bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inter‐laboratory validation of a harmonized PNH flow cytometry assay
Authors: Payne Daniel , Johansson Ulrika , Bloxham David , Couzens Stephen , Carter Anthony , Holtom Pamela , Baker Bronia , Hughes Mark , Knill Tara , Milne Tim , Morilla Alison , Morilla Ricardo , O'Brien David , Thomas Lisa 
Published: September 2018

BackgroundA network comprising 11 laboratories aimed to consolidate PNH testing by developing and validating an assay guided by previous guidelines and studies. Network analyses of >20 native samples yielded key findings that were used to create and reshape the final protocol.MethodsTwenty‐seven native samples were distributed to all participating laboratories for blind testing, local analysis, and subsequent re‐analysis by a central laboratory. Inter‐laboratory clone size precision (coefficient of variation [CV]) was monitored for each sample, and the findings used to refine the test protocol. Linearity and precision tests were performed, assay limits of blank and detection were calculated, and limits of quantification were determined.ResultsWhen using the final protocol, enumeration of cells with a PNH phenotype by all participating laboratories was comparable, with no clinically significant discrepancies or false‐positive or false‐negative results reported. Of note, the biological characteristics of the sample affected precision. For example, CVs were higher when PNH and normal cells showed contiguous expression of GPI‐linked antigens. A red cell gating strategy that eliminated non‐specific type II PNH phenotypic events was devised, enabling reliable reporting of events in the type II red cell gate. The final protocol provided an assay with a Limit of Quantification of 0.01% for neutrophils and red cells, and 0.1% for monocytes.ConclusionsWe describe a robust network‐validated PNH assay that may aid other laboratories to set up and validate high resolution PNH analysis. © 2018 International Clinical Cytometry Society
Lomerizine, trimetazidine and bis‐(4‐fluorophenyl)‐methylpiperazine in human urine after oral administration of lomerizine dihydrochloride: analysis by liquid chromatography‐high resolution‐tandem mass spectrometry
Authors: Okano Masato , Sato Mitsuhiko , Kageyama Shinji 
Published: September 2018

AbstractIn sports drugs testing, the differentiation between the abuse of the prohibited substance trimetazidine and that of the permitted drug lomerizine is required because trimetazidine is one of the metabolites of lomerizine. Therefore, it is important to identify a lomerizine‐specific metabolite in urine that allows making the distinction. In this study, a simple dilute‐and‐shoot method employing liquid chromatography–high resolution–tandem mass spectrometry for the quantification of trimetazidine, lomerizine and the specific metabolite bis‐(4‐fluorophenyl)‐methylpiperazine (M6) in urine was developed. An oral dose of 15 mg was administered to 10 male volunteers, after which urine samples collected during the following 276 hours were analyzed using the developed method, allowing for examination of the target analytes' excretion profile. The limit of detection of all target analytes was <0.02 ng/mL. In all volunteers, the metabolite M6 was detected up to 276 hours after administration. After more than 12 hours, all volunteers were found to have higher concentrations of the metabolite M6 than of trimetazidine. The concentrations of trimetazidine, lomerizine, M6, and the M6/trimetazidine ratio in the final sample collected after 276 hours were 0.2–0.9 ng/mL, <0.05–0.1 ng/mL, 14.1–38.3 ng/mL, and 28.8–122.9, respectively. The urinary excretion of trimetazidine, unchanged lomerizine, and the metabolite M6 within the first 276 hours was 0.64%, 0.006%, and 6.1%, respectively. Consequently, the absence of the metabolite M6 in doping control urine samples corroborates the conclusion that lomerizine is unlikely to be the source of trimetazidine. The results confirm that the M6 metabolite is the longest‐lasting urinary metabolite of lomerizine currently known.
Pharmacokinetic study of Sudaxine in dog plasma using novel LC–MS/MS method
Authors: Altawallbeh Ghaith , Smith Laura , Lewis Stephen J. , Authier Simon , Bujold Kim , Gaston Benjamin , Bederman Ilya 
Published: September 2018

