Kinetic modeling study of ethanol and dimethyl ether addition to premixed low-pressure propene–oxygen–argon flames

The chemical composition of flames of mixed hydrocarbon–oxygenate fuels was examined systematically for a series of laminar, premixed low-pressure propene–oxygen–argon flames blended with ethanol or dimethyl ether (DME). All flames were established at a carbon-to-oxygen ratio of C/O = 0.5 at 40 mbar. Propene was replaced incrementally by either additive, so that the entire range from pure propene to pure ethanol or pure DME was accessible. Experimental results have been reported previously (J. Wang et al., J. Chem. Phys. A 112 (2008) 9255–9265), including temperature profiles measured with laser-induced fluorescence (LIF) and quantitative mole fraction profiles for a large number of species obtained from molecular-beam mass spectrometry (MBMS), using electron ionization (EI) and vacuum-ultraviolet (VUV) photoionization (PI). The effects of oxygenate addition to the propene base flame were seen to result in interesting differences, especially regarding trends to form aldehydes. The entire flame series is now analyzed with a comprehensive kinetic model that combines the chemistries of propene, ethanol, and DME combustion. The flames of pure fuels are also compared with the predictions of different detailed mechanisms taken from the literature. Quantitative comparison of C₁- to C₆-species from this model with the measurements is provided. Major trends of propene replacement by the oxygenates are reproduced in quantitative agreement with the experiments, enabling a more detailed understanding of the combined reaction sequences in such fuel blends.     

Neural systems subserving valence and arousal during the experience of induced emotions.

The circumplex model of affect construes all emotions as linear combinations of 2 independent neurophysiological dimensions, valence and arousal. We used functional magnetic resonance imaging to identify the neural networks subserving valence and arousal, and we assessed, in 10 participants, the associations of the BOLD (blood oxygen level-dependent) response, an indirect index of neural activity, with ratings of valence and arousal during the emotional experiences induced by the presentation of evocative sentences. Unpleasant emotional experience was associated with increased BOLD signal intensities in the supplementary motor, anterior midcingulate, right dorsolateral prefrontal, occipito-temporal, inferior parietal, and cerebellar cortices. Highly arousing emotions were associated with increased BOLD signal intensities in the left thalamus, globus pallidus, caudate, parahippocampal gyrus, amygdala, premotor cortex, and cerebellar vermis. Separate analyses using a finite impulse response model confirmed these results and revealed that pleasant emotions engaged an additional network that included the midbrain, ventral striatum, and caudate nucleus, all portions of a reward circuit. These findings suggest the existence of distinct networks subserving the valence and arousal dimensions of emotions, with midline and medial temporal lobe structures mediating arousal and dorsal cortical areas and mesolimbic pathways mediating valence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Frameshift mutation in the survival motor neuron gene in a severe case of SMA type I

Recently, a spinal muscular atrophy (SMA) determining gene, termed survival motor neuron (SMN) gene, has been isolated from the 5q13 region and found deleted in most patients. A highly homologous copy of this gene has also been isolated and located in a centromeric position. We have analyzed 158 patients (SMA types I-IV) and found deletions of SMN exon 7 in 96.8%. Mutations other than gross deletions seem to be extremely rare. In one of the undeleted SMA type I patients, a newborn who survived for only 42 days, we detected a maternally inherited 5 bp microdeletion in exon 3, resulting in a premature stop codon. By RT-PCR and long range PCR amplification we were able to show that the deletion belongs to the SMN gene, rather than to the centromeric copy, and that the proposita had no paternal SMN gene. Analysis of the neuronal apoptosis inhibitor protein (NAIP) gene, which maps close to SMN and has been proposed as a SMA modifying gene, suggests the presence of at least one full-length copy. Haplotype analysis of closely linked polymorphic markers suggests that the proposita also lacks the maternally derived copy of the centromeric homologue of SMN supporting the hypothesis that the severity of the phenotype might depend on the reduced number of centromeric genes in addition to the frameshift mutation.     

Bayesian two-compartment and classic single-compartment minimal models: comparison on insulin modified IVGTT and effect of experiment reduction

Models describing plasma glucose and insulin concentration of an intravenous glucose tolerance test (IVGTT) allow a noninvasive cost-effective approach to estimate important indexes characterizing the efficiency of glucose-insulin control system, i.e., glucose effectiveness (S(G)) and insulin sensitivity (S(I)). To overcome some limitations of the classic single compartment minimal model (1CMM) of glucose kinetics , a two-compartment Bayesian minimal model (2CBMM) has been recently proposed for the standard IVGTT. This study aims to assess 2CBMM ability to describe the insulin-modified IVGTT (IM-IVGTT) which is the protocol of choice since it allows to study insulinopenic states. Both a full-length IM-IVGTT (240 min) as well as a reduced version (90 min) of it are studied. Results of the maximum a posteriori identification of IM-IVGTT (240 min) in 13 normals agree with those of standard IVGTT, i.e., a 42% decrease (P < 0.002) of S(G) and a 13% increase (P < 0.006) of S(I) with respect to ICMM. When identified from IM-IVGTT (90 min), 2CBMM not only provides S(G) and S(I) estimates 46% lower (P < 0.002) and 41% higher (P < 0.002) than 1CMM ones respectively, but also seems to overcome some limitations of the 240 min-based identification that probably arise because the minimal model is unable to properly account for the hyperglycemic hormonal response taking place in the second half of IM-IVGTT.     

