bluuebunny/crossref_metadata_2025 huggingface dataset:
Constitutional Pluralism and Authoritarianism
Authors: Avbelj Matej
Published: September 2020

This article examines the relationship between constitutional pluralism and authoritarianism. It does so since the Weiss decision of the FCC spurred unusual attacks on constitutional pluralism. This particular theoretical vision of European integration has been described as inherently dangerous and its abandonment has been called for out of chiefly instrumentalist reasons, in order to prevent constitutional pluralism turning into an autocrats’ refuge. The article argues this critique of constitutional pluralism does not succeed. Due to its truncated, exclusively positivist understanding of constitutional pluralism, it has failed to take into account pluralism’s normative core. The latter presents itself an antipode to authoritarianism, which means that the autocratic regimes simply cannot credibly avail themselves of the theory of constitutional pluralism to justify their authoritarian actions.
Interventions to improve antibiotic prescribing at hospital discharge: A systematic review
Authors: Daniels Lindsay M. , Weber David J.
Published: September 2020

A large proportion of antibiotic use associated with hospitalization occurs immediately after discharge, representing an important focus for antimicrobial stewardship programs. This review identified few studies evaluating the effect of interventions aimed at improving discharge antibiotic prescribing. Antimicrobial stewardship to improve postdischarge antibiotic prescribing is an unmet need warranting further study.
A Model of Global Beverage Markets
Authors: Wittwer Glyn , Anderson Kym
Published: September 2020

This article describes a new empirical model of the world's markets for alcoholic beverages and, to illustrate its usefulness, reports results from projections of those markets from 2016–2018 to 2025 under various scenarios. It not only revises and updates a model of the world's wine markets (Wittwer, Berger, and Anderson, 2003), but also adds beer and spirits so as to capture the substitutability of those beverages among consumers. The model has some of the features of an economy-wide computable general equilibrium model, with international trade linking the markets of its 44 countries and seven residual regions. It is used to simulate prospects for these markets by 2025 (business-as-usual), which points to Asia's rise. Then two alternative scenarios to 2025 are explored: one simulates the withdrawal of the United Kingdom from the European Union (EU); the other simulates the effects of the recent imposition of additional 25% tariffs on selected beverages imported by the United States from several EU member countries. Future applications of the model are discussed in the concluding section. (JEL Classifications: C53, F11, F17, Q13)
INTRODUCTION: HISTORY FROM BETWEEN AND THE GLOBAL CIRCULATIONS OF THE PAST IN ASIA AND EUROPE, 1600–1950
Authors: JENCO LEIGH K. , CHAPPELL JONATHAN
Published: September 2020

This article argues for a ‘history from between’ as the best lens through which to understand the construction of historical knowledge between East Asia and Europe. ‘Between’ refers to the space framed by East Asia and Europe, but also to the global circulations of ideas in that space, and to the subjective feeling of embeddedness in larger-than-local contexts that being in such a space makes possible. Our contention is that the outcomes of such entanglements are not merely reactive forms of knowledge, of the kind implied by older studies of translation and reception in global intellectual history. Instead they are themselves ‘co-productions’: they are the shared and mutually interactive inputs to enduring modes of uses of the past, across both East Asian and European traditions. Taking seriously the possibility that interpretations of the past were not transferred, but rather were co-produced between East Asia and Europe, we reconstruct the braided histories of historical narratives that continue to shape constructions of identity throughout Eurasia.
READING EUROPEAN UNIVERSAL HISTORIES IN JAPAN, 1790s–1840s
Authors: MERVART DAVID
Published: September 2020

This article offers a case study in the nature of uses of the European past in East Asia at a time when the search for the knowledge of the West was not yet motivated primarily by any sense of its civilizational, moral, or technological superiority. In the course of the later eighteenth century, as Dutch philological expertise gradually became another available tool – alongside the long-established Sinological erudition – for generating knowledge about the world, commentators around the Japanese archipelago began to turn not only to the medical and astronomical manuals of the occidentals but also to their histories. The translation-cum-commentaryMiscellanea from the western seasby Yamamura Saisuke (1801) is a case in point. The text became effectively a crossroads of two philological and historiographical bodies of knowledge that intersected in unexpected ways as the European past was subjected to a reinterpretation in terms of the classical Chinese precedent, while the product of that reinterpretation informed a different understanding of the recent and contemporary historical trajectory of a Japan now exposed to the dynamics of the global European presence.
NARRATING JAPAN'S EARLY MODERN SOUTHERN EXPANSION
Authors: TREMML-WERNER BIRGIT
Published: September 2020

