CXCL12 inhibits expression of the NMDA receptor's NR2B subunit through a histone deacetylase-dependent pathway contributing to neuronal survival

Homeostatic chemokines, such as CXCL12, can affect neuronal activity by the regulation of inhibitory and excitatory neurotransmission, but the mechanisms involved are still undefined. Our previous studies have shown that CXCL12 protects cortical neurons from excitotoxicity by promoting the function of the gene-repressor protein Rb, which is involved in the recruitment of chromatin modifiers (such as histone deacetylases (HDACs)) to gene promoters. In neurons, Rb controls activity-dependent genes essential to neuronal plasticity and survival, such as the N-methyl--aspartic acid (NMDA) receptor's subunit NR2B, the expression of which in the tetrameric ion channel largely affects calcium signaling by glutamate. In this study, we report that CXCL12 differentially modulates intracellular responses after stimulation of synaptic and extrasynaptic NMDA receptors, by a specific regulation of the NR2B gene that involves HDACs. Our results show that CXCL12 selectively inhibits NR2B expression in vitro and in vivo altering NMDA-induced calcium responses associated with neuronal death, while promoting prosurvival pathways that depend on stimulation of synaptic receptors. Along with previous studies, these findings underline the role of CXCL12/CXCR4 in the regulation of crucial components of glutamatergic transmission. These novel effects of CXCL12 may be involved in the physiological function of the chemokine in both developing and mature brains

Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties.

Genetic and bioinformatic analyses have identified missense mutations in GRIN2B encoding the NMDA receptor GluN2B subunit in autism, intellectual disability, Lennox Gastaut and West Syndromes. Here, we investigated several such mutations using a near-complete, hybrid 3D model of the human NMDAR and studied their consequences with kinetic modelling and electrophysiology. The mutants revealed reductions in glutamate potency; increased receptor desensitisation; and ablation of voltage-dependent Mg block. In addition, we provide new views on Mg and NMDA channel blocker binding sites. We demonstrate that these mutants have significant impact on excitatory transmission in developing neurons, revealing profound changes that could underlie their associated neurological disorders. Of note, the NMDAR channel mutant GluN2B unusually allowed Mg permeation, whereas nearby N615I reduced Ca permeability. By identifying the binding site for an NMDAR antagonist that is used in the clinic to rescue gain-of-function phenotypes, we show that drug binding may be modified by some GluN2B disease-causing mutations

The Relative Impact of Climate Change on the Extinction Risk of Tree Species in the Montane Tropical Andes.

There are widespread concerns that anthropogenic climate change will become a major cause of global biodiversity loss. However, the potential impact of climate change on the extinction risk of species remains poorly understood, particularly in comparison to other current threats. The objective of this research was to examine the relative impact of climate change on extinction risk of upper montane tree species in the tropical Andes, an area of high biodiversity value that is particularly vulnerable to climate change impacts. The extinction risk of 129 tree species endemic to the region was evaluated according to the IUCN Red List criteria, both with and without the potential impacts of climate change. Evaluations were supported by development of species distribution models, using three methods (generalized additive models, recursive partitioning, and support vector machines), all of which produced similarly high AUC values when averaged across all species evaluated (0.82, 0.86, and 0.88, respectively). Inclusion of climate change increased the risk of extinction of 18-20% of the tree species evaluated, depending on the climate scenario. The relative impact of climate change was further illustrated by calculating the Red List Index, an indicator that shows changes in the overall extinction risk of sets of species over time. A 15% decline in the Red List Index was obtained when climate change was included in this evaluation. While these results suggest that climate change represents a significant threat to tree species in the tropical Andes, they contradict previous suggestions that climate change will become the most important cause of biodiversity loss in coming decades. Conservation strategies should therefore focus on addressing the multiple threatening processes currently affecting biodiversity, rather than focusing primarily on potential climate change impacts

The Effects of NR2 Subunit-Dependent NMDA Receptor Kinetics on Synaptic Transmission and CaMKII Activation

N-Methyl-d-aspartic acid (NMDA) receptors are widely expressed in the brain and are critical for many forms of synaptic plasticity. Subtypes of the NMDA receptor NR2 subunit are differentially expressed during development; in the forebrain, the NR2B receptor is dominant early in development, and later both NR2A and NR2B are expressed. In heterologous expression systems, NR2A-containing receptors open more reliably and show much faster opening and closing kinetics than do NR2B-containing receptors. However, conflicting data, showing similar open probabilities, exist for receptors expressed in neurons. Similarly, studies of synaptic plasticity have produced divergent results, with some showing that only NR2A-containing receptors can drive long-term potentiation and others showing that either subtype is capable of driving potentiation. In order to address these conflicting results as well as open questions about the number and location of functional receptors in the synapse, we constructed a Monte Carlo model of glutamate release, diffusion, and binding to NMDA receptors and of receptor opening and closing as well as a model of the activation of calcium-calmodulin kinase II, an enzyme critical for induction of synaptic plasticity, by NMDA receptor-mediated calcium influx. Our results suggest that the conflicting data concerning receptor open probabilities can be resolved, with NR2A- and NR2B-containing receptors having very different opening probabilities. They also support the conclusion that receptors containing either subtype can drive long-term potentiation. We also are able to estimate the number of functional receptors at a synapse from experimental data. Finally, in our models, the opening of NR2B-containing receptors is highly dependent on the location of the receptor relative to the site of glutamate release whereas the opening of NR2A-containing receptors is not. These results help to clarify the previous findings and suggest future experiments to address open questions concerning NMDA receptor function

