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Ground-based gamma-ray astronomy has had a major breakthrough with the impressive results obtained using systems of imaging atmospheric Cherenkov telescopes. Ground-based gamma-ray astronomy has a huge potential in astrophysics, particle physics and cosmology. CTA is an international initiative to build the next generation instrument, with a factor of 5-10 improvement in sensitivity in the 100 GeV-10 TeV range and the extension to energies well below 100 GeV and above 100 TeV. CTA will consist of two arrays (one in the north, one in the south) for full sky coverage and will be operated as open observatory. The design of CTA is based on currently available technology. This document reports on the status and presents the major design concepts of CTA.
Introducing the CTA concept
(2013)
The Cherenkov Telescope Array (CTA) is a new observatory for very high-energy (VHE) gamma rays. CTA has ambitions science goals, for which it is necessary to achieve full-sky coverage, to improve the sensitivity by about an order of magnitude, to span about four decades of energy, from a few tens of GeV to above 100 TeV with enhanced angular and energy resolutions over existing VHE gamma-ray observatories. An international collaboration has formed with more than 1000 members from 27 countries in Europe, Asia, Africa and North and South America. In 2010 the CTA Consortium completed a Design Study and started a three-year Preparatory Phase which leads to production readiness of CTA in 2014. In this paper we introduce the science goals and the concept of CTA, and provide an overview of the project.
Prospects for Cherenkov Telescope Array Observations of the Young Supernova Remnant RX J1713.7-3946
(2017)
We perform simulations for future Cherenkov Telescope Array (CTA) observations of RX J1713.7-3946, a young supernova remnant (SNR) and one of the brightest sources ever discovered in very high energy (VHE) gamma rays. Special attention is paid to exploring possible spatial (anti) correlations of gamma rays with emission at other wavelengths, in particular X-rays and CO/H I emission. We present a series of simulated images of RX J1713.7-3946 for CTA based on a set of observationally motivated models for the gamma-ray emission. In these models, VHE gamma rays produced by high-energy electrons are assumed to trace the nonthermal X-ray emission observed by XMM-Newton, whereas those originating from relativistic protons delineate the local gas distributions. The local atomic and molecular gas distributions are deduced by the NANTEN team from CO and H I observations. Our primary goal is to show how one can distinguish the emission mechanism(s) of the gamma rays (i.e., hadronic versus leptonic, or a mixture of the two) through information provided by their spatial distribution, spectra, and time variation. This work is the first attempt to quantitatively evaluate the capabilities of CTA to achieve various proposed scientific goals by observing this important cosmic particle accelerator.
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.
e-ASTROGAM is a concept for a breakthrough observatory space mission carrying a gamma-ray telescope dedicated to the study of the non-thermal Universe in the photon energy range from 0.15 MeV to 3 GeV. The lower energy limit can be pushed down to energies as low as 30 keV for gamma-ray burst detection with the calorimeter. The mission is based on an advanced space-proven detector technology, with unprecedented sensitivity, angular and energy resolution, combined with remarkable polarimetric capability. Thanks to its performance in the MeV-GeV domain, substantially improving its predecessors, e-ASTROGAM will open a new window on the non-thermal Universe, making pioneering observations of the most powerful Galactic and extragalactic sources, elucidating the nature of their relativistic outflows and their effects on the surroundings. With a line sensitivity in the MeV energy range one to two orders of magnitude better than previous and current generation instruments, e-ASTROGAM will determine the origin of key isotopes fundamental for the understanding of supernova explosion and the chemical evolution of our Galaxy. The mission will be a major player of the multiwavelength, multimessenger time-domain astronomy of the 2030s, and provide unique data of significant interest to a broad astronomical community, complementary to powerful observatories such as LISA, LIGO, Virgo, KAGRA, the Einstein Telescope and the Cosmic Explorer, IceCube-Gen2 and KM3NeT, SKA, ALMA, JWST, E-ELT, LSST, Athena, and the Cherenkov Telescope Array.
e-ASTROGAM (‘enhanced ASTROGAM’) is a breakthrough Observatory space mission, with a detector composed by a Silicon tracker, a calorimeter, and an anticoincidence system, dedicated to the study of the non-thermal Universe in the photon energy range from 0.3 MeV to 3 GeV – the lower energy limit can be pushed to energies as low as 150 keV, albeit with rapidly degrading angular resolution, for the tracker, and to 30 keV for calorimetric detection. The mission is based on an advanced space-proven detector technology, with unprecedented sensitivity, angular and energy resolution, combined with polarimetric capability. Thanks to its performance in the MeV-GeV domain, substantially improving its predecessors, e-ASTROGAM will open a new window on the non-thermal Universe, making pioneering observations of the most powerful Galactic and extragalactic sources, elucidating the nature of their relativistic outflows and their effects on the surroundings. With a line sensitivity in the MeV energy range one to two orders of magnitude better than previous generation instruments, e-ASTROGAM will determine the origin of key isotopes fundamental for the understanding of supernova explosion and the chemical evolution of our Galaxy. The mission will provide unique data of significant interest to a broad astronomical community, complementary to powerful observatories such as LIGO-Virgo-GEO600-KAGRA, SKA, ALMA, E-ELT, TMT, LSST, JWST, Athena, CTA, IceCube, KM3NeT, and the promise of eLISA.