This article explores how the Japanese translator-historian Murakami Naojirō created an understanding of the Japanese past that established seventeenth-century Japanese actors as equivalents to western European and overseas Chinese merchants. Creating a historical geography of the Southern Seas and the Pacific, Murakami celebrated Japan's expansionism, not only by stressing the seventeenth-century Japanese presence in South-east Asia, but also, more subtly, by identifying the existence of a progressive spirit in the Japanese individuals involved in it. His narrative strategy included implicit comparisons with the European age of expansion, whose protagonists in South-east Asia relied on the networks and services of both Japanesewakō(‘pirates’) and more complex actors such as the red seal merchant Yamada Nagamasa. The article is a case study for Japan's intellectual imperialism of the 1910s–1940s, which closely intertwined popular discourse and academic history.
30 years of parasitology research analysed by text mining
Authors: Ellis John T. , Ellis Bethany , Velez-Estevez Antonio , Reichel Michael P. , Cobo Manuel J.
Published: September 2020

Bibliometric methods were used to analyse the major research trends, themes and topics over the last 30 years in the parasitology discipline. The tools used were SciMAT, VOSviewer and SWIFT-Review in conjunction with the parasitology literature contained in the MEDLINE, Web of Science, Scopus and Dimensions databases. The analyses show that the major research themes are dynamic and continually changing with time, although some themes identified based on keywords such as malaria, nematode, epidemiology and phylogeny are consistently referenced over time. We note the major impact of countries like Brazil has had on the literature of parasitology research. The increase in recent times of research productivity on ‘antiparasitics’ is discussed, as well as the change in emphasis on different antiparasitic drugs and insecticides over time. In summary, innovation in parasitology is global, extensive, multidisciplinary, constantly evolving and closely aligned with the availability of technology.
Further evidence that Antarctic toothfish are important to Weddell seals
Authors: Ainley David G. , Cziko Paul A. , Nur Nadav , Rotella Jay J. , Eastman Joseph T. , Larue Michelle , Stirling Ian , Abrams Peter A.
Published: September 2020

Antarctic toothfish Dissostichus mawsoni and Weddell seals Leptonychotes weddellii are important mesopredators in the waters of the Antarctic continental shelf. They compete with each other for prey, yet the seals also prey upon toothfish. Such intraguild predation means that prevalence and respective demographic rates may be negatively correlated, but quantification is lacking. Following a review of their natural histories, we initiate an approach to address this deficiency by analysing scientific fishing catch per unit effort (CPUE; 1975–2011 plus sporadic effort to 2018) in conjunction with an annual index of seal abundance in McMurdo Sound, Ross Sea. We correlated annual variation in scientific CPUE to seal numbers over a 43 year period (1975–2018), complementing an earlier study in the same locality showing CPUE to be negatively correlated with spatial proximity to abundant seals. The observed relationship (more seals with lower CPUE, while controlling for annual trends in each) indicates the importance of toothfish as a dietary item to Weddell seals and highlights the probable importance of intra- and inter-specific competition as well as intraguild predation in seal-toothfish dynamics. Ultimately, it may be necessary to supplement fishery management with targeted ecosystem monitoring to prevent the fishery from having adverse effects on dependent species.
The provision of recipes and single-use herb/spice packets to increase egg and protein intake in community-dwelling older adults: a randomised controlled trial
Authors: van den Heuvel E , Murphy JL , Appleton KM
Published: September 2020

Objective:

This study investigated the impact of recipe and single-use herb/spice packet provision on egg intake and protein intake in community-dwelling individuals aged over 55 years.

