β-Caryophyllene ameliorates cisplatin-induced nephrotoxicity in a cannabinoid 2 receptor-dependent manner

(E)-β-caryophyllene (BCP) is a natural sesquiterpene found in many essential oils of spice (best known for contributing to the spiciness of black pepper) and food plants with recognized anti-inflammatory properties. Recently it was shown that BCP is a natural agonist of endogenous cannabinoid 2 (CB(2)) receptors, which are expressed in immune cells and mediate anti-inflammatory effects. In this study we aimed to test the effects of BCP in a clinically relevant murine model of nephropathy (induced by the widely used antineoplastic drug cisplatin) in which the tubular injury is largely dependent on inflammation and oxidative/nitrative stress. β-caryophyllene dose-dependently ameliorated cisplatin-induced kidney dysfunction, morphological damage, and renal inflammatory response (chemokines MCP-1 and MIP-2, cytokines TNF-α and IL-1β, adhesion molecule ICAM-1, and neutrophil and macrophage infiltration). It also markedly mitigated oxidative/nitrative stress (NOX-2 and NOX-4 expression, 4-HNE and 3-NT content) and cell death. The protective effects of BCP against biochemical and histological markers of nephropathy were absent in CB(2) knockout mice. Thus, BCP may be an excellent therapeutic agent to prevent cisplatin-induced nephrotoxicity through a CB(2) receptor-dependent pathway. Given the excellent safety profile of BCP in humans it has tremendous therapeutic potential in a multitude of diseases associated with inflammation and oxidative stress.

Post-translational tyrosine nitration of eosinophil granule toxins mediated by eosinophil peroxidase

Nitration of tyrosine residues has been observed during various acute and chronic inflammatory diseases. However, the mechanism of tyrosine nitration and the nature of the proteins that become tyrosine nitrated during inflammation remain unclear. Here we show that eosinophils but not other cell types including neutrophils contain nitrotyrosine-positive proteins in specific granules. Furthermore, we demonstrate that the human eosinophil toxins, eosinophil peroxidase (EPO), major basic protein, eosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP), and the respective murine toxins, are post-translationally modified by nitration at tyrosine residues during cell maturation. High resolution affinity-mass spectrometry identified specific single nitration sites at Tyr349 in EPO and Tyr33 in both ECP and EDN. ECP and EDN crystal structures revealed and EPO structure modeling suggested that the nitrated tyrosine residues in the toxins are surface exposed. Studies in EPO(-/-), gp91phox(-/-), and NOS(-/-) mice revealed that tyrosine nitration of these toxins is mediated by EPO in the presence of hydrogen peroxide and minute amounts of NOx. Tyrosine nitration of eosinophil granule toxins occurs during maturation of eosinophils, independent of inflammation. These results provide evidence that post-translational tyrosine nitration is unique to eosinophils.

Forcing of stratospheric chemistry and dynamics during the Dalton Minimum

The response of atmospheric chemistry and dynamics to volcanic eruptions and to a decrease in solar activity during the Dalton Minimum is investigated with the fully coupled atmosphere–ocean chemistry general circulation model SOCOL-MPIOM (modeling tools for studies of SOlar Climate Ozone Links-Max Planck Institute Ocean Model) covering the time period 1780 to 1840 AD. We carried out several sensitivity ensemble experiments to separate the effects of (i) reduced solar ultra-violet (UV) irradiance, (ii) reduced solar visible and near infrared irradiance, (iii) enhanced galactic cosmic ray intensity as well as less intensive solar energetic proton events and auroral electron precipitation, and (iv) volcanic aerosols. The introduced changes of UV irradiance and volcanic aerosols significantly influence stratospheric dynamics in the early 19th century, whereas changes in the visible part of the spectrum and energetic particles have smaller effects. A reduction of UV irradiance by 15%, which represents the presently discussed highest estimate of UV irradiance change caused by solar activity changes, causes global ozone decrease below the stratopause reaching as much as 8% in the midlatitudes at 5 hPa and a significant stratospheric cooling of up to 2 °C in the mid-stratosphere and to 6 °C in the lower mesosphere. Changes in energetic particle precipitation lead only to minor changes in the yearly averaged temperature fields in the stratosphere. Volcanic aerosols heat the tropical lower stratosphere, allowing more water vapour to enter the tropical stratosphere, which, via HOx reactions, decreases upper stratospheric and mesospheric ozone by roughly 4%. Conversely, heterogeneous chemistry on aerosols reduces stratospheric NOx, leading to a 12% ozone increase in the tropics, whereas a decrease in ozone of up to 5% is found over Antarctica in boreal winter. The linear superposition of the different contributions is not equivalent to the response obtained in a simulation when all forcing factors are applied during the Dalton Minimum (DM) – this effect is especially well visible for NOx/NOy. Thus, this study also shows the non-linear behaviour of the coupled chemistry-climate system. Finally, we conclude that especially UV and volcanic eruptions dominate the changes in the ozone, temperature and dynamics while the NOx field is dominated by the energetic particle precipitation. Visible radiation changes have only very minor effects on both stratospheric dynamics and chemistry.