AbstractContextSudaxine is a novel respiratory stimulant that increases ventilatory drive via NO+‐thiolate signaling and is under development for reversal of opioid‐induced respiratory depression and other critical care indications.ObjectiveThis study investigates the pharmacokinetic characteristics after intravenous administration of Sudaxine by using a simple liquid chromatography–tandem mass spectrometry (LC–MS/MS) method.Materials and methodsA sensitive LC–MS/MS method was validated to determine the concentration of Sudaxine in beagle dog plasma after intravenous administration of Sudaxine at (3, 10, 30, and 100 mg/kg). Blood samples (1 mL) were collected at designated time points and SDX concentration was measured for pharmacokinetic study.ResultsThe calibration curve was linear within the range of 50–5,000 ng/mL with the lower limit of quantification at 50 ng/mL. The CTmax for all doses was reached at 10 minutes (Tmax). Over the dose range studied, average concentration – time curves and systemic exposure (CTmax and AUC0–t) increased to Sudaxine dose. The terminal half‐life of Sudaxine in dogs ranged from 10 to 30 minutes and about 17.3 ± 1.0% of Sudaxine was protein‐bound in dog plasma.Discussion and conclusionsWe developed a novel LC–MS/MS method of Sudaxine detection and quantification and determined its pharmacokinetic profiles after intravenous administration in canine subjects. Sudaxine followed first‐order kinetics with rapid dose‐dependent clearance rates and short half‐life making it an ideal candidate for use in a critical care setting with intramuscular or IV administration.
Retinal Ganglion Cell Replacement: Current Status and Challenges Ahead
Authors: Miltner Adam M. , La Torre Anna 
Published: September 2018

AbstractThe neurons of the retina can be affected by a wide variety of inherited or environmental degenerations that can lead to vision loss and even blindness. Retinal ganglion cell (RGC) degeneration is the hallmark of glaucoma and other optic neuropathies that affect millions of people worldwide. Numerous strategies are being trialed to replace lost neurons in different degeneration models, and in recent years, stem cell technologies have opened promising avenues to obtain donor cells for retinal repair. Stem cell–based transplantation has been most frequently used for the replacement of rod photoreceptors, but the same tools could potentially be used for other retinal cell types, including RGCs. However, RGCs are not abundant in stem cell–derived cultures, and in contrast to the short‐distance wiring of photoreceptors, RGC axons take a long and intricate journey to connect with numerous brain nuclei. Hence, a number of challenges still remain, such as the ability to scale up the production of RGCs and a reliable and functional integration into the adult diseased retina upon transplantation. In this review, we discuss the recent advancements in the development of replacement therapies for RGC degenerations and the challenges that we need to overcome before these technologies can be applied to the clinic. Developmental Dynamics 248:118–128, 2019. © 2018 Wiley Periodicals, Inc.
Allometry and integration do not strongly constrain beak shape evolution in large‐billed (Corvus macrorhynchos) and carrion crows (Corvus corone)
Authors: Yamasaki Takeshi , Aoki Sou , Tokita Masayoshi 
Published: September 2018

AbstractA recent geometric morphometric study on certain landbird lineages revealed that a major part of the variation in beak shape is accounted for by skull size and cranial shape. The study interpreted this result as evidence for the presence of strong evolutionary constraints that severely prevented beak shape from evolving substantially away from predictions of allometry and morphological integration. However, there is another overlooked but similarly plausible explanation for this result: The reason why beak shape does not depart much from predictions might simply be that selection pressures favoring such changes in shape are themselves rare. Here, to evaluate the intensity of evolutionary constraints on avian beak shape more appropriately, we selected large‐billed (Corvus macrorhynchos) and carrion crows (Corvus corone) as study objects. These landbird species seem to experience selection pressures favoring a departure from an allometric trajectory. A landmark‐based geometric morphometric approach using three‐dimensional reconstructions of CT scan images revealed that only 45.4% of the total shape variation was explained by allometry and beak–braincase integration. This suggests that when a selection pressure acts in a different direction to allometry and integration, avian beak shape can react to it and evolve flexibly. As traditionally considered, evolutionary constraints on avian beak shape might not be all that strong.
Insights on the persistence of pines (Pinusspecies) in the Late Cretaceous and their increasing dominance in the Anthropocene
Authors: Singh Surendra P. , Inderjit   , Singh Jamuna S. , Majumdar Sudipto , Moyano Jaime , Nuñez Martin A. , Richardson David M. 
Published: September 2018

