MANP Activation Of The cGMP Inhibits Aldosterone Via PDE2 And CYP11B2 In H295R Cells And In Mice

Background: Aldosterone is a critical pathological driver for cardiac and renal diseases. We recently discovered that mutant atrial natriuretic peptide (MANP), a novel atrial natriuretic peptide (ANP) analog, possessed more potent aldosterone inhibitory action than ANP in vivo. MANP and natriuretic peptide (NP)-augmenting therapy sacubitril/valsartan are under investigations for human hypertension treatment. Understanding the elusive mechanism of aldosterone inhibition by NPs remains to be a priority. Conflicting results were reported on the roles of the pGC-A (particulate guanylyl cyclase A receptor) and NP clearance receptor in aldosterone inhibition. Furthermore, the function of PKG (protein kinase G) and PDEs (phosphodiesterases) on aldosterone regulation are not clear. Methods: In the present study, we investigated the molecular mechanism of aldosterone regulation in a human adrenocortical cell line H295R and in mice. Results: We first provided evidence to show that pGC-A, not NP clearance receptor, mediates aldosterone inhibition. Next, we confirmed that MANP inhibits aldosterone via PDE2 (phosphodiesterase 2) not PKG, with specific agonists, antagonists, siRNA silencing, and fluorescence resonance energy transfer experiments. Further, the inhibitory effect is mediated by a reduction of intracellular Ca2+ levels. We then illustrated that MANP directly reduces aldosterone synthase CYP11B2 (cytochrome p450 family 11 subfamily b member 2) expression via PDE2. Last, in PDE2 knockout mice, consistent with in vitro findings, embryonic adrenal CYP11B2 is markedly increased. Conclusions: Our results innovatively explore and expand the NP/pGC-A/3',5', cyclic guanosine monophosphate (cGMP)/PDE2 pathway for aldosterone inhibition by MANP in vitro and in vivo. In addition, our data also support the development of MANP as a novel ANP analog drug for aldosterone excess treatment

Electron Microprobe/SIMS Determinations of Al in Olivine: Applications to Solar Wind, Pallasites and Trace Element Measurements

Electron probe microanalyser measurements of trace elements with high accuracy are challenging. Accurate Al measurements in olivine are required to calibrate SIMS implant reference materials for measurement of Al in the solar wind. We adopt a combined EPMA/SIMS approach that is useful for producing SIMS reference materials as well as for EPMA at the ~100 µg g⁻¹ level. Even for mounts not polished with alumina photoelectron spectroscopy shows high levels of Al surface contamination. In order to minimise electron beam current density, a rastered 50 × 100 µm electron beam was adequate and minimised sensitivity to small Al‐rich contaminants. Reproducible analyses of eleven SIMS cleaned spots on San Carlos olivine agreed at 69.3 ± 1.0 µg g⁻¹. The known Al mass fraction was used to calibrate an Al implant into San Carlos. Accurate measurements of Al were made for olivines in the pallasites: Imilac, Eagle Station and Springwater. Our focus was on Al in olivine; but our technique could be refined to give accurate electron probe measurements for other contamination‐sensitive trace elements. For solar wind it is projected that the Al/Mg abundance ratio can be determined to 6%, a factor of 2 more precise than the solar spectroscopic ratio

Internal amplification controls have not been employed in fungal PCR hence potential false negative results

Polymerase chain reaction (PCR) is subject to false negative results. Samples of fungi with the genes of interest (e.g. a disease or mycotoxin) may be categorized as negative and safe as a consequence. Fungi are eukaryotic organisms that are involved in many fields of human activity such as antibiotic, toxin and food production. Certain taxa are implicated in human, animal and plant diseases. However, fungi are difficult to identify and PCR techniques have been proposed increasingly for this purpose. Internal amplification controls (IACs) will ameliorate the situation and need to become mandatory. These are nucleic acids that posses a sequence which will provide a PCR product (i) using the same primers employed for the target gene, and (ii) that will not coincide on the gel with the product of the target gene. Only one group of workers employed an IAC, to respond to potential inhibition, which was reported in 1995 from this present assessment of numerous reports. Inhibitors in cultures need to be minimized, and secondary metabolites are an obvious source. The fields reviewed herein include medical mycology, mycotoxicology, environmental mycology and plant mycology. The conclusion is that previous reports are compromised because IACs have not been employed in fungal PCR; future research must include this control at an early stage.Fundação para a Ciência e a Tecnologia (FCT