Childhood adversity plays an important role for development of major depressive disorder (MDD). There are differences in subcortical brain structures between patients with MDD and healthy controls, but the specific impact of childhood adversity on such structures in MDD remains unclear. Thus, aim of the present study was to investigate whether childhood adversity is associated with subcortical volumes and how it interacts with a diagnosis of MDD and sex. Within the ENIGMA-MDD network, nine university partner sites, which assessed childhood adversity and magnetic resonance imaging in patients with MDD and controls, took part in the current joint mega-analysis. In this largest effort world-wide to identify subcortical brain structure differences related to childhood adversity, 3036 participants were analyzed for subcortical brain volumes using FreeSurfer. A significant interaction was evident between childhood adversity, MDD diagnosis, sex, and region. Increased exposure to childhood adversity was associated with smaller caudate volumes in females independent of MDD. All subcategories of childhood adversity were negatively associated with caudate volumes in females - in particular emotional neglect and physical neglect (independently from age, ICV, imaging site and MDD diagnosis). There was no interaction effect between childhood adversity and MDD diagnosis on subcortical brain volumes. Childhood adversity is one of the contributors to brain structural abnormalities. It is associated with subcortical brain abnormalities that are relevant to psychiatric disorders such as depression. (C) 2016 Published by Elsevier Ltd.
Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model that mirrors the human disease closely. Acid sphingomyelinase is the enzyme that generates ceramide upstream of acid ceramidase in the lysosomes. Using our acid ceramidase deficiency model, we tested if acid sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional acid sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can’t achieve so far. As a proof-of-concept study, we first cross-bred acid ceramidase deficient mice with acid sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted acid sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of acid ceramidase deficient mice with the acid sphingomyelinase inhibitor amitriptyline was toxic to acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that acid sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional acid sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients
Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model that mirrors the human disease closely. Acid sphingomyelinase is the enzyme that generates ceramide upstream of acid ceramidase in the lysosomes. Using our acid ceramidase deficiency model, we tested if acid sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional acid sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can’t achieve so far. As a proof-of-concept study, we first cross-bred acid ceramidase deficient mice with acid sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted acid sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of acid ceramidase deficient mice with the acid sphingomyelinase inhibitor amitriptyline was toxic to acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that acid sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional acid sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients.
BACKGROUND: The orbitofrontal cortex (OFC) is implicated in depression. The hypothesis investigated was whether the OFC sensitivity to reward and nonreward is related to the severity of depressive symptoms.
METHODS: Activations in the monetary incentive delay task were measured in the IMAGEN cohort at ages 14 years (n = 1877) and 19 years (n = 1140) with a longitudinal design. Clinically relevant subgroups were compared at ages 19 (high-severity group: n = 116; low-severity group: n = 206) and 14.
RESULTS: The medial OFC exhibited graded activation increases to reward, and the lateral OFC had graded activation increases to nonreward. In this general population, the medial and lateral OFC activations were associated with concurrent depressive symptoms at both ages 14 and 19 years. In a stratified high-severity depressive symptom group versus control group comparison, the lateral OFC showed greater sensitivity for the magnitudes of activations related to nonreward in the high-severity group at age 19 (p = .027), and the medial OFC showed decreased sensitivity to the reward magnitudes in the high-severity group at both ages 14 (p = .002) and 19 (p = .002). In a longitudinal design, there was greater sensitivity to nonreward of the lateral OFC at age 14 for those who exhibited high depressive symptom severity later at age 19 (p = .003).
CONCLUSIONS: Activations in the lateral OFC relate to sensitivity to not winning, were associated with high depressive symptom scores, and at age 14 predicted the depressive symptoms at ages 16 and 19. Activations in the medial OFC were related to sensitivity to winning, and reduced reward sensitivity was associated with concurrent high depressive symptom scores.
BACKGROUND: The orbitofrontal cortex (OFC) is implicated in depression. The hypothesis investigated was whether the OFC sensitivity to reward and nonreward is related to the severity of depressive symptoms.
METHODS: Activations in the monetary incentive delay task were measured in the IMAGEN cohort at ages 14 years (n = 1877) and 19 years (n = 1140) with a longitudinal design. Clinically relevant subgroups were compared at ages 19 (high-severity group: n = 116; low-severity group: n = 206) and 14.
RESULTS: The medial OFC exhibited graded activation increases to reward, and the lateral OFC had graded activation increases to nonreward. In this general population, the medial and lateral OFC activations were associated with concurrent depressive symptoms at both ages 14 and 19 years. In a stratified high-severity depressive symptom group versus control group comparison, the lateral OFC showed greater sensitivity for the magnitudes of activations related to nonreward in the high-severity group at age 19 (p = .027), and the medial OFC showed decreased sensitivity to the reward magnitudes in the high-severity group at both ages 14 (p = .002) and 19 (p = .002). In a longitudinal design, there was greater sensitivity to nonreward of the lateral OFC at age 14 for those who exhibited high depressive symptom severity later at age 19 (p = .003).
