bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of adverse events associated with different spacers used with non-extrafine beclometasone dipropionate for asthma
Authors: Ming Simon Wan Yau , Haughney John , Ryan Dermot , Patel Shishir , Ochel Matthias , d’Alcontres Martina Stagno , Thornhill Susannah , Kocks Janwillem W. H. , Price David 
Published: February 2019

AbstractCo-prescription of Aerochamber® spacer with non-extrafine beclometasone diproprionate (non-EF BDP) is common but unlicensed. We report a comparison of inhaled corticosteroid (ICS)-related adverse events between patients co-prescribed Aerochamber compared to the licensed Volumatic® spacer. We utilised two historical cohorts: questionnaire-based and electronic medical record (EMR)-based, to assess patient-reported and EMR-recorded adverse events in patients with asthma prescribed non-EF BDP. Marginal effect estimate (MEE) was calculated to determine non-inferiority of Aerochamber compared to Volumatic in terms of patient-reported oral thrush and hoarseness with margin of 0.13. Other patient-reported adverse events (sore throat, bruising, weight gain, and coughing), and EMR-recorded adverse events were also assessed. Rate of patient-reported oral adverse events were non-inferior in 385 patients prescribed Aerochamber compared to 155 patients prescribed Volumatic (27.7 vs 29.9%; MEE, −0.043; 95% CI, −0.133 to 0.047). Total patient-reported adverse events did not differ significantly between Aerochamber and Volumatic (53.3 vs 49.7% with ≥1 adverse event). The EMR-based study of 1471 matched pairs of subjects did not show significantly different number of EMR-recorded adverse events between Aerochamber and Volumatic (12.5 vs 12.8% with ≥1 adverse events). Co-prescribing Aerochamber with non-EF BDP does not increase the risk for patient-reported and EMR-recorded ICS-related adverse events compared to co-prescribing Volumatic.
Turning the corner on therapeutic cancer vaccines
Authors: Hollingsworth Robert E. , Jansen Kathrin 
Published: February 2019

AbstractRecent advances in several areas are rekindling interest and enabling progress in the development of therapeutic cancer vaccines. These advances have been made in target selection, vaccine technology, and methods for reversing the immunosuppressive mechanisms exploited by cancers. Studies testing different tumor antigens have revealed target properties that yield high tumor versus normal cell specificity and adequate immunogenicity to affect clinical efficacy. A few tumor-associated antigens, normal host proteins that are abnormally expressed in cancer cells, have been demonstrated to serve as good targets for immunotherapies, although many do not possess the needed specificity or immunogenicity. Neoantigens, which arise from mutated proteins in cancer cells, are truly cancer-specific and can be highly immunogenic, though the vast majority are unique to each patient’s cancer and thus require development of personalized therapies. Lessons from previous cancer vaccine expeditions are teaching us the type and magnitude of immune responses needed, as well as vaccine technologies that can achieve these responses. For example, we are learning which vaccine approaches elicit the potent, balanced, and durable CD4 plus CD8 T cell expansion necessary for clinical efficacy. Exploration of interactions between the immune system and cancer has elucidated the adaptations that enable cancer cells to suppress and evade immune attack. This has led to breakthroughs in the development of new drugs, and, subsequently, to opportunities to combine these with cancer vaccines and dramatically increase patient responses. Here we review this recent progress, highlighting key steps that are bringing the promise of therapeutic cancer vaccines within reach.
The molecular characterization of fixed inversions breakpoints unveils the ancestral character of the Drosophila guanche chromosomal arrangements
Authors: Orengo Dorcas J. , Puerma Eva , Aguadé Montserrat 
Published: February 2019

AbstractCytological studies revealed that the number of chromosomes and their organization varies across species. The increasing availability of whole genome sequences of multiple species across specific phylogenies has confirmed and greatly extended these cytological observations. In the Drosophila genus, the ancestral karyotype consists of five rod-like acrocentric chromosomes (Muller elements A to E) and one dot-like chromosome (element F), each exhibiting a generally conserved gene content. Chromosomal fusions and paracentric inversions are thus the major contributors, respectively, to chromosome number variation among species and to gene order variation within chromosomal element. The subobscura cluster of Drosophila consists in three species that retain the genus ancestral karyotype and differ by a reduced number of fixed inversions. Here, we have used cytological information and the D. guanche genome sequence to identify and molecularly characterize the breakpoints of inversions that became fixed since the D. guanche-D. subobscura split. Our results have led us to propose a modified version of the D. guanche cytological map of its X chromosome, and to establish that (i) most inversions became fixed in the D. subobscura lineage and (ii) the order in which the four X chromosome overlapping inversions occurred and became fixed.
Factorial design-assisted supercritical carbon-dioxide extraction of cytotoxic active principles from Carica papaya leaf juice
Authors: Khaw Kooi-Yeong , Parat Marie-Odile , Shaw Paul Nicholas , Nguyen Thao T. T. , Pandey Saurabh , Thurecht Kristofer J. , Falconer James Robert 
Published: February 2019

