bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lower ototoxicity and absence of hidden hearing loss point to gentamicin C1a and apramycin as promising antibiotics for clinical use
Authors: Ishikawa Masaaki , García-Mateo Nadia , Čusak Alen , López-Hernández Iris , Fernández-Martínez Marta , Müller Marcus , Rüttiger Lukas , Singer Wibke , Löwenheim Hubert , Kosec Gregor , Fujs Štefan , Martínez-Martínez Luis , Schimmang Thomas , Petković Hrvoje , Knipper Marlies , Durán-Alonso M. Beatriz 
Published: February 2019

AbstractSpread of antimicrobial resistance and shortage of novel antibiotics have led to an urgent need for new antibacterials. Although aminoglycoside antibiotics (AGs) are very potent anti-infectives, their use is largely restricted due to serious side-effects, mainly nephrotoxicity and ototoxicity. We evaluated the ototoxicity of various AGs selected from a larger set of AGs on the basis of their strong antibacterial activities against multidrug-resistant clinical isolates of the ESKAPE panel: gentamicin, gentamicin C1a, apramycin, paromomycin and neomycin. Following local round window application, dose-dependent effects of AGs on outer hair cell survival and compound action potentials showed gentamicin C1a and apramycin as the least toxic. Strikingly, although no changes were observed in compound action potential thresholds and outer hair cell survival following treatment with low concentrations of neomycin, gentamicin and paromomycin, the number of inner hair cell synaptic ribbons and the compound action potential amplitudes were reduced. This indication of hidden hearing loss was not observed with gentamicin C1a or apramycin at such concentrations. These findings identify the inner hair cells as the most vulnerable element to AG treatment, indicating that gentamicin C1a and apramycin are promising bases for the development of clinically useful antibiotics.
Morphological changes in starch grains after dehusking and grinding with stone tools
Authors: Ma Zhikun , Perry Linda , Li Quan , Yang Xiaoyan 
Published: February 2019

AbstractResearch on the manufacture, use, and use-wear of grinding stones (including slabs and mullers) can provide a wealth of information on ancient subsistence strategy and plant food utilization. Ancient residues extracted from stone tools frequently exhibit damage from processing methods, and modern experiments can replicate these morphological changes so that they can be better understood. Here, experiments have been undertaken to dehusk and grind grass grain using stone artifacts. To replicate ancient activities in northern China, we used modern stone tools to dehusk and grind twelve cultivars of foxtail millet (Setaria italica), two cultivars of broomcorn millet (Panicum miliaceum) and three varieties of green bristlegrass (Setaira viridis). The residues from both used and unused facets of the stone tools were then extracted, and the starch grains studied for morphological features and changes from the native states. The results show that (1) Dehusking did not significantly change the size and morphology of millet starch grains; (2) After grinding, the size of millet starch grains increases up to 1.2 times larger than native grains, and a quarter of the ground millet starch grains bore surface damage and also exhibited distortion of the extinction cross. This indicator will be of significance in improving the application of starch grains to research in the functional inference of grinding stone tools, but we are unable to yet distinguish dehusked forms from native.
Mechanism of E. coli Inactivation by Direct-in-liquid Electrical Discharge Plasma in Low Conductivity Solutions
Authors: Estifaee P. , Su X. , Yannam S. K. , Rogers S. , Thagard S. Mededovic 
Published: February 2019

AbstractThis work investigates and reveals the main mechanism(s) responsible for inactivation of E. coli by in-liquid pulsed electrical discharge plasma in low conductivity solutions. Experiments were designed and performed to explore the effects of plasma-emitted UV light, oxidative radicals, and electric field on E. coli inactivation curves, rate of DNA leakage and visual appearance of the treated microorganisms. Results showed that electric field had the main role in inactivation; scanning electron microscopy images revealed that both plasma and the isolated electric field result in extensive cell wall disruptions. While this damage in the case of plasma treatment was extensive and distributed randomly along the envelope, the electric field-induced damage resulted in disruption primarily at the poles of the bacterial rods. Subsequent experiments conducted with an oxidative radical scavenger suggested that plasma-generated radicals do not contribute directly to the inactivation but assist in cell wall deterioration and extension of the ruptures first generated by the electric field.
A critical evaluation of TRPA1-mediated locomotor behavior in zebrafish as a screening tool for novel anti-nociceptive drug discovery
Authors: Ko Mee Jung , Ganzen Logan C. , Coskun Emre , Mukadam Arbaaz A. , Leung Yuk Fai , van Rijn Richard M. 
Published: February 2019

