
Methods
The OBOEdit2 software was used for the construction of the ontology. IDOMAL is based on the Basic Formal Ontology (BFO) and follows the rules set by the OBO Foundry consortium.
Results
The first version of the malaria ontology covers both clinical and epidemiological aspects of the disease, as well as disease and vector biology. IDOMAL is meant to later become the nucleation site for a much larger ontology of vector borne diseases, which will itself be an extension of a large ontology of infectious diseases (IDO). The latter is currently being developed in the frame of a large international collaborative effort.
Conclusions
IDOMAL, already freely available in its first version, will form part of a suite of ontologies that will be used to drive IT tools and databases specifically constructed to help control malaria and, later, other vector-borne diseases. This suite already consists of the ontology described here as well as the one on insecticide resistance that has been available for some time. Additional components are being developed and introduced into IDOMAL.
doi:10.1186/1475-2875-9-230
PMCID: PMC2925367  PMID: 20698959
12.  Anopheles Immune Genes and Amino Acid Sites Evolving Under the Effect of Positive Selection 
PLoS ONE  2010;5(1):e8885.
Background
It has long been the goal of vector biology to generate genetic knowledge that can be used to “manipulate” natural populations of vectors to eliminate or lessen disease burden. While long in coming, progress towards reaching this goal has been made. Aiming to increase our understanding regarding the interactions between Plasmodium and the Anopheles immune genes, we investigated the patterns of genetic diversity of four anti-Plasmodium genes in the Anopheles gambiae complex of species.
Methodology/Principal Findings
Within a comparative phylogenetic and population genetics framework, the evolutionary history of four innate immunity genes within the An. gambiae complex (including the two most important human malaria vectors, An. gambiae and An. arabiensis) is reconstructed. The effect of natural selection in shaping the genes' diversity is examined.
Introgression and retention of ancestral polymorphisms are relatively rare at all loci. Despite the potential confounding effects of these processes, we could identify sites that exhibited dN/dS ratios greater than 1.
Conclusions/Significance
In two of the studied genes, CLIPB14 and FBN8, several sites indicated evolution under positive selection, with CLIPB14 exhibiting the most consistent evidence. Considering only the sites that were consistently identified by all methods, two sites in CLIPB14 are adaptively driven. However, the analysis inferring the lineage -specific evolution of each gene was not in favor of any of the Anopheles lineages evolving under the constraints imposed by positive selection. Nevertheless, the loci and the specific amino acids that were identified as evolving under strong evolutionary pressure merit further investigation for their involvement in the Anopheles defense against microbes in general.
doi:10.1371/journal.pone.0008885
PMCID: PMC2811201  PMID: 20126662
13.  MIRO and IRbase: IT Tools for the Epidemiological Monitoring of Insecticide Resistance in Mosquito Disease Vectors 
Background
Monitoring of insect vector populations with respect to their susceptibility to one or more insecticides is a crucial element of the strategies used for the control of arthropod-borne diseases. This management task can nowadays be achieved more efficiently when assisted by IT (Information Technology) tools, ranging from modern integrated databases to GIS (Geographic Information System). Here we describe an application ontology that we developed de novo, and a specially designed database that, based on this ontology, can be used for the purpose of controlling mosquitoes and, thus, the diseases that they transmit.
Methodology/Principal Findings
The ontology, named MIRO for Mosquito Insecticide Resistance Ontology, developed using the OBO-Edit software, describes all pertinent aspects of insecticide resistance, including specific methodology and mode of action. MIRO, then, forms the basis for the design and development of a dedicated database, IRbase, constructed using open source software, which can be used to retrieve data on mosquito populations in a temporally and spatially separate way, as well as to map the output using a Google Earth interface. The dependency of the database on the MIRO allows for a rational and efficient hierarchical search possibility.
Conclusions/Significance
The fact that the MIRO complies with the rules set forward by the OBO (Open Biomedical Ontologies) Foundry introduces cross-referencing with other biomedical ontologies and, thus, both MIRO and IRbase are suitable as parts of future comprehensive surveillance tools and decision support systems that will be used for the control of vector-borne diseases. MIRO is downloadable from and IRbase is accessible at VectorBase, the NIAID-sponsored open access database for arthropod vectors of disease.