Psychophysiology of prospective memory

Prospective memory involves the self-initiated retrieval of an intention upon an appropriate retrieval cue. Cue identification can be considered as an orienting reaction and may thus trigger a psychophysiological response. Here we present two experiments in which skin conductance responses (SCRs) elicited by prospective memory cues were compared to SCRs elicited by aversive stimuli to test whether a single prospective memory cue triggers a similar SCR as an aversive stimulus. In Experiment 2 we also assessed whether cue specificity had a differential influence on prospective memory performance and on SCRs. We found that detecting a single prospective memory cue is as likely to elicit a SCR as an aversive stimulus. Missed prospective memory cues also elicited SCRs. On a behavioural level, specific intentions led to better prospective memory performance. However, on a psychophysiological level specificity had no influence. More generally, the results indicate reliable SCRs for prospective memory cues and point to psychophysiological measures as valuable approach, which offers a new way to study one-off prospective memory tasks. Moreover, the findings are consistent with a theory that posits multiple prospective memory retrieval stages.

Optimizing the size of the area surveyed for monitoring a Eurasian lynx (Lynx lynx) population in the Swiss Alps by means of photographic capture-recapture

We studied the influence of surveyed area size on density estimates by means of camera-trapping in a low-density felid population (1-2 individuals/100 km(2) ). We applied non-spatial capture-recapture (CR) and spatial CR (SCR) models for Eurasian lynx during winter 2005/2006 in the northwestern Swiss Alps by sampling an area divided into 5 nested plots ranging from 65 to 760 km(2) . CR model density estimates (95% CI) for models M0 and Mh decreased from 2.61 (1.55-3.68) and 3.6 (1.62-5.57) independent lynx/100 km(2) , respectively, in the smallest to 1.20 (1.04-1.35) and 1.26 (0.89-1.63) independent lynx/100 km(2) , respectively, in the largest area surveyed. SCR model density estimates also decreased with increasing sampling area but not significantly. High individual range overlaps in relatively small areas (the edge effect) is the most plausible reason for this positive bias in the CR models. Our results confirm that SCR models are much more robust to changes in trap array size than CR models, thus avoiding overestimation of density in smaller areas. However, when a study is concerned with monitoring population changes, large spatial efforts (area surveyed ≥760 km(2) ) are required to obtain reliable and precise density estimates with these population densities and recapture rates.