AbstractCurrent medications inadequately treat the symptoms of chronic pain experienced by over 50 million people in the United States, and may come with substantial adverse effects signifying the need to find novel treatments. One novel therapeutic target is the Transient Receptor Potential A1 channel (TRPA1), an ion channel that mediates nociception through calcium influx of sensory neurons. Drug discovery still relies heavily on animal models, including zebrafish, a species in which TRPA1 activation produces hyperlocomotion. Here, we investigated if this hyperlocomotion follows zebrafish TRPA1 pharmacology and evaluated the strengths and limitations of using TRPA1-mediated hyperlocomotion as potential preclinical screening tool for drug discovery. To support face validity of the model, we pharmacologically characterized mouse and zebrafish TRPA1 in transfected HEK293 cells using calcium assays as well as in vivo. TRPA1 agonists and antagonists respectively activated or blocked TRPA1 activity in HEK293 cells, mice, and zebrafish in a dose-dependent manner. However, our results revealed complexities including partial agonist activity of TRPA1 antagonists, bidirectional locomotor activity, receptor desensitization, and off-target effects. We propose that TRPA1-mediated hyperlocomotion in zebrafish larvae has the potential to be used as in vivo screening tool for novel anti-nociceptive drugs but requires careful evaluation of the TRPA1 pharmacology.
Sex differences in the 1H NMR metabolic profile of serum in cardiovascular risk patients
Authors: Barba Ignasi , Andrés Mireia , Picón Irene , Aguade-Bruix Santiago , Garcia-Dorado David 
Published: February 2019

AbstractPersonalized diagnosis and risk stratification of cardiovascular diseases would allow optimizing therapeutic strategies and lifestyle changes. Metabolomics is a promising technique for personalized diagnosis and prognosis; however, various physiological parameters, including sex, influence the metabolic profile thus hampering its translation to the clinic. Knowledge of the variation in the metabolic profile associated with sex would facilitate metabolomic translation to the clinic. The objective of the present work was to investigate the possible differences in the metabolic 1H NMR profile associated to sex beyond lipoproteins. 1H NMR spectra from whole serum and methanol deproteinized samples from 39 patients (22 males, 17 females) between 55–70 years old with suspected coronary artery disease that underwent a stress test that was considered negative where included. Deproteinized serum could be used to differentiate sex based on higher levels of lactate and glucose in women. Lipoprotein region was the most variable area of the spectra between individuals, but spectra of whole serum were able to differentiate sex based on lipoproteins. There are sex-related differences in the 1H NMR metabolic profile of individuals with suspected cardiovascular disease beyond lipoproteins. These findings may help the translation of metabolomics to the clinic.
Tailing miniSOG: structural bases of the complex photophysics of a flavin-binding singlet oxygen photosensitizing protein
Authors: Torra Joaquim , Lafaye Céline , Signor Luca , Aumonier Sylvain , Flors Cristina , Shu Xiaokun , Nonell Santi , Gotthard Guillaume , Royant Antoine 
Published: February 2019

AbstractminiSOG is the first flavin-binding protein that has been developed with the specific aim of serving as a genetically-encodable light-induced source of singlet oxygen (1O2). We have determined its 1.17 Å resolution structure, which has allowed us to investigate its mechanism of photosensitization using an integrated approach combining spectroscopic and structural methods. Our results provide a structural framework to explain the ability of miniSOG to produce 1O2 as a competition between oxygen- and protein quenching of its triplet state. In addition, a third excited-state decay pathway has been identified that is pivotal for the performance of miniSOG as 1O2 photosensitizer, namely the photo-induced transformation of flavin mononucleotide (FMN) into lumichrome, which increases the accessibility of oxygen to the flavin FMN chromophore and makes protein quenching less favourable. The combination of the two effects explains the increase in the 1O2 quantum yield by one order of magnitude upon exposure to blue light. Besides, we have identified several surface electron-rich residues that are progressively photo-oxidized, further contributing to facilitate the production of 1O2. Our results help reconcile the apparent poor level of 1O2 generation by miniSOG and its excellent performance in correlative light and electron microscopy experiments.
Prediction of response to anti-cancer drugs becomes robust via network integration of molecular data
Authors: Franco Marcela , Jeggari Ashwini , Peuget Sylvain , Böttger Franziska , Selivanova Galina , Alexeyenko Andrey 
Published: February 2019