CONCLUSIONS: Activations in the lateral OFC relate to sensitivity to not winning, were associated with high depressive symptom scores, and at age 14 predicted the depressive symptoms at ages 16 and 19. Activations in the medial OFC were related to sensitivity to winning, and reduced reward sensitivity was associated with concurrent high depressive symptom scores.
INTEGRAL tripled the number of super-giant high-mass X-ray binaries (sgHMXB) known in the Galaxy by revealing absorbed and fast transient (SFXT) systems. Quantitative constraints on the wind clumping of massive stars can be obtained from the study of the hard X-ray variability of SFXT. A large fraction of the hard X-ray emission is emitted in the form of flares with a typical duration of 3 ksec, frequency of 7 days and luminosity of $10^{36}$ erg/s. Such flares are most probably emitted by the interaction of a compact object orbiting at $\sim10~R_*$ with wind clumps ($10^{22 ... 23}$ g) representing a large fraction of the stellar mass-loss rate. The density ratio between the clumps and the inter-clump medium is $10^{2 ... 4}$. The parameters of the clumps and of the inter-clump medium, derived from the SFXT flaring behavior, are in good agreement with macro-clumping scenario and line-driven instability simulations. SFXT are likely to have larger orbital radius than classical sgHMXB.
The application of electrical resistivity tomography to peatlands supports conventional coring by providing data on the current condition of peatlands, including data on stratigraphy, peat properties and thickness of organic deposits. Data on the current condition of drained peatlands are particularly required to improve estimates of carbon storage as well as losses and emissions from agriculturally used peatlands. However, most of the studies focusing on electrical resistivity tomography surveys have been conducted on natural peatlands with higher groundwater levels. Peatlands drained for agriculture have not often been studied using geophysical techniques. Drained sites are characterized by low groundwater levels and high groundwater fluctuations during the year, which lead to varying levels of water saturation. To validate better electrical resistivity tomography surveys of drained peatlands, the aim of this laboratory study is to investigate the influence of varying water saturation levels on electrical conductivity (reciprocal of resistivity) for a variety of peat and gyttja types, as well as for different degrees of peat decomposition. Results show that different levels of water saturation strongly influence bulk electrical conductivity. Distinct differences in this relationship exist between peat and gyttja substrates and between different degrees of peat decomposition. Peat shows an exponential relationship for all degrees of decomposition, whereas gyttja, in particular organic-rich gyttja, is characterized by a rather unimodal relationship. The slopes for the relationship between electrical conductivity and water content are steeper at high degrees of decomposition than for peat of low degrees of decomposition. These results have direct implications for field electrical resistivity tomography surveys. In drained peatlands that are strongly susceptible to drying, electrical resistivity tomography surveys have a high potential to monitor the actual field water content. In addition, at comparable water saturations, high or low degrees of decomposition can be inferred from electrical conductivity.
The determination of the total carbon storage of peatlands is of high relevance in the context of climate-change mitigation efforts. This determination relies on data about stratigraphy and peat properties, which are conventionally collected by coring. Ground-penetrating radar (GPR) and electrical resistivity imaging (ERI) can support these point data by providing subsoil information in two-dimensional cross-sections. In this study, GPR and ERI were conducted at two groundwater-fed fen sites located in the temperate zone in north-east Germany. The fens of this region are embedded in low conductive glacial sand and are characterised by thick layers of gyttja, which can be either mineral or organic. The two study sites are representative of this region with respect to stratigraphy (total thickness, peat and gyttja types) and ecological conditions (pH-value, trophic condition). The aim of this study is to assess the suitability of GPR and ERI to detect stratigraphy and peat properties under these characteristic site conditions. Results show that GPR clearly detects the interfaces between (i) Carex and brown-moss peat, (ii) brown-moss peat and organic gyttja, (iii) organic- and mineral gyttja, and (iv) mineral gyttja and the parent material (glacial sand). These layers differ in bulk density and the related organic matter content. ERI, however, does not delineate these layers; rather it delineates regions of varying properties. At our base-rich site, pore fluid conductivity and cation.exchange capacity are the main factors that determine peat electrical conductivity (reverse of resistivity), whereas organic matter and water content are most influential at the more acidic site. Thus the correlation between peat properties and electrical conductivity are driven by site-specific conditions, which are mainly determined by the solute load in the groundwater at fens. When the total organic deposits exceed a thickness of 5 m, the depth of investigation by GPR is limited due to increasing attenuation. This is not a limiting factor for ERI, where the transition from organic deposits to glacial sand is visible at both sites. Due to these specific sensitivities, a combined application of GPR and ERI meets the demand for up-to-date information on carbon storage of peatlands, which is, moreover, very site-specific because of the inherent variety of ecological conditions and stratigraphy between peatlands in general and between fens and bogs in particular. (C) 2016 Elsevier B.V. All rights reserved.