AbstractThe aims of this study are to investigate the selective cytotoxic activity of supercritical carbon dioxide (scCO2)-extracted freeze-dried leaf juice (FDLJ) of Carica papaya on squamous cell carcinoma (SCC25) cells, and to delineate the best small scale extraction parameters allowing maximal extract activity. Using scCO2 as a solvent, six operating parameters were studied and the supercritical fluid extraction (SFE) process investigated using a factorial design 26-2. The processing values promoting cytotoxic activity towards SCC-25 are: high pressure (250 bar), low temperature (35 °C), extended processing time (180 minutes), as well as a large amount of starting material (5 g). The factorial experimental design successfully identified the key parameters controlling the SFE of molecules cytotoxic to SCC cells from C. papaya juice. This study also validated the extraction method and showed that the SFE yield was reproducible. The chromatographic and mass spectrometric profiles of the scCO2 extract acquired with high-resolution quadrupole time-of-flight mass spectrometry (LC-QToF-MS) were used to tentatively identify the bioactive compounds using comparative analysis. The principal compounds were likely to be mainly vitamins and phytosterols, some of which are documented to be cytotoxic to cancer cells.
Role of nutrient concentrations and water movement on diatom’s productivity in culture
Authors: Orefice Ida , Musella Margherita , Smerilli Arianna , Sansone Clementina , Chandrasekaran Raghu , Corato Federico , Brunet Christophe 
Published: February 2019

AbstractMicroalgal growth maximization is becoming a duty for enhancing the biotechnological fate of these photosynthetic microorganisms. This study, based on an extensive set of data, aims to revisit diatom’s cultivation in laboratory with the objective to increase growth rate and biomass production. We investigated the growth ability and resource requirements of the coastal diatom Skeletonema marinoi Sarno & Zingone grown in laboratory in the conventional f/2 medium with aeration and in two modified conditions: (i) the same medium with water movement inside and (ii) an enriched medium with the same water movement. Results revealed that, by doubling the concentration of phosphate, silicate, microelements and vitamins, growth rate was successfully enhanced, preventing phosphate or silicate limitation in the f/2 culture medium. Yet, irrespective of the media (f/2 or enriched one), water movement induced an increase of growth efficiency compared to aeration, affecting nutrients’ requirement and consumption by diatoms. This study is an important step for enhancing diatom biomass production, reducing its cost, as required in the blue biotechnology context.
Flunarizine related movement disorders: a nationwide population-based study
Authors: Jhang Kai-Ming , Huang Jing-Yang , Nfor Oswald Ndi , Tung Yu-Chun , Ku Wen-Yuan , Jan Cheng-Feng , Liaw Yung-Po 
Published: February 2019

AbstractFlunarizine (fz) causes side effects such as movement disorders (MDs). We investigated risk factors associated with fz-related MDs. Participants were recruited from the longitudinal health insurance databases and included patients who took fz for more than 1 month. Patients with one of the underlying diseases, or with concomitant drug use (antipsychotics, metoclopramide or reserpine), and those diagnosed with MDs before fz use were excluded. Fz-related MD was defined as a new diagnosis of parkinsonism or hyperkinetic syndrome including dyskinesia or secondary dystonia during fz use or within 3 months after drug discontinuation. After exposure, 288 individuals had fz-related MDs (parkinsonism, n = 240; hyperkinesia, n = 48). Risk factors associated with these disorders were higher-dose exposure (cumulative defined daily dose [cDDD] ≥87.75, odds ratio [OR]: 3.80; 95% CI: 2.61–5.52), older age (OR: 1.07; 95% CI: 1.06–1.09), history of essential tremor (OR: 6.39; 95% CI: 2.29–17.78) and cardiovascular disease (CVD) (OR: 1.47; 95% CI: 1.14–1.9). The optimal value of cDDD to predict MDs was 58.5 (sensitivity: 0.67, specificity: 0.60), indicating an overall exposure of 585 mg. Higher exposure dose and duration, older age, history of essential tremor, and CVD were associated with fz-associated MDs. Clinicians ought to watch for extrapyramidal side effects when prescribing fz.
The future of extreme climate in Iran
Authors: Vaghefi Saeid Ashraf , Keykhai Malihe , Jahanbakhshi Farshid , Sheikholeslami Jaleh , Ahmadi Azadeh , Yang Hong , Abbaspour Karim C. 
Published: February 2019

