Macroscopic effects in noncollinear high-order harmonic generation.

We study two-color high-order harmonic generation using an intense driving field and its weak second harmonic, crossed under a small angle in the focus. Employing sum- and difference-frequency generation processes, such a noncollinear scheme can be used to measure and control macroscopic phase matching effects by utilizing a geometrical phase mismatch component, which depends on the noncollinear angle. We further show how spatial phase effects in the generation volume are mapped out into the far field allowing a direct analogy with temporal carrier envelope effects in attosecond pulse generation.

Polyhydroxyalkanoate (PHA) production from sludge and municipal wastewater treatment.

Polyhydroxyalkanoates (PHAs) are biodegradable polyesters with comparable properties to some petroleum-based polyolefins. PHA production can be achieved in open, mixed microbial cultures and thereby coupled to wastewater and solid residual treatment. In this context, waste organic matter is utilised as a carbon source in activated sludge biological treatment for biopolymer synthesis. Within the EU project Routes, the feasibility of PHA production has been evaluated in processes for sludge treatment and volatile fatty acid (VFA) production and municipal wastewater treatment. This PHA production process is being investigated in four units: (i) wastewater treatment with enrichment and production of a functional biomass sustaining PHA storage capacity, (ii) acidogenic fermentation of sludge for VFA production, (iii) PHA accumulation from VFA-rich streams, and (iv) PHA recovery and characterisation. Laboratory- and pilot-scale studies demonstrated the feasibility of municipal wastewater and solid waste treatment alongside production of PHA-rich biomass. The PHA storage capacity of biomass selected under feast-famine with municipal wastewater has been increased up to 34% (g PHA g VSS(-1)) in batch accumulations with acetate during 20 h. VFAs obtained from waste activated sludge fermentation were found to be a suitable feedstock for PHA production.

GABA-A receptor modulating steroids in acute and chronic stress; relevance for cognition and dementia?

Cognitive dysfunction, dementia and Alzheimer's disease (AD) are increasing as the population worldwide ages. Therapeutics for these conditions is an unmet need. This review focuses on the role of the positive GABA-A receptor modulating steroid allopregnanolone (APα), it's role in underlying mechanisms for impaired cognition and of AD, and to determine options for therapy of AD. On one hand, APα given intermittently promotes neurogenesis, decreases AD-related pathology and improves cognition. On the other, continuous exposure of APα impairs cognition and deteriorates AD pathology. The disparity between these two outcomes led our groups to analyze the mechanisms underlying the difference. We conclude that the effects of APα depend on administration pattern and that chronic slightly increased APα exposure is harmful to cognitive function and worsens AD pathology whereas single administrations with longer intervals improve cognition and decrease AD pathology. These collaborative assessments provide insights for the therapeutic development of APα and APα antagonists for AD and provide a model for cross laboratory collaborations aimed at generating translatable data for human clinical trials.

Spectral phase measurement of a Fano resonance using tunable attosecond pulses.

Electron dynamics induced by resonant absorption of light is of fundamental importance in nature and has been the subject of countless studies in many scientific areas. Above the ionization threshold of atomic or molecular systems, the presence of discrete states leads to autoionization, which is an interference between two quantum paths: direct ionization and excitation of the discrete state coupled to the continuum. Traditionally studied with synchrotron radiation, the probability for autoionization exhibits a universal Fano intensity profile as a function of excitation energy. However, without additional phase information, the full temporal dynamics cannot be recovered. Here we use tunable attosecond pulses combined with weak infrared radiation in an interferometric setup to measure not only the intensity but also the phase variation of the photoionization amplitude across an autoionization resonance in argon. The phase variation can be used as a fingerprint of the interactions between the discrete state and the ionization continua, indicating a new route towards monitoring electron correlations in time.

Integrated production of polyhydroxyalkanoates (PHAs) with municipal wastewater and sludge treatment at pilot scale.

A pilot-scale process was operated over 22 months at the Brussels North Wastewater Treatment Plant (WWTP) in order to evaluate polyhydroxyalkanoate (PHA) production integration with services of municipal wastewater and sludge management. Activated sludge was produced with PHA accumulation potential (PAP) by applying feast-famine selection while treating the readily biodegradable COD from influent wastewater (average removals of 70% COD, 60% CODsol, 24% nitrogen, and 46% phosphorus). The biomass PAP was evaluated to be in excess of 0.4gPHA/gVSS. Batch fermentation of full-scale WWTP sludge at selected temperatures (35, 42 and 55 °C) produced centrate (6-9.4 gCODVFA/L) of consistent VFA composition, with optimal fermentation performance at 42 °C. Centrate was used to accumulate PHA up to 0.39 gPHA/gVSS. The centrate nutrients are a challenge to the accumulation process but producing a biomass with 0.5 gPHA/gVSS is considered to be realistically achievable within the typically available carbon flows at municipal waste management facilities.