AbstractAlthough gymnosperms were nearly swept away by the rise of the angiosperms in the Late Cretaceous, conifers, and pines (Pinusspecies) in particular, survived and regained their dominance in some habitats. Diversification of pines into fire‐avoiding (subgenusHaploxylon) and fire‐adapted (subgenusDiploxylon) species occurred in response to abiotic and biotic factors in the Late Cretaceous such as competition with emerging angiosperms and changing fire regimes. Adaptations/traits that evolved in response to angiosperm‐fuelled fire regimes and stressful environments in the Late Cretaceous were key to pine success and are also contributing to a new “pine rise” in some areas in the Anthropocene. Human‐mediated activities exert both positive and negative impacts of range size and expansion and invasions of pines. Large‐scale afforestation with pines, human‐mediated changes to fire regimes, and other ecosystem processes are other contributing factors. We discuss traits that evolved in response to angiosperm‐mediated fires and stressful environments in the Cretaceous and that continue to contribute to pine persistence and dominance and the numerous ways in which human activities favor pines.
A Bayesian spatial hierarchical model for extreme precipitation in Great Britain
Authors: Sharkey Paul , Winter Hugo C. 
Published: September 2018

AbstractIntense precipitation events are commonly known to be associated with an increased risk of flooding. As a result of the societal and infrastructural risks linked with flooding, extremes of precipitation require careful modeling. Extreme value analysis is typically used to model large precipitation events, although an independent analysis of neighboring sites can produce very different estimates of risk. In reality, one would expect neighboring locations to exhibit similar extremal behavior. A common method of inducing spatial similarity of extremal behavior is to define a spatial structure on the parameters of a generalized Pareto distribution in a Bayesian hierarchical modeling framework. These methods are often implemented under the assumption of conditional independence in time and space, with the consequence that standard errors of parameter estimates are too small. We present an approach for accounting for spatial and temporal dependence when quantifying the uncertainty in Bayesian hierarchical models when the misspecification of conditional independence has been made. We also present comparisons of performance between this class of models and alternative approaches, applied to precipitation data in Great Britain.
The evolution of the human foot
Authors: McNutt Ellison J. , Zipfel Bernhard , DeSilva Jeremy M. 
Published: September 2018

AbstractThere are 26 bones in each foot (52 in total), meaning that roughly a quarter of the human skeleton consists of foot bones. Yet, early hominin foot fossils are frustratingly rare, making it quite difficult to reconstruct the evolutionary history of the human foot. Despite the continued paucity of hominid or hominin foot fossils from the late Miocene and early Pliocene, the last decade has witnessed the discovery of an extraordinary number of early hominin foot bones, inviting a reassessment of how the human foot evolved, and providing fresh new evidence for locomotor diversity throughout hominin evolution. Here, we provide a review of our current understanding of the evolutionary history of the hominin foot.
Mechanisms shaping the mutational landscape of the FRA3B/FHIT‐deficient cancer genome
Authors: Saldivar Joshua C. , Park Dongju 
Published: September 2018

AbstractGenome instability is an enabling characteristic of cancer that facilitates the acquisition of oncogenic mutations that drive tumorigenesis. Underlying much of the instability in cancer is DNA replication stress, which causes both chromosome structural changes and single base‐pair mutations. Common fragile sites are some of the earliest and most frequently altered loci in tumors. Notably, the fragile locus, FRA3B, lies within the fragile histidine triad (FHIT) gene, and consequently deletions within FHIT are common in cancer. We review the evidence in support of FHIT as a DNA caretaker and discuss the mechanism by which FHIT promotes genome stability. FHIT increases thymidine kinase 1 (TK1) translation to balance the deoxyribonucleotide triphosphates (dNTPs) for efficient DNA replication. Consequently, FHIT‐loss causes replication stress, DNA breaks, aneuploidy, copy‐number changes (CNCs), small insertions and deletions, and point mutations. Moreover, FHIT‐loss‐induced replication stress and DNA breaks cooperate with APOBEC3B overexpression to catalyze DNA hypermutation in cancer, as APOBEC family enzymes prefer single‐stranded DNA (ssDNA) as substrates and ssDNA is enriched at sites of both replication stress and DNA breaks. Consistent with the frequent loss of FHIT across a broad spectrum of cancer types, FHIT‐deficiency is highly associated with the ubiquitous, clock‐like mutation signature 5 occurring in all cancer types thus far examined. The ongoing destabilization of the genome caused by FHIT loss underlies recurrent inactivation of tumor suppressors and activation of oncogenes. Considering that more than 50% of cancers are FHIT‐deficient, we propose that FRA3B/FHIT fragility shapes the mutational landscape of cancer genomes.
Efficient Harvesting of Nannochloropsis Microalgae via Optimized Chitosan‐Mediated Flocculation
Authors: Chua Elvis T. , Eltanahy Eladl , Jung Heejae , Uy Manuel , Thomas‐Hall Skye R. , Schenk Peer M. 
Published: September 2018

AbstractFood‐grade rather than synthetic or chemical flocculants are needed for microalgae harvesting by settling, if used for food products. Chitosan is effective in harvesting freshwater microalgae, but it is expensive and typically not suitable for marine microalgae like Nannochloropsis. To minimize costs for food‐grade flocculation, a number of potentially important parameters are considered, including chitosan solubility and optimized chitosan‐mediated flocculation of Nannochloropsis sp. BR2 by a five‐factor central composite design experiment. Results show that an optical density (440 nm) of 2 (0.23 g dry weight L−1), initial pH of 6, final pH of 10, and 22 ppm chitosan with a viscosity of 1808 cP provide optimum flocculation efficiency, which is predicted to be in the range of 97.01% to 99.93%. These predictions are verified on 4.5 and 8 L Nannochloropsis sp. BR2 cultures.
A Review of State‐of‐the‐Art Microfluidic Technologies for Environmental Applications: Detection and Remediation
Authors: Yew Maxine , Ren Yong , Koh Kai Seng , Sun Chenggong , Snape Colin 
Published: September 2018

AbstractMicrofluidic systems have advanced beyond natural and life science applications and lab‐on‐a‐chip uses. A growing trend of employing microfluidic technologies for environmental detection has emerged thanks to the precision, time‐effectiveness, and cost‐effectiveness of advanced microfluidic systems. This paper reviews state‐of‐the‐art microfluidic technologies for environmental applications, such as on‐site environmental monitoring and detection. Microdevices are extensively used in collecting environmental samples as a means to facilitate detection and quantification of targeted components with minimal quantities of samples. Likewise, microfluidic‐inspired approaches for separation and treatment of contaminated water and air, such as the removal of heavy metals and waterborne pathogens from wastewater and carbon capture are also investigated.
Acid Mine Drainage Treatment Using Bayer Precipitates Obtained from Seawater Neutralization of Bayer Liquor
Authors: Kaur Gurkiran , Couperthwaite Sara J. , Millar Graeme J. 
Published: September 2018

AbstractBayer precipitates from the seawater neutralization of Bayer liquor waste from the alumina industry are shown to be a prospective solution for the remediation of acid mine drainage (AMD) water. Precipitates are varied in composition, albeit they are generally comprised of hydrotalcite (Mg6Al2(OH)16CO3∙xH2O), calcite (CaCO3), aragonite (CaCO3), mixed metal hydroxides (Mg2Al(OH)7), and halite (NaCl). Brucite (Mg(OH)2) is detected for lower Bayer liquor concentrations (1–3 g L−1 Al2O3) when the concentrations of aluminum and hydroxyl species are insufficient to promote hydrotalcite formation. The neutralizing capacity of the precipitates also varies with Bayer liquor composition. Treatment of AMD water with Bayer precipitates met discharge pH guidelines. The dissolution of hydrotalcite and brucite (1–3 g L−1 Bayer precipitates only) is responsible for the Bayer precipitate's neutralizing capacity, while calcium carbonate has a buffering affect at around pH 7. Manganese ions are the most challenging species to remove because high pH values are required (pH > 9), which is not possible with all precipitates tested. One caveat is that increasing the degree of manganese removal generates issues with excessive dissolved aluminum which exceeds discharge limits. Future research should address this latter problem and facilitate implementation of this approach to AMD remediation.
Distinct patterns of glia repair and remyelination in antibody‐mediated demyelination models of multiple sclerosis and neuromyelitis optica
Authors: Liu Yiting , Given Katherine S. , Owens Gregory P. , Macklin Wendy B. , Bennett Jeffrey L. 
Published: September 2018