Design:

Using a randomised-controlled intervention design, 100 older adults were randomised to receive (n 53) or not receive (n 47) high-protein egg-based recipes and herb/spice packets through the post for 12 weeks, from June to December 2016. Egg intake, protein intake, adverse events, lean body mass and functional measures of lean body mass were measured at baseline, after the 12 weeks and after a further 12 weeks.

Setting:

Bournemouth, UK.

Participants:

Community-dwelling older adults.

Results:

Intention-to-treat data were analysed using regression, controlling for various demographic and lifestyle characteristics. Ninety-three individuals (intervention, n 50; control, n 43) completed assessments at all three time points. Egg intakes increased by end of intervention in both groups (mean: 4–5 eggs/month). After a further 12 weeks, higher egg intakes were sustained in the intervention group, while egg intakes in the control group returned to baseline levels (between-group difference: β = −0·124, P = 0·047). No differences were found in other measures (largest β = −0·106, P = 0·12).

Conclusions:

The provision of high-protein egg-based recipes and single-use herb/spice packets over 12 weeks increased egg intakes up to 12 weeks after end of intervention. Other factors may explain increased egg intakes during the intervention, but the sustained effects most plausibly result directly from recipe provision. Limited effects in other measures suggest that the recipes may have replaced as opposed to added to existing protein intakes.
Die Rolle der Klinischen Neuropsychologie im Rahmen der reformierten universitären Masterstudiengänge zur Vorbereitung auf das Staatsexamen Psychotherapie
Authors: Thoma Patrizia , Teismann Tobias , Wannemüller Andre , Friedrich Sören , Margraf Jürgen , Schneider Silvia , Suchan Boris
Published: September 2020

Zusammenfassung. Das Gesetz zur Reform der Psychotherapeutenausbildung bringt Veränderungen mit sich, die eine Neupositionierung der Klinischen Neuropsychologie im Rahmen der neuen Masterstudiengänge zur Vorbereitung auf das Staatsexamen Psychotherapie ermöglichen, aber auch erforderlich machen. Da künftig der Zugang zur Approbation und zur vertieften Ausbildung in Psychotherapieverfahren ausschließlich über den Klinischen Master möglich sein wird, ist es von essenzieller Bedeutung, auf eine klinisch-neuropsychologische Tätigkeit vorbereitende Inhalte so im Rahmen des Masterstudienganges zu verankern, dass der Nachwuchs für den Bereich der Klinischen Neuropsychologie entsprechend früh gewonnen wird. Der Artikel führt aus, wie wir dies in Zusammenarbeit mit den Lehrstühlen für Klinische Psychologie und Psychotherapie sowie für Klinische Kinder- und Jugendlichenpsychologie an der Ruhr-Universität Bochum erreichen möchten.
A Near‐Term Iterative Forecasting System Successfully Predicts Reservoir Hydrodynamics and Partitions Uncertainty in Real Time
Authors: Thomas R. Quinn , Figueiredo Renato J. , Daneshmand Vahid , Bookout Bethany J. , Puckett Laura K. , Carey Cayelan C.
Published: September 2020

Freshwater ecosystems are experiencing greater variability due to human activities, necessitating new tools to anticipate future water quality. In response, we developed and deployed a real‐time iterative water temperature forecasting system (FLARE—Forecasting Lake And Reservoir Ecosystems). FLARE is composed of water temperature and meteorology sensors that wirelessly stream data, a data assimilation algorithm that uses sensor observations to update predictions from a hydrodynamic model and calibrate model parameters, and an ensemble‐based forecasting algorithm to generate forecasts that include uncertainty. Importantly, FLARE quantifies the contribution of different sources of uncertainty (driver data, initial conditions, model process, and parameters) to each daily forecast of water temperature at multiple depths. We applied FLARE to Falling Creek Reservoir (Vinton, Virginia, USA), a drinking water supply, during a 475‐day period encompassing stratified and mixed thermal conditions. Aggregated across this period, root mean square error (RMSE) of daily forecasted water temperatures was 1.13°C at the reservoir's near‐surface (1.0 m) for 7‐day ahead forecasts and 1.62°C for 16‐day ahead forecasts. The RMSE of forecasted water temperatures at the near‐sediments (8.0 m) was 0.87°C for 7‐day forecasts and 1.20°C for 16‐day forecasts. FLARE successfully predicted the onset of fall turnover 4–14 days in advance in two sequential years. Uncertainty partitioning identified meteorology driver data as the dominant source of uncertainty in forecasts for most depths and thermal conditions, except for the near‐sediments in summer, when model process uncertainty dominated. Overall, FLARE provides an open‐source system for lake and reservoir water quality forecasting to improve real‐time management.
Rational Planning of Land Use Can Maintain Water Yield Without Damaging Ecological Stability in Upstream of Inland River: Case Study in the Hei River Basin of China
Authors: Su Tongxuan , Zhang Baoqing , He Xiaogang , Shao Rui , Li Yao , Tian Jie , Long Biao , He Chansheng
Published: September 2020

Upstream inland rivers provide most of water resources for midstream and downstream in arid and semiarid regions. From the perspective of ecological rehabilitation, it is necessary to simultaneously ensure upstream streamflow while still maintaining economy‐ecosystem balance in upstream. However, vegetation dynamics effects caused by ecological rehabilitation cannot be well evaluated in previous studies due to the sparseness of observations at regional scales. With increased availability of vegetation and hydrological data, it is now possible to explore the relationship between water yield and ecological balance affected by vegetation dynamics. This study takes Upper Hei River Basin, part of the Asia's water tower—the Qinghai‐Tibet Plateau, as an example and uses the Eagleson's ecohydrological model to explore the effects of vegetation dynamics on streamflow and ecology in growing seasons during 1992–2015. We compare scenarios with and without vegetation changes and find that there is limited evidence that ecological rehabilitation could enhance water yield. Approximately 51.31% of Upper Hei River Basin vegetation cover (M) tends to deviate from ecological optimization state compared to equilibrium vegetation cover (Meq). In order to explore ways to ensure streamflow and maintain ecology, different vegetation scenarios are simulated. Results show that on average, grazing in area where M is larger than Meq could increase streamflow by approximately 7.3%/year and planting trees in other area could increase streamflow by approximately 2.9%/year. Therefore, effective control on vegetation dynamics can simultaneously ensure streamflow and maintain ecological balance, which can also provide guidance and theoretical support for upstream inland river planning.
Evaluation of Cloud and Precipitation Response to Aerosols in WRF‐Chem With Satellite Observations
Authors: Liu Zhoukun , Wang Minghuai , Rosenfeld Daniel , Zhu Yannian , Bai Heming , Cao Yang , Liang Yuan
Published: September 2020

Large uncertainties remain in the key physical processes associated with aerosol‐cloud interactions (ACI) in models. With the help of A‐Train satellite observations, the Weather Research and Forecasting Model with chemistry (WRF‐Chem) model with two microphysical schemes, Morrison (MOR) and Lin (LIN), is evaluated by quantifying the susceptibilities of cloud properties, precipitation characteristics, and warm rain process to aerosols for marine stratocumulus over the Southeast Pacific. We reduced the meteorological control on clouds by stratifying them using cloud geometric thickness. Our results show that while the cloud fraction increases with increasing cloud droplet number concentration (Nd) in observation and simulations, the susceptibility of cloud fraction to Nd in simulations are only half of that in the observation. The cloud liquid water path increases with Nd in simulations but decreases slightly in the observation. Compared with the observations, the warm rain in WRF‐Chem simulations is generally less suppressed by aerosols, and it initiates at a much smaller cloud droplet effective radius (Re). The conversion from cloud to rain is substantially faster in simulations compared to satellite observations. The conversion rate accelerates at Re ≈ 13 μm in observations and at Re ≈ 9 μm in simulations.
Seasonal Differences and Variability of Concentrations, Chemical Composition, and Cloud Condensation Nuclei of Marine Aerosol Over the North Atlantic
Authors: Saliba Georges , Chen Chia‐Li , Lewis Savannah , Russell Lynn M. , Quinn Patricia K. , Bates Timothy S. , Bell Thomas G. , Lawler Michael J. , Saltzman Eric S. , Sanchez Kevin J. , Moore Richard , Shook Michael , Rivellini Laura‐Helena , Lee Alex , Baetge Nicholas , Carlson Craig A. , Behrenfeld Michael J.
Published: September 2020

The majority of the aerosol particle number (condensation nuclei or CN) in the marine boundary layer (MBL) consists of sulfate and organic compounds that have been shown to provide a large fraction of the cloud condensation nuclei (CCN). Here we use submicron non‐refractory Aerosol Mass Spectrometer (AMS) and filter measurements of organic and sulfate components of aerosol particles measured during four North Atlantic Aerosol and Marine Ecosystems Study (NAAMES) research cruises to assess the sources and contributions of submicron organic and sulfate components for CCN concentrations in the MBL during four different seasons. Submicron hydroxyl group organic mass (OM) correlated strongly to sodium concentrations during clean marine periods (R = 0.9), indicating that hydroxyl group OM can serve as a proxy for sea‐spray OM in ambient measurements. Sea‐spray OM contributed 45% of the sum of sea‐spray OM and sea salt during late spring (biomass climax phase) compared to <20% for other seasons, but the seasonal difference was not statistically significant. The contribution of non‐combustion sources during clean marine periods to submicron OM was 47 to 88% and to non‐sea‐salt sulfate 31 to 86%, with likely sources being marine and biogenic. The remaining submicron OM and sulfate were likely associated with ship or continental sources, including biomass burning, even during clean marine periods. The seasonal contribution from secondary sulfate and OM components to submicron aerosol mass was highest during late spring (60%), when biogenic emissions are expected to be highest, and lowest during winter (18%). Removing submicron sea‐spray OM decreased CCN concentrations by <10% because of competing effects from increased hygroscopicity and decreased particle size. During all seasons, adding biogenic secondary sulfate increased hygroscopicity, particle size, and CCN concentrations at 0.1–0.3% supersaturations by 5–66%. The largest change was during early spring when the fraction of hygroscopic sulfate components in the 0.1–0.2 μm size range was highest (80%). During continental periods, the increased contribution from low‐hygroscopicity organic components to 0.1–0.2 μm diameter particles reduces the CCN/CN by 20–100% for three seasons despite the increased CN and mass concentrations. These results illustrate the important role of the chemical composition of particles with diameters 0.1–0.2 μm for controlling CCN in the MBL.
Bihemispheric Warming in the Miocene Climatic Optimum as Seen From the Danish North Sea
Authors: Herbert Timothy D. , Rose Rebecca , Dybkjær Karen , Rasmussen Erik S. , Śliwińska Kasia K.
Published: September 2020

The Miocene epoch witnessed major changes in climate. The marine oxygen isotope record, our best single continuous representation of the time interval, contains large shifts indicating substantial changes in the glaciation of Antarctica and/or deep ocean temperatures, with the interval of the most depleted isotopic composition occurring between ~18 and 13.9 Ma (mid‐Miocene Climatic Optimum [MCO]). We present here a record of alkenone unsaturation estimates from a borehole penetrating marine sediments spanning most of the Miocene at ~56°N. Marine temperatures reconstructed for the Miocene are up to 20°C warmer than present day. A maximum occurs at the time of the MCO. The record is strikingly similar to discontinuous alkenone results published from other North Atlantic sites. As in the southern hemisphere, ocean temperature gradients were extraordinarily low in the North Atlantic in comparison to today. Our findings suggest that the MCO was a global temperature maximum and link the partial deglaciation of the Antarctic and subsequent “refrigeration” to a global forcing process. However, the small magnitude of the ocean cooling from ~14 to 10 Ma suggests a highly nonlinear (threshold) relationship between East Antarctic ice volume and global temperature.
An Exhumation Pulse From the Nascent Franciscan Subduction Zone (California, USA)
Authors: Rutte Daniel , Garber Joshua , Kylander‐Clark Andrew , Renne Paul R.
Published: September 2020

We investigated a suite of metabasite blocks from serpentinite matrix and shale matrix mélanges of the California Coast Ranges. Our new data set consists of 40Ar/39Ar dates of amphibole and phengite and U‐Pb dates of metamorphic zircon. Combined with published geochronology, including prograde Lu‐Hf garnet ages from the same blocks, we can reconstruct the timing and time scales of prograde and retrograde metamorphism of individual blocks. In particular we find that exhumation from amphibole‐eclogite facies conditions occurred as a single episode at 165–157 Ma, with an apparent southward younging trend. The rate and timing of exhumation were initially uniform (when comparing individual blocks) and fast (with cooling rates up to ~140°C/Ma). In the cooler and shallower blueschist facies, exhumation slowed and became less uniform among blocks. Considering the subduction zone system, the high‐grade exhumation temporally correlates with a magmatic arc pulse (Sierra Nevada) and the termination of forearc spreading (Coast Range Ophiolite). Our findings suggest that a geodynamic one‐time event led to exhumation of amphibole‐eclogite facies rocks. We propose that interaction of the Franciscan subduction zone with a spreading ridge led to extraction of the forearc mantle wedge from its position between forearc crust and subducting crust. The extraction led to fast and uniform exhumation of subducted rocks into the blueschist facies. We also show that the Franciscan subduction zone did not undergo significant cooling over time and that its initiation was not coeval with blueschist‐facies metamorphism of the Red Ant schist of the Sierra Nevada foothills.
Current practices underestimate environmental exposures to methamphetamine: inhalation exposures are important
Authors: Wright Jackie , Symons Bob , Angell Jonathon , Ross Kirstin E. , Walker Stewart
Published: September 2020

Current practice for determining the exposure to methamphetamine in contaminated homes relies on the analysis of surface wipe sample to address direct contact exposures. The movement of methamphetamine into the air phase, and the potential for inhalation exposures to occur within residential homes contaminated from former clandestine manufacture or smoking of methamphetamine has been generally poorly characterised and understood. All available risk-based guidelines for determining safe levels of methamphetamine in residential properties do not include any consideration of the inhalation pathway as an exposure route. This study showed that methamphetamine can readily move from contaminated materials in a home into the air phase. This movement of methamphetamine into the air phase provides both an exposure pathway and a mechanism for the transfer of methamphetamine throughout a property. The inhalation exposure pathway has the potential to result in significant intake of methamphetamine, adding to dermal absorption and ingestion exposure routes. Guidelines that are established for the assessment of methamphetamine contaminated properties that ignore inhalation exposures can significantly underestimate exposure and result in guidelines that are not adequately protective of health. This study also demonstrates that sampling methamphetamine in air can be undertaken using commercially available sorption tubes and analytical methods.
Immortalization of human primary prostate epithelial cells via CRISPR inactivation of the CDKN2A locus and expression of telomerase
Authors: Zhao Ziran , Fowle Holly , Valentine Henkel , Liu Zemin , Tan Yinfei , Pei Jianming , Badal Simone , Testa Joseph R. , Graña Xavier
Published: September 2020

Background

Immortalization of primary prostate epithelial cells (PrEC) with just hTERT expression is particularly inefficient in the absence of DNA tumor viral proteins or p16INK4A knockdown.

Materials and methods

Here, we describe the establishment of immortalized normal prostate epithelial cell line models using CRISPR technology to inactivate the CDKN2A locus concomitantly with ectopic expression of an hTERT transgene.

Results

Using this approach, we have obtained immortal cell clones that exhibit fundamental characteristics of normal cells, including diploid genomes, near normal karyotypes, normal p53 and pRB cell responses, the ability to form non-invasive spheroids, and a non-transformed phenotype. Based on marker expression, these clones are of basal cell origin.

Conclusions

Use of this approach resulted in the immortalization of independent clones of PrEC that retained normal characteristics, were stable, and non-transformed. Thus, this approach could be used for the immortalization of normal primary prostate cells. This technique could also be useful for establishing cell lines from prostate tumor tissues of different tumor grades and/or from patients of diverse ethnicities to generate cell line models that facilitate the study of the molecular basis of disease disparity.
Mesenchymal stem cells derived extracellular vesicles improve behavioral and biochemical deficits in a phencyclidine model of schizophrenia
Authors: Tsivion-Visbord Hadas , Perets Nisim , Sofer Tamar , Bikovski Lior , Goldshmit Yona , Ruban Angela , Offen Daniel
Published: September 2020

