Ethanol enhances neurosteroidogenesis in hippocampal pyramidal neurons by paradoxical NMDA receptor activation

Using an antibody against 5α-reduced neurosteroids, predominantly allopregnanolone, we found that immunostaining in the CA1 region of rat hippocampal slices was confined to pyramidal neurons. This neurosteroid staining was increased following 15 min administration of 60 mm but not 20 mm ethanol, and the enhancement was blocked by finasteride and dutasteride, selective inhibitors of 5α-reductase, a key enzyme required for allopregnanolone synthesis. Consistent with a prior report indicating that N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation can promote steroid production, we observed that D-2-amino-5-phosphonovalerate (APV), a competitive NMDAR antagonist, blocked the effects of 60 mm ethanol on staining. We previously reported that 60 mm ethanol inhibits the induction of long-term potentiation (LTP), a cellular model for memory formation, in the CA1 region. In the present study, LTP inhibition by 60 mm ethanol was also overcome by both the 5α-reductase inhibitors and by APV. Furthermore, the effects of ethanol on neurosteroid production and LTP were mimicked by a low concentration of NMDA (1 μm), and the ability of NMDA to inhibit LTP and to enhance neurosteroid staining was reversed by finasteride and dutasteride, as well as by APV. These results indicate that ethanol paradoxically enhances GABAergic neurosteroid production by activation of unblocked NMDARs and that acute LTP inhibition by ethanol represents a form of NMDAR-mediated metaplasticity

Midazolam inhibits hippocampal long-term potentiation and learning through dual central and peripheral benzodiazepine receptor activation and neurosteroidogenesis

Benzodiazepines (BDZs) enhance GABA(A) receptor inhibition by direct actions on central BDZ receptors (CBRs). Although some BDZs also bind mitochondrial receptors [translocator protein (18 kDa) (TSPO)] and promote the synthesis of GABA-enhancing neurosteroids, the role of neurosteroids in the clinical effects of BDZs is unknown. In rat hippocampal slices, we compared midazolam, an anesthetic BDZ, with clonazepam, an anticonvulsant/anxiolytic BDZ that activates CBRs selectively. Midazolam, but not clonazepam, increased neurosteroid levels in CA1 pyramidal neurons without changing TSPO immunostaining. Midazolam, but not clonazepam, also augmented a form of spike inhibition after stimulation adjacent to the pyramidal cell layer and inhibited induction of long-term potentiation. These effects were prevented by finasteride, an inhibitor of neurosteroid synthesis, or 17PA [17-phenyl-(3α,5α)-androst-16-en-3-ol], a blocker of neurosteroid effects on GABA(A) receptors. Moreover, the synaptic effects were mimicked by a combination of clonazepam with FGIN (2-[2-(4-fluorophenyl)-1H-indol-3-yl]-N,N-dihexylacetamide), a selective TSPO agonist, or a combination of clonazepam with exogenous allopregnanolone. Consistent with these in vitro results, finasteride abolished the effects of midazolam on contextual fear learning when administrated 1 d before midazolam injection. Thus, dual activation of CBRs and TSPO appears to result in unique actions of clinically important BDZs. Furthermore, endogenous neurosteroids are shown to be important regulators of pyramidal neuron function and synaptic plasticity

Cross-Relation Characterization of Knowledge Networks

Knowledge networks have become increasingly important as a changing repository of data which can be represented, studied and modeled by using complex networks concepts and methodologies. Here we report a study of knowledge networks corresponding to the areas of Physics and Theology, obtained from the Wikipedia and taken at two different dates separated by 4 years. The respective two versions of these networks were characterized in terms of their respective cross-relation signatures, being summarized in terms of modification indices obtained for each of the nodes that are preserved among the two versions. The proposed methodology is first evaluated on Erdos-Renyi (ER) and Barabasi-Albert model (BA) networks, before being tested on the knowledge networks obtained from the Wikipedia respectively to the areas of Physics and Theology. In the former study, it has been observed that the nodes at the core and periphery of both types of theoretical models yielded similar modification indices within these two groups of nodes, but with distinct values when taken across these two groups. The study of the Physics and Theology networks indicated that these two networks have signatures respectively similar to those of the BA and ER models, as well as that higher modification values being obtained for the periphery nodes, as compared to the respective core nodes.Comment: 23 pages, 15 figure

