628 research outputs found
Systems analysis of host-parasite interactions.
Parasitic diseases caused by protozoan pathogens lead to hundreds of thousands of deaths per year in addition to substantial suffering and socioeconomic decline for millions of people worldwide. The lack of effective vaccines coupled with the widespread emergence of drug-resistant parasites necessitates that the research community take an active role in understanding host-parasite infection biology in order to develop improved therapeutics. Recent advances in next-generation sequencing and the rapid development of publicly accessible genomic databases for many human pathogens have facilitated the application of systems biology to the study of host-parasite interactions. Over the past decade, these technologies have led to the discovery of many important biological processes governing parasitic disease. The integration and interpretation of high-throughput -omic data will undoubtedly generate extraordinary insight into host-parasite interaction networks essential to navigate the intricacies of these complex systems. As systems analysis continues to build the foundation for our understanding of host-parasite biology, this will provide the framework necessary to drive drug discovery research forward and accelerate the development of new antiparasitic therapies
SURVEYING FOR RANAVIRUS IN GREEN FROGS (LITHOBATES CLAMITANS) AT FIVE LOCATIONS IN INDIANA
Ranaviruses are an emerging pathogen within the United States that infects amphibians, reptiles, and fish. A Frog Virus 3-like (FV3) ranavirus has been detected at only two locations in Indiana; however, there have been few attempts to broadly sample for ranaviruses to determine their distribution across the state. This knowledge is necessary for the continued management and conservation of native amphibian populations. Our objective was to assess the occurrence of FV3-like ranaviruses in larval Green Frog (Lithobates clamitans) populations at five sites located in different regions of Indiana. Tissue samples were collected from 166 individuals and were assayed using both conventional and qPCR methods. We did not detect the presence of any FV3-like ranaviruses at any of the five sites with either PCR method, suggesting the possibility that at these sites, FV3-like ranaviruses may not be present. However, continued sampling should be carried out to monitor the status of the presence of ranaviruses in this portion of the Midwest
Infection of laboratory-colonized Anopheles darlingi mosquitoes by Plasmodium vivax.
Anopheles darlingi Root is the most important malaria vector in the Amazonia region of South America. However, continuous propagation of An. darlingi in the laboratory has been elusive, limiting entomological, genetic/genomic, and vector-pathogen interaction studies of this mosquito species. Here, we report the establishment of an An. darlingi colony derived from wild-caught mosquitoes obtained in the northeastern Peruvian Amazon region of Iquitos in the Loreto Department. We show that the numbers of eggs, larvae, pupae, and adults continue to rise at least to the F6 generation. Comparison of feeding Plasmodium vivax ex vivo of F4 and F5 to F1 generation mosquitoes showed the comparable presence of oocysts and sporozoites, with numbers that corresponded to blood-stage asexual parasitemia and gametocytemia, confirming P. vivax vectorial capacity in the colonized mosquitoes. These results provide new avenues for research on An. darlingi biology and study of An. darlingi-Plasmodium interactions
Esterase mutation is a mechanism of resistance to antimalarial compounds
Pepstatin is a potent peptidyl inhibitor of various malarial aspartic proteases, and also has parasiticidal activity. Activity of pepstatin against cultured Plasmodium falciparum is highly variable depending on the commercial source. Here we identify a minor contaminant (pepstatin butyl ester) as the active anti-parasitic principle. We synthesize a series of derivatives and characterize an analogue (pepstatin hexyl ester) with low nanomolar activity. By selecting resistant parasite mutants, we find that a parasite esterase, PfPARE (P. falciparum Prodrug Activation and Resistance Esterase) is required for activation of esterified pepstatin. Parasites with esterase mutations are resistant to pepstatin esters and to an open source antimalarial compound, MMV011438. Recombinant PfPARE hydrolyses pepstatin esters and de-esterifies MMV011438. We conclude that (1) pepstatin is a potent but poorly bioavailable antimalarial; (2) PfPARE is a functional esterase that is capable of activating prodrugs; (3) Mutations in PfPARE constitute a mechanism of antimalarial resistance