To study the role of the TTR-RBP4-ROH complex components (transthyretin, serum retinol binding protein, retinol) and of angiogenic factors PlGF (placental growth factor) and sFlt-1 (soluble fms-like tyrosine kinase-1) in pregnancies complicated by small for gestational age infants (SGA). Case control study conducted on maternal serum collected between 11 + 0 to 13 + 6 weeks of gestation. TTR, RBP4, ROH, PlGF and sFlt-1 were measured in SGA patients (birth weight < 10%) who delivered at term (n = 37) and before 37 weeks of gestation (n = 17) and in a matched control group with uneventful pregnancies (n = 37). We found decreased RBP4 in SGA patients that delivered fetuses < 3% and in fetuses delivered after the 37 weeks of gestation compared to controls [1.50 (95% CI 1.40-1.75) vs 1.62 (95% CI 1.47-1.98), p < 0.05]. Further, we found lower PlGF and sFlt-1 concentrations in SGA that delivered before 37 weeks of gestation compared to controls (respectively, PIGF and sFlt-1: 39.7 pg/ml (95% CI 32.3-66.3) vs 62.9 pg/ml (95% CI 45.2-78.4) and 906 pg/ml (95% CI 727-1626) vs 1610 pg/ml (95% CI 1088-212), p < 0.05). First trimester maternal serum RBP4 and angiogenic factors PlGF and sFlt-1 can differently predict the timing of delivery of pregnancies complicated by SGA fetuses.
BACKGROUND: Physical and chemical characteristics of implant materials determine the fate of long-term cardiovascular devices. However, there is still a lack of fundamental understanding of the molecular mechanisms occurring in the material-tissue interphase. In a previous study, soft covalently crosslinked poly(n-butyl acrylate) networks (cPnBA) were introduced as sterilizable, non-toxic and immuno-compatible biomaterials with mechanical properties adjustable to blood vessels. Here we study the influence of different surface treatments in particular oxygen plasma modification and fibrinogen deposition as well as a combinatorial approach on the adhesion and viability of fibroblasts. RESULTS: Compared to non-treated cPnBAs the advancing water-contact angles were found to be reduced after all surface modifications (p<0.05, each), while lowest values were observed after the combined surface treatment (OPT+FIB). The latter differed significantly from the single OPT and FIB. The number of adherent fibroblasts and their adherence behavior differed on both pristine cPnBA networks. The fibroblast density on cPnBA04 was 743 +/- 434 cells. mm(-2), was about 6.5 times higher than on cPnBA73 with 115 +/- 73 cells. mm(-2). On cPnBA04 about 20% of the cells were visible as very small, round and buckled cells while all other cells were in a migrating status. On cPnBA73, nearly 50% of fibroblasts were visible as very small, round and buckled cells. The surface functionalization either using oxygen plasma treatment or fibrinogen coating led to a significant increase of adherent fibroblasts, particularly the combination of both techniques, for both cPnBA networks. It is noteworthy to mention that the fibrinogen coating overruled the characteristics of the pristine surfaces; here, the fibroblast densities after seeding were identical for both cPnBAnetworks. Thus, the binding rather depended on the fibrinogen coating than on the substrate characteristics anymore. While the integrity of the fibroblasts membrane was comparable for both polymers, the MTS tests showed a decreased metabolic activity of the fibroblasts on cPnBA. CONCLUSION: The applied surface treatments of cPnBA successfully improved the adhesion of viable fibroblasts. Under resting conditions as well as after shearing the highest fibroblast densities were found on surfaces with combined post-treatment.
In this BEEBOOK paper we present a set of established methods for quantifying honey bee behaviour. We start with general methods for preparing bees for behavioural assays. Then we introduce assays for quantifying sensory responsiveness to gustatory, visual and olfactory stimuli. Presentation of more complex behaviours like appetitive and aversive learning under controlled laboratory conditions and learning paradigms under free-flying conditions will allow the reader to investigate a large range of cognitive skills in honey bees. Honey bees are very sensitive to changing temperatures. We therefore present experiments which aim at analysing honey bee locomotion in temperature gradients. The complex flight behaviour of honey bees can be investigated under controlled conditions in the laboratory or with sophisticated technologies like harmonic radar or RFID in the field. These methods will be explained in detail in different sections. Honey bees are model organisms in behavioural biology for their complex yet plastic division of labour. To observe the daily behaviour of individual bees in a colony, classical observation hives are very useful. The setting up and use of typical observation hives will be the focus of another section. The honey bee dance language has important characteristics of a real language and has been the focus of numerous studies. We here discuss the background of the honey bee dance language and describe how it can be studied. Finally, the mating of a honey bee queen with drones is essential to survival of the entire colony. We here give detailed and structured information how the mating behaviour of drones and queens can be observed and experimentally manipulated.
The ultimate goal of this chapter is to provide the reader with a comprehensive set of experimental protocols for detailed studies on all aspects of honey bee behaviour including investigation of pesticide and insecticide effects.