Schizophrenia is a debilitating psychiatric disorder with a significant number of patients not adequately responding to treatment. Phencyclidine (PCP) is used as a validated model for schizophrenia, shown to reliably induce positive, negative and cognitive-like behaviors in rodents. It was previously shown in our lab that behavioral phenotypes of PCP-treated mice can be alleviated after intracranial transplantation of mesenchymal stem cells (MSC). Here, we assessed the feasibility of intranasal delivery of MSCs-derived-extracellular vesicles (EVs) to alleviate schizophrenia-like behaviors in a PCP model of schizophrenia. As MSCs-derived EVs were already shown to concentrate at the site of lesion in the brain, we determined that in PCP induced injury the EVs migrate to the prefrontal cortex (PFC) of treated mice, a most involved area of the brain in schizophrenia. We show that intranasal delivery of MSC-EVs improve social interaction and disruption in prepulse inhibition (PPI) seen in PCP-treated mice. In addition, immunohistochemical studies demonstrate that the EVs preserve the number of parvalbumin-positive GABAergic interneurons in the PFC of treated mice. Finally, MSCs-EVs reduced glutamate levels in the CSF of PCP-treated mice, which might explain the reduction of toxicity. In conclusion, we show that MSCs-EVs improve the core schizophrenia-like behavior and biochemical markers of schizophrenia and might be used as a novel treatment for this incurable disorder.
Using the West Midlands CONCERT to characterise regional incidence of acute-onset post cataract surgery endophthalmitis
Authors: Moussa George , Bhatt Hetvi , Reekie Ian , Butt Gibran , Ng Aaron , Blanch Richard ,   The West Midlands CONCERT, Fusi-Rubiano William , Al-Ibrahim Jalil , Quinlan Michael , Virdee Jasvir , Dawson Sarah , Patel Amit , Low Liying , Mushtaq Fizza , Nambiar Seena , Routledge Claire , Yang Yit , Barry Robert J. , Burdon Michael , Barua Ankur , De Silva Ian , Panthagani Jesse , Qureshi Madyan , Pherwani Anupama , Sigona Mark , Morphis George , Rauz Saaeha
Published: September 2020

Background

Whilst research and innovation is embedded within the UK’s National Health Service (NHS) constitution, Doctors-in-training have little opportunity to contribute to designing, leading and recruiting into clinical trials or cohort studies. We formed the West MidlandsCollaborativeOphthalmologyNetwork forClinicalEffectiveness &Research byTrainees (The West Midlands CONCERT) and undertook a characterisation of post cataract surgery endophthalmitis as a proof-of-concept study to test the feasibility of the CONCERT model.

Methods

Doctors-in-training formed a collaborative working group to test the concept of delivering a pan-regional clinical effectiveness study across multiple hospital sites by performing retrospective analyses of post cataract endophthalmitis over a 6-year period.

Results

Overall, 157,653 cataract surgeries were performed by participating centres accredited to deliver the Royal College of Ophthalmologists training curriculum. Thirty-eight cases of post cataract endophthalmitis were identified, giving an incidence of 2.41 per 10,000 cases (0.0241%). A further 15 endophthalmitis cases presented who had surgery in non-training centres, giving a total of 53 cases. The most common organisms were S. epidermidis (14 (51.9%)) and P. aeruginosa (5 (18.5%)). Anterior-chamber and vitreous sampling yielded positive culture in 33.3% (6/18) and 50.9% (27/53), respectively. At 6 months follow-up, 19 (51.4%) patients achieved visual acuities of ≤0.5 LogMAR. Repeat intravitreal injections (11 (20.8%)) and vitrectomy (n = 22 (41.5%)) were not associated with better outcomes.