Cosmogenic production rates and recoil loss effects in micrometeorites and interplanetary dust particles

We present a purely physical model to determine cosmogenic production rates for noble gases and radionuclides in micrometeorites (MMs) and interplanetary dust particles (IDPs) by solar cosmic-rays (SCR) and galactic cosmic-rays (GCR) fully considering recoil loss effects. Our model is based on various nuclear model codes to calculate recoil cross sections, recoil ranges, and finally the percentages of the cosmogenic nuclides that are lost as a function of grain size, chemical composition of the grain, and the spectral distribution of the projectiles. The main advantage of our new model compared with earlier approaches is that we consider the entire SCR particle spectrum up to 240 MeV and not only single energy points. Recoil losses for GCR-produced nuclides are assumed to be equal to recoil losses for SCR-produced nuclides. Combining the model predictions with Poynting-Robertson orbital lifetimes, we calculate cosmic-ray exposure ages for recently studied MMs, cosmic spherules, and IDPs. The ages for MMs and the cosmic-spherule are in the range <2.2–233 Ma, which corresponds, according to the Poynting-Robertson drag, to orbital distances in the range 4.0–34 AU. For two IDPs, we determine exposure ages of longer than 900 Ma, which corresponds to orbital distances larger than 150 AU. The orbital distance in the range 4–6 AU for one MM and the cosmic spherule indicate an origin either in the asteroid belt or release from comets coming either from the Kuiper Belt or the Oort Cloud. Three of the studied MMs have orbital distances in the range 23–34 AU, clearly indicating a cometary origin, either from short-period comets from the Kuiper Belt or from the Oort Cloud. The two IDPs have orbital distances of more than 150 AU, indicating an origin from Oort Cloud comets.

Daily ozone cycle in the stratosphere: global, regional and seasonal behaviour modelled with the Whole Atmosphere Community Climate Model

The Whole Atmosphere Community Climate Model (WACCM) is utilised to study the daily ozone cycle and underlying photochemical and dynamical processes. The analysis is focused on the daily ozone cycle in the middle stratosphere at 5 hPa where satellite-based trend estimates of stratospheric ozone are most biased by diurnal sampling effects and drifting satellite orbits. The simulated ozone cycle shows a minimum after sunrise and a maximum in the late afternoon. Further, a seasonal variation of the daily ozone cycle in the stratosphere was found. Depending on season and latitude, the peak-to-valley difference of the daily ozone cycle varies mostly between 3 and 5% (0.4 ppmv) with respect to the midnight ozone volume mixing ratio. The maximal variation of 15% (0.8 ppmv) is found at the polar circle in summer. The global pattern of the strength of the daily ozone cycle is mainly governed by the solar zenith angle and the sunshine duration. In addition, we find synoptic-scale variations in the strength of the daily ozone cycle. These variations are often anti-correlated to regional temperature anomalies and are due to the temperature dependence of the rate coefficients k2 and k3 of the Chapman cycle reactions. Further, the NOx catalytic cycle counteracts the accumulation of ozone during daytime and leads to an anti-correlation between anomalies in NOx and the strength of the daily ozone cycle. Similarly, ozone recombines with atomic oxygen which leads to an anti-correlation between anomalies in ozone abundance and the strength of the daily ozone cycle. At higher latitudes, an increase of the westerly (easterly) wind cause a decrease (increase) in the sunshine duration of an air parcel leading to a weaker (stronger) daily ozone cycle.

From emotion perception to emotion experience: Emotions evoked by pictures and classical music.

Most previous neurophysiological studies evoked emotions by presenting visual stimuli. Models of the emotion circuits in the brain have for the most part ignored emotions arising from musical stimuli. To our knowledge, this is the first emotion brain study which examined the influence of visual and musical stimuli on brain processing. Highly arousing pictures of the International Affective Picture System and classical musical excerpts were chosen to evoke the three basic emotions of happiness, sadness and fear. The emotional stimuli modalities were presented for 70 s either alone or combined (congruent) in a counterbalanced and random order. Electroencephalogram (EEG) Alpha-Power-Density, which is inversely related to neural electrical activity, in 30 scalp electrodes from 24 right-handed healthy female subjects, was recorded. In addition, heart rate (HR), skin conductance responses (SCR), respiration, temperature and psychometrical ratings were collected. Results showed that the experienced quality of the presented emotions was most accurate in the combined conditions, intermediate in the picture conditions and lowest in the sound conditions. Furthermore, both the psychometrical ratings and the physiological involvement measurements (SCR, HR, Respiration) were significantly increased in the combined and sound conditions compared to the picture conditions. Finally, repeated measures ANOVA revealed the largest Alpha-Power-Density for the sound conditions, intermediate for the picture conditions, and lowest for the combined conditions, indicating the strongest activation in the combined conditions in a distributed emotion and arousal network comprising frontal, temporal, parietal and occipital neural structures. Summing up, these findings demonstrate that music can markedly enhance the emotional experience evoked by affective pictures.