Yeast Protein Interactome Topology Provides Framework for Coordinated-Functionality
The architecture of the network of protein-protein physical interactions in
Saccharomyces cerevisiae is exposed through the combination of two
complementary theoretical network measures, betweenness centrality and
`Q-modularity'. The yeast interactome is characterized by well-defined
topological modules connected via a small number of inter-module protein
interactions. Should such topological inter-module connections turn out to
constitute a form of functional coordination between the modules, we speculate
that this coordination is occurring typically in a pair-wise fashion, rather
than by way of high-degree hub proteins responsible for coordinating multiple
modules. The unique non-hub-centric hierarchical organization of the
interactome is not reproduced by gene duplication-and-divergence stochastic
growth models that disregard global selective pressures.Comment: Final, revised version. 13 pages. Please see Nucleic Acids open
access article for higher resolution figure
The mating-specific Gα interacts with a kinesin-14 and regulates pheromone-induced nuclear migration in budding yeast
As a budding yeast cell elongates toward its mating partner, cytoplasmic microtubules connect the nucleus to the cell cortex at the growth tip. The Kar3 kinesin-like motor protein is then thought to stimulate plus-end depolymerization of these microtubules, thus drawing the nucleus closer to the site where cell fusion and karyogamy will occur. Here, we show that pheromone stimulates a microtubule-independent interaction between Kar3 and the mating-specific Gα protein Gpa1 and that Gpa1 affects both microtubule orientation and cortical contact. The membrane localization of Gpa1 was found to polarize early in the mating response, at about the same time that the microtubules begin to attach to the incipient growth site. In the absence of Gpa1, microtubules lose contact with the cortex upon shrinking and Kar3 is improperly localized, suggesting that Gpa1 is a cortical anchor for Kar3. We infer that Gpa1 serves as a positional determinant for Kar3-bound microtubule plus ends during mating. © 2009 by The American Society for Cell Biology
Psychopathological characteristics in patients with arginine vasopressin deficiency (central diabetes insipidus) and primary polydipsia compared to healthy controls
Objective: Distinguishing arginine vasopressin deficiency (AVP-D; central diabetes insipidus) from primary polydipsia (PP), commonly referred to as psychogenic polydipsia, is challenging. Psychopathologic findings, commonly used for PP diagnosis in clinical practice, are rarely evaluated in AVP-D patients, and no comparative data between the two conditions currently exist. Design: Data from two studies involving 82 participants [39 AVP-D, 28 PP, and 15 healthy controls (HC)]. Methods: Psychological evaluations were conducted using standardized questionnaires measuring anxiety [State-Trait Anxiety Inventory (STAI)], alexithymia [Toronto Alexithymia Scale (TAS-20)], depressive symptoms (Beck’s Depression Inventory-II (BDI-II), and overall mental health [Short Form-36 Health Survey (SF-36)]. Higher STAI, TAS-20, and BDI-II scores suggest elevated anxiety, alexithymia, and depression, while higher SF-36 scores signify better overall mental health. Results: Compared to HC, patients with AVP-D and PP showed higher levels of anxiety (HC 28 points [24–31] vs AVP-D 36 points [31–45]; vs PP 38 points [33–46], P < .01), alexithymia (HC 30 points [29–37] vs AVP-D 43 points [35–54]; vs PP 46 points [37–55], P < .01), and depression (HC 1 point [0–2] vs AVP-D 7 points [4–14]; vs PP 7 points [3–13], P < .01). Levels of anxiety, alexithymia, and depression showed no difference between both patient groups (P = .58, P = .90, P = .50, respectively). Compared to HC, patients with AVP-D and PP reported similarly reduced self-reported overall mental health scores (HC 84 [68–88] vs AVP-D 60 [52–80], P = .05; vs PP 60 [47–74], P < .01).Conclusion: This study reveals heightened anxiety, alexithymia, depression, and diminished overall mental health in patients with AVP-D and PP. The results emphasize the need for careful interpretation of psychopathological characteristics to differentiate between AVP-D and PP.</p