AbstractIran is experiencing unprecedented climate-related problems such as drying of lakes and rivers, dust storms, record-breaking temperatures, droughts, and floods. Here, we use the ensemble of five high-resolution climate models to project maximum and minimum temperatures and rainfall distribution, calculate occurrences of extreme temperatures (temperatures above and below the historical 95th and 5th percentiles, respectively), analyze compound of precipitation and temperature extremes, and determine flooding frequencies across the country. We found that compared to the period of 1980–2004, in the period of 2025–2049, Iran is likely to experience more extended periods of extreme maximum temperatures in the southern part of the country, more extended periods of dry (for ≥120 days: precipitation <2 mm, Tmax ≥30 °C) as well as wet (for ≤3 days: total precipitation ≥110 mm) conditions, and higher frequency of floods. Overall, the combination of these results projects a climate of extended dry periods interrupted by intermittent heavy rainfalls, which is a recipe for increasing the chances of floods. Without thoughtful adaptability measures, some parts of the country may face limited habitability in the future.
Introduction of ‘Generalized Genomic Signatures’ for the quantification of neighbour preferences leads to taxonomy- and functionality-based distinction among sequences
Authors: Apostolou-Karampelis Konstantinos , Polychronopoulos Dimitris , Almirantis Yannis 
Published: February 2019

AbstractAnalysis of DNA composition at several length scales constitutes the bulk of many early studies aimed at unravelling the complexity of the organization and functionality of genomes. Dinucleotide relative abundances are considered an idiosyncratic feature of genomes, regarded as a ‘genomic signature’. Motivated by this finding, we introduce the ‘Generalized Genomic Signatures’ (GGSs), composed of over- and under-abundances of all oligonucleotides of a given length, thus filtering out compositional trends and neighbour preferences at any shorter range. Previous works on alignment-free genomic comparisons mostly rely on k-mer frequencies and not on distance-dependent neighbour preferences. Therein, nucleotide composition and proximity preferences are combined, while in the present work they are strictly separated, focusing uniquely on neighbour relationships. GGSs retain the potential or even outperform genomic signatures defined at the dinucleotide level in distinguishing between taxonomic subdivisions of bacteria, and can be more effectively implemented in microbial phylogenetic reconstruction. Moreover, we compare DNA sequences from the human genome corresponding to protein coding segments, conserved non-coding elements and non-functional DNA stretches. These classes of sequences have distinctive GGSs according to their genomic role and degree of conservation. Overall, GGSs constitute a trait characteristic of the evolutionary origin and functionality of different genomic segments.
Re-evaluation of transcription factor function in tomato fruit development and ripening with CRISPR/Cas9-mutagenesis
Authors: Wang Rufang , Tavano Eveline Carla da Rocha , Lammers Michiel , Martinelli Adriana Pinheiro , Angenent Gerco C. , de Maagd Ruud A. 
Published: February 2019

AbstractTomato (Solanum lycopersicum) is a model for climacteric fleshy fruit ripening studies. Tomato ripening is regulated by multiple transcription factors together with the plant hormone ethylene and their downstream effector genes. Transcription Factors APETALA2a (AP2a), NON-RIPENING (NOR) and FRUITFULL (FUL1/TDR4 and FUL2/MBP7) were reported as master regulators controlling tomato fruit ripening. Their proposed functions were derived from studies of the phenotype of spontaneous mutants or RNAi knock-down lines rather than, as it appears now, actual null mutants. To study TF function in tomato fruit ripening in more detail, we used CRISPR/Cas9-mediated mutagenesis to knock out the encoding genes, and phenotypes of these mutants are reported for the first time. While the earlier ripening, orange-ripe phenotype of ap2a mutants was confirmed, the nor null mutant exhibited a much milder phenotype than the spontaneous nor mutant. Additional analyses revealed that the severe phenotype in the spontaneous mutant is caused by a dominant-negative allele. Our approach also provides new insight into the independent and overlapping functions of FUL1 and FUL2. Single and combined null alleles of FUL1 and FUL2 illustrate that these two genes have partially redundant functions in fruit ripening, but also unveil an additional role for FUL2 in early fruit development.
Thermodynamic evidence of magnetic-field-induced complete valley polarization in bismuth
Authors: Iwasa Ayumu , Kondo Akihiro , Kawachi Shiro , Akiba Kazuto , Nakanishi Yoshiki , Yoshizawa Masahito , Tokunaga Masashi , Kindo Koichi 
Published: February 2019

