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Aims. We aim to characterize the multiwavelength emission from Markarian 501 (Mrk 501), quantify the energy-dependent variability, study the potential multiband correlations, and describe the temporal evolution of the broadband emission within leptonic theoretical scenarios. Methods. We organized a multiwavelength campaign to take place between March and July of 2012. Excellent temporal coverage was obtained with more than 25 instruments, including the MAGIC, FACT and VERITAS Cherenkov telescopes, the instruments on board the Swift and Fermi spacecraft, and the telescopes operated by the GASP-WEBT collaboration. Results. Mrk 501 showed a very high energy (VHE) gamma-ray flux above 0.2 TeV of similar to 0.5 times the Crab Nebula flux (CU) for most of the campaign. The highest activity occurred on 2012 June 9, when the VHE flux was similar to 3 CU, and the peak of the high-energy spectral component was found to be at similar to 2 TeV. Both the X-ray and VHE gamma-ray spectral slopes were measured to be extremely hard, with spectral indices <2 during most of the observing campaign, regardless of the X-ray and VHE flux. This study reports the hardest Mrk 501 VHE spectra measured to date. The fractional variability was found to increase with energy, with the highest variability occurring at VHE. Using the complete data set, we found correlation between the X-ray and VHE bands; however, if the June 9 flare is excluded, the correlation disappears (significance <3 sigma) despite the existence of substantial variability in the X-ray and VHE bands throughout the campaign. Conclusions. The unprecedentedly hard X-ray and VHE spectra measured imply that their low- and high-energy components peaked above 5 keV and 0.5 TeV, respectively, during a large fraction of the observing campaign, and hence that Mrk 501 behaved like an extreme high-frequency-peaked blazar (EHBL) throughout the 2012 observing season. This suggests that being an EHBL may not be a permanent characteristic of a blazar, but rather a state which may change over time. The data set acquired shows that the broadband spectral energy distribution (SED) of Mrk 501, and its transient evolution, is very complex, requiring, within the framework of synchrotron self-Compton (SSC) models, various emission regions for a satisfactory description. Nevertheless the one-zone SSC scenario can successfully describe the segments of the SED where most energy is emitted, with a significant correlation between the electron energy density and the VHE gamma-ray activity, suggesting that most of the variability may be explained by the injection of high-energy electrons. The one-zone SSC scenario used reproduces the behavior seen between the measured X-ray and VHE gamma-ray fluxes, and predicts that the correlation becomes stronger with increasing energy of the X-rays.
To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 x 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 x 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height(1), their effects on infant head circumference were largely independent of height (P = 3.8 x 10(-7) for rs7980687 and P = 1.3 x 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 x 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume(2), Parkinson's disease and other neurodegenerative diseases(3-5), indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
This review presents recommended nomenclature for the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs), a rapidly growing class of natural products. The current knowledge regarding the biosynthesis of the >20 distinct compound classes is also reviewed, and commonalities are discussed.
Reward-dependent instrumental behavior must continuously be re-adjusted according to environmental conditions. Failure to adapt to changes in reward contingencies may incur psychiatric disorders like anxiety and depression. When an expected reward is omitted, behavior undergoes extinction. While extinction involves active re-learning, it is also accompanied by emotional behaviors indicative of frustration, anxiety, and despair (extinction-induced depression). Here, we report evidence for a sphingolipid mechanism in the extinction of behavior. Rapid extinction, indicating efficient re-learning, coincided with a decrease in the activity of the enzyme acid sphingomyelinase (ASM), which catalyzes turnover of sphingomyelin to ceramide, in the dorsal hippocampus of rats. The stronger the decline in ASM activity, the more rapid was the extinction. Sphingolipid-focused lipidomic analysis showed that this results in a decline of local ceramide species in the dorsal hippocampus. Ceramides shape the fluidity of lipid rafts in synaptic membranes and by that way can control neural plasticity. We also found that aging modifies activity of enzymes and ceramide levels in selective brain regions. Aging also changed how the chronic treatment with corticosterone (stress) or intranasal dopamine modified regional enzyme activity and ceramide levels, coinciding with rate of extinction. These data provide first evidence for a functional ASM-ceramide pathway in the brain involved in the extinction of learned behavior. This finding extends the known cellular mechanisms underlying behavioral plasticity to a new class of membrane-located molecules, the sphingolipids, and their regulatory enzymes, and may offer new treatment targets for extinction- and learning-related psychopathological conditions.