Background: Retinol-binding protein 4 (RBP4) levels are elevated in the serum of patients with kidney dysfunction. We recently showed that RBP4 isoforms including apo-RBP4 (RBP4 not bound to retinol) and RBP4 truncated at the C-terminus (RBP4-L, RBP4-LL) are increased in the serum of patients with kidney diseases but not in serum of patients with various liver diseases. The aim of this study was to investigate the effect of renal replacement therapy on RBP4 isoforms. Methods: We investigated serum levels of RBP4, apo-RBP4, holo-RBP4, RBP4-L, RBP4-LL, retinol and transthyretin (TTR) in 18 hemodialysis (HD) patients, 30 patients after renal transplantation (RTx) and in 35 healthy controls. RBP4 and TTR levels were measured by enzyme-linked immunosorbent assay, apo- and holo-RBP4 by native electrophoresis, retinol by high performance liquid chromatography and RBP4-L and RBP4-LL were analyzed by mass spectrometry. Results: HD and RTx patients had elevated RBP4, apo-RBP4 and RBP4-LL levels compared to controls. RTx patients had elevated amounts of RBP4-L compared to controls and elevated RBP4 and apo-RBP4 levels compared to HD patients. Conclusion: The results demonstrate a strong correlation between kidney function and RBP4 isoforms and provide data for investigating the relation of RBP4 and insulin resistance in these patients.
Occludin is a self-associating transmembrane tight junction protein affected in oxidative stress. However, its function is unknown. The cytosolic C-terminal tail contains a coiled coil-domain forming dimers contributing to the self- association. Studying the hypothesis that the self-association is redox-sensitive, we found that the dimerization of the domain depended on the sulfhydryl concentration of the environment in low-millimolar range. Under physiological conditions, monomers and dimers were detected. Masking the sulfhydryl residues in the domain prevented the dimerization but affected neither its helical structure nor cylindric shape. Incubation of cell extracts containing full-length occludin with sulfhydryl reagents prevented the dimerization; a cysteine/alanine exchange mutant also did not show dimer formation. This demonstrates, for the first time, that disulfide bridge formation of the domain is involved in the occludin dimerization. It is concluded that the redox-dependent dimerization of occludin may play a regulatory role in the tight junction assembly under physiological and pathological conditions.
The Pleistocene archeological record in East Africa has revealed unusual accumulations of Acheulean handaxes at prehistoric sites. In particular, there has been intensive debate concerning whether the artifact accumulation at the Middle Pleistocene Olorgesailie (Southern Kenya Rift) and Kariandusi (Central Kenya Rift) sites were a result of fluvial reworking or of in situ deposition by hominids. We used a two-step approach to test the hypothesis of fluvial reworking. Firstly, the behavior of handaxes in water currents was investigated in a current flume and the flow threshold required to reorientate the handaxes was determined. The results of these experiments suggested that, in relatively high energy and non-steady flow conditions, handaxes will reorientate themselves perpendicular to the current direction. Secondly, an automated image analysis routine was developed and applied to archeological plans from three Acheulean sites, two at Olorgesailie and one at Kariandusi, in order to determine the orientations of the handaxes. A Rayleigh test was then applied to the orientation data to test for a preferred orientation. The results revealed that the handaxes at the Upper Kariandusi Site and the Olorgesailie Main Site Mid Trench had a preferential orientation, suggesting reworking by a paleocurrent. The handaxes from the Olorgesailie Main Site H/6A, however, appeared to be randomly oriented and in situ deposition by the producers therefore remains a possibility.
It is assumed that effects of the thiol antioxidant N-acetylcysteine (NAC) are mediated by interaction with protein-associated cysteine residues, however, information on protein level in vivo are missing. Therefore, we analyzed NAC-induced modifications of the protein transthyretin (TTR) in plasma of hemodialysis patients in a randomized, placebo-controlled study. TTR was selected due to its low molecular weight and the free cysteine residue in the polypeptide chain, which is known to be extensively modified by formation of mixed disulfides. The intravenous application of NAC during a hemodialysis session resulted in a substantial increase of native TTR from median 15% (range 8.8%-30%) to median 40% (37-50) and reduction of S-cysteinylated TTR [51% (44-60) vs. 6.6% (2.4-10)]. Additionally the pronounced formation of a TTR-NAC adduct was detected. However, all these modifications seemed to be reversible. Additionally, in vitro incubation of plasma with NAC confirmed the in vivo results and indicated that changes in post-translational modification pattern of TTR were a function of NAC concentration. Based on these observations and the essential metabolic and biochemical role of protein-associated cysteine residues we hypothesize that the interaction of NAC with proteins may explain altered protein functions due to modification of cysteine residues. Antioxid. Redox Signal. 19, 1166-1172.
Retinol-binding protein 4 (RBP4) is elevated in patients with chronic kidney disease (CKD) and has been discussed as marker of kidney function. In addition to an elevated concentration, the existence of truncated RBP4 species, RBP4-L (truncated at last C-terminal leucine) and RBP4-LL (truncated at both C-terminal leucines), has been reported in serum of hemodialysis patients. Since little is known about the occurrence of RBP4 species during the progression of CKD it was the aim of this study to analyse this possible association. The presence of RBP4, RBP4-L, RBP4- LL and transthyretin (TTR) was assessed in serum of 45 healthy controls and 52 patients with stage 2-5 of CKD using ELISA and RBP4 immunoprecipitation with subsequent MALDI-TOF-MS analysis. A reduction of glomerular filtration rate was accompanied by a gradual elevation of RBP4 serum levels and relative amounts of RBP4-LL. Correlation analysis revealed a strong association of the RBP4-TTR ratio with parameters of lipid metabolism and with diabetes-related factors. In conclusion, RBP4 serum concentration and the appearance of RBP4-LL seem to be influenced by kidney function. Furthermore, the RBP4-TTR ratio may provide diagnostic potential with regard to metabolic complications in CKD patients.
High nitrogen (N) efficiency, characterized by high grain yield under N limitation, is an important agricultural trait in Brassica napus L. cultivars related to delayed senescence of older leaves during reproductive growth (a syndrome called stay-green). The aim of this study was thus to identify genes whose expression is specifically altered during N starvation-induced leaf senescence and that can be used as markers to distinguish cultivars at early stages of senescence prior to chlorophyll loss. To this end, the transcriptomes of leaves of two B. napus cultivars differing in stay-green characteristics and N efficiency were analyzed 4 days after the induction of senescence by either N starvation, leaf shading or detaching. In addition to N metabolism genes, N starvation mostly (and specifically) repressed genes related to photosynthesis, photorespiration and cell-wall structure, while genes related to mitochondrial electron transport and flavonoid biosynthesis were predominately up-regulated. A kinetic study over a period of 12 days with four B. napus cultivars differing in their stay-green characteristics confirmed the cultivar-specific regulation of six genes in agreement with their senescence behavior: the senescence regulator ANAC029, the anthocyanin synthesis-related genes ANS and DFR-like1, the ammonium transporter AMT1:4, the ureide transporter UPSS, and SPS1 involved in sucrose biosynthesis. The identified genes represent markers for the detection of cultivar-specific differences in N starvation-induced leaf senescence and can thus be employed as valuable tools in B. napus breeding. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
Farber disease (FD) is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments are clinically available and affected patients have a severely shortened lifespan. Due to the low incidence, the pathogenesis of FD is still poorly understood. Here, we report a novel acid ceramidase mutant mouse model that enables the study of pathogenic mechanisms of FD and ceramide accumulation. Asah1(tmEx1) mice were generated by deletion of the acid ceramidase signal peptide sequence. The effects on lysosomal targeting and activity of the enzyme were assessed. Ceramide and sphingomyelin levels were quantified by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and disease manifestations in several organ systems were analyzed by histology and biochemistry. We show that deletion of the signal peptide sequence disrupts lysosomal targeting and enzyme activity, resulting in ceramide and sphingomyelin accumulation. The affected mice fail to thrive and die early. Histiocytic infiltrations were observed in many tissues, as well as lung inflammation, liver fibrosis, muscular disease manifestations and mild kidney injury. Our new mouse model mirrors human FD and thus offers further insights into the pathogenesis of this disease. In the future, it may also facilitate the development of urgently needed therapies.
PaRDeS, the journal of the German Association for Jewish Studies, aims at exploring the fruitful and multifarious cultures of Judaism as well as their relations to their environment within diverse areas of research. In addition, the journal promotes Jewish Studies within academic discourse and reflects on its historic and social responsibilities.
The response of rapidly compressed highly oriented pyrolytic graphite (HOPG) normal to its basal plane was investigated at a pressure of & SIM;80 GPa. Ultrafast x-ray diffraction using & SIM;100 fs pulses at the Materials Under Extreme Conditions sector of the Linac Coherent Light Source was used to probe the changes in crystal structure resulting from picosecond timescale compression at laser drive energies ranging from 2.5 to 250 mJ. A phase transformation from HOPG to a highly textured hexagonal diamond structure is observed at the highest energy, followed by relaxation to a still highly oriented, but distorted graphite structure following release. We observe the formation of a highly oriented lonsdaleite within 20 ps, subsequent to compression. This suggests that a diffusionless martensitic mechanism may play a fundamental role in phase transition, as speculated in an early work on this system, and more recent static studies of diamonds formed in impact events. Published by AIP Publishing.
Permafrost thaw subjects previously frozen soil organic carbon (SOC) to microbial degradation to the greenhouse gases carbon dioxide (CO2) and methane (CH4). Emission of these gases constitutes a positive feedback to climate warming. Among numerous uncertainties in estimating the strength of this permafrost carbon feedback (PCF), two are: (i) how mineralization of permafrost SOC thawed in saturated anaerobic conditions responds to changes in temperature and (ii) how microbial communities and temperature sensitivities change over time since thaw. To address these uncertainties, we utilized a thermokarst-lake sediment core as a natural chronosequence where SOC thawed and incubated in situ under saturated anaerobic conditions for up to 400 years following permafrost thaw. Initial microbial communities were characterized, and sediments were anaerobically incubated in the lab at four temperatures (0 °C, 3 °C, 10 °C, and 25 °C) bracketing those observed in the lake's talik. Net CH4 production in freshly-thawed sediments near the downward-expanding thaw boundary at the base of the talik were most sensitive to warming at the lower incubation temperatures (0 °C to 3 °C), while the overlying sediments which had been thawed for centuries had initial low abundant methanogenic communities (< 0.02%) and did not experience statistically significant increases in net CH4 production potentials until higher incubation temperatures (10 °C to 25 °C). We propose these observed differences in temperature sensitivities are due to differences in SOM quality and functional microbial community composition that evolve over time; however further research is necessary to better constrain the roles of these factors in determining temperature controls on anaerobic C mineralization.
