Update on Dihydropteroate Synthase (DHPS) Mutations in Pneumocystis jirovecii

A Pneumocystis jirovecii is one of the most important microorganisms that cause pneumonia in immunosupressed individuals. The guideline for treatment and prophylaxis of Pneumocystis pneumonia (PcP) is the use of a combination of sulfa drug-containing trimethroprim and sulfamethoxazole. In the absence of a reliable method to culture Pneumocystis, molecular techniques have been developed to detect mutations in the dihydropteroate synthase gene, the target of sulfa drugs, where mutations are related to sulfa resistance in other microorganisms. The presence of dihydropteroate synthase (DHPS) mutations has been described at codon 55 and 57 and found almost around the world. In the current work, we analyzed the most common methods to identify these mutations, their geographical distribution around the world, and their clinical implications. In addition, we describe new emerging DHPS mutations. Other aspects, such as the possibility of transmitting Pneumocystis mutated organisms between susceptible patients is also described, as well as a brief summary of approaches to study these mutations in a heterologous expression system

Performance evaluation of a hybrid vehicle and sensor network to prevent traffic accidents

In recent years, wireless networks have become a widespread communication technology as well as a research challenge. Many contributions have been made on ad hoc networks, such as wireless sensor networks (WSNs) and vehicular ad hoc networks (VANETs). Recently, the number of cars on our streets, roads, and highways has been increasing, giving rise to a great interest in vehicular communication technologies. This paper presents an hybrid sensor and vehicular network (HSVN) platform, as well as the description and evaluation of a communication protocol between VANETs and WSNs using a network simulator for its evaluation

Means and covariance functions for geostatistical compositional data: an axiomatic approach

This work focuses on the characterization of the central tendency of a sample of compositional data. It provides new results about theoretical properties of means and covariance functions for compositional data, with an axiomatic perspective. Original results that shed new light on the geostatistical modeling of compositional data are presented. As a first result, it is shown that the weighted arithmetic mean is the only central tendency characteristic satisfying a small set of axioms, namely continuity, reflexivity and marginal stability. Moreover, this set of axioms also implies that the weights must be identical for all parts of the composition. This result has deep consequences on the spatial multivariate covariance modeling of compositional data. In a geostatistical setting, it is shown as a second result that the proportional model of covariance functions (i.e., the product of a covariance matrix and a single correlation function) is the only model that provides identical kriging weights for all components of the compositional data. As a consequence of these two results, the proportional model of covariance function is the only covariance model compatible with reflexivity and marginal stability

Adenosine A2A receptor modulation of hippocampal CA3-CA1 synapse plasticity during associative learning in behaving mice

© 2009 Nature Publishing Group All rights reservedPrevious in vitro studies have characterized the electrophysiological and molecular signaling pathways of adenosine tonic modulation on long-lasting synaptic plasticity events, particularly for hippocampal long-term potentiation(LTP). However, it remains to be elucidated whether the long-term changes produced by endogenous adenosine in the efficiency of synapses are related to those required for learning and memory formation. Our goal was to understand how endogenous activation of adenosine excitatory A2A receptors modulates the associative learning evolution in conscious behaving mice. We have studied here the effects of the application of a highly selective A2A receptor antagonist, SCH58261, upon a well-known associative learning paradigm - classical eyeblink conditioning. We used a trace paradigm, with a tone as the conditioned stimulus (CS) and an electric shock presented to the supraorbital nerve as the unconditioned stimulus(US). A single electrical pulse was presented to the Schaffer collateral–commissural pathway to evoke field EPSPs (fEPSPs) in the pyramidal CA1 area during the CS–US interval. In vehicle-injected animals, there was a progressive increase in the percentage of conditioning responses (CRs) and in the slope of fEPSPs through conditioning sessions, an effect that was completely prevented (and lost) in SCH58261 (0.5 mg/kg, i.p.)-injected animals. Moreover, experimentally evoked LTP was impaired in SCH58261- injected mice. In conclusion, the endogenous activation of adenosine A2A receptors plays a pivotal effect on the associative learning process and its relevant hippocampal circuits, including activity-dependent changes at the CA3-CA1 synapse.This study was supported by grants from the Spanish Ministry of Education and Research (BFU2005-01024 and BFU2005-02512), Spanish Junta de Andalucía (BIO-122 and CVI-02487), and the Fundación Conocimiento y Cultura of the Pablo de Olavide University (Seville, Spain).B. Fontinha was in receipt of a studentship from a project grant (POCI/SAU-NEU/56332/2004) supported by Fundação para a Ciência e Tecnologia (FCT, Portugal), and of an STSM from Cost B30 concerted action of the EU

