Electrophysiological, pharmacological and molecular profile of the transient outward rectifying conductance in neonatal rat symapthetic preganglionic neurons in vitro.

Transient outward rectifying conductances or A-like conductances in sympathetic preganglionic neurons (SPN) are prolonged, lasting for hundreds of milliseconds to seconds and are thought to play a key role in the regulation of SPN firing frequency. Here, a multidisciplinary electrophysiological, pharmacological and molecular single-cell rt-PCR approach was used to investigate the kinetics, pharmacological profile and putative K + channel subunits underlying the transient outward rectifying conductance expressed in SPN. SPN expressed a 4-aminopyridine (4-AP) sensitive transient outward rectification with significantly longer decay kinetics than reported for many other central neurons. The conductance and corresponding current in voltage-clamp conditions was also sensitive to the Kv4.2 and Kv4.3 blocker phrixotoxin-2 (1-10 µM) and the blocker of rapidly inactivating Kv channels, pandinotoxin-Ka (50 nM). The conductance and corresponding current was only weakly sensitive to the Kv1 channel blocker tityustoxin-Ka and insensitive to dendrotoxin I (200 nM) and the Kv3.4 channel blocker BDS-II (1 µM). Single-cell RT-PCR revealed mRNA expression for the a-subunits Kv4.1 and Kv4.3 in the majority and Kv1.5 in less than half of SPN. mRNA for accessory ß-subunits was detected for Kvß2 in all SPN with differential expression of mRNA for KChIP1, Kvß1 and Kvß3 and the peptidase homologue DPP6. These data together suggest that the transient outwardly rectifying conductance in SPN is mediated by members of the Kv4 subfamily (Kv4.1 and Kv4.3) in association with the ß-subunit Kvß2. Differential expression of the accessory ß subunits, which may act to modulate channel density and kinetics in SPN, may underlie the prolonged and variable time-course of this conductance in these neurons. © 2011 IBRO.

Time-Dependent Density Diagnostics of Solar Flare Plasmas Using SDO/EVE

Temporally resolved electron density measurements of solar flare plasmas are presented using data from the EUV Variability Experiment (EVE) on board the Solar Dynamics Observatory. The EVE spectral range contains emission lines formed between 104 and 107 K, including transitions from highly ionized iron (gsim10 MK). Using three density-sensitive Fe XXI ratios, peak electron densities of 1011.2-1012.1 cm–3 were found during four X-class flares. While previous measurements of densities at such high temperatures were made at only one point during a flaring event, EVE now allows the temporal evolution of these high-temperature densities to be determined at 10 s cadence. A comparison with GOES data revealed that the peak of the density time profiles for each line ratio correlated well with that of the emission measure time profile for each of the events studied.

Generation of high-energy-density ion bunches by ultraintense laser-cone-target interaction

A scheme in which carbon ion bunches are accelerated to a high energy and density by a laser pulse (∼10 W/cm) irradiating cone targets is proposed and investigated using particle-in-cell simulations. The laser pulse is focused by the cone and drives forward an ultrathin foil located at the cone's tip. In the course of the work, best results were obtained employing target configurations combining a low-Z cone with a multispecies foil transversely shaped to match the laser intensity profile. © 2014 AIP Publishing LLC.

Universal tight binding model for chemical reactions in solution and at surfaces. II. Water

A revised water model intended for use in condensed phase simulations in the framework of the self consistent polarizable ion tight binding theory is constructed. The model is applied to water monomer, dimer, hexamers, ice, and liquid, where it demonstrates good agreement with theoretical results obtained by more accurate methods, such as DFT and CCSD(T), and with experiment. In particular, the temperature dependence of the self diffusion coefficient in liquid water predicted by the model, closely reproduces experimental curves in the temperature interval between 230 K and 350 K. In addition, and in contrast to standard DFT, the model properly orders the relative densities of liquid water and ice. A notable, but inevitable, shortcoming of the model is underestimation of the static dielectric constant by a factor of two. We demonstrate that the description of inter and intramolecular forces embodied in the tight binding approximation in quantum mechanics leads to a number of valuable insights which can be missing from ab initio quantum chemistry and classical force fields. These include a discussion of the origin of the enhanced molecular electric dipole moment in the condensed phases, and a detailed explanation for the increase of coordination number in liquid water as a function of temperature and compared with ice-leading to insights into the anomalous expansion on freezing. The theory holds out the prospect of an understanding of the currently unexplained density maximum of water near the freezing point. 