The Dual Role of the GABAA Receptor in Peripheral Inflammation and Neuroinflammation: A Study in Hyperammonemic Rats

Cognitive and motor impairment in minimal hepatic encephalopathy (MHE) are mediated by neuroinflammation, which is induced by hyperammonemia and peripheral inflammation. GABAergic neurotransmission in the cerebellum is altered in rats with chronic hyperammonemia. The mechanisms by which hyperammonemia induces neuroinflammation remain unknown. We hypothesized that GABA_A receptors can modulate cerebellar neuroinflammation. The GABA_A antagonist bicuculline was administrated daily (i.p.) for four weeks in control and hyperammonemic rats. Its effects on peripheral inflammation and on neuroinflammation as well as glutamate and GABA neurotransmission in the cerebellum were assessed. In hyperammonemic rats, bicuculline decreases IL-6 and TNFα and increases IL-10 in the plasma, reduces astrocyte activation, induces the microglia M2 phenotype, and reduces IL-1β and TNFα in the cerebellum. However, in control rats, bicuculline increases IL-6 and decreases IL-10 plasma levels and induces microglial activation. Bicuculline restores the membrane expression of some glutamate and GABA transporters restoring the extracellular levels of GABA in hyperammonemic rats. Blocking GABA_A receptors improves peripheral inflammation and cerebellar neuroinflammation, restoring neurotransmission in hyperammonemic rats, whereas it induces inflammation and neuroinflammation in controls. This suggests a complex interaction between GABAergic and immune systems. The modulation of GABA_A receptors could be a suitable target for improving neuroinflammation in MHE.     

Development of Fragment‐Based n‐FABS NMR Screening Applied to the Membrane Enzyme FAAH

Despite the recognized importance of membrane proteins as pharmaceutical targets, the reliable identification of fragment hits that are able to bind these proteins is still a major challenge. Among different ¹⁹F NMR spectroscopic methods, n‐fluorine atoms for biochemical screening (n‐FABS) is a highly sensitive technique that has been used efficiently for fragment screening, but its application for membrane enzymes has not been reported yet. Herein, we present the first successful application of n‐FABS to the discovery of novel fragment hits, targeting the membrane‐bound enzyme fatty acid amide hydrolase (FAAH), using a library of fluorinated fragments generated based on the different local environment of fluorine concept. The use of the recombinant fusion protein MBP‐FAAH and the design of compound 11 as a suitable novel fluorinated substrate analogue allowed n‐FABS screening to be efficiently performed using a very small amount of enzyme. Notably, we have identified 19 novel fragment hits that inhibit FAAH with a median effective concentration (IC₅₀) in the low mM –μM range. To the best of our knowledge, these results represent the first application of a ¹⁹F NMR fragment‐based functional assay to a membrane protein.     

Identification of Novel GSK-3β Hits Using Competitive Biophysical Assays

Glycogen synthase kinase 3 beta (GSK-3β) is an evolutionarily conserved serine-threonine kinase dysregulated in numerous pathologies, such as Alzheimer’s disease and cancer. Even though GSK-3β is a validated pharmacological target most of its inhibitors have two main limitations: the lack of selectivity due to the high homology that characterizes the ATP binding site of most kinases, and the toxicity that emerges from GSK-3β complete inhibition which translates into the impairment of the plethora of pathways GSK-3β is involved in. Starting from a 1D ¹⁹F NMR fragment screening, we set up several biophysical assays for the identification of GSK-3β inhibitors capable of binding protein hotspots other than the ATP binding pocket or to the ATP binding pocket, but with an affinity able of competing with a reference binder. A phosphorylation activity assay on a panel of several kinases provided selectivity data that were further rationalized and corroborated by structural information on GSK-3β in complex with the hit compounds. In this study, we identified promising fragments, inhibitors of GSK-3β, while proposing an alternative screening workflow that allows facing the flaws that characterize the most common GSK-3β inhibitors through the identification of selective inhibitors and/or inhibitors able to modulate GSK-3β activity without leading to its complete inhibition.     

A Virtual Screening Study of the 18 kDa Translocator Protein using Pharmacophore Models Combined with 3D‐QSAR Studies

In the present study, we considered various pharmacophore hypotheses for TSPO ligands and an optimal one was selected on the basis of 3D‐QSAR studies. This hypothesis was used in a ligand‐based virtual screening study on the Maybridge database with the aim of identifying new TSPO ligands. Binding assays revealed that all selected compounds displayed TSPO affinity at 10 μM , and among them two compounds exhibited sub‐micromolar K_i values. These results validated our applied methodologies, and the two compounds with sub‐micromolar affinity could be used as interesting leads for the development of new active TSPO ligands.