Dynamic RNA profiling in Plasmodium falciparum synchronized blood stages exposed to lethal doses of artesunate

<p>Abstract</p> <p>Background</p> <p>Translation of the genome sequence of <it>Plasmodium sp</it>. into biologically relevant information relies on high through-put genomics technology which includes transcriptome analysis. However, few studies to date have used this powerful approach to explore transcriptome alterations of <it>P. falciparum </it>parasites exposed to antimalarial drugs.</p> <p>Results</p> <p>The rapid action of artesunate allowed us to study dynamic changes of the parasite transcriptome in synchronous parasite cultures exposed to the drug for 90 minutes and 3 hours. Developmentally regulated genes were filtered out, leaving 398 genes which presented altered transcript levels reflecting drug-exposure. Few genes related to metabolic pathways, most encoded chaperones, transporters, kinases, Zn-finger proteins, transcription activating proteins, proteins involved in proteasome degradation, in oxidative stress and in cell cycle regulation. A positive bias was observed for over-expressed genes presenting a subtelomeric location, allelic polymorphism and encoding proteins with potential export sequences, which often belonged to subtelomeric multi-gene families. This pointed to the mobilization of processes shaping the interface between the parasite and its environment. In parallel, pathways were engaged which could lead to parasite death, such as interference with purine/pyrimidine metabolism, the mitochondrial electron transport chain, proteasome-dependent protein degradation or the integrity of the food vacuole.</p> <p>Conclusion</p> <p>The high proportion of over-expressed genes encoding proteins exported from the parasite highlight the importance of extra-parasitic compartments as fields for exploration in drug research which, to date, has mostly focused on the parasite itself rather than on its intra and extra erythrocytic environment. Further work is needed to clarify which transcriptome alterations observed reflect a specific response to overcome artesunate toxicity or more general perturbations on the path to cellular death.</p

Integrated Multiscale Modeling of the Nervous System: Predicting Changes in Hippocampal Network Activity by a Positive AMPA Receptor Modulator

One of the fundamental characteristics of the brain is its hierarchical organization. Scales in both space and time that must be considered when integrating across hierarchies of the nervous system are sufficiently great as to have impeded the development of routine multilevel modeling methodologies. Complex molecular interactions at the level of receptors and channels regulate activity at the level of neurons; interactions between multiple populations of neurons ultimately give rise to complex neural systems function and behavior. This spatial complexity takes place in the context of a composite temporal integration of multiple, different events unfolding at the millisecond, second, minute, hour, and longer time scales. In this study, we present a multiscale modeling methodology that integrates synaptic models into single neuron, and multineuron, network models. We have applied this approach to the specific problem of how changes at the level of kinetic parameters of a receptor-channel model are translated into changes in the temporal firing pattern of a single neuron, and ultimately, changes in the spatiotemporal activity of a network of neurons. These results demonstrate how this powerful methodology can be applied to understand the effects of a given local process within multiple hierarchical levels of the nervous system

Simulation of Postsynaptic Glutamate Receptors Reveals Critical Features of Glutamatergic Transmission

Activation of several subtypes of glutamate receptors contributes to changes in postsynaptic calcium concentration at hippocampal synapses, resulting in various types of changes in synaptic strength. Thus, while activation of NMDA receptors has been shown to be critical for long-term potentiation (LTP) and long term depression (LTD) of synaptic transmission, activation of metabotropic glutamate receptors (mGluRs) has been linked to either LTP or LTD. While it is generally admitted that dynamic changes in postsynaptic calcium concentration represent the critical elements to determine the direction and amplitude of the changes in synaptic strength, it has been difficult to quantitatively estimate the relative contribution of the different types of glutamate receptors to these changes under different experimental conditions. Here we present a detailed model of a postsynaptic glutamatergic synapse that incorporates ionotropic and mGluR type I receptors, and we use this model to determine the role of the different receptors to the dynamics of postsynaptic calcium with different patterns of presynaptic activation. Our modeling framework includes glutamate vesicular release and diffusion in the cleft and a glutamate transporter that modulates extracellular glutamate concentration. Our results indicate that the contribution of mGluRs to changes in postsynaptic calcium concentration is minimal under basal stimulation conditions and becomes apparent only at high frequency of stimulation. Furthermore, the location of mGluRs in the postsynaptic membrane is also a critical factor, as activation of distant receptors contributes significantly less to calcium dynamics than more centrally located ones. These results confirm the important role of glutamate transporters and of the localization of mGluRs in postsynaptic sites in their signaling properties, and further strengthen the notion that mGluR activation significantly contributes to postsynaptic calcium dynamics only following high-frequency stimulation. They also provide a new tool to analyze the interactions between metabotropic and ionotropic glutamate receptors

