Search

Though wind power predictions have been consistently improved in the last decade, persistent reasons for remaining uncertainties are sudden large changes in wind speed, so‐called ramps. Here, we analyse the occurrence of ramp events in a wind farm in Eastern Germany and the performance of a wind power prediction tool in forecasting these events for forecasting horizons of 15 and 30 min. Results on the seasonality of ramp events and their diurnal cycle are presented for multiple ramp definition thresholds. Ramps were found to be most frequent in March and April and least frequent in November and December. For the analysis, the wind power prediction tool is fed by different wind velocity forecast products, for example, numerical weather prediction (NWP) model and measurement data. It is shown that including observational wind speed data for very short‐term wind power forecasts improves the performance of the power prediction tool compared to the NWP reference, both in terms of ramp detection and in decreasing the mean absolute error between predicted and generated wind power. This improvement is enhanced during ramp events, highlighting the importance of wind observations for very short‐term wind power prediction. [ABSTRACT FROM AUTHOR]

A catalysis‐based regioselective 1,4‐fluorofunctionalization of trifluoromethyl substituted 1,3‐dienes has been developed to access compact, highly functionalized products. The process allows E,Z‐mixed dienes to be processed to a single E‐alkene isomer, and leverages an inexpensive and operationally convenient I(I)/I(III) catalysis platform. The first example of catalytic 1,4‐difluorination is disclosed and subsequently evolved to enable 1,4‐hetero‐difunctionalization, which allows δ‐fluoro‐alcohol and amine derivatives to be forged in a single operation. The protocol is compatible with a variety of nucleophiles including fluoride, nitriles, carboxylic acids, alcohols and even water thereby allowing highly functionalized products, with a stereocenter bearing both C(sp3)−F and C(sp3)−CF3 groups, to be generated rapidly. Scalability (up to 3 mmol), and facile post‐reaction modifications are demonstrated to underscore the utility of the method in expanding organofluorine chemical space. [ABSTRACT FROM AUTHOR]

Flower clouds are trade‐wind shallow cumuli, with tops reaching 3 km altitude, organised into 100‐km wide clusters. They are widespread over the subtropics and associated with the strongest cloud radiative effect among trade‐wind cumuli mesoscale organisations. In the context of large uncertainty in climate projections due to the representation of shallow clouds, major knowledge gaps remain about the global impact of mesoscale organisations and the local processes driving them. Here, the processes governing the flower organisation are investigated based on the case study of February 2, 2020 from the Elucidate the Couplings Between Clouds, Convection, and Circulation (EUREC4$$ {}^4 $$A) campaign, east of Barbados. One flower cloud is simulated with a large‐eddy simulation (LES), using the Meso‐NH model at 100‐m horizontal grid spacing, and validated extensively with high‐resolution observations from the High Altitude and Long‐range Research Aircraft (HALO), dropsondes, and satellite measurements. The cloud‐top altitudes exhibit a trimodal distribution. The processes shaping flower clouds are wide cold pools and cloudy updrafts organised in one large arc at the western edge. These updrafts are responsible for the highest cloud tops and drive most of the vertical turbulent fluxes of sensible heat, humidity, and momentum. A mesoscale circulation takes place at the scale of the flower clouds and makes them very similar to deep mesoscale convective systems. [ABSTRACT FROM AUTHOR]

The regio‐ and enantio‐selective, intermolecular vicinal fluoroamination of α‐trifluoromethyl styrenes has been achieved by enantioselective II/IIII catalysis. Leveraging C2‐symmetric resorcinol‐based aryl iodide catalysts, it has been possible to intercept the transient iodonium intermediate using simple nitriles, which function as both the solvent and nucleophile. In situ Ritter reaction provides direct access to the corresponding amides (up to 89 % yield, e.r. 93 : 7). This main group catalysis paradigm inverts the intrinsic regioselectivity of the uncatalyzed process, thereby providing facile access to tertiary, benzylic stereocenters bearing both CF3 and F groups. Privileged phenethylamine pharmacophores can be generated in which there is complete local partial charge inversion (CF3δ−/Fδ− versus CH3δ+/Hδ+). Crystallographic analyses of representative β‐fluoroamide products reveal highly pre‐organized conformations that manifest the stereoelectronic gauche effect. [ABSTRACT FROM AUTHOR]

Die regio‐ und enantioselektive, intermolekulare vicinale Fluoraminierung von α‐CF3‐Styrolen wurde durch enantioselektive II/IIII‐Katalyse erreicht. Unter Nutzung von C2‐symmetrischen, Resorcinol‐basierten Aryl Iodid‐Katalysatoren war es möglich, das kurzlebige Iodonium‐Zwischenprodukt mit einfachen Nitrilen abzufangen, die sowohl als Lösungsmittel als auch als Nucleophil fungieren. Die in situ Ritter‐Reaktion bietet direkten Zugang zu den entsprechenden Amiden (>25 Beispiele, bis zu 89 % Ausbeute und 93 : 7 e.r.). Dieses Paradigma der Hauptgruppenkatalyse kehrt die intrinsische Regioselektivität des unkatalysierten Prozesses um und bietet so einen einfachen Zugang zu tertiären, benzylischen Stereozentren, die sowohl eine CF3‐Gruppe als auch ein Fluor tragen. Es können privilegierte Phenethylamin‐Pharmakophore erzeugt werden, bei denen die vollständige lokale partielle Ladungsumkehr vorliegt (CF3δ−/Fδ− versus CH3δ+/Hδ+). Kristallographische Analysen von repräsentativen β‐Fluoramid‐Produkten zeigen Konformationen, die den stereoelektronischen Gauche‐Effekt verdeutlichen. [ABSTRACT FROM AUTHOR]

Background: Strong opioids can have unintended effects. Clinical studies of strong opioids mainly report physical side effects, psychiatric or opioid use disorders. To date, too little attention has been paid to the psychological effects of opioids to treat patients with chronic noncancer pain (CNCP). This study aims to identify and measure (i) the nature and frequency of physical and psychological effects and (ii) the degree of physician counseling of patients with CNCP taking strong opioids. Methods: Within a cross‐sectional survey—conducted as part of a randomised controlled online intervention trial (ERONA [Experiencing the risk of overusing opioids among patients with chronic non‐cancer pain in ambulatory care])—300 German CNCP patients were surveyed via patient‐reported outcome measures regarding on both the side effects from their use of strong opioids as well as their counselling experience. Results: Among the patients' reported effects, the psychological outcomes of the opioids in CNCP were: feeling relaxed (84%), fatigue (76%), dizziness (57%), listlessness (37%), difficulty with mental activities (23%), dulled emotions (17%) and poor memory (17%). Ninety‐two per cent of the patients reported having received information about opioid effects, and 46% had discussed cessation of the opioid medication with their physicians before commencing the prescription. Conclusions: In addition to the well‐known physical side effects, patients with CNCP taking strong opioids experience significant psychological effects. In view of these effects, discontinuation of opioid therapy should be discussed early to ensure their benefits do not outweigh their harm. Significance: In this study, patients with non‐cancer pain notice that opioids they have taken do not only cause physical side effects but also may have an impact on their psyche and their emotions and, thus, may also affect quality of life substantially. Clinical trial number: DRKS00020358. [ABSTRACT FROM AUTHOR]

Progranulin (PGRN) is a neurotrophic and anti-inflammatory factor with protective effects in animal models of ischemic stroke, subarachnoid hemorrhage, and traumatic brain injury (TBI). Administration of recombinant (r) PGRN prevents exaggerated brain pathology after TBI in Grn-deficient mice, suggesting that local injection of recombinant progranulin (rPGRN) provides therapeutic benefit in the acute phase of TBI. To test this hypothesis, we subjected adult male C57Bl/6N mice to the controlled cortical impact model of TBI, administered a single dose of rPGRN intracerebroventricularly (ICV) shortly before the injury, and examined behavioral and biological effects up to 5 days post injury (dpi). The anti-inflammatory bioactivity of rPGRN was confirmed by its capability to inhibit the inflammation-induced hypertrophy of murine primary microglia and astrocytes in vitro. In C57Bl/6N mice, however, ICV administration of rPGRN failed to attenuate behavioral deficits over the 5-day observation period. (Immuno)histological gene and protein expression analyses at 5 dpi did not reveal a therapeutic benefit in terms of brain injury size, brain inflammation, glia activation, cell numbers in neurogenic niches, and neuronal damage. Instead, we observed a failure of TBI-induced mRNA upregulation of the tight junction protein occludin and increased extravasation of serum immunoglobulin G into the brain parenchyma at 5 dpi. In conclusion, single ICV administration of rPGRN had not the expected protective effects in the acute phase of murine TBI, but appeared to cause an aggravation of blood-brain barrier disruption. The data raise questions about putative PGRN-boosting approaches in other types of brain injuries and disease. [ABSTRACT FROM AUTHOR]

An I(I)/(III) catalysis strategy to construct an enantioenriched fluorinated isostere of the iPr group is reported. The difluorination of readily accessible α‐CF3‐styrenes is enabled by the in situ generation of a chiral ArIF2 species to forge a stereocentre with the substituents F, CH2F and CF3 (up to 95 %, >20:1 vicinal:geminal difluorination). The replacement of the metabolically labile benzylic proton results in a highly preorganised scaffold as was determined by X‐ray crystallography (π→σ* and stereoelectronic gauche σ→σ* interactions). A process of catalyst editing is disclosed in which preliminary validation of enantioselectivity is placed on a structural foundation. [ABSTRACT FROM AUTHOR]

Copyright of Angewandte Chemie is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background and Purpose: All-trans retinoic acid (ATRA) is a vitamin A metabolite, important in the developing and mature brain. Pre-injury ATRA administration ameliorates ischaemic brain insults in rodents. This study examined the effects of post-traumatic ATRA treatment in experimental traumatic brain injury (TBI).Experimental Approach: Male adult mice were subjected to the controlled cortical impact model of TBI or sham procedure and killed at 7 or 30 days post-injury (dpi). ATRA (10 mg kg-1, i.p.) was given immediately after the injury and 1, 2 and 3 dpi. Neurological function and sensorimotor coordination were evaluated. Brains were processed for (immuno-) histological, mRNA and protein analyses (qPCR and western blot).Key Results: ATRA treatment reduced brain lesion size, reactive astrogliosis and axonal injury at 7 dpi, and hippocampal granule cell layer (GCL) integrity was protected at 7 and 30 dpi, independent of cell proliferation in neurogenic niches and blood-brain barrier damage. Neurological and motor deficits over time and the brain tissue loss at 30 dpi were not affected by ATRA treatment. ATRA decreased gene expression of markers for damage-associated molecular pattern (HMGB1), apoptosis (caspase-3 and Bax), activated microglia (TSPO), and reactive astrogliosis (GFAP, SerpinA3N) at 7 dpi and a subset of markers at 30 dpi (TSPO, GFAP).Conclusion and Implications: In experimental TBI, post-traumatic ATRA administration exerted brain protective effects, including long-term protection of GCL integrity, but did not affect neurological and motor deficits. Further investigations are required to optimize treatment regimens to enhance ATRA's brain protective effects and improve outcomes. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury elicits spinal microgliosis, contributing to neuropathic pain. The aurora kinases A (AURKA), B (AURKB), and C (AURKC) are potential therapeutic targets in proliferating cells. However, their role has not been clarified in microglia. The aim of this study was to examine the regulation of aurora kinases and their roles and druggability in spinal microgliosis and neuropathic pain. Sprague–Dawley rats received chronic constriction injury (CCI). Gene expression of aurora kinases A‐C was evaluated by quantitative RT‐PCR and western blot, respectively, in spinal cords at 1, 3, 7, and 14 days after CCI. AURKB gene and protein expression was up‐regulated concomitantly with the development of spinal microgliosis and neuropathic pain. Using lentiviral over‐expression and adeno‐associated viral knockdown approaches, the function of AURKB was further investigated by western blot, immunohistochemistry, RNA sequencing, and pain behavior tests. We found that AURKB over‐expression in naive rats caused spinal microgliosis and pain hypersensitivity, whereas AURKB knockdown reduced microgliosis and alleviated CCI‐induced neuropathic pain. Accordingly, RNA sequencing data revealed down‐regulation of genes critically involved in signaling pathways associated with spinal microgliosis and neuropathic pain after AURKB knockdown in CCI rats. To examine its therapeutic potential for treatment of neuropathic pain, animals were treated intrathecally with the pharmacological AURKB inhibitor AZD1152‐HQPA resulting in the alleviation of CCI‐induced pain. Taken together, our findings indicated that AURKB plays a critical role in spinal microgliosis and neuropathic pain. Targeting AURKB may be an efficient method for treatment of neuropathic pain subsequent to peripheral nerve injury. [ABSTRACT FROM AUTHOR]

Copyright of Journal der Deutschen Dermatologischen Gesellschaft is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Summary: The present guidelines are aimed at residents and board‐certified specialists in the fields of dermatology, ophthalmology, ENT, pediatrics, neurology, virology, infectious diseases, anesthesiology, general medicine and any other medical specialties involved in the management of patients with herpes zoster. They are also intended as a guide for policymakers and health insurance funds. The guidelines were developed by dermatologists, virologists, ophthalmologists, ENT physicians, neurologists, pediatricians and anesthesiologists/pain specialists using a formal consensus process (S2k). Readers are provided with an overview of the clinical and molecular diagnostic workup, including antigen detection, antibody tests and viral culture. Special diagnostic situations and complicated disease courses are discussed. The authors address general and special aspects of antiviral therapy for herpes zoster and postherpetic neuralgia. Furthermore, the guidelines provide detailed information on pain management including a schematic overview, and they conclude with a discussion of topical treatment options. [ABSTRACT FROM AUTHOR]

Clinical and animal studies have revealed sex‐specific differences in histopathological and neurological outcome after traumatic brain injury (TBI). The impact of perioperative administration of sex steroid inhibitors on TBI is still elusive. Here, we subjected male and female C57Bl/6N mice to the controlled cortical impact (CCI) model of TBI and applied pharmacological inhibitors of steroid hormone synthesis, that is, letrozole (LET, inhibiting estradiol synthesis by aromatase) and finasteride (FIN, inhibiting dihydrotestosterone synthesis by 5α‐reductase), respectively, starting 72 h prior CCI, and continuing for a further 48 h after CCI. Initial gene expression analyses showed that androgen (Ar) and estrogen receptors (Esr1) were sex‐specifically altered 72 h after CCI. When examining brain lesion size, we found larger lesions in male than in female mice, but did not observe effects of FIN or LET treatment. However, LET treatment exacerbated neurological deficits 24 and 72 h after CCI. On the molecular level, FIN administration reduced calpain‐dependent spectrin breakdown products, a proxy of excitotoxicity and disturbed Ca2+ homeostasis, specifically in males, whereas LET increased the reactive astrocyte marker glial fibrillary acid protein specifically in females. Examination of neurotrophins (brain‐derived neurotrophic factor, neuronal growth factor, NT‐3) and their receptors (p75NTR, TrkA, TrkB, TrkC) revealed CCI‐induced down‐regulation of TrkB and TrkC protein expression, which was reduced by LET in both sexes. Interestingly, FIN decreased neuronal growth factor mRNA expression and protein levels of its receptor TrkA only in males. Taken together, our data suggest a sex‐specific impact on pathogenic processes in the injured brain after TBI. Sex hormones may thus modulate pathogenic processes in experimental TBI. [ABSTRACT FROM AUTHOR]

Objective: Plasminogen activator inhibitor-1 (PAI-1) is the key endogenous inhibitor of fibrinolysis, and enhances clot formation after injury. In traumatic brain injury, dysregulation of fibrinolysis may lead to sustained microthrombosis and accelerated lesion expansion. In the present study, we hypothesized that PAI-1 mediates post-traumatic malfunction of coagulation, with inhibition or genetic depletion of PAI-1 attenuating clot formation and lesion expansion after brain trauma.Methods: We evaluated PAI-1 as a possible new target in a mouse controlled cortical impact (CCI) model of traumatic brain injury. We performed the pharmacological inhibition of PAI-1 with PAI-039 and stimulation by tranexamic acid, and we confirmed our results in PAI-1-deficient animals.Results: PAI-1 mRNA was time-dependently upregulated, with a 305-fold peak 12 hours after CCI, which effectively counteracted the 2- to 3-fold increase in cerebral tissue-type/urokinase plasminogen activator expression. PAI-039 reduced brain lesion volume by 26% at 24 hours and 43% at 5 days after insult. This treatment also attenuated neuronal apoptosis and improved neurofunctional outcome. Moreover, intravital microscopy demonstrated reduced post-traumatic thrombus formation in the pericontusional cortical microvasculature. In PAI-1-deficient mice, the therapeutic effect of PAI-039 was absent. These mice also displayed 13% reduced brain damage compared with wild type. In contrast, inhibition of fibrinolysis with tranexamic acid increased lesion volume by 25% compared with vehicle.Interpretation: This study identifies impaired fibrinolysis as a critical process in post-traumatic secondary brain damage and suggests that PAI-1 may be a central endogenous inhibitor of the fibrinolytic pathway, promoting a procoagulatory state and clot formation in the cerebral microvasculature. Ann Neurol 2019;85:667-680. [ABSTRACT FROM AUTHOR]

The enantioselective, catalytic vicinal difluorination of alkenes is reported by II/IIII catalysis using a novel, C2‐symmetric resorcinol derivative. Catalyst turnover via in situ generation of an ArIIIIF2 species is enabled by Selectfluor oxidation and addition of an inexpensive HF–amine complex. The HF:amine ratio employed in this process provides a handle for regioselective orthogonality as a function of Brønsted acidity. Selectivity reversal from the 1,1‐difluorination pathway (geminal) to the desired 1,2‐difluorination (vicinal) is disclosed (>20:1 in both directions). Validation with electron deficient styrenes facilitates generation of chiral bioisosteres of the venerable CF3 unit that is pervasive in drug discovery (20 examples, up to 94:06 e.r.). An achiral variant of the reaction is also presented using p‐TolI (up to >95 % yield). [ABSTRACT FROM AUTHOR]

Cannabis-based medicines are being approved for pain management in an increasing number of European countries. There are uncertainties and controversies on the role and appropriate use of cannabis-based medicines for the management of chronic pain. EFIC convened a European group of experts, drawn from a diverse range of basic science and relevant clinical disciplines, to prepare a position paper to empower and inform specialist and nonspecialist prescribers on appropriate use of cannabis-based medicines for chronic pain. The expert panel reviewed the available literature and harnessed the clinical experience to produce these series of recommendations. Therapy with cannabis-based medicines should only be considered by experienced clinicians as part of a multidisciplinary treatment and preferably as adjunctive medication if guideline-recommended first- and second-line therapies have not provided sufficient efficacy or tolerability. The quantity and quality of evidence are such that cannabis-based medicines may be reasonably considered for chronic neuropathic pain. For all other chronic pain conditions (cancer, non-neuropathic noncancer pain), the use of cannabis-based medicines should be regarded as an individual therapeutic trial. Realistic goals of therapy have to be defined. All patients must be kept under close clinical surveillance. As with any other medical therapy, if the treatment fails to reach the predefined goals and/or the patient is additionally burdened by an unacceptable level of adverse effects and/or there are signs of abuse and misuse of the drug by the patient, therapy with cannabis-based medicines should be terminated.Significance: This position paper provides expert recommendations for nonspecialist and specialist healthcare professionals in Europe, on the importance and the appropriate use of cannabis-based medicines as part of a multidisciplinary approach to pain management, in properly selected and supervised patients. [ABSTRACT FROM AUTHOR]

Abstract: Ceres’ surface has commonly been linked with carbonaceous chondrites (CCs) by ground‐based telescopic observations, because of its low albedo, flat to red‐sloped spectra in the visible and near‐infrared (VIS/NIR) wavelength region, and the absence of distinct absorption bands, though no currently known meteorites provide complete spectral matches to Ceres. Spatially resolved data of the Dawn Framing Camera (FC) reveal a generally dark surface covered with bright spots exhibiting reflectance values several times higher than Ceres’ background. In this work, we investigated FC data from High Altitude Mapping Orbit (HAMO) and Ceres eXtended Juling (CXJ) orbit (~140 m/pixel) for global spectral variations. We found that the cerean surface mainly differs by spectral slope over the whole FC wavelength region (0.4–1.0 μm). Areas exhibiting slopes <−10% μm−1 constitute only ~3% of the cerean surface and mainly occur in the bright material in and around young craters, whereas slopes ≥−10% μm−1 occur on more than 90% of the cerean surface; the latter being denoted as Ceres’ background material in this work. FC and Visible and Infrared Spectrometer (VIR) spectra of this background material were compared to the suite of CCs spectrally investigated so far regarding their VIS/NIR region and 2.7 μm absorption, as well as their reflectance at 0.653 μm. This resulted in a good match to heated CI Ivuna (heated to 200–300 °C) and a better match for CM1 meteorites, especially Moapa Valley. This possibly indicates that the alteration of CM2 to CM1 took place on Ceres. [ABSTRACT FROM AUTHOR]

Motor neuron diseases such as amyotrophic lateral sclerosis (ALS) are now recognized as multi-system disorders also involving various non-motor neuronal cell types. The precise extent and mechanistic basis of non-motor neuron damage in human ALS and ALS animal models remain however unclear. To address this, we here studied progressive motor neuronopathy ( pmn) mice carrying a missense loss-of-function mutation in tubulin binding cofactor E (TBCE). These mice manifest a particularly aggressive form of motor axon dying back and display a microtubule loss, similar to that induced by human ALS-linked TUBA4A mutations. Using whole nerve confocal imaging of pmn × thy1.2-YFP16 fluorescent reporter mice and electron microscopy, we demonstrate axonal discontinuities, bead-like spheroids and ovoids in pmn suralis nerves indicating prominent sensory neuropathy. The axonal alterations qualitatively resemble those in phrenic motor nerves but do not culminate in the loss of myelinated fibers. We further show that the pmn mutation decreases the level of TBCE, impedes microtubule polymerization in dorsal root ganglion (DRG) neurons and causes progressive loss of microtubules in large and small caliber suralis axons. Live imaging of axonal transport using GFP-tagged tetanus toxin C-fragment (GFP-TTC) demonstrates defects in microtubule-based transport in pmn DRG neurons, providing a potential explanation for the axonal alterations in sensory nerves. This study unravels sensory neuropathy as a pathological feature of mouse pmn, and discusses the potential contribution of cytoskeletal defects to sensory neuropathy in human motor neuron disease. [ABSTRACT FROM AUTHOR]

Background. A wide range for the prevalence of Molar-Incisor-Hypomineralisation (MIH) has been found in regional studies. Aim. The aim of this study was to determine the prevalence of MIH in Germany and to compare the findings with other studies. Design. In the compulsory dental school examination, the first permanent molars, permanent incisors, and second primary molars were examined according to EAPD criteria in 2395 children (8.1 ± 0.8 years) in four regions in Germany for the presence of MIH. Examinations were performed by five calibrated examiners (j = 0.9) on clean teeth after toothbrushing. Results. The prevalence of MIH at the four regions differed considerably (4.3-14.6%) with a mean prevalence of 10.1%. The DMFT/dmft was generally low, but children with MIH exhibited statistically significant higher caries values. A total of 12.0% of the children with MIH also had at least one affected primary molar, which resulted in a statistically significant correlation between primary and permanent teeth. Most of the affected teeth had demarcated opacities, but more than half of the affected children showed at least one tooth with severe MIH. Conclusions. Molar-Incisor-Hypomineralisation is a prevalent finding in German school children. The prevalence varies highly in different regions, and the high rate of severe forms has clinically relevant implications. [ABSTRACT FROM AUTHOR]

We present an analysis of olivine-rich exposures at Bellicia and Arruntia craters using Dawn Framing Camera ( FC) color data. Our results confirm the existence of olivine-rich materials at these localities as described by Ammannito et al. () using Visual Infrared Spectrometer ( VIR) data. Analyzing laboratory spectra of various howardite-eucrite-diogenite meteorites, high-Ca pyroxenes, olivines, and olivine-orthopyroxene mixtures, we derive three FC spectral band parameters that are indicators of olivine-rich materials. Combining the three band parameters allows us, for the first time, to reliably identify sites showing modal olivine contents >40%. The olivine-rich exposures at Bellicia and Arruntia are mapped using higher spatial resolution FC data. The exposures are located on the slopes of outer/inner crater walls, on the floor of Arruntia, in the ejecta, as well as in nearby fresh small impact craters. The spatial extent of the exposures ranges from a few hundred meters to few kilometers. The olivine-rich exposures are in accordance with both the magma ocean and the serial magmatism model (e.g., Righter and Drake ; Yamaguchi et al. ). However, it remains unsolved why the olivine-rich materials are mainly concentrated in the northern hemisphere (approximately 36-42°N, 46-74°E) and are almost absent in the Rheasilvia basin. [ABSTRACT FROM AUTHOR]

HIF-1α is pivotal for cellular homeostasis in response to cerebral ischemia. Pharmacological inhibition of HIF-1α may reduce secondary brain damage by targeting post-translational mechanisms associated with its proteasomal degradation and nuclear translocation. This study examined the neuroprotective effects of 2-methoxyestradiol (2 ME2), the involved HIF-1α-dependent response, and alternative splicing in exon 14 of HIF-1α ( HIF-1α∆Ex14) after traumatic brain injury ( TBI) in mice. Intraperitoneal 2 ME2 administration 30 min after TBI caused a dose-dependent reduction in secondary brain damage after 24 h. 2 ME2 was physiologically tolerated, showed no effects on immune cell brain migration, and mitigated trauma-induced brain expression of neuropathologically relevant HIF-1α target genes encoding for Plasminogen activator inhibitor 1 and tumor necrosis factor alpha. Moreover, TBI-induced expression of pro-apoptotic BNIP3 was attenuated by 2 ME2 treatment. Alternatively, spliced HIF-1α∆Ex14 was substantially up-regulated from 6 to 48 h after TBI. In vitro, nuclear location and gene transcription activity of HIF-1α∆Ex14 were impaired compared to full-length HIF-1α, but no effects on nuclear translocation of the transcriptional complex partner HIF-1β were observed. This study demonstrates that 2 ME2 confers neuroprotection after TBI. While the role of alternatively spliced HIF-1α∆Ex14 remains elusive, the in vivo data provide evidence that inhibition of a maladaptive HIF-1α-dependent response contributes to the neuroprotective effects of 2 ME2. [ABSTRACT FROM AUTHOR]

Background and Purpose The hippocampal cell line HT22 is an excellent model for studying the consequences of endogenous oxidative stress. Extracellular glutamate depletes cellular glutathione by blocking the glutamate/cystine antiporter system xc−. Glutathione depletion induces a well-defined programme of cell death characterized by an increase in reactive oxygen species and mitochondrial dysfunction. Experimental Approach We compared the mitochondrial shape, the abundance of mitochondrial complexes and the mitochondrial respiration of HT22 cells, selected based on their resistance to glutamate, with those of the glutamate-sensitive parental cell line. Key Results Glutamate-resistant mitochondria were less fragmented and displayed seemingly contradictory features: mitochondrial calcium and superoxide were increased while high-resolution respirometry suggested a reduction in mitochondrial respiration. This was interpreted as a reverse activity of the ATP synthase under oxidative stress, leading to hydrolysis of ATP to maintain or even elevate the mitochondrial membrane potential, suggesting these cells endure ineffective energy metabolism to protect their membrane potential. Glutamate-resistant cells were also resistant to oligomycin, an inhibitor of the ATP synthase, but sensitive to deoxyglucose, an inhibitor of hexokinases. Exchanging glucose with galactose rendered resistant cells 1000-fold more sensitive to oligomycin. These results, together with a strong increase in cytosolic hexokinase 1 and 2, a reduced lactate production and an increased activity of glucose-6-phosphate dehydrogenase, suggest that glutamate-resistant HT22 cells shuttle most available glucose towards the hexose monophosphate shunt to increase glutathione recovery. Conclusions and Implications These results indicate that mitochondrial and metabolic adaptations play an important role in the resistance of cells to oxidative stress. Linked Articles This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit [ABSTRACT FROM AUTHOR]

Output capacitance (Cout) measurements on AlGaN-GaN HEMTs with different field plate (FP) sizes and different EPI configurations as well as different sheet resistances owing to surface preparation have been performed at VDS = 10 and 40 V. A model is proposed where Cout is composed by a horizontal intrinsic part C1 and a vertical FP part C2. It could be shown that in case of large FPs and at high voltage measurements Cout via C2 is very sensitive to the vertical layer-sequence including surface preparation. Simulations performed on the same transistor structures and at same meas- urement conditions confirm well the measured values by assumption of surface traps in the 1012 cm-2-range. Additionally, it could be demonstrated that the output RF-power of the transistors with FP and at high voltage is directly correlated to Cout on transistors with high SD-voltage. It is proposed that by such Cout-measurements important information can be deduced about the vertical layer configuration including surface states and the transistor performance, e.g. regarding output power. (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [ABSTRACT FROM AUTHOR]