AbstractDespite the widening range of high-throughput platforms and exponential growth of generated data volume, the validation of biomarkers discovered from large-scale data remains a challenging field. In order to tackle cancer heterogeneity and comply with the data dimensionality, a number of network and pathway approaches were invented but rarely systematically applied to this task. We propose a new method, called NEAmarker, for finding sensitive and robust biomarkers at the pathway level. scores from network enrichment analysis transform the original space of altered genes into a lower-dimensional space of pathways. These dimensions are then correlated with phenotype variables. The method was first tested usingin vitrodata from three anti-cancer drug screens and then on clinical data of The Cancer Genome Atlas. It proved superior to the single-gene and alternative enrichment analyses in terms of (1) universal applicability to different data types with a possibility of cross-platform integration, (2) consistency of the discovered correlates between independent drug screens, and (3) ability to explain differential survival of treated patients. Our new screen of anti-cancer compounds validated the performance of multivariate models of drug sensitivity. The previously proposed methods of enrichment analysis could achieve comparable levels of performance in certain tests. However, only our method could discover predictors of bothin vitroresponse and patient survival given administration of the same drug.
A novel benzamine lead compound of histone deacetylase inhibitor ZINC24469384 can suppresses HepG2 cells proliferation by upregulating NR1H4
Authors: Song Qiuhang , Li Mingyue , Fan Cong , Liu Yucui , Zheng Lihua , Bao Yongli , Sun Luguo , Yu Chunlei , Song Zhenbo , Sun Ying , Wang Guannan , Huang Yanxin , Li Yuxin 
Published: February 2019

AbstractHistone deacetylases (HDACs) can enzymatically transferred acetyl functional group from protein or lysine residues of histone, so they can regulate the expression of lots of genes. Now HDACs are used as drug targets and many HDAC inhibitors (HDACis) were approved for cancer therapy or in clinical trials. However, the physiological mechanisms and regulatory processes of HDACi anti-cancer effects are largely unexplored and uncompleted. Here we use the virtual screening workflow obtained 25 hit compounds and ZINC24469384 can significantly inhibit HDAC activity while arrest cell cycle at G1/S phase and significantly induced HepG2 cell apoptosis, time-course RNA-seq demonstrate that HepG2 cells transcriptionally respond to ZINC24469384. Pathway analysis of DEGs and DASGs reveal that NR1H4 may play an important role in ZINC24469384-induced anti-proliferation effect and is dramatically alleviated by down-regulating the SOCS2 expression and promoting STAT3 phosphorylation in knockdown NR1H4 HepG2 cells. Analysis based on TCGA database indicated that NR1H4 and SOCS2 were downregulated in liver cancer, this suggest NR1H4 and SOCS2 may play an important role in tumorigenesis. These results indicated that ZINC24469384 is a novel benzamine lead compound of HDACi and provides a novel mechanism for HDACi to inhibit cancer.
Incentive salience attribution, “sensation-seeking” and “novelty-seeking” are independent traits in a large sample of male and female heterogeneous stock rats
Authors: Hughson Alesa R. , Horvath Aidan P. , Holl Katie , Palmer Abraham A. , Solberg Woods Leah C. , Robinson Terry E. , Flagel Shelly B. 
Published: February 2019

AbstractThere are a number of traits that are thought to increase susceptibility to addiction, and some of these are modeled in preclinical studies. For example, “sensation-seeking” is predictive of the initial propensity to take drugs; whereas “novelty-seeking” predicts compulsive drug-seeking behavior. In addition, the propensity to attribute incentive salience to reward cues can predict the propensity to approach drug cues, and reinstatement or relapse, even after relatively brief periods of drug exposure. The question addressed here is the extent to which these three ‘vulnerability factors’ are related; that is, predictive of one another. Some relationships have been reported in small samples, but here a large sample of 1,598 outbred male and female heterogeneous stock rats were screened for Pavlovian conditioned approach behavior (to obtain an index of incentive salience attribution; ‘sign-tracking’), and subsequently tested for sensation-seeking and novelty-seeking. Despite the large N there were no significant correlations between these traits, in either males or females. There were, however, novel relationships between multiple measures of incentive salience attribution and, based on these findings, we generated a new metric that captures “incentive value”. Furthermore, there were sex differences on measures of incentive salience attribution and sensation-seeking behavior that were not previously apparent.
Convallatoxin enhance the ligand-induced mu-opioid receptor endocytosis and attenuate morphine antinociceptive tolerance in mice
Authors: Chao Po-Kuan , Chang Hsiao-Fu , Ou Li-Chin , Chuang Jian-Ying , Lee Pin-Tse , Chang Wan-Ting , Chen Shu-Chun , Ueng Shau-Hua , Hsu John Tsu-An , Tao Pao-Luh , Law Ping-Yee , Loh Horace H. , Yeh Shiu-Hwa 
Published: February 2019

AbstractMorphine is a unique opioid analgesic that activates the mu-opioid receptor (MOR) without efficiently promoting its endocytosis that may underlie side effects. Our objective was to discover a novel enhancer of ligand-induced MOR endocytosis and determine its effects on analgesia, tolerance and dependence. We used high-throughput screening to identify convallatoxin as an enhancer of ligand-induced MOR endocytosis with high potency and efficacy. Treatment of cells with convallatoxin enhanced morphine-induced MOR endocytosis through an adaptor protein 2 (AP2)/clathrin-dependent mechanism, attenuated morphine-induced phosphorylation of MOR, and diminished desensitization of membrane hyperpolarization. Furthermore, co-treatment with chronic convallatoxin reduced morphine tolerance in animal models of acute thermal pain and chronic inflammatory pain. Acute convallatoxin administration reversed morphine tolerance and dependence in morphine-tolerant mice. These findings suggest convallatoxin are potentially therapeutic for morphine side effects and open a new avenue to study MOR trafficking.
Which Questions Do Children With Cochlear Implants Understand? An Eye-Tracking Study
Authors: Schouwenaars Atty , Finke Mareike , Hendriks Petra , Ruigendijk Esther 
Published: February 2019

PurposeThe purpose of this study was to investigate the processing of morphosyntactic cues (case and verb agreement) by children with cochlear implants (CIs) in Germanwhich-questions, where interpretation depends on these morphosyntactic cues. The aim was to examine whether children with CIs who perceive the different cues also make use of them in speech comprehension and processing in the same way as children with normal hearing (NH).MethodThirty-three children with CIs (age 7;01–12;04 years;months,M= 9;07, bilaterally implanted before age 3;3) and 36 children with NH (age 7;05–10;09 years,M= 9;01) received a picture selection task with eye tracking to test their comprehension of subject, object, and passivewhich-questions. Two screening tasks tested their auditory discrimination of case morphology and their perception and comprehension of subject–verb agreement.ResultsChildren with CIs who performed well on the screening tests still showed more difficulty on the comprehension of object questions than children with NH, whereas they comprehended subject questions and passive questions equally well as children with NH. There was large interindividual variability within the CI group. The gaze patterns of children with NH showed reanalysis effects for object questions disambiguated later in the sentence by verb agreement, but not for object questions disambiguated by case at the first noun phrase. The gaze patterns of children with CIs showed reanalysis effects even for object questions disambiguated at the first noun phrase.ConclusionsEven when children with CIs perceive case and subject–verb agreement, their ability to use these cues for offline comprehension and online processing still lags behind normal development, which is reflected in lower performance rates and longer processing times. Individual variability within the CI group can partly be explained by working memory and hearing age.Supplemental Materialhttps://doi.org/10.23641/asha.7728731
The ALMA Lupus protoplanetary disk survey: evidence for compact gas disks and molecular rings from CN
Authors: van Terwisga S. E. , van Dishoeck E. F. , Cazzoletti P. , Facchini S. , Trapman L. , Williams J. P. , Manara C. F. , Miotello A. , van der Marel N. , Ansdell M. , Hogerheijde M. R. , Tazzari M. , Testi L. 
Published: February 2019