Impact of geomagnetic excursions on atmospheric chemistry and dynamics

Geomagnetic excursions, i.e. short periods in time with much weaker geomagnetic fields and substantial changes in the position of the geomagnetic pole, occurred repeatedly in the Earth's history, e.g. the Laschamp event about 41 kyr ago. Although the next such excursion is certain to come, little is known about the timing and possible consequences for the state of the atmosphere and the ecosystems. Here we use the global chemistry climate model SOCOL-MPIOM to simulate the effects of geomagnetic excursions on atmospheric ionization, chemistry and dynamics. Our simulations show significantly increased concentrations of nitrogen oxides (NOx) in the entire stratosphere, especially over Antarctica (+15%), due to enhanced ionization by galactic cosmic rays. Hydrogen oxides (HOx) are also produced in greater amounts (up to +40%) in the tropical and subtropical lower stratosphere, while their destruction by reactions with enhanced NOx prevails over the poles and in high altitudes (by −5%). Stratospheric ozone concentrations decrease globally above 20 km by 1–2% and at the northern hemispheric tropopause by up to 5% owing to the accelerated NOx-induced destruction. A 5% increase is found in the southern lower stratosphere and troposphere. In response to these changes in ozone and the concomitant changes in atmospheric heating rates, the Arctic vortex intensifies in boreal winter, while the Antarctic vortex weakens in austral winter and spring. Surface wind anomalies show significant intensification of the southern westerlies at their poleward edge during austral winter and a pronounced northward shift in spring. Major impacts on the global climate seem unlikely.

The Silencing of N-myc Downstream-Regulated Gene-1 in an Orthotopic Pancreatic Cancer Model Leads to More Aggressive Tumor Growth and Metastases

BACKGROUND: The understanding of molecular mechanisms leading to poor prognosis in pancreatic cancer may help develop treatment options. N-myc downstream-regulated gene-1 (NDRG1) has been correlated to better prognosis in pancreatic cancer. Therefore, we thought to analyze how the loss of NDRG1 affects progression in an orthotopic xenograft animal model of recurrence. METHODS: Capan-1 cells were silenced for NDRG1 (C(sil)) or transfected with scrambled shRNA (C(scr)) and compared for anchorage-dependent and anchorage-independent growth, invasion and tube formation in vitro. In an orthotopic xenograft model of recurrence tumors were grown in the pancreatic tail. The effect of NDRG1 silencing was evaluated on tumor size and metastasis. RESULTS: The silencing of NDRG1 in Capan-1 cells leads to more aggressive tumor growth and metastasis. We found faster cell growth, double count of invaded cells and 1.8-fold increase in tube formation in vitro. In vivo local tumors were 5.9-fold larger (p = 0.006) and the number of metastases was higher in animals with tumors silenced for NDRG1 primarily (3 vs. 1.1; p = 0.005) and at recurrence (3.3 vs. 0.9; p = 0.015). CONCLUSION: NDRG1 may be an interesting therapeutic target as its silencing in human pancreatic cancer cells leads to a phenotype with more aggressive tumor growth and metastasis.