Developmental malformation of the corpus callosum: a review of typical callosal development and examples of developmental disorders with callosal involvement

This review provides an overview of the involvement of the corpus callosum (CC) in a variety of developmental disorders that are currently defined exclusively by genetics, developmental insult, and/or behavior. I begin with a general review of CC development, connectivity, and function, followed by discussion of the research methods typically utilized to study the callosum. The bulk of the review concentrates on specific developmental disorders, beginning with agenesis of the corpus callosum (AgCC)—the only condition diagnosed exclusively by callosal anatomy. This is followed by a review of several genetic disorders that commonly result in social impairments and/or psychopathology similar to AgCC (neurofibromatosis-1, Turner syndrome, 22q11.2 deletion syndrome, Williams yndrome, and fragile X) and two forms of prenatal injury (premature birth, fetal alcohol syndrome) known to impact callosal development. Finally, I examine callosal involvement in several common developmental disorders defined exclusively by behavioral patterns (developmental language delay, dyslexia, attention-deficit hyperactive disorder, autism spectrum disorders, and Tourette syndrome)

Buoyancy-driven flow between two rooms coupled by two openings at different levels

The stack-driven flow between two interconnected rooms produced by a single heat source is studied. In particular, the features of the transient flow for different positions and areas of two openings in the shared vertical wall are analysed. An analytical model provides the time evolution of the stratified flows in rooms of any size. The concept of an equivalent layer representing a non-uniform density profile, which is useful in other contexts, is included in the theoretical approach and provides physical insight and aids the mathematical solution of the problem. New salt-bath experiments are performed to simulate the thermal forcing between the rooms, to validate the model and to analyse the mixing generated and the effects of a source of volume in the configuration studied

Short-Path-Distillation Process of Lemongrass Essential Oil: Physicochemical Characterization and Assessment Quality of the Distillate and the Residue Products

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Short-path distillation (SPD), a special high-tech thermal separation technique operating at high vacuum, was used in order to increase the citral concentration in lemongrass essential oil, without adding any extra components to the system, causing minimal thermal impact and reaching high quality for the essential oil extracted at the distillate stream. Experiments were carried out using a centrifugal molecular distillation unit with an evaporator temperature (EVT) from 60 to 120 degrees C and a feed flow rate (Q) from 1.5 to 4.5 mL . min(-1). Experimental protocols for oil and fat analysis were used to characterize the materials extracted. Results (obtained using GC-MS) showed that bSPD was successful in the separation and purification of essential oil. High-quality essential oil was confirmed because of citral concentration increases from 19.816 mg(citral) . mL(-1) (initial sample) to 40.963 mg(citral) . mL(-1) (at 120 degrees C and 4.5 mL . min(-1)), reaching a concentration of the bioactive compound (citral) in the distillate stream of 2.1 times the concentration in the original sample. The density, dynamic viscosity, and free fatty acids were 0.901 g . cm(-3), 2.069 mPa.s(-1), and 1.26 wt % (oleic acid), respectively, satisfying the oil quality criterion and avoiding thermal degradation.501381858194Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Factorial design applied to concentrate bioactive component of Cymbopogon citratus essential oil using short path distillation

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Cymbopogon citratus (DC.) Stapf (Gramineae) is the scientific name of a plant known as lemongrass. it is characterized by the high concentrations of citral. This work aimed to analyze the influence of short path distillation process variables (evaporator temperature (EVT), volumetric feed flow rate (Q) and interactions between them), on the concentration of citral in the distillate stream of the process. Factorial design experiments were carried out, starting with a 2(2) design trials at experimental range from 60 to 80 degrees C for EVT and from 1.5 to 6.0 mL/min for Q followed by 2(2) with central point design trials at experimental range from 60 to 120 degrees C for EVT and between 1.5 and 4.5 mL/min for Q. The concentration of citral in the distillate (CCD) was analyzed by gas chromatography-mass spectrometry (GC-MS). The effect of each variable studied on the dependent variable (CCD), is indicated by influence of EVT and Q on CCD. The increase of EVT increases CCD to 2.048 x 10(3) mg citral/g sample, when compared with the initial sample of essential oil, which presented a CCD of 9.908 x 10(2) mg citral/g sample. The linear model, statistically significant, describes the dependence of the variable CCD with the variables of the process inside the experimental range. (C) 2009 The Institution of Chemical Engineers. Published by Elsevier B.V All rights reserved.882A239244Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq