julilili42/papers huggingface dataset:
Zolpidem Activation of Alpha 1-Containing GABAA Receptors Selectively Inhibits High Frequency Action Potential Firing of Cortical Neurons
2019-01-09

<b>Introduction:</b> High frequency neuronal activity in the cerebral cortex can be induced by noxious stimulation during surgery, brain injury or poisoning. In this scenario, it is essential to block cortical hyperactivity to protect the brain against damage, e.g., by using drugs that act as positive allosteric modulators at GABA<sub>A</sub> receptors. Yet, cortical neurons express multiple, functionally distinct GABA<sub>A</sub> receptor subtypes. Currently there is a lack of knowledge which GABA<sub>A</sub> receptor subtypes would be a good pharmacological target to reduce extensive cortical activity. <b>Methods:</b> Spontaneous action potential activity was monitored by performing extracellular recordings from organotypic neocortical slice cultures of wild type and GABA<sub>A</sub>R-α1(H101R) mutant mice. Phases of high neuronal activity were characterized using peri-event time histograms. Drug effects on within-up state firing rates were quantified via Hedges' g. <b>Results:</b> We quantified the effects of zolpidem, a positive modulator of GABA<sub>A</sub> receptors harboring α1-subunits, and the experimental benzodiazepine SH-053-2'F-S-CH3, which preferably acts at α2/3/5- but spares α1-subunits. Both agents decreased spontaneous action potential activity but altered the firing patterns in different ways. Zolpidem reduced action potential firing during highly active network states. This action was abolished by flumazenil, suggesting that it was mediated by benzodiazepine-sensitive GABA<sub>A</sub> receptors. SH-053-2'F-S-CH3 also attenuated neuronal activity, but unlike zolpidem, failed to reduce high frequency firing. To confirm that zolpidem actions were indeed mediated via α1-dependent actions, it was evaluated in slices from wild type and α(H101R) knock-in mice. Inhibition of high frequency action potential firing was observed in slices from wild type but not mutant mice. <b>Conclusion:</b> Our results suggest that during episodes of scarce and high neuronal activity action potential firing of cortical neurons is controlled by different GABA<sub>A</sub> receptor subtypes. Exaggerated firing of cortical neurons is reduced by positive modulation of α1-, but not α2/3/5-subunit containing GABA<sub>A</sub> receptors.
The Impact of Age on Perioperative Complications after Extremity Reconstruction with the Free Gracilis Flap: A Retrospective Cohort Study Involving 153 Patients
2019-01-09

Background The need for plastic and reconstructive surgery on elderly patients has been on the rise due to an increase in life expectancy in the past decades. Therefore, a study was conducted on young and elderly patients following microsurgical extremity reconstructions with free gracilis muscle flaps with the primary aim to investigate the influence of age and the American Society of Anesthesiologists (ASA) score on the general outcome, as well as surgical and medical complications. Methods A retrospective analysis of 153 patients receiving free gracilis muscle flaps for extremity reconstructions between November 2009 and January 2018 was performed at two partner institutions specialized in microsurgical reconstructions. A logistic regression analysis was performed to correlate age and the ASA score with postoperative complication probability. Patients younger than 70 years were directly compared with elderly patients with respect to age, gender, ASA score, preexisting comorbidities, localization, and postoperative medical and surgical complications. Results Age turned out to be not significantly associated with major flap complications (p = 0.925) but with higher ASA scores (p = 0.016). However, an age-related significant increase in minor flap complications could be observed in the elderly (p = 0.008). A significant correlation between minor medical complications and age could be observed (p = 0.001) in contrast to ASA score (p = 0.912). Conclusion An increased minor flap, as well as minor and major medical complications, must be expected in extremity reconstructions with free gracilis flaps in elderly patients. Higher ASA scores correlate with a higher incidence of major flap complications. Septuagenarians are more prone to develop perioperative major medical complications than patients younger than 70 years. Age and general medical condition, coupled with the performance of each patient, should be thoroughly assessed individually to facilitate a tailored reconstructive approach using risk assessment tools and established scoring systems.
Anger in Wikipedia: Perceived intentionality and threat appraisal as mediators of anger about man‐made attacks
2019-01-09

Abstract The online encyclopedia Wikipedia has established strict guidelines for the objectivity of content. At the same time, Wikipedia includes articles on negative events, such as disasters or man‐made attacks. These events can elicit strong emotions, which in turn may spill over into Wikipedia articles. Previous research has shown that Wikipedia articles on man‐made attacks contain more anger‐related content than Wikipedia articles on disasters. Building on these findings, we aimed to investigate whether the threat that Wikipedia authors experience when they learn of an attack is relevant as a factor in explaining the anger effect. Threat is known to elicit active and engaged reactions, such as anger, which is why it is a likely explaining factor. Our research also aimed to replicate the findings from the linguistic analysis of the Wikipedia articles using controlled scenario‐based laboratory experiments. Three studies demonstrated that man‐made attacks (terrorist attack, shooting rampage) elicited more threat, more anger, and more expressions of anger‐related content in Wikipedia texts than nature‐made disasters (earthquake, flood) and man‐made disasters (train accident). Moreover, threat was relevant as a factor in explaining the effects on anger and anger‐related content in the Wikipedia texts. These mediations could be explained by the perceived intentionality of the event. This research highlights the findings that perceived intentionality and threat are relevant mediating factors for feelings and expressions of anger after man‐made attacks.
Beyond maps: Patterns of formation processes at the Middle Pleistocene open-air site of Marathousa 1, Megalopolis Basin, Greece
2019-01-09

Recent excavations at the Middle Pleistocene open-air site of Marathousa 1 have unearthed in one of the two investigated areas (Area A) a partial skeleton of a single individual of Palaeoloxodon antiquus and other faunal remains in spatial and stratigraphic association with lithic artefacts. In Area B, a much higher number of lithic artefacts was collected, spatially and stratigraphically associated also with faunal remains. The two areas are stratigraphically correlated, the main fossiliferous layers representing an en mass depositional process in a lake margin context. Evidence of butchering (cut-marks) has been identified on bones of the elephant skeleton, as well on elephant and other mammal bones from Area B. However, due to the secondary deposition of the main find-bearing units, it is of primary importance to evaluate the degree and reliability of the spatial association of the lithic artefacts with the faunal remains. Indeed, spatial association does not necessarily imply causation, since natural syn- and post-depositional processes may equally produce spatial association. Assessing the degree and extent of post-depositional reworking processes is crucial to fully comprehend the archaeological record, and therefore to reliably interpret past human behaviours. The present study uses a comprehensive set of spatial statistics in order to disentangle the depositional processes behind the distribution of the archaeological and palaeontological record at Marathousa 1. Preliminary results of our analyses suggest that a high-energy erosional process, attributed to a hyperconcentrated flow deposited at the margin of a swamp, reworked an autochthonous, exposed or slightly buried, scatter of lithic artefacts and faunal remains. Minor reworking and substantial spatial association of the lithic and faunal assemblages support the current interpretation of Marathousa 1 as a butchering site.
Draft Genome Sequence of Micromonospora sp. Strain MW-13, a Bacterial Strain with Antibacterial Properties and Plant Growth Promotion Potential Isolated from the Rhizosphere of Wheat in Iran
2019-01-09

Strain MW13 exhibited broad-spectrum antibacterial activity toward Gram-positive and Gram-negative pathogens. The 7.1-Mb draft genome gives insight into the complete secondary metabolite production capacity and reveals genes putatively responsible for its antibacterial activity, as well as genes which contribute to plant growth promotion.
Adapting Engineering Education to Industry 4.0 Vision
2019-01-10

Industry 4.0 is originally a future vision described in the high-tech strategy of the German government that is conceived upon information and communication technologies like Cyber-Physical Systems, Internet of Things, Physical Internet, and Internet of Services to achieve a high degree of flexibility in production (individualized mass production), higher productivity rates through real-time monitoring and diagnosis, and a lower wastage rate of material in production. An important part of the tasks in the preparation for Industry 4.0 is the adaption of the higher education to the requirements of this vision, in particular the engineering education. In this work, we introduce a road map consisting of three pillars describing the changes/enhancements to be conducted in the areas of curriculum development, lab concept, and student club activities. We also report our current application of this road map at the Turkish German University, Istanbul.
Simulating rewetting events in intermittent rivers and ephemeral streams: A global analysis of leached nutrients and organic matter
2019-01-10

Abstract Climate change and human pressures are changing the global distribution and the extent of intermittent rivers and ephemeral streams (IRES), which comprise half of the global river network area. IRES are characterized by periods of flow cessation, during which channel substrates accumulate and undergo physico‐chemical changes (preconditioning), and periods of flow resumption, when these substrates are rewetted and release pulses of dissolved nutrients and organic matter (OM). However, there are no estimates of the amounts and quality of leached substances, nor is there information on the underlying environmental constraints operating at the global scale. We experimentally simulated, under standard laboratory conditions, rewetting of leaves, riverbed sediments, and epilithic biofilms collected during the dry phase across 205 IRES from five major climate zones. We determined the amounts and qualitative characteristics of the leached nutrients and OM, and estimated their areal fluxes from riverbeds. In addition, we evaluated the variance in leachate characteristics in relation to selected environmental variables and substrate characteristics. We found that sediments, due to their large quantities within riverbeds, contribute most to the overall flux of dissolved substances during rewetting events (56%–98%), and that flux rates distinctly differ among climate zones. Dissolved organic carbon, phenolics, and nitrate contributed most to the areal fluxes. The largest amounts of leached substances were found in the continental climate zone, coinciding with the lowest potential bioavailability of the leached OM. The opposite pattern was found in the arid zone. Environmental variables expected to be modified under climate change (i.e. potential evapotranspiration, aridity, dry period duration, land use) were correlated with the amount of leached substances, with the strongest relationship found for sediments. These results show that the role of IRES should be accounted for in global biogeochemical cycles, especially because prevalence of IRES will increase due to increasing severity of drying events.
The blood transcriptome of childhood malaria
2019-01-10

Differences in gene expression profile reflect distinct immunopathological mechanisms of P. falciparum infection. They emerge as potential prognostic markers for early therapeutic measures and need to be validated further. FUND: This work was supported by a grant of the NGFN (Nationales Genomforschungsnetz 01GS0114) and by a CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil) PhD scholarship for A. B. W. Boldt. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Infectious Entry of Merkel Cell Polyomavirus
2019-01-10

MCPyV is the first polyomavirus directly implicated in the development of an aggressive human cancer, Merkel cell carcinoma (MCC). Although MCPyV is constantly shed from healthy skin, the MCC incidence increases among aging and immunocompromised individuals. To date, the events connecting initial MCPyV infection and subsequent transformation still remain elusive. MCPyV differs from other known polyomaviruses concerning its cell tropism, entry receptor requirements, and infection kinetics. In this study, we examined the cellular requirements for endocytic entry as well as the subcellular localization of incoming virus particles. A thorough understanding of the determinants of the infectious entry pathway and the specific biological niche will benefit prevention of virus-derived cancers such as MCC.
The 2014 TeV γ-Ray Flare of Mrk 501 Seen with H.E.S.S.: Temporal and Spectral Constraints on Lorentz Invariance Violation
2019-01-10

Abstract The blazar Mrk 501 ( z = 0.034) was observed at very-high-energy (VHE, E ≳ 100 GeV) gamma-ray wavelengths during a bright flare on the night of 2014 June 23–24 (MJD 56832) with the H.E.S.S. phase-II array of Cherenkov telescopes. Data taken that night by H.E.S.S. at large zenith angle reveal an exceptional number of gamma-ray photons at multi-TeV energies, with rapid flux variability and an energy coverage extending significantly up to 20 TeV. This data set is used to constrain Lorentz invariance violation (LIV) using two independent channels: a temporal approach considers the possibility of an energy dependence in the arrival time of gamma-rays, whereas a spectral approach considers the possibility of modifications to the interaction of VHE gamma-rays with extragalactic background light (EBL) photons. The non-detection of energy-dependent time delays and the non-observation of deviations between the measured spectrum and that of a supposed power-law intrinsic spectrum with standard EBL attenuation are used independently to derive strong constraints on the energy scale of LIV ( E QG ) in the subluminal scenario for linear and quadratic perturbations in the dispersion relation of photons. For the case of linear perturbations, the 95% confidence level limits obtained are E QG,1 &gt; 3.6 × 10 17 GeV using the temporal approach and E QG,1 &gt; 2.6 × 10 19 GeV using the spectral approach. For the case of quadratic perturbations, the limits obtained are E QG,2 &gt; 8.5 × 10 10 GeV using the temporal approach and E QG,2 &gt; 7.8 × 10 11 GeV using the spectral approach.
The Burkholderia Type VI Secretion System 5: Composition, Regulation and Role in Virulence
2019-01-10