A meta-analysis of previous falls and subsequent fracture risk in cohort studies

NC Harvey acknowledges funding from the UK Medical Research Council (MC_PC_21003; MC_PC_21001). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, and 75N92021D00005. Funding for the MrOS USA study comes from the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. Funding for the SOF study comes from the National Institute on Aging (NIA), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), supported by grants (AG05407, AR35582, AG05394, AR35584, and AR35583). Funding for the Health ABC study was from the Intramural research program at the National Institute on Aging under the following contract numbers: NO1-AG-6–2101, NO1-AG-6–2103, and NO1-AG-6–2106.Peer reviewedPostprin

Evidence for distinct prototype sequences within the Plasmodium falciparum Pf60 multigene family

International audienceUsing oligonucleotides derived from Pf60.1, a member of the Plasmodium falciparum Pf60 multigene family, numerous fragments were amplified from genomic and cDNA from the 3D7 P. falciparum clone. DNA sequencing showed that the various fragments presented considerable diversity, indicating that the 3D7 repertoire contains at least 20 distinct versions of the region analysed. The various sequences aligned with either of two prototype sequences. Characteristic of the A-type was the presence of a 21 bp motif, present in variable copy number, as well as a sequence homologous to the Babesia sp. RAP-1 consensus. The B prototype sequence did not present such features and substantially differed from the A-type, due to accumulation of point mutations and numerous triplet deletions. Consistent with the marked differences between both sub-families, individual members from each sub-family did not cross-hybridise, produced distinct multiple band patterns on Southern blots and distinct chromosome profiles. Numerous hybrid sequences were observed. Interestingly, most var genes and var-related unspliced cDNAs described so far are of A/B hybrid type. These data suggest that the family has evolved by successive amplifications from two ancestral copies, with accumulation of mutations, as well as recombination and/or gene conversion events

VDS23-Situationsanalyse – schwierige Situationen, die zur Symptombildung führen und Fokus therapeutischer Veränderung sind

Es sind die individuell problematischen und schwierigen Situationen im zwischenmenschlichen Kontext, die zur Symptombildung führen, ob tiefenpsychologisch Auslöser oder lernpsychologisch Stimulus genannt. Die schwierigen Situationen im Vorfeld einer psychischen oder psychosomatischen Erkrankung sind Gegenstand zahlloser Therapiegespräche. Deshalb ist ihre systematische Erfassung ein naheliegender Schritt der psychotherapeutischen Diagnostik. Der VDS23-Situationsanalyse-Selbstbeurteilungsfragebogen hat 63 Items, von 0 bis 5 skaliert. Die Reliabilität der Gesamtskala ist sehr gut (0,95). Sechs Situationsfaktoren (Beziehung bedroht; Freiraum u. Grenzen bedroht; Bedürfnisfrustration; öffentliche Ablehnung droht; Verlust von Einfluss; Unterlegenheit) erklären 50 % der Gesamtvarianz. Sie korrelieren mit dysfunktionalen Persönlichkeitszügen und Entwicklungsstufen nach Piaget. Einsatzmöglichkeiten einer systematischen Situationsanalyse für die Fallkonzeption und die Therapiestrategie werden diskutiert

Modelling glutamatergic synapses : insights into mechanisms regulating synaptic efficacy

International audienceThe hippocampal formation is critically involved for the long-term storage of various forms of information, and it is widely believed that the phenomenon of long-term potentiation (LTP) of synaptic transmission is a molecular/cellular mechanism participating in memory formation. Although several high level models of hippocampal function have been developed, they do not incorporate detailed molecular information of the type necessary to understand the contribution of individual molecular events to the mechanisms underlying LTP and learning and memory. We are therefore developing new technological tools based on mathematical modeling and computer simulation of the molecular processes taking place in realistic biological networks to reach such an understanding. This article briefly summarizes the approach we are using and illustrates it by presenting data regarding the effects of changing the number of AMPA receptors on various features of glutamatergic transmission, including NMDA receptor-mediated responses and paired-pulse facilitation. We conclude by discussing the significance of these results and providing some ideas for future directions with this approach

A fully parallel in time and space algorithm for simulating the electrical activity of a neural tissue

International audienceThe resolution of a model describing the electrical activity of neural tissue and itspropagation within this tissue is highly consuming in term of computing time and requires strongcomputing power to achieve good results.New method: In this study, we present a method to solve a model describing the electricalpropagation in neuronal tissue, using parareal algorithm, coupling with parallelization space usingCUDA in graphical processing unit (GPU).Results: We applied the method of resolution to different dimensions of the geometry of our model(1-D, 2-D and 3-D). The GPU results are compared with simulations from a multi-core processorcluster, using message-passing interface (MPI), where the spatial scale was parallelized in order toreach a comparable calculation time than that of the presented method using GPU. A gain of afactor 100 in term of computational time between sequential results and those obtained using theGPU has been obtained, in the case of 3-D geometry. Given the structure of the GPU, this factorincreases according to the fineness of the geometry used in the computation.Comparison with existing method(s): To the best of our knowledge, it is the first time such amethod is used, even in the case of neuroscience.Conclusion: Parallelization time coupled with GPU parallelization space allows for drasticallyreducing computational time with a fine resolution of the model describing the propagation of theelectrical signal in a neuronal tissue