The extracellular matrix protein Reelin is an essential regulator of neuronal migration and lamination in the developing and mature brain. Lack of Reelin causes severe disturbances in cerebral layering, such as the reeler phenotype and granule cell dispersion in temporal lobe epilepsy. Reelin is synthesized and secreted by Cajal-Retzius cells and GABAergic interneurons, and its function depends on proteolytic cleavage after secretion. The mechanisms regulating these processes are largely unknown. Here, we used rat hip- pocampal slice cultures to investigate the effect of neuronal activation and hyperexcitation on Reelin synthesis, secretion, and proteolytic processing. We show that enhanced neuronal activity does not modulate Reelin synthesis or secretion. Moreover, we found that intracellular Reelin resides predominantly in the endoplasmic reticulum before it is constitutively secreted via the early secretory pathway. Epileptiform activity, however, impairs the proteolytic processing of Reelin and leads to accumulation of Reelin in the extracellular matrix. We found that both conditions, epileptiform activity and impaired proteolytic cleavage of Reelin, cause granule cell dispersion via inhibition of metalloproteinases. Taken together, our results strongly suggest that secretion of Reelin is activity-independent and that proteolytic processing of Reelin is required for the maintenance of granule cell lamination in the dentate gyrus. [ABSTRACT FROM AUTHOR]

Abstract: The cell adhesion molecule L1 is implicated in several processes in the developing and adult nervous system. Intracellular trafficking of L1 is important for cell migration, neurite growth and adhesion. We demonstrate here that L1 is ubiquitinated at the plasma membrane and in early endosomes. Mono-ubiquitination regulates L1 intracellular trafficking by enhancing its lysosomal degradation. We propose that L1’s ubiquitination might be an additional mechanism to control its re-appearance at the cell surface thereby influencing processes like neurite growth and cell adhesion. [ABSTRACT FROM AUTHOR]

Stress induces analgesia by mechanisms within and outside the brain. Here we show that the sympathetic nervous system is an essential trigger of intrinsic opioid analgesia within peripheral injured tissue. Noradrenaline, injected directly into inflamed hind paws of male Wistar rats, produced dose-dependent antinociception, reversible by α1-, α2- and β2-antagonists. α1-, α2- and β2-adrenergic receptors were demonstrated on β-endorphin-containing immune cells and noradrenaline induced adrenergic receptor-specific release of β-endorphin from immune cell suspensions. This antinociceptive effect of noradrenaline was reversed by µ- and δ-opioid antagonists as well as by anti-β-endorphin. Stress-induced peripheral analgesia was abolished by chemical sympathectomy and by adrenergic antagonists. These findings indicate that sympathetic neuron-derived noradrenaline stimulates adrenergic receptors on inflammatory cells to release β-endorphin, which induces analgesia via activation of peripheral opioid receptors. [ABSTRACT FROM AUTHOR]

1: Control of inflammatory pain can result from activation of opioid receptors on peripheral sensory nerves by opioid peptides secreted from leukocytes in response to stress (e.g. experimental swim stress or surgery). The extravasation of immunocytes to injured tissues involves rolling, adhesion and transmigration through the vessel wall, orchestrated by various adhesion molecules. 2: Here we evaluate the relative contribution of selectins, integrins a4 and ß2, and platelet-endothelial cell adhesion molecule-1 (PECAM-1) to the opioid-mediated inhibition of inflammatory pain. 3: We use flow cytometry, double immunofluorescence and nociceptive (paw pressure) testing in rats with unilateral hind paw inflammation induced by complete Freund's adjuvant. 4: In inflamed tissue, 43-58% of hematopoietic cells (CD45+) expressed opioid peptides. L-selectin and ß2 were coexpressed by 7 and 98% of opioid-containing leukocytes, respectively. Alpha4 integrin was expressed in low levels by the majority of leukocytes. Opioid-containing cells, vascular P- and E-selectin and PECAM-1 were simultaneously upregulated. 5: Swim stress produced potent opioid-mediated antinociception in inflamed tissue, unaffected by blockade of PECAM-1. However, blockade of L- and P-selectins by fucoidin, or of a4 and ß2 by monoclonal antibodies completely abolished peripheral stress-induced antinociception. This coincided with a 40% decrease in the migration of opioid-containing leukocytes to inflamed tissue. 6: These findings establish selectins and integrins a4 and ß2, but not PECAM-1, as important molecules involved in stress-induced opioid-mediated antinociception in inflammation. They point to a cautious use of anti-inflammatory treatments applying anti-selectin, anti-a4 and anti-ß2 strategies because they may impair intrinsic pain inhibition.British Journal of Pharmacology (2004) 142, 772-780. doi:10.1038/sj.bjp.0705837 [ABSTRACT FROM AUTHOR]