Universal tight binding model for chemical reactions in solution and at surfaces. I. Organic molecules

As is now well established, a first order expansion of the Hohenberg-Kohn total energy density functional about a trial input density, namely, the Harris-Foulkes functional, can be used to rationalize a non self consistent tight binding model. If the expansion is taken to second order then the energy and electron density matrix need to be calculated self consistently and from this functional one can derive a charge self consistent tight binding theory. In this paper we have used this to describe a polarizable ion tight binding model which has the benefit of treating charge transfer in point multipoles. This admits a ready description of ionic polarizability and crystal field splitting. It is necessary in constructing such a model to find a number of parameters that mimic their more exact counterparts in the density functional theory. We describe in detail how this is done using a combination of intuition, exact analytical fitting, and a genetic optimization algorithm. Having obtained model parameters we show that this constitutes a transferable scheme that can be applied rather universally to small and medium sized organic molecules. We have shown that the model gives a good account of static structural and dynamic vibrational properties of a library of molecules, and finally we demonstrate the model's capability by showing a real time simulation of an enolization reaction in aqueous solution. In two subsequent papers, we show that the model is a great deal more general in that it will describe solvents and solid substrates and that therefore we have created a self consistent quantum mechanical scheme that may be applied to simulations in heterogeneous catalysis.

Oxygen reduction reaction mechanism on nitrogen-doped graphene:A density functional theory study

Nitrogen-doped graphene (N-graphene) was reported to exhibit a good activity experimentally as an electrocatalyst of oxygen reduction reaction (ORR) on the cathode of fuel cells under the condition of electropotential of similar to 0.04 V (vs. NNE) and pH of 14. This material is promising to replace or partially replace the conventionally used Pt. In order to understand the experimental results. ORR catalyzed by N-graphene is studied using density functional theory (DFT) calculations under experimental conditions taking the solvent, surface adsorbates, and coverages into consideration. Two mechanisms, i.e., dissociative and associative mechanisms, over different N-doping configurations are investigated. The results show that N-graphene surface is covered by O with 1/6 monolayer, which is used for reactions in this work. The transition state of each elementary step was identified using four different approaches, which give rise to a similar chemistry. A full energy profile including all the reaction barriers shows that the associative mechanism is more energetically favored than the dissociative one and the removal of O species from the surface is the rate-determining step. (C) 2011 Elsevier Inc. All rights reserved.

Impact of enhanced compliance initiatives on the efficacy of rosuvastatin in reducing low density lipoprotein cholesterol levels in patients with primary hypercholesterolaemia.

The effectiveness of lipid-lowering medication critically depends on the patients' compliance and the efficacy of the prescribed drug. The primary objective of this multicentre study was to compare the efficacy of rosuvastatin with or without access to compliance initiatives, in bringing patients to the Joint European Task Force's (1998) recommended low-density lipoprotein cholesterol (LDL-C) level goal (LDL-C, <3.0 mmol/L) at week 24. Secondary objectives were comparison of the number and percentage of patients achieving European goals (1998, 2003) for LDL-C and other lipid parameters. Patients with primary hypercholesterolaemia and a 10-year coronary heart disease risk of >20% received open label rosuvastatin treatment for 24 weeks with or without access to compliance enhancement tools. The initial daily dosage of 10 mg could be doubled at week 12. Compliance tools included: a) a starter pack for subjects containing a videotape, an educational leaflet, a passport/goal diary and details of the helpline and/or website; b) regular personalised letters to provide message reinforcement; c) a toll-free helpline and a website. The majority of patients (67%) achieved the 1998 European goal for LDL-C at week 24. 31% required an increase in dosage of rosuvastatin to 20 mg at week 12. Compliance enhancement tools did not increase the number of patients achieving either the 1998 or the 2003 European target for plasma lipids. Rosuvastatin was well tolerated during this study. The safety profile was comparable with other drugs of the same class. 63 patients in the 10 mg group and 58 in the 10 mg Plus group discontinued treatment. The main reasons for discontinuation were adverse events (39 patients in the 10 mg group; 35 patients in the 10 mg Plus group) and loss to follow-up (13 patients in the 10 mg group; 9 patients in the 10 mg Plus group). The two most frequently reported adverse events were myalgia (34 patients, 3% respectively) and back pain (23 patients, 2% respectively). The overall rate of temporary or permanent study discontinuation due to adverse events was 9% (n = 101) in patients receiving 10 mg rosuvastatin and 3% (n = 9) in patients titrated up to 20 mg rosuvastatin. Rosuvastatin was effective in lowering LDL-C values in patients with hypercholesterolaemia to the 1998 European target at week 24. However, compliance enhancement tools did not increase the number of patients achieving any European targets for plasma lipids.

