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- SourceAvailable from: Abhishek Subramanian[Show abstract] [Hide abstract]
ABSTRACT: Leishmania infantum, causative agent of visceral leishmaniasis in humans, illustrates a complex lifecycle pertaining to two extreme environments, namely, the gut of the sandfly vector and human macrophages. Leishmania is capable of dynamically adapting and tactically switching between these critically hostile situations. The possible metabolic routes ventured by the parasite to achieve this exceptional adaptation to its varying environments are still poorly understood. In this study, we present an extensively reconstructed energy metabolism network of Leishmania infantum as an attempt to identify certain strategic metabolic routes preferred by the parasite to optimize its survival in such dynamic environments. The reconstructed network consists of 142 genes encoding for enzymes performing 237 reactions distributed across five distinct model compartments. We annotated the subcellular locations of different enzymes and their reactions on the basis of strong literature evidence and sequence-based detection of cellular localization signal within a protein sequence. To explore the diverse features of parasite metabolism the metabolic network was implemented and analyzed as a constraint-based model. Using a systems-based approach, we also put forth an extensive set of lethal reaction knockouts; some of which were validated using published data on Leishmania species. Performing a robustness analysis, the model was rigorously validated and tested for the secretion of overflow metabolites specific to Leishmania under varying extracellular oxygen uptake rate. Further, the fate of important non-essential amino acids in L. infantum metabolism was investigated. Stage-specific scenarios of L. infantum energy metabolism were incorporated in the model and key metabolic differences were outlined. Analysis of the model revealed the essentiality of glucose uptake, succinate fermentation, glutamate biosynthesis and an active TCA cycle as driving forces for parasite energy metabolism and its optimal growth. Finally, through our in silico knockout analysis, we could identify possible therapeutic targets that provide experimentally testable hypotheses.PLoS ONE 10/2015; 10(9). DOI:10.1371/journal.pone.0137976
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ABSTRACT: The cognitive problems experienced by people with schizophrenia not only impede recovery but also interfere with treatments designed to improve overall functioning. Hence there has been a proliferation of new therapies to treat cognitive problems with the hope that improvements will benefit future intervention and recovery outcomes. Cognitive remediation therapy (CR) that relies on intensive task practice can support basic cognitive functioning but there is little evidence on how these therapies lead to transfer to real life skills. However, there is increasing evidence that CR including elements of transfer training (e.g., strategy use and problem solving schemas) produce higher functional outcomes. It is hypothesized that these therapies achieve higher transfer by improving metacognition. People with schizophrenia have metacognitive problems; these include poor self-awareness and difficulties in planning for complex tasks. This paper reviews this evidence as well as research on why metacognition needs to be explicitly taught as part of cognitive treatments. The evidence is based on research on learning spanning from neuroscience to the field of education. Learning programmes, and CRT, may be able to achieve better outcomes if they explicitly teach metacognition including metacognitive knowledge (i.e., awareness of the cognitive requirements and approaches to tasks) and metacognitive regulation (i.e., cognitive control over the different task relevant cognitive requirements). These types of metacognition are essential for successful task performance, in particular, for controlling effort, accuracy and efficient strategy use. We consider metacognition vital for the transfer of therapeutic gains to everyday life tasks making it a therapy target that may yield greater gains compared to cognition alone for recovery interventions.Frontiers in Psychology 09/2015; 6:1259. DOI:10.3389/fpsyg.2015.01259
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ABSTRACT: Conventional modes of environmental governance, which typically exclude those stakeholders that are most directly linked to the specific place, frequently fail to have the desired impact. Using the example of lake water management in Loweswater, a small hamlet within the English Lake District, we consider the ways in which new "collectives" for local, bottom-up governance of water bodies can reframe problems in ways which both bind lay and professional people to place, and also recast the meaning of "solutions" in thought-provoking ways.PLoS Biology 03/2015; 13(3):e1002081. DOI:10.1371/journal.pbio.1002081
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