The soil saprophyte and Tier I select agent <i>Burkholderia pseudomallei</i> can cause rapidly fatal infections in humans and animals. The capability of switching to an intracellular life cycle during infection appears to be a decisive trait of <i>B. pseudomallei</i> for causing disease. <i>B. pseudomallei</i> harbors multiple type VI secretion systems (T6SSs) orthologs of which are present in the surrogate organism <i>Burkholderia thailandensis</i>. Upon host cell entry and vacuolar escape into the cytoplasm, <i>B. pseudomallei</i> and <i>B. thailandensis</i> manipulate host cells by utilizing the T6SS-5 (also termed T6SS1) to form multinucleated giant cells for intercellular spread. Disruption of the T6SS-5 in <i>B. thailandensis</i> causes a drastic attenuation of virulence in wildtype but not in mice lacking the central innate immune adapter protein MyD88. This result suggests that the T6SS-5 is deployed by the bacteria to overcome innate immune responses. However, important questions in this field remain unsolved including the mechanism underlying T6SS-5 activity and its physiological role during infection. In this review, we summarize the current knowledge on the components and regulation of the T6SS-5 as well as its role in virulence in mammalian hosts.
Highly Active Sm2O3‐Ni Xerogel Catalysts for CO2 Methanation
2019-01-10

Abstract We report on a new synthesis route for pure Sm 2 O 3 and Sm 2 O 3 ‐Ni xerogels by modifying the well‐known epoxide addition method. The resulting xerogels are used to prove the suitability of samaria as a highly effective catalyst support and to determine the optimal Ni loading. Therefore, a set of five catalysts with Ni loadings between 4 wt % and 89 wt % Ni was prepared and fully characterized by X‐ray diffraction, N 2 physisorption, transmission electron microscopy and H 2 temperature‐programmed reduction. Catalytic measurements reveal that the catalyst with 39 wt % Ni shows the best catalytic performance, outperforming even highly active literature known systems. Stability runs indicate that the catalyst deactivates independently of the Ni loading as well as conversion level over 600 min due to, most likely, carbonate formation. This deactivation, however, is reversible by a simple regeneration step. As shown by simultaneous CO 2 /CO methanation measurements, the Ni−Sm 2 O 3 catalysts are also highly efficient for CO methanation. In this case, CO is preferentially converted to methane compared to CO 2 .
A Strategy to Optimize the Generation of Stable Chromobody Cell Lines for Visualization and Quantification of Endogenous Proteins in Living Cells
2019-01-10

Single-domain antibodies have emerged as highly versatile nanoprobes for advanced cellular imaging. For real-time visualization of endogenous antigens, fluorescently labelled nanobodies (chromobodies, CBs) are introduced as DNA-encoded expression constructs in living cells. Commonly, CB expression is driven from strong, constitutively active promoters. However, high expression levels are sometimes accompanied by misfolding and aggregation of those intracellular nanoprobes. Moreover, stable cell lines derived from random genomic insertion of CB-encoding transgenes bear the risk of disturbed cellular processes and inhomogeneous CB signal intensities due to gene positioning effects and epigenetic silencing. In this study we propose a strategy to generate optimized CB expressing cell lines. We demonstrate that expression as ubiquitin fusion increases the fraction of intracellularly functional CBs and identified the elongation factor 1α (EF1-α) promoter as highly suited for constitutive CB expression upon long-term cell line cultivation. Finally, we applied a CRISPR/Cas9-based gene editing approach for targeted insertion of CB expression constructs into the adeno-associated virus integration site 1 (AAVS1) safe harbour locus of human cells. Our results indicate that this combinatorial approach facilitates the generation of fully functional and stable CB cell lines for quantitative live-cell imaging of endogenous antigens.
Scaffold Effects on Halogen Bonding Strength
2019-01-10