Identification of hepatic molecular mechanisms of action of alpha-tocopherol using global gene expression profile analysis in rats

The recent discovery that vitamin E (VE) regulates gene activity at the transcriptional level indicates that VE may exert part of its biological effects by mechanisms which may be independent of its well-recognised antioxidant function. The objective of this study was the identification of hepatic vitamin E-sensitive genes and examination of the effects of VE on their corresponding biological endpoints. Two groups of male rats were randomly assigned to either a VE-sufficient diet or to a control diet deficient in VE for 290 days. High-density oligonucleotide microarrays comprising over 7000 genes were used to assess the transcriptional response of the liver. Differential gene expression was monitored over a period of 9 months, at four different time-points, and rats were individually profiled. This experimental strategy identified several VE-sensitive genes, which were chronically altered by dietary VE. VE supplementation down-regulated scavenger receptor CD36, coagulation factor IX and 5-alpha-steroid reductase type 1 mRNA levels while hepatic gamma glutamyl-cysteinyl synthetase was significantly up-regulated. Measurement of the corresponding biological endpoints such as activated partial thromboplastin time, plasma dihydrotestosterone and hepatic glutathione substantiated the gene chip data which indicated that dietary VE plays an important role in a range of metabolic processes within the liver. (C) 2004 Elsevier B.V. All rights reserved.

Vertical profile measurements of lower troposphere ionisation

Vertical soundings of the atmospheric ion production rate have been obtained from Geiger counters integrated with conventional meteorological radiosondes. In launches made from Reading (UK) during 2013-2014, the Regener-Pfotzer ionisation maximum was at an altitude equivalent to a pressure of (63.1±2.4) hPa, or, expressed in terms of the local air density, (0.101±0.005) kgm−3. The measured ionisation profiles have been evaluated against the Usoskin-Kovaltsov model and, separately, surface neutron monitor data from Oulu. Model ionisation rates agree well with the observed cosmic ray ionisation below 20 km altitude. Above 10 km, the measured ionisation rates also correlate well with simultaneous neutron monitor data, although, consistently with previous work, measured variability at the ionisation maximum is greater than that found by the neutron monitor. However, in the lower atmosphere (below 5 km altitude), agreement between the measurements and simultaneous neutron monitor data is poor. For studies of transient lower atmosphere phenomena associated with cosmic ray ionisation, this indicates the need for in situ ionisation measurements and improved lower atmosphere parameterisations.

Dysregulation of granulosal bone morphogenetic protein receptor 1B density is associated with reduced ovarian reserve and the age-related decline in human fertility

Reproductive ageing is linked to the depletion of ovarian primordial follicles, which causes an irreversible change to ovarian cellular function and the capacity to reproduce. The current study aimed to profile the expression of bone morphogenetic protein receptor, (BMPR1B) in 53 IVF patients exhibiting different degrees of primordial follicle depletion. The granulosa cell receptor density was measured in 403 follicles via flow cytometry. A decline in BMPR1B density occurred at the time of dominant follicle selection and during the terminal stage of folliculogenesis in the 23-30 y good ovarian reserve patients. The 40+ y poor ovarian reserve patients experienced a reversal of this pattern. The results demonstrate an association between age-induced depletion of the ovarian reserve and BMPR1B receptor density at the two critical time points of dominant follicle selection and pre-ovulatory follicle maturation. Dysregulation of BMP receptor signalling may inhibit the normal steroidogenic differentiation required for maturation in older patients.