NOX3-Targeted Therapies for Inner Ear Pathologies

Inner ear pathologies are associated with major morbidity and loss of life quality in affected patients. In many of these conditions, production of reactive oxygen-species (ROS) is thought to be a key pathological mechanism. While the sources of ROS are complex (including for example mitochondria), there is increasing evidence that activation of NOX enzymes, in particular NOX3, plays a key role. NOX3 is a multi-subunit NADPH oxidase, functionally and structurally closely related to NOX1 and NOX2. In both the vestibular and the cochlear compartments of the inner ear, high levels of NOX3 mRNA are expressed. In NOX3 mutant mice, the vestibular function is perturbed due to a lack of otoconia, while only minor alterations of hearing have been documented. However, there is increasing evidence that activation of NOX3 through drugs, noise and probably also aging, leads to hearing loss. Thus, NOX3 is an interesting target to treat and prevent inner ear pathologies and a few first animal models based on drug - or molecular therapy have been reported. So far however, there are no specific NOX3 inhibitors with a documented penetration into the inner ear. Nevertheless, certain antioxidants and non-specific NOX inhibitors diminish hearing loss in animal models. Development of small molecules inhibitors or molecular strategies against NOX3 could improve specificity and efficiency of redox-targeted treatments. In this review, we will discuss arguments for the involvement of NOX3 in inner ear pathologies and therapeutic approaches to target NOX3 activity.

Ethnic disparity in defensive coping endothelial responses: The SABPA study

OBJECTIVES Defensive coping (DefS) in Blacks has been associated with greater cardiovascular risk than in their White counterparts. We examined associations between endothelial function mental stress responses and markers of vascular structure in a bi-ethnic cohort. METHODS We examined vascular function and structure in 368 Black (43.84±8.31years) and White Africans (44.78±10.90years). Fasting blood samples, 24h blood pressure, left carotid intima-media thickness of the far wall (L-CIMTf), and left carotid cross-sectional wall area (L-CSWA) values were obtained. von Willebrand factor (VWF), endothelin-1 (ET-1) and nitric oxide metabolite (NOx) responses to the Stroop mental stress test were calculated to assess endothelial function. DefS was assessed using the Coping Strategy Indicator questionnaire. Interaction between main effects was demonstrated for 283 participants with DefS scores above the mean of 26 for L-CIMTf. RESULTS Blunted stress responses for VWF (men 16.71% vs. 51.10%; women 0.85% vs. 42.09%, respectively) and NOx (men -64.52% vs. 74.89%; women -76.16% vs. 113.29%, respectively) were evident in the DefS Blacks compared to the DefS Whites (p<0.001). ET-1 increased more in Blacks (men 150% and women 227%, p<0.001) compared to the Whites (men 61.25% and women 35.49%, p<0.001). Ambulatory pulse pressure, but not endothelial function markers, contributed to L-CIMTf (ΔR(2)=0.11 p<0.001), and L-CSWA (ΔR(2)=0.08, p<0.001) in DefS African men but not in any other group. CONCLUSIONS Blunted stress-induced NOx and VWF responses and augmented ET-1 responses in DefS Blacks indicate endothelial dysfunction. DefS may facilitate disturbed endothelial responses and enforce vascular remodelling via compensatory increases in pulse pressure in Black men. These observations may indicate an increased risk of cardiovascular incidents via functional and structural changes of the vasculature in DefS Blacks.

Estimating the uptake of traffic-derived NO2 from 15N abundance in Norway spruce needles

The 15N ratio of nitrogen oxides (NOx) emitted from vehicles, measured in the air adjacent to a highway in the Swiss Middle Land, was very high [δ15N(NO2) = +5.7‰]. This high 15N abundance was used to estimate long-term NO2 dry deposition into a forest ecosystem by measuring δ15N in the needles and the soil of potted and autochthonous spruce trees [Picea abies (L.) Karst] exposed to NO2 in a transect orthogonal to the highway. δ15N in the current-year needles of potted trees was 2.0‰ higher than that of the control after 4 months of exposure close to the highway, suggesting a 25% contribution to the N-nutrition of these needles. Needle fall into the pots was prevented by grids placed above the soil, while the continuous decomposition of needle litter below the autochthonous trees over previous years has increased δ15N values in the soil, resulting in parallel gradients of δ15N in soil and needles with distance from the highway. Estimates of NO2 uptake into needles obtained from the δ15N data were significantly correlated with the inputs calculated with a shoot gas exchange model based on a parameterisation widely used in deposition modelling. Therefore, we provide an indication of estimated N inputs to forest ecosystems via dry deposition of NO2 at the receptor level under field conditions.