Permafrost thaw subjects previously frozen organic carbon (OC) to microbial decomposition, generating the greenhouse gases (GHG) carbon dioxide (CO2) and methane (CH4) and fueling a positive climate feedback. Over one quarter of permafrost OC is stored in deep, ice-rich Pleistocene-aged yedoma permafrost deposits. We used a combination of anaerobic incubations, microbial sequencing, and ultrahigh-resolution mass spectrometry to show yedoma OC biolability increases with depth along a 12-m yedoma profile. In incubations at 3 degrees C and 13 degrees C, GHG production per unit OC at 12-versus 1.3-m depth was 4.6 and 20.5 times greater, respectively. Bacterial diversity decreased with depth and we detected methanogens at all our sampled depths, suggesting that in situ microbial communities are equipped to metabolize thawed OC into CH4. We concurrently observed an increase in the relative abundance of reduced, saturated OC compounds, which corresponded to high proportions of C mineralization and positively correlated with anaerobic GHG production potentials and higher proportions of OC being mineralized as CH4. Taking into account the higher global warming potential (GWP) of CH4 compared to CO2, thawed yedoma sediments in our study had 2 times higher GWP at 12-versus 9.0-m depth at 3 degrees C and 15 times higher GWP at 13 degrees C. Considering that yedoma is vulnerable to processes that thaw deep OC, our findings imply that it is important to account for this increasing GHG production and GWP with depth to better understand the disproportionate impact of yedoma on the magnitude of the permafrost carbon feedback.
In animals and humans, behavior can be influenced by irrelevant stimuli, a phenomenon called Pavlovian-to-instrumental transfer (PIT). In subjects with substance use disorder, PIT is even enhanced with functional activation in the nucleus accumbens (NAcc) and amygdala. While we observed enhanced behavioral and neural PIT effects in alcohol-dependent subjects, we here aimed to determine whether behavioral PIT is enhanced in young men with high-risk compared to low-risk drinking and subsequently related functional activation in an a-priori region of interest encompassing the NAcc and amygdala and related to polygenic risk for alcohol consumption. A representative sample of 18-year old men (n = 1937) was contacted: 445 were screened, 209 assessed: resulting in 191 valid behavioral, 139 imaging and 157 genetic datasets. None of the subjects fulfilled criteria for alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders-IV-TextRevision (DSM-IV-TR). We measured how instrumental responding for rewards was influenced by background Pavlovian conditioned stimuli predicting action-independent rewards and losses. Behavioral PIT was enhanced in high-compared to low-risk drinkers (b = 0.09, SE = 0.03, z = 2.7, p < 0.009). Across all subjects, we observed PIT-related neural blood oxygen level-dependent (BOLD) signal in the right amygdala (t = 3.25, p(SVC) = 0.04, x = 26, y = -6, z = -12), but not in NAcc. The strength of the behavioral PIT effect was positively correlated with polygenic risk for alcohol consumption (r(s) = 0.17, p = 0.032). We conclude that behavioral PIT and polygenic risk for alcohol consumption might be a biomarker for a subclinical phenotype of risky alcohol consumption, even if no drug-related stimulus is present. The association between behavioral PIT effects and the amygdala might point to habitual processes related to out PIT task. In non-dependent young social drinkers, the amygdala rather than the NAcc is activated during PIT; possible different involvement in association with disease trajectory should be investigated in future studies.
The influence of Pavlovian conditioned stimuli on ongoing behavior may contribute to explaining how alcohol cues stimulate drug seeking and intake. Using a Pavlovian-instrumental transfer task, we investigated the effects of alcohol-related cues on approach behavior (i.e., instrumental response behavior) and its neural correlates, and related both to the relapse after detoxification in alcohol-dependent patients. Thirty-one recently detoxified alcohol-dependent patients and 24 healthy controls underwent instrumental training, where approach or non-approach towards initially neutral stimuli was reinforced by monetary incentives. Approach behavior was tested during extinction with either alcohol-related or neutral stimuli (as Pavlovian cues) presented in the background during functional magnetic resonance imaging (fMRI). Patients were subsequently followed up for 6 months. We observed that alcohol-related background stimuli inhibited the approach behavior in detoxified alcohol-dependent patients (t = -3.86, p < .001), but not in healthy controls (t = -0.92, p = .36). This behavioral inhibition was associated with neural activation in the nucleus accumbens (NAcc) (t((30)) = 2.06, p < .05). Interestingly, both the effects were only present in subsequent abstainers, but not relapsers and in those with mild but not severe dependence. Our data show that alcohol-related cues can acquire inhibitory behavioral features typical of aversive stimuli despite being accompanied by a stronger NAcc activation, suggesting salience attribution. The fact that these findings are restricted to abstinence and milder illness suggests that they may be potential resilience factors.