Debate persists concerning the timing and geodynamics of intercontinental collision, style of syncollisional deformation, and development of topography and fold-and-thrust belts along the >1,700-km-long Izmir-Ankara-Erzincan suture zone (IAESZ) in Turkey. Resolving this debate is a necessary precursor to evaluating the integrity of convergent margin models and kinematic, topographic, and biogeographic reconstructions of the Mediterranean domain. Geodynamic models argue either for a synchronous or diachronous collision during either the Late Cretaceous and/or Eocene, followed by Eocene slab breakoff and postcollisional magmatism. We investigate the collision chronology in western Anatolia as recorded in the sedimentary archives of the 90-km-long Saricakaya Basin perched at shallow structural levels along the IAESZ. Based on new zircon U-Pb geochronology and depositional environment and sedimentary provenance results, we demonstrate that the Saricakaya Basin is an Eocene sedimentary basin with sediment sourced from both the IAESZ and Sogut Thrust fault to the south and north, respectively, and formed primarily by flexural loading from north-south shortening along the syncollisional Sogut Thrust. Our results refine the timing of collision between the Anatolides and Pontide terranes in western Anatolia to Maastrichtian-Middle Paleocene and Early Eocene crustal shortening and basin formation. Furthermore, we demonstrate contemporaneous collision, deformation, and magmatism across the IAESZ, supporting synchronous collision models. We show that regional postcollisional magmatism can be explained by renewed underthrusting instead of slab breakoff. This new IAESZ chronology provides additional constraints for kinematic, geodynamic, and biogeographic reconstructions of the Mediterranean domain.
Major depression is a highly prevalent severe mood disorder that is treated with antidepressants. The molecular targets of antidepressants require definition. We investigated the role of the acid sphingomyelinase (Asm)-ceramide system as a target for antidepressants. Therapeutic concentrations of the antidepressants amitriptyline and fluoxetine reduced Asm activity and ceramide concentrations in the hippocampus, increased neuronal proliferation, maturation and survival and improved behavior in mouse models of stress-induced depression. Genetic Asm deficiency abrogated these effects. Mice overexpressing Asm, heterozygous for acid ceramidase, treated with blockers of ceramide metabolism or directly injected with C16 ceramide in the hippocampus had higher ceramide concentrations and lower rates of neuronal proliferation, maturation and survival compared with controls and showed depression-like behavior even in the absence of stress. The decrease of ceramide abundance achieved by antidepressant-mediated inhibition of Asm normalized these effects. Lowering ceramide abundance may thus be a central goal for the future development of antidepressants.
This study aims to compare impacts of climate change on streamflow in four large representative African river basins: the Niger, the Upper Blue Nile, the Oubangui and the Limpopo. We set up the eco-hydrological model SWIM (Soil and Water Integrated Model) for all four basins individually. The validation of the models for four basins shows results from adequate to very good, depending on the quality and availability of input and calibration data.
For the climate impact assessment, we drive the model with outputs of five bias corrected Earth system models of Coupled Model Intercomparison Project Phase 5 (CMIP5) for the representative concentration pathways (RCPs) 2.6 and 8.5. This climate input is put into the context of climate trends of the whole African continent and compared to a CMIP5 ensemble of 19 models in order to test their representativeness. Subsequently, we compare the trends in mean discharges, seasonality and hydrological extremes in the 21st century. The uncertainty of results for all basins is high. Still, climate change impact is clearly visible for mean discharges but also for extremes in high and low flows. The uncertainty of the projections is the lowest in the Upper Blue Nile, where an increase in streamflow is most likely. In the Niger and the Limpopo basins, the magnitude of trends in both directions is high and has a wide range of uncertainty. In the Oubangui, impacts are the least significant. Our results confirm partly the findings of previous continental impact analyses for Africa. However, contradictory to these studies we find a tendency for increased streamflows in three of the four basins (not for the Oubangui). Guided by these results, we argue for attention to the possible risks of increasing high flows in the face of the dominant water scarcity in Africa. In conclusion, the study shows that impact intercomparisons have added value to the adaptation discussion and may be used for setting up adaptation plans in the context of a holistic approach.
In Germany, active bat rabies surveillance was conducted between 1993 and 2012. A total of 4546 oropharyngeal swab samples from 18 bat species were screened for the presence of EBLV-1- , EBLV-2- and BBLV-specific RNA. Overall, 0 center dot 15% of oropharyngeal swab samples tested EBLV-1 positive, with the majority originating from Eptesicus serotinus. Interestingly, out of seven RT-PCR-positive oropharyngeal swabs subjected to virus isolation, viable virus was isolated from a single serotine bat (E. serotinus). Additionally, about 1226 blood samples were tested serologically, and varying virus neutralizing antibody titres were found in at least eight different bat species. The detection of viral RNA and seroconversion in repeatedly sampled serotine bats indicates long-term circulation of the virus in a particular bat colony. The limitations of random-based active bat rabies surveillance over passive bat rabies surveillance and its possible application of targeted approaches for future research activities on bat lyssavirus dynamics and maintenance are discussed.
Synchrotron radiation facilities routinely operate in a multi-bunch regime, but applications relying on time-of-flight schemes require single bunch operation. Here we show that pulse picking by resonant excitation in a storage ring creates in addition to the multi-bunch operation a distinct and separable single bunch soft X-ray source. It has variable polarization, a photon flux of up to 10(7)-10(9) ph s(-1)/0.1%BW at purity values of 10(4)-10(2) and a repetition rate of 1.25 MHz. The quasi-resonant excitation of incoherent betatron oscillations of electrons allows horizontal pulse separation at variable (also circular) polarization accessible for both, regular 30 ps pulses and ultrashort pulses of 2-3 ps duration. Combined with a new generation of angularly resolving electron spectrometers this creates unique opportunities for time-resolved photoemission studies as confirmed by time-of-flight spectra. Our pulse picking scheme is particularly suited for surface physics at diffraction-limited light sources promising ultimate spectral resolution.