Halogen bonds have become increasingly popular interactions in molecular design and drug discovery. One of the key features is the strong dependence of the size and magnitude of the halogen's σ-hole on the chemical environment of the ligand. The term σ-hole refers to a region of lower electronic density opposite to a covalent bond, e.g., the C-X bond. It is typically (but not always) associated with a positive electrostatic potential in close proximity to the extension of the covalent bond. Herein, we use a variety of 30 nitrogen-bearing heterocycles, halogenated systematically by chlorine, bromine, or iodine, yielding 468 different ligands that are used to exemplify scaffold effects on halogen bonding strength. As a template interaction partner, we have chosen N-methylacetamide representing the ubiquitously present protein backbone. Adduct formation energies were obtained at a MP2/TZVPP level of theory. We used the local maximum of the electrostatic potential on the molecular surface in close proximity to the σ-hole, V <sub>S,max</sub>, as a descriptor for the magnitude of the positive electrostatic potential characterizing the tuning of the σ-hole. Free optimization of the complexes gave reasonable correlations with V <sub>S,max</sub> but was found to be of limited use because considerable numbers of chlorinated and brominated ligands lost their halogen bond or showed significant secondary interactions. Thus, starting from a close to optimal geometry of the halogen bond, we used distance scans to obtain the best adduct formation energy for each complex. This approach provided superior results for all complexes exhibiting correlations with R<sup>2</sup> > 0.96 for each individual halogen. We evaluated the dependence of V <sub>S,max</sub> from the molecular surface onto which the positive electrostatic potential is projected, altering the isodensity values from 0.001 au to 0.050 au. Interestingly, the best overall fit using a third-order polynomial function (R<sup>2</sup> = 0.99, RMSE = 0.562 kJ/mol) with rather smooth transitions between all halogens was obtained for V <sub>S,max</sub> calculated from an isodensity surface at 0.014 au.
A Polygenic Risk Score of Lipolysis-Increasing Alleles Determines Visceral Fat Mass and Proinsulin Conversion
2019-01-10

We found evidence for a genetic basis of adipose tissue lipolysis resulting from common SNPs in CIDEA, AMP-activated protein kinase subunits, and cAMP signaling components. A genetic score of lipolysis-increasing alleles determined lower visceral fat mass and lower proinsulin conversion.
Recurrent ischaemic cerebrovascular events as presenting manifestations of myeloproliferative neoplasms
2019-01-10

Background and purpose Myeloproliferative neoplasms ( MPN s) – polycythemia vera, essential thrombocythemia and primary myelofibrosis – are associated with increased risk for ischaemic cerebrovascular events ( ICVE s). Due to their low prevalence, MPN s often remain undiagnosed as the cause of ICVE s. Methods Case records at the University of Tübingen between 2014 and 2017 were screened to identify patients with MPN ‐related ICVE s. Clinical features, brain imaging, laboratory findings, applied treatments and neurological outcomes were assessed. Results In all, 3318 patients with ICVE s were identified, and amongst them 17 patients with MPN ‐related ICVE s were included in a retrospective study. In 58% of these patients, ICVE s were the first manifestation of the underlying MPN ; 24% presented with transient ischaemic attack and 76% with ischaemic stroke. Potentially concurrent ICVE etiologies were noted in 70% of the patients. The majority (94%) of patients were positive for the JAK 2 V617F mutation, whilst in 29% recurrent ICVE s (range two to three) were noted prior to MPN diagnosis. Early MPN diagnosis and management was the only significant prognostic factor for ICVE recurrence ( P &lt; 0.001). Discussion Evidence is provided that, although rare, MPN s represent an underdiagnosed cause of recurrent ICVE s. High clinical awareness is warranted to identify an underlying MPN in patients presenting with sustained, abnormal blood count findings. Clinical algorithms for prompt MPN diagnosis and initiation of MPN treatment (e.g. cytoreductive therapy, phlebotomy) are required. As MPN management comprises a significant protective factor against ICVE recurrence, induction of MPN treatment should be regarded as an integral component of secondary stroke prevention in MPN ‐associated ICVE s.