AbstractMultiple sclerosis (MS) and neuromyelitis optica (NMO) are inflammatory demyelinating disorders of the central nervous system with evidence of antibody‐mediated pathology. Using ex vivo organotypic mouse cerebellar slice cultures, we have demonstrated that recombinant antibodies (rAbs) cloned from cerebrospinal fluid plasmablasts of MS and NMO patients target myelin‐ and astrocyte‐specific antigens to induce disease‐specific oligodendrocyte loss and myelin degradation. In this study, we examined glial cell responses and myelin integrity during recovery from disease‐specific antibody‐mediated injury. Following exposure to MS rAb and human complement (HC) in cerebellar explants, myelinating oligodendrocytes repopulated the demyelinated tissue and formed new myelin sheaths along axons. Remyelination was accompanied by pronounced microglial activation. In contrast, following treatment with NMO rAb and HC, there was rapid regeneration of astrocytes and pre‐myelinating oligodendrocytes but little formation of myelin sheaths on preserved axons. Deficient remyelination was associated with progressive axonal loss and the return of microglia to a resting state. Our results indicate that antibody‐mediated demyelination in MS and NMO show distinct capacities for recovery associated with differential injury to adjacent axons and variable activation of microglia. Remyelination was rapid in MS rAb plus HC‐induced demyelination. By contrast, oligodendrocyte maturation and remyelination failed following NMO rAb‐mediated injury despite the rapid restoration of astrocytes and preservation of axons in early lesions.
Astrocytes, the rising stars of the glioblastoma microenvironment
Authors: Brandao Mayra , Simon Thomas , Critchley Giles , Giamas Georgios 
Published: September 2018

AbstractGlioblastoma (GBM) is an aggressive primary tumor, causing thousands of deaths worldwide every year. The mean survival of patients with GBM remains below 20 months despite current available therapies. GBM cells' interactions with their stromal counterparts are crucial for tumor development. Astrocytes are glial cells that comprise ~50% of all brain cells and are therefore likely to establish direct contact with GBM cells. As other tumor cell types can hijack fibroblasts or immune cells to facilitate tumor growth, GBM cells can actually activate astrocytes, namely, the tumor associated astrocytes (TAAs), to promote GBM invasion in the healthy tissue. TAAs have thus been shown to be involved in GBM cells growth and limited response to radiation or chemotherapy (i.e., Temozolomide). Nevertheless, even though the interest in the cancer research community is increasing, the role of TAAs during GBM development is still overlooked. Yet, obtaining an in‐depth understanding of the mechanisms by which TAAs influence GBM progression might lead to the development of new therapeutic strategies. This article therefore reports the different levels of GBM progression at which TAAs have been recently described to be involved in, including tumor cells' proliferation/invasion and resistance to therapies, especially through the activity of extracellular vesicles.
The neural oscillatory markers of phonetic convergence during verbal interaction
Authors: Mukherjee Sankar , Badino Leonardo , Hilt Pauline M. , Tomassini Alice , Inuggi Alberto , Fadiga Luciano , Nguyen Noël , D'Ausilio Alessandro 
Published: September 2018

AbstractDuring a conversation, the neural processes supporting speech production and perception overlap in time and, based on context, expectations and the dynamics of interaction, they are also continuously modulated in real time. Recently, the growing interest in the neural dynamics underlying interactive tasks, in particular in the language domain, has mainly tackled the temporal aspects of turn‐taking in dialogs. Besides temporal coordination, an under‐investigated phenomenon is the implicit convergence of the speakers toward a shared phonetic space. Here, we used dual electroencephalography (dual‐EEG) to record brain signals from subjects involved in a relatively constrained interactive task where they were asked to take turns in chaining words according to a phonetic rhyming rule. We quantified participants' initial phonetic fingerprints and tracked their phonetic convergence during the interaction via a robust and automatic speaker verification technique. Results show that phonetic convergence is associated to left frontal alpha/low‐beta desynchronization during speech preparation and by high‐beta suppression before and during listening to speech in right centro‐parietal and left frontal sectors, respectively. By this work, we provide evidence that mutual adaptation of speech phonetic targets, correlates with specific alpha and beta oscillatory dynamics. Alpha and beta oscillatory dynamics may index the coordination of the “when” as well as the “how” speech interaction takes place, reinforcing the suggestion that perception and production processes are highly interdependent and co‐constructed during a conversation.