In animals and humans, behavior can be influenced by irrelevant stimuli, a phenomenon called Pavlovian-to-instrumental transfer (PIT). In subjects with substance use disorder, PIT is even enhanced with functional activation in the nucleus accumbens (NAcc) and amygdala. While we observed enhanced behavioral and neural PIT effects in alcohol-dependent subjects, we here aimed to determine whether behavioral PIT is enhanced in young men with high-risk compared to low-risk drinking and subsequently related functional activation in an a-priori region of interest encompassing the NAcc and amygdala and related to polygenic risk for alcohol consumption. A representative sample of 18-year old men (n = 1937) was contacted: 445 were screened, 209 assessed: resulting in 191 valid behavioral, 139 imaging and 157 genetic datasets. None of the subjects fulfilled criteria for alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders-IV-TextRevision (DSM-IV-TR). We measured how instrumental responding for rewards was influenced by background Pavlovian conditioned stimuli predicting action-independent rewards and losses. Behavioral PIT was enhanced in high-compared to low-risk drinkers (b = 0.09, SE = 0.03, z = 2.7, p < 0.009). Across all subjects, we observed PIT-related neural blood oxygen level-dependent (BOLD) signal in the right amygdala (t = 3.25, p(SVC) = 0.04, x = 26, y = -6, z = -12), but not in NAcc. The strength of the behavioral PIT effect was positively correlated with polygenic risk for alcohol consumption (r(s) = 0.17, p = 0.032). We conclude that behavioral PIT and polygenic risk for alcohol consumption might be a biomarker for a subclinical phenotype of risky alcohol consumption, even if no drug-related stimulus is present. The association between behavioral PIT effects and the amygdala might point to habitual processes related to out PIT task. In non-dependent young social drinkers, the amygdala rather than the NAcc is activated during PIT; possible different involvement in association with disease trajectory should be investigated in future studies.
In detoxified alcohol-dependent patients, alcohol-related stimuli can promote relapse. However, to date, the mechanisms by which contextual stimuli promote relapse have not been elucidated in detail. One hypothesis is that such contextual stimuli directly stimulate the motivation to drink via associated brain regions like the ventral striatum and thus promote alcohol seeking, intake and relapse. Pavlovian-to-Instrumental-Transfer (PIT) may be one of those behavioral phenomena contributing to relapse, capturing how Pavlovian conditioned (contextual) cues determine instrumental behavior (e.g. alcohol seeking and intake). We used a PIT paradigm during functional magnetic resonance imaging to examine the effects of classically conditioned Pavlovian stimuli on instrumental choices in n=31 detoxified patients diagnosed with alcohol dependence and n=24 healthy controls matched for age and gender. Patients were followed up over a period of 3 months. We observed that (1) there was a significant behavioral PIT effect for all participants, which was significantly more pronounced in alcohol-dependent patients; (2) PIT was significantly associated with blood oxygen level-dependent (BOLD) signals in the nucleus accumbens (NAcc) in subsequent relapsers only; and (3) PIT-related NAcc activation was associated with, and predictive of, critical outcomes (amount of alcohol intake and relapse during a 3 months follow-up period) in alcohol-dependent patients. These observations show for the first time that PIT-related BOLD signals, as a measure of the influence of Pavlovian cues on instrumental behavior, predict alcohol intake and relapse in alcohol dependence.
In this paper we report on a long multi-wavelength observational campaign of the supergiant fast X-ray transient prototype IGR J17544-2619. A 150 ks-long observation was carried out simultaneously with XMM-Newton and NuSTAR, catching the source in an initial faint X-ray state and then undergoing a bright X-ray outburst lasting approximately 7 ks. We studied the spectral variability during outburst and quiescence by using a thermal and bulk Comptonization model that is typically adopted to describe the X-ray spectral energy distribution of young pulsars in high mass X-ray binaries. Although the statistics of the collected X-ray data were relatively high, we could neither confirm the presence of a cyclotron line in the broad-band spectrum of the source (0.5-40 keV), nor detect any of the previously reported tentative detections of the source spin period. The monitoring carried out with Swift/XRT during the same orbit of the system observed by XMM-Newton and NuSTAR revealed that the source remained in a low emission state for most of the time, in agreement with the known property of all supergiant fast X-ray transients being significantly sub-luminous compared to other supergiant X-ray binaries. Optical and infrared observations were carried out for a total of a few thousand seconds during the quiescence state of the source detected by XMM-Newton and NuSTAR. The measured optical and infrared magnitudes were slightly lower than previous values reported in the literature, but compatible with the known micro-variability of supergiant stars. UV observations obtained with the UVOT telescope on-board Swift did not reveal significant changes in the magnitude of the source in this energy domain compared to previously reported values.