Plasmodium falciparum glutamate dehydrogenase a is dispensable and not a drug target during erythrocytic development

<p>Background: Plasmodium falciparum contains three genes encoding potential glutamate dehydrogenases. The protein encoded by gdha has previously been biochemically and structurally characterized. It was suggested that it is important for the supply of reducing equivalents during intra-erythrocytic development of Plasmodium and, therefore, a suitable drug target.</p> <p>Methods: The gene encoding the NADP(H)-dependent GDHa has been disrupted by reverse genetics in P. falciparum and the effect on the antioxidant and metabolic capacities of the resulting mutant parasites was investigated.</p> <p>Results: No growth defect under low and elevated oxygen tension, no up-or down-regulation of a number of antioxidant and NADP(H)-generating proteins or mRNAs and no increased levels of GSH were detected in the D10(Delta gdha) parasite lines. Further, the fate of the carbon skeleton of [(13)C] labelled glutamine was assessed by metabolomic studies, revealing no differences in the labelling of a-ketoglutarate and other TCA pathway intermediates between wild type and mutant parasites.</p> <p>Conclusions: First, the data support the conclusion that D10(Delta gdha) parasites are not experiencing enhanced oxidative stress and that GDHa function may not be the provision of NADP(H) for reductive reactions. Second, the results imply that the cytosolic, NADP(H)-dependent GDHa protein is not involved in the oxidative deamination of glutamate but that the protein may play a role in ammonia assimilation as has been described for other NADP(H)dependent GDH from plants and fungi. The lack of an obvious phenotype in the absence of GDHa may point to a regulatory role of the protein providing glutamate (as nitrogen storage molecule) in situations where the parasites experience a limiting supply of carbon sources and, therefore, under in vitro conditions the enzyme is unlikely to be of significant importance. The data imply that the protein is not a suitable target for future drug development against intra-erythrocytic parasite development.</p&gt

MAVERICK: A Synthetic Murder Mystery Network Dataset to Support Sensemaking Research

AbstractThe MAVERICK dataset was created to support a series of empirical studies looking at the effectiveness of network visualizations intended to support information foraging and human sensemaking within the domain of counterinsurgency intelligence analysis. This synthetic dataset is structured as a forensic mystery with the central goal of solving a fictional murder. The dataset includes 181 text-based reports, with additional media included with some messages as attachments, collected from various sources of varying reliability. The reports are framed as being collected from the perspective of a reporter investigating the murder through interviews with suspects and observations taken at the site the murder. The dataset includes intentional and unintentional deception along with calculated source reliabilities based on available evidence. The dataset is dynamic in nature, as the information in the dataset evolves and expands over a simulated period of time. This is done to both to simulate a real-world scenario, and to allow for evolutionary tasks and experiments to be performed using the dataset. The dataset is designed to be complex enough to simulate a real-world, while remaining accessible to individuals without experience in a specific domain of interest. This meant that it had to be on a topic that did not require prior domain knowledge to understand available information or to understand what strategies should be applied during analysis of the dataset. The solution to these challenges was the development of a fictional murder mystery. The plot involves a murder that took place over the course of a weekend with several possible suspects at a large private estate. This scenario allowed for a great deal of complexity; however, it was also a subject matter that could be easily understood by participants without prerequisite domain experience

Research Opportunities in Contextualized Fusion Systems. The Harbor Surveillance Case

Proceedings of: International Workshop of Intelligent Systems for Context-Based Information Fusion (ISCIF 2011) associated to 11th International Work-Conference on Artificial Neural Networks, IWANN, Torremolinos-Málaga, Spain, June 8-10, 2011.The design of modern Information Fusion (IF) systems involves a complex process to achieve the requirements in the selected applications, especially in domains with a high degree of customization. In general, an advanced fusion system is required to show robust, context-sensitive behavior and efficient performance in real time. It is necessary to exploit all potentially relevant sensor and contextual information in the most appropriate way. Among modern applications for IF technology is the case of surveillance of complex harbor environments that are comprised of large numbers of surface vessels, high-value and dangerous facilities, and many people. The particular conditions and open needs in the harbor scenario are reviewed in this paper, highlighting research opportunities to explore in the development of fusion systems in this area.This work was supported in part by Projects CICYT TIN2008-06742-C02-02/TSI, CICYT TEC2008-06732-C02-02/TEC and CAM CONTEXTS S2009/TIC-1485.Publicad

High-Level Information Fusion in Visual Sensor Networks

Information fusion techniques combine data from multiple sensors, along with additional information and knowledge, to obtain better estimates of the observed scenario than could be achieved by the use of single sensors or information sources alone. According to the JDL fusion process model, high-level information fusion is concerned with the computation of a scene representation in terms of abstract entities such as activities and threats, as well as estimating the relationships among these entities. Recent experiences confirm that context knowledge plays a key role in the new-generation high-level fusion systems, especially in those involving complex scenarios that cause the failure of classical statistical techniques –as it happens in visual sensor networks. In this chapter, we study the architectural and functional issues of applying context information to improve high-level fusion procedures, with a particular focus on visual data applications. The use of formal knowledge representations (e.g. ontologies) is a promising advance in this direction, but there are still some unresolved questions that must be more extensively researched.The UC3M Team gratefully acknowledges that this research activity is supported in part by Projects CICYT TIN2008-06742-C02-02/TSI, CICYT TEC2008-06732-C02-02/TEC, CAM CONTEXTS (S2009/TIC-1485) and DPS2008-07029-C02-02