AbstractWe investigated the fundamental physical properties in the ultra-quantum limit state of bismuth through measurements of magnetoresistance, magnetization, magnetostriction, and ultrasound attenuation in magnetic fields up to 60T. For magnetic fields applied along the bisectrix direction of a single crystal, a drastic sign reversal in magnetostriction was observed at approximately 39T, which could be ascribed to the complete valley polarization in the electron Fermi pockets. The application of magnetic fields along the binary direction presented an anomalous feature at approximately 50T only in the magnetoresistance. The emergence of a field-induced splitting of a valley was proposed as a possible origin of this anomaly.
Probing the Inhibition of Microtubule Affinity Regulating Kinase 4 by N-Substituted Acridones
Authors: Voura Maria , Khan Parvez , Thysiadis Savvas , Katsamakas Sotiris , Queen Aarfa , Hasan Gulam Mustafa , Ali Sher , Sarli Vasiliki , Hassan Md. Imtaiyaz 
Published: February 2019

AbstractMicrotubule affinity regulating kinase 4 (MARK4) becomes a unique anti-cancer drug target as its overexpression is responsible for different types of cancers. In quest of novel, effective MARK4 inhibitors, some acridone derivatives were synthesized, characterized and evaluated for inhibitory activity against human MARK4. Among all the synthesized compounds, three (7b, 7dand7f) were found to have better binding affinity and enzyme inhibition activity in µM range as shown by fluorescence binding, ITC and kinase assays. Here we used functional assays of selected potential lead molecules with commercially available panel of 26 kinases of same family. A distinctive kinase selectivity profile was observed for each compound. The selective compounds were identified with submicromolar cellular activity against MARK4. Furthermore,in vitroantitumor evaluation against cancerous cells (MCF-7 and HepG2) revealed that compounds7b, 7dand7finhibit cell proliferation and predominantly induce apoptosis in MCF-7 cells, with IC50values of 5.2 ± 1.2 μM, 6.3 ± 1.2 μM, and 5.8 ± 1.4 μM respectively. In addition, these compounds significantly upsurge the oxidative stress in cancerous cells. Our observations support our approach for the synthesis of effective inhibitors against MARK4 that can be taken forward for the development of novel anticancer molecules targeting MARK4.
Evolution of Pairing Orders between Pseudogap and Superconducting Phases of Cuprate Superconductors
Authors: Tu Wei-Lin , Lee Ting-Kuo 
Published: February 2019

AbstractOne of the most puzzling problems of high temperature cuprate superconductor is the pseudogap phase (PG) at temperatures above the superconducting transition temperature in the underdoped regime. The PG phase is found by the angle-resolved photoemission spectra (ARPES) to have a gap at some regions in momentum space and a fraction of Fermi surface remained, known as Fermi arcs. The arc turns into a d-wave SC gap with a node below the SC transition temperature. Here, by studying a strongly correlated model at low temperatures, we obtained a phase characterized by two kinds of pairing order parameters with the total momentum of the Cooper pair to be zero and finite. The finite momentum pairing is accompanied with a spatial modulation of pairing order, i.e. a pair density wave (PDW). These PDW phases are intertwined with modulations of charge density and intra-unit cell form factors. The coexistence of the two different pairing orders provides the unique two-gaps like spectra observed by ARPES for superconducting cuprates. As temperature raises, the zero-momentum pairing order vanishes while the finite momentum pairing orders are kept, thus Fermi arcs are realized. The calculated quasiparticle spectra have the similar doping and temperature dependence as reported by ARPES and scanning tunneling spectroscopy (STS). The consequence of breaking symmetry between x and y due to the unidirectional PDW and the possibility to probe such a PDW state in the PG phase is discussed.
Ionic current correlations are ubiquitous across phyla
Authors: Tran Trinh , Unal Cagri T. , Severin Daniel , Zaborszky Laszlo , Rotstein Horacio G. , Kirkwood Alfredo , Golowasch Jorge 
Published: February 2019