The effects of lipoic acid and alpha-tocopherol supplementation on the lipid profile and insulin sensitivity of patients with type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled trial

Antioxidants probably play an important role in the etiology of type 2 diabetes (DM2). This study evaluated the effects of supplementation with lipoic acid (LA) and alpha-tocopherol on the lipid profile and insulin sensitivity of DM2 patients. A randomized, double-blind, placebo-controlled trial involving 102 DM2 patients divided into four groups to receive daily supplementation for 4 months with: 600 mg LA (n = 26); 800 mg alpha-tocopherol (n = 25); 800 mg alpha-tocopherol + 600 mg LA (n = 25); placebo (n = 26). Plasma alpha-tocopherol, lipid profile, glucose, insulin, and the HOMA index were determined before and after supplementation. Differences within and between groups were compared by ANOVA using Bonferroni correction. Student`s t-test was used to compare means of two independent variables. The vitamin E/total cholesterol ratio improved significantly in patients supplemented with vitamin E + LA and vitamin E alone (p <= 0.001). There were improvements of the lipid fractions in the groups receiving LA and vitamin E alone or in combination, and on the HOMA index in the LA group, but not significant. The results suggest that LA and vitamin E supplementation alone or in combination did not affect the lipid profile or insulin sensitivity of DM2 patients. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Electronegative Low-Density Lipoprotein is Associated with Dense Low-Density Lipoprotein in Subjects with Different Levels of Cardiovascular Risk

Dyslipidemias and physicochemical changes in low-density lipoprotein (LDL) are very important factors for the development of coronary artery disease (CAD). However, pathophysiological properties of electronegative low-density lipoprotein [LDL(-)] remain a controversial issue. Our objective was to investigate LDL(-) content in LDL and its subfractions (phenotypes A and B) of subjects with different cardiovascular risk. Seventy-three subjects were randomized into three groups: normolipidemic (N; n = 30) and hypercholesterolemic (HC; n = 33) subjects and patients with CAD (n = 10). After fasting, blood samples were collected and total, dense and light LDL were isolated. LDL(-) content in total LDL and its subfractions was determined by ELISA. LDL(-) content in total LDL was lower in the N group as compared to the HC (P < 0.001) and CAD (P = 0.006) groups. In the total sample and in those of the N, HC, and CAD groups, LDL(-) content in dense LDL was higher than in light LDL (P = 0.001, 0.001, 0.001, and 0.033, respectively) The impact of LDL(-) on cardiovascular risk was reinforced when LDL(-) content in LDL showed itself to have a positive association with total cholesterol (beta = 0.003; P < 0.001), LDL-C (beta = 0.003; p < 0.001), and non-HDL-C (beta = 0.003; P < 0.001) and a negative association with HDL-C (beta = -0.32; P = 0.04). Therefore, LDL(-) is an important biomarker that showed association with the lipid profile and the level of cardiovascular risk.

Programs to compute magnetization to density ratio and the magnetization inclination from 3-D gravity and magnetic anomalies

Vector field formulation based on the Poisson theorem allows an automatic determination of rock physical properties (magnetization to density ratio-MDR-and the magnetization inclination-MI) from combined processing of gravity and magnetic geophysical data. The basic assumptions (i.e., Poisson conditions) are: that gravity and magnetic fields share common sources, and that these sources have a uniform magnetization direction and MDR. In addition, the previously existing formulation was restricted to profile data, and assumed sufficiently elongated (2-D) sources. For sources that violate Poisson conditions or have a 3-D geometry, the apparent values of MDR and MI that are generated in this way have an unclear relationship to the actual properties in the subsurface. We present Fortran programs that estimate MDR and MI values for 3-D sources through processing of gridded gravity and magnetic data. Tests with simple geophysical models indicate that magnetization polarity can be successfully recovered by MDR-MI processing, even in cases where juxtaposed bodies cannot be clearly distinguished on the basis of anomaly data. These results may be useful in crustal studies, especially in mapping magnetization polarity from marine-based gravity and magnetic data. (c) 2007 Elsevier Ltd. All rights reserved.