Chemoenzymatic synthesis of sulfoquinovosylmonoacylglycerols (SQMG) as anti-tumor-promoters

During our search for new glycoglycerolipids active in cancer chemoprevention, in recent years we have synthesized a number of esters of 2-O-beta-D-glycosylglycerols in which the length, shape, number and position of the acyl chain, and the type of sugar (alpha\uf020and beta glucose or galactose) were varied. These compounds were found to be very active in inhibiting the tumor-promoting activity of the phorbol ester TPA both in in vitro and in in vivo tests, being such activities mainly influenced by the changes of the acyl chains length. Sulfoquinovosylacylglycerols are acylated sulfoglycolipids in which sulfoquinovose (6-deoxy-6-sulfo-glucose) is alpha-linked to the sn-3 position of glycerol. These compounds exhibit noteworthy biological activities, that make them very attractive for their use in cancer therapy. Here we report the synthesis of 6\u2019-sulfo-derivatives (SQMG) based on the skeleton of 2-O-beta-D-glucosylglycerol to which previously synthesized biologically active glucoglycerolipid analogues are related. A chemoenzymatic strategy has been used to selectively insert the proper chemical functionalities (i.e. acyl chain) at the desired position of glucosylglycerol to obtain the target compounds. Their potential as anti-tumor-promoters will be also discussed

Comparison of basal metabolic rate by indirect calorimetry and predictive model

The objective of this study was to compare the values of basal metabolic rate (BMR) obtained by indirect calorimetry (IC) and by predictive model (PM). Methodology: 6 women, age (23.8 ± 3.1 years), height (165 ± 5.8 cm), body mass (55.9 ± 4.9 kg), fat free mass (43 ± 2.1 kg), fat body mass (12.9 ± 3.3 kg), percentage of body fat (22.8 ± 4.2%) were subjected to the test of IC. The IC test was done early in the morning, after 12 hours of fasting, without attainment of physical activity within the last 24 hours and abstinence of alcohol in the last 48 hours. Initially, the volunteers remained at rest for 20 minutes, followed by 20 minutes of measurement by gas analyzer VO2000. To obtain the BMR by the EP the Harris Benedict formula was used , applied for women between 15-74 years: 655.0955 + 9.5634 (weight kg) + 1.8496 (height cm) - 4.6756 (age). For the processing of data the statistical program Instat was used through the paired t test (p \u3c0.05), and the results were expressed as mean and standard deviation of the mean. Results: The value of BMR through the IC was 1423.0±6 calories and through PM 1383.5±6 calories, with no statistically significant differences between the two methods. There was no significant difference between the methods, and thus, the PM can be considered a useful tool to estimate the BMR, as a more accessible and less costly method to this population

Revival of the side-to-side approach for distal coronary anastomosis

Side-to-side anastomosis was employed by just ten proportional stitches while performing distal anastomosis during coronary artery surgery. This technique is simple and quick. Here this simple technique is described in detail and the postoperative status of grafted conduits is reported

A fabrication guide for planar silicon quantum dot heterostructures

We describe important considerations to create top-down fabricated planar quantum dots in silicon, often not discussed in detail in literature. The subtle interplay between intrinsic material properties, interfaces and fabrication processes plays a crucial role in the formation of electrostatically defined quantum dots. Processes such as oxidation, physical vapor deposition and atomic-layer deposition must be tailored in order to prevent unwanted side effects such as defects, disorder and dewetting. In two directly related manuscripts written in parallel we use techniques described in this work to create depletion-mode quantum dots in intrinsic silicon, and low-disorder silicon quantum dots defined with palladium gates. While we discuss three different planar gate structures, the general principles also apply to 0D and 1D systems, such as self-assembled islands and nanowires.Comment: Accepted for publication in Nanotechnology. 31 pages, 12 figure