AbstractIonic currents, whether measured as conductance amplitude or as ion channel transcript numbers, can vary many-fold within a population of identified neurons. In invertebrate neuronal types multiple currents can be seen to vary while at the same time their magnitudes are correlated. These conductance amplitude correlations are thought to reflect a tight homeostasis of cellular excitability that enhances the robustness and stability of neuronal activity over long stretches of time. Although such ionic conductance correlations are well documented in invertebrates, they have not been reported in vertebrates. Here we demonstrate with two examples, identified mouse hippocampal granule cells (GCs) and cholinergic basal forebrain neurons, that the correlation of ionic conductance amplitudes between different ionic currents also exists in vertebrates, and we argue that it is a ubiquitous phenomenon expressed by many species across phyla. We further demonstrate that in dentate gyrus GCs these conductance correlations are likely regulated in a circadian manner. This is reminiscent of the known conductance regulation by neuromodulators in crustaceans. However, in GCs we observe a more nuanced regulation, where for some conductance pairs the correlations are completely eliminated while for others the correlation is quantitatively modified but not obliterated.
The discovery of Lake Hephaestus, the youngest athalassohaline deep-sea formation on Earth
Authors: La Cono Violetta , Bortoluzzi Giovanni , Messina Enzo , La Spada Gina , Smedile Francesco , Giuliano Laura , Borghini Mireno , Stumpp Christine , Schmitt-Kopplin Philippe , Harir Mourad , O’Neill William K. , Hallsworth John E. , Yakimov Michail 
Published: February 2019

AbstractHydrated, magnesium-rich minerals and subglacial brines exist on the martian surface, so the habitability of high-Mg2+ environments on Earth has extraterrestrial (as well as terrestrial) implications. Here, we report the discovery of a MgCl2-dominated (4.72 M) brine lake on the floor of the Mediterranean Ridge that underlies a 3500-m water column, and name it Lake Hephaestus. Stable isotope analyses indicated that the Hephaestus brine is derived from interactions between ancient bishofite-enriched evaporites and subsurface fluids. Analyses of sediment pore waters indicated that the Hephaestus depression had contained the MgCl2 brine for a remarkably short period; only 700 years. Lake Hephaestus is, therefore, the youngest among currently known submarine athalassohaline brine lakes on Earth. Due to its biologically hostile properties (low water-activity and extreme chaotropicity), the Hephaestus brine is devoid of life. By contrast, the seawater-Hephaestus brine interface has been shown to act as refuge for extremely halophilic and magnesium-adapted stratified communities of microbes, even at MgCl2 concentrations that approach the water-activity limit for life (0.653).
Precise U-Pb age constrains on the Ediacaran biota in Podolia, East European Platform, Ukraine
Authors: Soldatenko Y. , El Albani A. , Ruzina M. , Fontaine C. , Nesterovsky V. , Paquette J.-L. , Meunier A. , Ovtcharova M. 
Published: February 2019

AbstractThe Neoproterozoic Era was characterized by rapidly changing paleogeography, global climate changes and especially by the rise and fall of the Ediacaran macro-biota. The correlation between disparate Ediacaran fossil-bearing localities and the tentative reconstruction of their paleoenvironmental and paleogeographic contexts are usually complicated by the lack of precise and accurate age data. For this reason, Neoproterozoic sedimentary sections associating Ediacaran biota fossils and fresh volcanic material are especially valuable for radioisotopic dating. Our research in the Podolya Basin, southwestern Ukraine, revealed the presence of four Neoproterozoic volcanic ash deposits (potassium-bentonite layers) within Ediacaran fossil-bearing siliciclastic rocks of the Mohyliv-Podilskyi Group. We used zircon U-Pb LA-ICPMS and CA-ID-TIMS methods to date two of those layers. The results indicate that a diverse assemblage of body and trace Ediacaran fossils occurred as early as 556.78 ± 0.18 million years (Ma) ago. By combining morphological evidence and new age determinations, we suggest a closer paleobiogeographical relationship between the Ukrainian Ediacaran assemblage and the Avalon paleocontinent than previously estimated.