The effects of stocking density in physiological parameters and growth of the endangered teleost species piabanha, Brycon insignis (Steindachner, 1877)

This study investigated the effects of stocking density on the growth and fatty acid (FA) of Brycon insignis metabolism. Fingerlings (360) were distributed into eight ponds at two stocking densities (105 and 210 g/m(3)). The analysis of growth showed that the condition factor (K) and the coefficient of variation (CV) for body mass were not affected by stocking density. However, final body mass and length, specific growth rate (SGR), and weight gain (WG) were higher in the low stocking density group, which also presented a higher feed efficiency (FE) and survival (S). By contrast, muscle protein levels were higher in the high stocking density group. The plasma and muscle lipid content were not affected by stocking density, but fish reared at lower stocking density presented higher lipid concentration in the liver, with no differences in hepatosomatic index values. Even with the differences observed in metabolic and growth parameters, plasma cortisol was not affected by stocking density. The FA profile in the muscle and liver neutral fraction were not affected by stocking density, but the FA in the polar fractions differed between the two stocking densities. In the liver, total polyunsaturated fatty acids (PUFA) and PUFA n - 3 increased in higher stocking density, mainly due to an increase in docosahexaenoic acid (DHA). In addition, PUFA n - 6 were also increased in the higher stocking density group, mainly due to an increase in arachidonic acid (AA) and docosadienoic acid (22:2n - 6). In the muscle polar fraction, the saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) decreased in the animals from the higher stocking density group, and this reduction was compensated by an increase in PUFA n - 3 and PUFA n - 6, mainly the FA with 20-22 carbons (20:4n - 6: 22:4:n - 6; 22:5n - 6, 22:5n - 3, and 22:6n - 3). A different profile was observed for the C18 PUFAs, mainly 18:2n - 6 and 18:4n - 6, which were higher in the lower density stocking group. The data suggest that when living in high stocking density, B. insignis differentially utilizes the hepatic lipids as energy source and remodels the membrane fatty acids, with higher amounts of DHA in the polar muscle fraction compensated for by a decrease in MUFA. The zootechnical and physiological indices reveal that the lower stocking density group achieve overall better performance. (C) 2010 Elsevier B.V. All rights reserved.

Lack of effects of isoflavones on the lipid profile of Brazilian postmenopausal women

Objective: To evaluate the effects of soy isoflavone supplementation on profile lipid and endogenous hormone levels. Methods: In this double-blind, placebo-controlled Study, 47 post menopausal women 47-66 v of age received 40 mg of isoflavone (n = 25) or 40 mg of casein placebo (11 = 22). Cardiovascular risk factors were assessed by evaluating lipid profile at baseline and after 6 mo of treatment. To examine the effects of this regime on endogenous hormone levels, follicle-stimulating hormone and beta-estradiol were measured. Urinary isoflavone concentrations (genistein and daidzein) were measured as markers of both compliance and absorption using high performance liquid chromatography. Baseline characteristics were compared by the unpaired Student`s t-test. Within-group changes were determined by paired Student`s t-test and comparison between the isoflavone and casein placebo groups were determined by analysis of variance. Results: Lipid levels (low-density lipoprotein and total cholesterol) similarly decreased in both,groups. High-density lipoprotein increased significantly in both groups and cannot thus be attributable to treatment: the reason for Such variation is unknown and can be attributed to chance or to bias (even that of a real placebo effect in both groups or perhaps in spontaneous changes in exercise and dietary habits of patients after their inclusion). Furthermore, in both groups very low-density lipoprotein and triacylglycerol levels increased in a non-significant manner. Conclusion: The results of the present Study do not support any biologically significant estrogenic effects of isoflavone on the parameters assessed. Further research will he necessary to definitively assess the safety and efficacy of isoflavone. (C) 2008 Elsevier Inc. All rights reserved.