Heteroreceptor complexes formed by dopamine D1, histamine H3 and N-methyl-D-aspartate glutamate receptors as targets to prevent neuronal death in Alzheimer's disease

Alzheimer’s disease (AD) is a neurodegenerative disorder causing progressive memory loss and cognitive dysfunction. Anti-AD strategies targeting cell receptors consider them as isolated units. However, many cell surface receptors cooperate and physically contact each other forming complexes having different biochemical properties than individual receptors. We here report the discovery of dopamine D , histamine H , and N-methylD-aspartate (NMDA) glutamate receptor heteromers in heterologous systems and in rodent brain cortex. Heteromers were detected by coimmunoprecipitation and in situ proximity ligation assays (PLA) in the rat cortex where H receptor agonists, via negative cross-talk, and H receptor antagonists, via cross-antagonism, decreased D receptor agonist signaling determined by ERK1/2 or Akt phosphorylation and counteracted D receptormediated excitotoxic cell death. Both D and H receptor antagonists also counteracted NMDA toxicity suggesting a complex interaction between NMDA receptors and D -H receptor heteromer function. Likely due to heteromerization, H receptors act as allosteric regulator for D and NMDA receptors. By bioluminescence resonance energy transfer (BRET), we demonstrated that D or H receptors form heteromers with NR1A/NR2B NMDA receptor subunits. D -H -NMDA receptor complexes were confirmed by BRET combined with fluorescence complementation. The endogenous expression of complexes in mouse cortex was determined by PLA and similar expression was observed in wild-type and APP/PS1 mice. Consistent with allosteric receptor-receptor interactions within the complex, H receptor antagonists reduced NMDA or D receptor-mediated excitotoxic cell death in cortical organotypic cultures. Moreover, H receptor antagonists reverted the toxicity induced by ß -amyloid peptide. Thus, histamine H receptors in D -H -NMDA heteroreceptor complexes arise as promising targets to prevent neurodegeneration

Motor-Coordination-Dependent Learning, More than Others, Is Impaired in Transgenic Mice Expressing Pseudorabies Virus Immediate-Early Protein IE180

The cerebellum in transgenic mice expressing pseudorabies virus immediate-early protein IE180 (TgIE96) was substantially diminished in size, and its histoarchitecture was severely disorganized, resulting in severe ataxia. TgIE96 mice can therefore be used as an experimental model to study the involvement of cerebellar circuits in different learning tasks. The performance of three-month-old TgIE96 mice was studied in various behavioral tests, including associative learning (classical eyeblink conditioning), object recognition, spatial orientation (water maze), startle response and prepulse inhibition, and passive avoidance, and compared with that of wild-type mice. Wild-type and TgIE96 mice presented similar reflexively evoked eyeblinks, and acquired classical conditioned eyelid responses with similar learning curves for both trace and delay conditioning paradigms. The two groups of mice also had similar performances during the object recognition test. However, they showed significant differences for the other three tests included in this study. Although both groups of animals were capable of swimming, TgIE96 mice failed to learn the water maze task during the allowed time. The startle response to a severe tone was similar in both control and TgIE96 mice, but the latter were unable to produce a significant prepulse inhibition. TgIE96 mice also presented evident deficits for the proper accomplishment of a passive avoidance test. These results suggest that the cerebellum is not indispensable for the performance of classical eyeblink conditioning and for object recognition tasks, but seems to be necessary for the proper performance of water maze, prepulse inhibition, and passive avoidance tests

Impact of protozoan cell death on parasite-host interactions and pathogenesis

PCD in protozoan parasites has emerged as a fascinating field of parasite biology. This not only relates to the underlying mechanisms and their evolutionary implications but also to the impact on the parasite-host interactions within mammalian hosts and arthropod vectors. During recent years, common functions of apoptosis and autophagy in protozoa and during parasitic infections have emerged. Here, we review how distinct cell death pathways in Trypanosoma, Leishmania, Plasmodium or Toxoplasma may contribute to regulation of parasite cell densities in vectors and mammalian hosts, to differentiation of parasites, to stress responses, and to modulation of the host immunity. The examples provided indicate crucial roles of PCD in parasite biology. The existence of PCD pathways in these organisms and the identification as being critical for parasite biology and parasite-host interactions could serve as a basis for developing new anti-parasitic drugs that take advantage of these pathways