Electron Microprobe/SIMS Determinations of Al in Olivine: Applications to Solar Wind, Pallasites and Trace Element Measurements

Electron probe microanalyser measurements of trace elements with high accuracy are challenging. Accurate Al measurements in olivine are required to calibrate SIMS implant reference materials for measurement of Al in the solar wind. We adopt a combined EPMA/SIMS approach that is useful for producing SIMS reference materials as well as for EPMA at the ~100 µg g⁻¹ level. Even for mounts not polished with alumina photoelectron spectroscopy shows high levels of Al surface contamination. In order to minimise electron beam current density, a rastered 50 × 100 µm electron beam was adequate and minimised sensitivity to small Al‐rich contaminants. Reproducible analyses of eleven SIMS cleaned spots on San Carlos olivine agreed at 69.3 ± 1.0 µg g⁻¹. The known Al mass fraction was used to calibrate an Al implant into San Carlos. Accurate measurements of Al were made for olivines in the pallasites: Imilac, Eagle Station and Springwater. Our focus was on Al in olivine; but our technique could be refined to give accurate electron probe measurements for other contamination‐sensitive trace elements. For solar wind it is projected that the Al/Mg abundance ratio can be determined to 6%, a factor of 2 more precise than the solar spectroscopic ratio

Association of Ambient Air Pollution with Respiratory Hospitalization in a Government-Designated “Area of Concern”: The Case of Windsor, Ontario

This study is part of a larger research program to examine the relationship between ambient air quality and health in Windsor, Ontario, Canada. We assessed the association between air pollution and daily respiratory hospitalization for different age and sex groups from 1995 to 2000. The pollutants included were nitrogen dioxide, sulfur dioxide, carbon monoxide, ozone, particulate matter ≤10 μm in diameter (PM(10)), coefficient of haze (COH), and total reduced sulfur (TRS). We calculated relative risk (RR) estimates using both time-series and case-crossover methods after controlling for appropriate confounders (temperature, humidity, and change in barometric pressure). The results of both analyses were consistent. We found associations between NO(2), SO(2), CO, COH, or PM(10) and daily hospital admission of respiratory diseases especially among females. For females 0–14 years of age, there was 1-day delayed effect of NO(2) (RR = 1.19, case-crossover method), a current-day SO(2) (RR = 1.11, time series), and current-day and 1- and 2-day delayed effects for CO by case crossover (RR = 1.15, 1.19, 1.22, respectively). Time-series analysis showed that 1-day delayed effect of PM(10) on respiratory admissions of adult males (15–64 years of age), with an RR of 1.18. COH had significant effects on female respiratory hospitalization, especially for 2-day delayed effects on adult females, with RRs of 1.15 and 1.29 using time-series and case-crossover analysis, respectively. There were no significant associations between O(3) and TRS with respiratory admissions. These findings provide policy makers with current risks estimates of respiratory hospitalization as a result of poor ambient air quality in a government designated “area of concern.

Direct Detection of Hydrogen Bonds in Supramolecular Systems Using ¹H–¹⁵N Heteronuclear Multiple Quantum Coherence Spectroscopy

Hydrogen-bonded supramolecular systems are usually characterized in solution through analysis of NMR data such as complexation-induced shifts and nuclear Overhauser effects (nOe). Routine direct detection of hydrogen bonding particularly in multicomponent mixtures, even with the aid of 2D NMR experiments for full assignment, is more challenging. We describe an elementary rapid 1H–15N HMQC NMR experiment which addresses these challenges without the need for complex pulse sequences. Under readily accessible conditions (243/263 K, 50 mM solutions) and natural 15N abundance, unambiguous assignment of 15N resonances facilitates direct detection of intra- and intermolecular hydrogen bonds in mechanically interlocked structures and quadruply hydrogen-bonded dimers─of dialkylaminoureidopyrimidinones, ureidopyrimidinones, and diamidonaphthyridines─in single or multicomponent mixtures to establish tautomeric configuration, conformation, and, to resolve self-sorted speciation

The taxonomy of graphite nanoplatelets and the influence of nanocomposite processing