Potential antipsychotic agents 5. Synthesis and antidopaminergic properties of substituted 5,6-dimethoxysalicylamides and related compounds.

A series of 3-substituted 5,6-dimethoxysalicylamides III (9-13 and 15) has been synthesized from the corresponding 2,5,6-trimethoxybenzoic acids. Relaxation times T1 and carbon chemical shifts of the methoxy groups in III showed that the 6-methoxy group adopts a nearly perpendicular orientation and the 5-methoxy group takes on a more coplanar orientation with respect to the ring plane in solution. The salicylamides III display a very high and stereoselective affinity for the [3H]spiperone and [3H]raclopride binding sites in vitro. Regioisomeric salicylamides IV also exhibit pronounced, but lower than III, affinity for the [3H]spiperone binding site. The structural requirements were further assessed by studies of the related amino analogues 23 and 24 and hydroxy analogue 27. The 3-bromo compound 11 (FLB 463) was studied in various in vivo models and compared with the dopamine-D2 antagonists sulpiride, raclopride, eticlopride, and haloperidol. The high potency of 11 to selectively block dopamine-D2 receptors in vitro and in vivo combined with indications on a low potential for motor side effects makes it a very interesting new member of the class of substituted salicylamides.

Inhibitors of neuronal monoamine uptake. 2. Selective inhibition of 5-hydroxytryptamine uptake by alpha-amino acid esters of phenethyl alcohols.

A series of alpha-amino acid esters of substituted phenethyl alcohols was prepared and tested as inhibitors of the neuronal reuptake of noradrenaline and 5-hydroxytryptamine. Some of the compounds are potent and very selective in blocking the 5-hydroxytryptamine uptake, as evidenced by biochemical data and behavioral tests. The most promising agent, alaproclate [2-(4-chlorophenyl)-1,1-dimethylethyl 2-aminopropanoate hydrochloride (I, IV)], was selected for further studies as a potential antidepressant agent. A discussion on structure--activity relationships (SAR) is given. In an attempt to explain the selective action on the mechanism of 5-hydroxytryptamine uptake by the new inhibitors, their structures are compared with those of the two neurotransmitters. From the tentative pharmacophore and conformations of transmitter (5-HT) and inhibitor (alaproclate) derived from SAR, a hypothetic carrier site for 5-HT uptake is deduced in terms of geometry and electronic properties.

Brain activation during odor perception in males and females.

Several studies indicate that women outperform men in olfactory identification tasks. The psychophysical data are more divergent when it comes to gender differences at levels of odor processing which are cognitively less demanding. We therefore compared cerebral activation with H2(15)O PET in 12 females and 11 males during birhinal passive smelling of odors and odorless air. The odorous compounds (odorants) were pure olfactory, or mixed olfactory and weakly trigeminal. Using odorless air as the baseline condition, activations were found bilaterally in the amygdala, piriform and insular cortices in both sexes, irrespective of the odor. No gender difference was detected in the pattern of cerebral activation (random effect analysis SPM99, corrected p < 0.05) or in the subjective perception of odors. Males and females seem to use similar cerebral circuits during the passive perception of odors. The reported female superiority in assessing olfactory information including odor identification is probably an effect of a difference at a cognitive, rather than perceptive level of olfactory processing.

Synthesis and binding properties of the fluorinated substituted benzamide [3H]NCQ 115, a new selective dopamine D2 receptor ligand.

[3H]NCQ 115 [R)-5-bromo-2,3-dimethoxy-N-[1-([2,5-3H]-4- fluorobenzyl)-2-pyrrolidinyl)methyl)benzamide) was prepared by acylation of (R)-(2-aminomethyl)-1- ([2,5-3H]-4-fluorobenzyl)pyrrolidine, which was obtained in a stereo-conservative synthesis from (R)-prolinamide. Purification by reversed phase high performance liquid chromatography (HPLC) gave [3H]NCQ 115 with a radiochemical purity of greater than 99% and a specific activity of 0.97 GBq/mumol (36 Ci/mmol). Saturation analyses, association and dissociation kinetics as well as binding competition with several compounds of various classes were performed with [3H]NCQ 115 in rat striatal homogenates. Saturation analyses in vitro showed that [3H]NCQ 115 bound to a single binding site with a Kd = 214 pM and Bmax = 35.4 fmol/mg. The binding of [3H]NCQ 115 was dependent upon sodium ions, since the number of binding sites was altered when sodium ions were excluded from the incubation medium. NCQ 115 inhibited the binding of [3H]raclopride to dopamine D2 receptors with high affinity (Ki = 147 pM), having much lower affinity for other receptors. The affinity of this substituted 1-benzyl-2-pyrrolidinylmethyl benzamide was confined to the (R)-enantiomer, which contrasts with that of the corresponding N-ethyl derivatives such as FLB 457, raclopride, eticlopride, sulpiride and NCQ 298, where the pharmacological activity is found in the (S)-enantiomer. It can be concluded that [3H]NCQ 115 binds to dopamine D2 receptors in the rat striatum with high affinity and high selectivity. [3H]NCQ 115 can also be used for in vivo binding studies of the brain. [18F]NCQ 115 may be a suitable ligand for positron emission tomography (PET) studies of the human brain in vivo.