Psychopathological characteristics in patients with arginine vasopressin deficiency (central diabetes insipidus) and primary polydipsia compared to healthy controls
Objective: Distinguishing arginine vasopressin deficiency (AVP-D; central diabetes insipidus) from primary polydipsia (PP), commonly referred to as psychogenic polydipsia, is challenging. Psychopathologic findings, commonly used for PP diagnosis in clinical practice, are rarely evaluated in AVP-D patients, and no comparative data between the two conditions currently exist. Design: Data from two studies involving 82 participants [39 AVP-D, 28 PP, and 15 healthy controls (HC)]. Methods: Psychological evaluations were conducted using standardized questionnaires measuring anxiety [State-Trait Anxiety Inventory (STAI)], alexithymia [Toronto Alexithymia Scale (TAS-20)], depressive symptoms (Beck’s Depression Inventory-II (BDI-II), and overall mental health [Short Form-36 Health Survey (SF-36)]. Higher STAI, TAS-20, and BDI-II scores suggest elevated anxiety, alexithymia, and depression, while higher SF-36 scores signify better overall mental health. Results: Compared to HC, patients with AVP-D and PP showed higher levels of anxiety (HC 28 points [24–31] vs AVP-D 36 points [31–45]; vs PP 38 points [33–46], P < .01), alexithymia (HC 30 points [29–37] vs AVP-D 43 points [35–54]; vs PP 46 points [37–55], P < .01), and depression (HC 1 point [0–2] vs AVP-D 7 points [4–14]; vs PP 7 points [3–13], P < .01). Levels of anxiety, alexithymia, and depression showed no difference between both patient groups (P = .58, P = .90, P = .50, respectively). Compared to HC, patients with AVP-D and PP reported similarly reduced self-reported overall mental health scores (HC 84 [68–88] vs AVP-D 60 [52–80], P = .05; vs PP 60 [47–74], P < .01).Conclusion: This study reveals heightened anxiety, alexithymia, depression, and diminished overall mental health in patients with AVP-D and PP. The results emphasize the need for careful interpretation of psychopathological characteristics to differentiate between AVP-D and PP.</p
Combining stage specificity and metabolomic profiling to advance antimalarial drug discovery
We report detailed susceptibility profiling of asexual blood stages of the malaria parasite Plasmodium falciparum to clinical and experimental antimalarials, combined with metabolomic fingerprinting. Results revealed a variety of stage-specific and metabolic profiles that differentiated the modes of action of clinical antimalarials including chloroquine, piperaquine, lumefantrine, and mefloquine, and identified late trophozoite-specific peak activity and stage-specific biphasic dose-responses for the mitochondrial inhibitors DSM265 and atovaquone. We also identified experimental antimalarials hitting previously unexplored druggable pathways as reflected by their unique stage specificity and/or metabolic profiles. These included several ring-active compounds, ones affecting hemoglobin catabolism through distinct pathways, and mitochondrial inhibitors with lower propensities for resistance than either DSM265 or atovaquone. This approach, also applicable to other microbes that undergo multiple differentiation steps, provides an effective tool to prioritize compounds for further development within the context of combination therapies
A Systems-Based Analysis of Plasmodium vivax Lifecycle Transcription from Human to Mosquito
Most of the 250 million malaria cases outside of Africa are caused by the parasite Plasmodium vivax. Although drugs can be used to treat P. vivax malaria, drug resistance is spreading and there is no available vaccine. Because this species cannot be readily grown in the laboratory there are added challenges to understanding the function of the many hypothetical genes in the genome. We isolated transcriptional messages from parasites growing in human blood and in mosquitoes, labeled the messages and measured how their levels for different parasite growth conditions. The data for 5,419 parasite genes shows extensive changes as the parasite moves between human and mosquito and reveals highly expressed genes whose proteins might represent new therapeutic targets for experimental vaccines. We discover sets of genes that are likely to play a role in the earliest stages of hepatocyte infection. We find intriguing differences in the expression patterns of different blood stage parasites that may be related to host-response status
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