The reinforcement efficiency of graphene in a nanocomposite relies on the size, morphology, defects and agglomeration of flakes. However, the characterisation is usually undertaken only for the raw materials and any changes that take place during processing are not taken into consideration. In this work, epoxy nanocomposites reinforced by graphite nanoplatelet (GNP) were prepared and nano-scale X-ray computed tomography was used to visualize the geometry, morphology and defects of the flakes, as well as the three dimensional agglomerates that are normally difficult to characterise by other techniques. In combination with micromechanical analysis, the taxonomy of the nanoplatelets is shown to be of great importance in controlling the mechanical properties of nanocomposites, and this has been shown to explain the deviations of the predictions of micromechanical models from the measured values. Particularly, it is shown that taking single average values of flake size may not be appropriate and the entire distribution of flake size need to be taken into consideration. Furthermore, it is shown that the Young's modulus of a nanocomposite is controlled principally by a small number of large flakes and that volume average distributions of flake size are more appropriate to use rather than number average ones

Multisensory information facilitates reaction speed by enlarging activity difference between superior colliculus hemispheres in rats

Animals can make faster behavioral responses to multisensory stimuli than to unisensory stimuli. The superior colliculus (SC), which receives multiple inputs from different sensory modalities, is considered to be involved in the initiation of motor responses. However, the mechanism by which multisensory information facilitates motor responses is not yet understood. Here, we demonstrate that multisensory information modulates competition among SC neurons to elicit faster responses. We conducted multiunit recordings from the SC of rats performing a two-alternative spatial discrimination task using auditory and/or visual stimuli. We found that a large population of SC neurons showed direction-selective activity before the onset of movement in response to the stimuli irrespective of stimulation modality. Trial-by-trial correlation analysis showed that the premovement activity of many SC neurons increased with faster reaction speed for the contraversive movement, whereas the premovement activity of another population of neurons decreased with faster reaction speed for the ipsiversive movement. When visual and auditory stimuli were presented simultaneously, the premovement activity of a population of neurons for the contraversive movement was enhanced, whereas the premovement activity of another population of neurons for the ipsiversive movement was depressed. Unilateral inactivation of SC using muscimol prolonged reaction times of contraversive movements, but it shortened those of ipsiversive movements. These findings suggest that the difference in activity between the SC hemispheres regulates the reaction speed of motor responses, and multisensory information enlarges the activity difference resulting in faster responses

Electronic structure of fluorides: general trends for ground and excited state properties

The electronic structure of fluorite crystals are studied by means of density functional theory within the local density approximation for the exchange correlation energy. The ground-state electronic properties, which have been calculated for the cubic structures $CaF_{2}$,$SrF_{2}$, $BaF_{2}$, $CdF_{2}$, $HgF_{2}$, $\beta$-$PbF_{2}$, using a plane waves expansion of the wave functions, show good comparison with existing experimental data and previous theoretical results. The electronic density of states at the gap region for all the compounds and their energy-band structure have been calculated and compared with the existing data in the literature. General trends for the ground-state parameters, the electronic energy-bands and transition energies for all the fluorides considered are given and discussed in details. Moreover, for the first time results for $HgF_{2}$ have been presented

Ground reaction force, spinal kinematics and their relationship to lower back pain and injury in cricket fast bowling: A review

BACKGROUND: Fast bowlers display a high risk of lower back injury and pain. Studies report factors that may increase this risk, however exact mechanisms remain unclear. OBJECTIVE: To provide a contemporary analysis of literature, up to April 2016, regarding fast bowling, spinal kinematics, ground reaction force (GRF), lower back pain (LBP) and pathology. METHOD: Key terms including biomechanics, bowling, spine and injury were searched within MEDLINE, Google Scholar, SPORTDiscuss, Science Citation Index, OAIster, CINAHL, Academic Search Complete, Science Direct and Scopus. Following application of inclusion criteria, 56 studies (reduced from 140) were appraised for quality and pooled for further analysis. RESULTS: Twelve times greater risk of lumbar injury was reported in bowlers displaying excessive shoulder counter-rotation (SCR), however SCR is a surrogate measure which may not describe actual spinal movement. Little is known about LBP specifically. Weighted averages of 5.8 ± 1.3 times body weight (BW) vertically and 3.2 ± 1.1 BW horizontally were calculated for peak GRF during fast bowling. No quantitative synthesis of kinematic data was possible due to heterogeneity of reported results. CONCLUSIONS: Fast bowling is highly injurious especially with excessive SCR. Studies adopted similar methodologies, constrained to laboratory settings. Future studies should focus on methods to determine biomechanics during live play