Author Summary
It is a historical fact that a successful campaign against vector populations is one of the prerequisites for effectively fighting and eventually eradicating arthropod-borne diseases, be that in an epidemic or, even more so, in endemic cases. Based mostly on the use of insecticides and environmental management, vector control is now increasingly hampered by the occurrence of insecticide resistance that manifests itself, and spreads rapidly, briefly after the introduction of a (novel) chemical substance. We make use here of a specially built ontology, MIRO, to drive a new database, IRbase, dedicated to storing data on the occurrence of insecticide resistance in mosquito populations worldwide. The ontological approach to the design of databases offers the great advantage that these can be searched in an efficient way. Moreover, it also provides for an increased interoperability of present and future epidemiological tools. IRbase is now being populated by both older data from the literature and data recently collected from field.
doi:10.1371/journal.pntd.0000465
PMCID: PMC2694272  PMID: 19547750
14.  VectorBase: a data resource for invertebrate vector genomics 
Nucleic Acids Research  2008;37(Database issue):D583-D587.
VectorBase (http://www.vectorbase.org) is an NIAID-funded Bioinformatic Resource Center focused on invertebrate vectors of human pathogens. VectorBase annotates and curates vector genomes providing a web accessible integrated resource for the research community. Currently, VectorBase contains genome information for three mosquito species: Aedes aegypti, Anopheles gambiae and Culex quinquefasciatus, a body louse Pediculus humanus and a tick species Ixodes scapularis. Since our last report VectorBase has initiated a community annotation system, a microarray and gene expression repository and controlled vocabularies for anatomy and insecticide resistance. We have continued to develop both the software infrastructure and tools for interrogating the stored data.
doi:10.1093/nar/gkn857
PMCID: PMC2686483  PMID: 19028744
15.  VectorBase: a home for invertebrate vectors of human pathogens 
Nucleic Acids Research  2006;35(Database issue):D503-D505.
VectorBase () is a web-accessible data repository for information about invertebrate vectors of human pathogens. VectorBase annotates and maintains vector genomes providing an integrated resource for the research community. Currently, VectorBase contains genome information for two organisms: Anopheles gambiae, a vector for the Plasmodium protozoan agent causing malaria, and Aedes aegypti, a vector for the flaviviral agents causing Yellow fever and Dengue fever.
doi:10.1093/nar/gkl960
PMCID: PMC1751530  PMID: 17145709
16.  Plasmodium berghei calcium-dependent protein kinase 3 is required for ookinete gliding motility and mosquito midgut invasion 
Molecular Microbiology  2006;60(6):1355-1363.
Apicomplexan parasites critically depend on a unique form of gliding motility to colonize their hosts and to invade cells. Gliding requires different stage and species-specific transmembrane adhesins, which interact with an intracellular motor complex shared across parasite stages and species. How gliding is regulated by extracellular factors and intracellular signalling mechanisms is largely unknown, but current evidence suggests an important role for cytosolic calcium as a second messenger. Studying a Plasmodium berghei gene deletion mutant, we here provide evidence that a calcium-dependent protein kinase, CDPK3, has an important function in regulating motility of the ookinete in the mosquito midgut. We show that a cdpk3– parasite clone produces morphologically normal ookinetes, which fail to engage the midgut epithelium, due to a marked reduction in their ability to glide productively, resulting in marked reduction in malaria transmission to the mosquito. The mutant was successfully complemented with an episomally maintained cdpk3 gene, restoring mosquito transmission to wild-type level. cdpk3– ookinetes maintain their full genetic differentiation potential when microinjected into the mosquito haemocoel and cdpk3– sporozoites produced in this way are motile and infectious, suggesting an ookinete-limited essential function for CDPK3.
doi:10.1111/j.1365-2958.2006.05189.x
PMCID: PMC1513514  PMID: 16796674

Results 1-16 (16)