Context. The cyanide radical CN is abundant in protoplanetary disks, with line fluxes often comparable to those of 13CO. It is known to be sensitive to UV irradiation of the upper disk atmosphere, with models predicting ring-shaped emission.
Aims. We seek to characterize the CN emission from 94 Class-II disks in the Lupus star-forming region, compare it to observations in other regions, and interpret our observations with a grid of models. The CN emission morphology is discussed for two primordial disks, Sz 71 and Sz 98, and is modeled in more detail.
Methods. ALMA observed CN N = 3−2 in Lupus disks down to sensitivities better than previous surveys. Models constructed with the physico-chemical code DALI are used to study the integrated fluxes of the disks and resolved emission of CN in disks without (dust) substructures.
Results. CN N = 3−2 is bright, and detected in 38% of sources, but its disk-integrated flux is not strongly correlated to either 13CO or continuum flux. Compared to pre-ALMA single-dish surveys, no significant difference in the CN flux distributions in Lupus and Taurus–Auriga is found, although ρ Ophiuchus disks may be fainter on average. We find ring-shaped CN emission with peak radii of ~50 AU in two resolved disks.
Conclusions. A large fraction of sources are faint in CN; only exponential gas surface density cutoffs at Rc ≤ 15 AU can reconcile observations with models. This is the first observational evidence of such a compact gas disk population in Lupus. Absolute intensities and the emission morphology of CN are reproduced by DALI models without the need for any continuum substructure; they are unrelated to the CO snowline location. The observations presented here, together with the modeling of these rings, provide a new probe of the structure and conditions in disks, and particularly their incident UV radiation field, if disk size is determined from the data.
MRT-Bildgebung der Orbita: Indikationsspektrum und diagnostische Möglichkeiten
Authors: Posch Helena , Erb-Eigner Katharina 
Published: February 2019

ZusammenfassungDie Magnetresonanztomografie gilt heute als bevorzugte Bilddiagnostik für Auge und Orbita. In diesem Beitrag werden die Charakteristika relevanter Pathologien illustriert (die Bandbreite reicht fallbasiert von vaskulären, entzündlichen und neoplastischen Ätiologien bis zum Trauma-Setting). Dabei wird das Potenzial innovativer Sequenzen gezeigt, die neben der reinen Morphologie funktionelle Gewebemerkmale abbilden und so die Beurteilung erleichtern.
Gesundheit von Asylsuchenden in Bielefeld: eine Querschnitt-Pilotstudie
Authors: Heuvel Rick van den , Stammnitz Anke 
Published: February 2019

ZUSAMMENFASSUNGSeit 2015 sind viele Flüchtlinge nach Deutschland gekommen, dennoch fehlen adäquate Gesundheitsdaten dieser heterogenen Gruppe. Ziel dieser Querschnitt- Pilotstudie ist es, relevante demografische und gesundheitliche Daten der Asylsuchenden der Erstaufnahmeeinrichtung (EAE) in Bielefeld zu identifizieren. Diese Studie basiert auf der Analyse von Managementdaten der Einrichtung und der Auswertung von 99,6 % der erstellten Gesundheitskarten von 2671 Bewohnern der EAE Bielefeld. Die Studie zeigt, dass die meisten Asylsuchenden jung und ohne nennenswerte gesundheitliche Probleme waren. Dennoch präsentierte sich 3 % der Gruppe mit komplexen Gesundheitsthemen. Weiterhin gab es bemerkenswerte Unterschiede in Gesundheits- und Krankheitsprävalenzen zwischen Asylsuchenden aus unterschiedlichen Herkunftsländern. Weitere Studien mit Beteiligung von mehreren Asylzentren in Deutschland sind zur Feststellung von validen Gesundheitsdaten der Asylsuchenden in diesem Land notwendig.
Eindellende Operationstechniken
Authors: Bopp Silvia 
Published: February 2019

ZusammenfassungEin hoher Anteil der primär lochbedingten Netzhautablösungen kann durch eindellende chirurgische Verfahren behandelt werden. Dieser Artikel stellt diese Operationsmethoden vor, die – bei prinzipiell gleichem Konzept – erheblich variieren. Die Erfolgsraten betragen 54 – 97%. Re-Operationen werden in der Regel als Vitrektomie durchgeführt, diese werden in einem folgenden Artikel beschrieben.