PNAS plus: plasmodium falciparum responds to amino acid starvation by entering into a hibernatory state

The human malaria parasite Plasmodium falciparum is auxotrophic for most amino acids. Its amino acid needs are met largely through the degradation of host erythrocyte hemoglobin; however the parasite must acquire isoleucine exogenously, because this amino acid is not present in adult human hemoglobin. We report that when isoleucine is withdrawn from the culture medium of intraerythrocytic P. falciparum, the parasite slows its metabolism and progresses through its developmental cycle at a reduced rate. Isoleucine-starved parasites remain viable for 72 h and resume rapid growth upon resupplementation. Protein degradation during starvation is important for maintenance of this hibernatory state. Microarray analysis of starved parasites revealed a 60% decrease in the rate of progression through the normal transcriptional program but no other apparent stress response. Plasmodium parasites do not possess a TOR nutrient-sensing pathway and have only a rudimentary amino acid starvation-sensing eukaryotic initiation factor 2α (eIF2α) stress response. Isoleucine deprivation results in GCN2-mediated phosphorylation of eIF2α, but kinase-knockout clones still are able to hibernate and recover, indicating that this pathway does not directly promote survival during isoleucine starvation. We conclude that P. falciparum, in the absence of canonical eukaryotic nutrient stress-response pathways, can cope with an inconsistent bloodstream amino acid supply by hibernating and waiting for more nutrient to be provided

Importance of nephron number in the regulation of arterial pressure and renal function during ageing

The physiological importance of the kidneys in the long-term control of extracellular volume and arterial pressure has been demonstrated in studies showing that an alteration of renal function leads to the development of hypertension and other cardiovascular dysfunctions (1-4). It has also been proposed that the development of hypertension may be secondary to an altered nephron endowment during the nephrogenic period (3,4). A cause-effect link between nephron number at birth and hypertension has been proposed in clinical and experimental studies showing that essential hypertensive patients have a reduced nephron number (3-6), and that the alteration of nephrogenesis leads to the development of hypertension during the adult life (3,4,7-10). A deficient nephrogenesis has been observed in offspring of pregnant mothers taking a low protein diet, or treated with either corticoids or a cyclooxygenase-2 (COX-2) inhibitor (3,4). The renin-angiotensin system (RAS) seems to play an important role in the regulation of nephrogenesis because its activity is reduced in these situations (3,4), and it is known that angiotensin II (Ang II) is involved in regulating renal growth and differentiation (11). The role of Ang II in renal development has been confirmed in studies demonstrating an elevation of all RAS components during the nephrogenic period and showing that the administration of either a converting enzyme inhibitor or an Ang II AT1 receptor antagonist during this period leads to a significant reduction in nephron number and an alteration of the normal kidney structure (7,8).Sociedad Argentina de Fisiologí

Chaotic oscillations in a map-based model of neural activity

We propose a discrete time dynamical system (a map) as phenomenological model of excitable and spiking-bursting neurons. The model is a discontinuous two-dimensional map. We find condition under which this map has an invariant region on the phase plane, containing chaotic attractor. This attractor creates chaotic spiking-bursting oscillations of the model. We also show various regimes of other neural activities (subthreshold oscillations, phasic spiking etc.) derived from the proposed model

Strategies and Techniques for Use and Exploitation of Contextual Information in High-Level Fusion Architectures

Proceedings of: 13th Conference on Information Fusion (FUSION 2010): Edinburgh, UK. 26-29 July 2010.Contextual Information is proving to be not only an additional exploitable information source for improving entity and situational estimates in certain Information Fusion systems, but can also be the entire focus of estimation for such systems as those directed to Ambient Intelligence (AI) and Context-Aware(CA) applications. This paper will discuss the role(s) of Contextual Information (CI) in a wide variety of IF applications to include AI, CA, Defense, and Cyber-security among possible others, the issues involved in designing strategies and techniques for CI use and exploitation, provide some exemplars of evolving CI use/exploitation designs on our current projects, and describe some general frameworks that are evolving in various application domains where CI is proving critical.The UC3M Team gratefully acknowledge that this research activity is supported in part by Projects CICYT TIN2008-06742-C02-02/TSI, CICYT TEC2008-06732- C02-02/TEC, CAM CONTEXTS (S2009/TIC-1485) and DPS2008-07029-C02-02. UC3M also thanks Prof. James Llinas for his helpful comments during his stay, which has been supported by the collaboration agreement ‘Chairs of Excellence’ between University Carlos III and Banco Santander. The US/UB Team gratefully acknowledge that this research activity is supported by a Multidisciplinary University Research Initiative (MURI) grant (Number W911NF-09-1-0392) for “Unified Research on Networkbased Hard/Soft Information Fusion”, issued by the US Army Research Office (ARO) under the program management of Dr. John LaveryPublicad