Validation of EUCAST zone diameter breakpoints against reference broth microdilution.

The European Committee on Antimicrobial Susceptibility Testing (EUCAST) began harmonizing clinical breakpoints in Europe 2002. In 2009, work to develop a disc diffusion method began and the first disc diffusion breakpoints calibrated to EUCAST clinical MIC breakpoints were published in December 2009. In this study we validated EUCAST clinical zone diameter breakpoints against the International Standard Organization (ISO) reference broth microdilution. A collection of 544 isolates (238 Gram-negative and 306 Gram-positive) were tested against a panel of antimicrobial agents. Antimicrobial susceptibility testing was performed with broth microdilution as described by ISO and disc diffusion in accordance with EUCAST methodology. Inhibition zone diameters and MIC values were interpreted and categorized (S, I and R) according to EUCAST clinical breakpoint table version 2.0. Categorical agreement (CA) as well as minor (mD), major (MD) and very major (VMD) discrepancies were determined. There was in general good correlation between susceptibility test results obtained with disc diffusion and broth microdilution. Overall CA was 97.3% for all combinations of organisms and antimicrobial agents (n = 5231) and the overall discrepancy rates were 110 (2.1%) mD, 24 (0.5%) MD and 7 (0.1%) VMD. The overall CA for Gram-positive and Gram-negative organisms were 98.7% (2346 tests) and 96.2% (2942 tests), respectively. Seven VMD were observed, five for Gram-positive organisms (coagulase negative staphylococci (n = 2) and Staphylococcus aureus (n = 3)) and two for Gram-negative organisms (Pseudomonas aeruginosa). Minor discrepancies were mainly observed in Gram-negatives and were related to different antimicrobial agents and species.

Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons.

Some women have negative mood symptoms, caused by progestagens in hormonal contraceptives or sequential hormone therapy or by progesterone in the luteal phase of the menstrual cycle, which may be attributed to metabolites acting on the GABA-A receptor. The GABA system is the major inhibitory system in the adult CNS and most positive modulators of the GABA-A receptor (benzodiazepines, barbiturates, alcohol, GABA steroids), induce inhibitory (e.g. anesthetic, sedative, anticonvulsant, anxiolytic) effects. However, some individuals have adverse effects (seizures, increased pain, anxiety, irritability, aggression) upon exposure. Positive GABA-A receptor modulators induce strong paradoxical effects including negative mood in 3%-8% of those exposed, while up to 25% have moderate symptoms. The effect is biphasic: low concentrations induce an adverse anxiogenic effect while higher concentrations decrease this effect and show inhibitory, calming properties. The prevalence of premenstrual dysphoric disorder (PMDD) is also 3%-8% among women in fertile ages, and up to 25% have more moderate symptoms of premenstrual syndrome (PMS). Patients with PMDD have severe luteal phase-related symptoms and show changes in GABA-A receptor sensitivity and GABA concentrations. Findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA-A receptor, which may be explained by one or more of three hypotheses regarding the paradoxical effect of GABA steroids on behavior: (1) under certain conditions, such as puberty, the relative fraction of certain GABA-A receptor subtypes may be altered, and at those subtypes the GABA steroids may act as negative modulators in contrast to their usual role as positive modulators; (2) in certain brain areas of vulnerable women the transmembrane Cl(-) gradient may be altered by factors such as estrogens that favor excitability; (3) inhibition of inhibitory neurons may promote disinhibition, and hence excitability. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.

Mixed culture polyhydroxyalkanoates production from sugar molasses: the use of a 2-stage CSTR system for culture selection.

Polyhydroxyalkanoates (PHAs) are promising biodegradable polymers. The use of mixed microbial cultures (MMC) and low cost feedstocks have a positive impact on the cost-effectiveness of the process. It has typically been carried out in Sequencing Batch Reactors (SBR). In this study, a 2-stage CSTR system (under Feast and Famine conditions) was used to effectively select for PHA-storing organisms using fermented molasses as feedstock. The effect of influent substrate concentration (60-120 Cmmol VFA/L) and HRT ratio between the reactors (0.2-0.5h/h) on the system's selection efficiency was assessed. It was shown that Feast reactor residual substrate concentration impacted on the selective pressure for PHA storage (due to substrate-dependent kinetic limitation). Moreover, a residual substrate concentration coming from the Feast to the Famine reactor did not jeopardize the physiological adaptation required for enhanced PHA storage. The culture reached a maximum PHA content of 61%. This success opens new perspectives to the use of wastewater treatment infrastructure for PHA production, thus valorizing either excess sludge or wastewaters.