Conclusions

Using post cataract endophthalmitis as a pilot cohort, this study highlights the feasibility of using the CONCERT model for studies across multiple sites. A UK-CONCERT could provide a powerful infrastructure enabling characterisation of patient cohorts and a platform for high-quality interventional studies, improving patient care.
Precise and error-prone CRISPR-directed gene editing activity in human CD34+ cells varies widely among patient samples
Authors: Modarai Shirin R. , Kanda Sambee , Bloh Kevin , Opdenaker Lynn M. , Kmiec Eric B.
Published: September 2020

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and their associated CRISPR-associated nucleases (Cas) are among the most promising technologies for the treatment of hemoglobinopathies including Sickle Cell Disease (SCD). We are only beginning to identify the molecular variables that influence the specificity and the efficiency of CRISPR- directed gene editing, including the position of the cleavage site and the inherent variability among patient samples selected for CRISPR-directed gene editing. Here, we target the beta globin gene in human CD34+ cells to assess the impact of these two variables and find that both contribute to the global diversity of genetic outcomes. Our study demonstrates a unique genetic profile of indels that is generated based on where along the beta globin gene attempts are made to correct the SCD single base mutation. Interestingly, even within the same patient sample, the location of where along the beta globin gene the DNA is cut, HDR activity varies widely. Our data establish a framework upon which realistic protocols inform strategies for gene editing for SCD overcoming the practical hurdles that often impede clinical success.
CRISPR/Cas9-mediated VvPR4b editing decreases downy mildew resistance in grapevine (Vitis vinifera L.)
Authors: Li Meng-Yuan , Jiao Yun-Tong , Wang Yu-Ting , Zhang Na , Wang Bian-Bian , Liu Rui-Qi , Yin Xiao , Xu Yan , Liu Guo-Tian
Published: September 2020

Downy mildew of grapevine (Vitis vinifera L.), caused by the oomycete pathogen Plasmopara viticola, is one of the most serious concerns for grape production worldwide. It has been widely reported that the pathogenesis-related 4 (PR4) protein plays important roles in plant resistance to diseases. However, little is known about the role of PR4 in the defense of grapevine against P. viticola. In this study, we engineered loss-of-function mutations in the VvPR4b gene from the cultivar “Thompson Seedless” using the CRISPR/Cas9 system and evaluated the consequences for downy mildew resistance. Sequencing results showed that deletions were the main type of mutation introduced and that no off-target events occurred. Infection assays using leaf discs showed that, compared to wild-type plants, the VvPR4b knockout lines had increased susceptibility to P. viticola. This was accompanied by reduced accumulation of reactive oxygen species around stomata. Measurement of the relative genomic abundance of P. viticola in VvPR4b knockout lines also demonstrated that the mutants had increased susceptibility to the pathogen. Our results confirm that VvPR4b plays an active role in the defense of grapevine against downy mildew.
Diurnal T2-changes of the intervertebral discs of the entire spine and the influence of weightlifting
Authors: Jentzsch Thorsten , Farshad-Amacker Nadja A. , Mächler Philipp , Farei-Campagna Jan , Hoch Armando , Rosskopf Andrea B. , Werner Clément M. L.
Published: September 2020

The purpose was to study if (1) diurnal changes occur in the entire spine and if (2) intervertebral discs (IVDs) of weightlifters (WL) have decreased baseline T2-values in the morning as well as (3) increased diurnal changes throughout the day. This prospective cohort study investigated healthy volunteers between 2015 and 2017. WL were required to have participated in weightlifting ≥ 4×/week for ≥ 5 years, while non-weightlifters (NWL) were limited to < 2×/week for ≥ 5 years. Both groups underwent magnetic resonance imaging (MRI) of the entire spine in the morning and evening. WL were requested to perform weightlifting in-between imaging. IVD regions of interest (nucleus pulposus) were defined and T2-maps were measured. Analysis consisted of unpaired t-test, paired t-test, propensity-score matching (adjusting for age and sex), and Pearson correlation. Twenty-five individuals (15 [60.0%] males) with a mean age of 29.6 (standard deviation [SD 6.9]) years were analyzed. Both groups (WL: n = 12 versus [vs.] NWL: n = 13) did not differ demographic characteristics. Mean IVD T2-values of all participants significantly decreased throughout the day (95.7 [SD 15.7] vs. 86.4 [SD 13.9] milliseconds [ms]) in IVDs of the cervical (71.8 [SD 13.4] vs. 64.4 [SD 14.1] ms), thoracic (98.8 [SD 19.9] vs. 88.6 [SD 16.3] ms), and lumbar (117.0 [SD 23.7] vs. 107.5 [SD 21.6] ms) spine (P < 0.001 each). There were no differences between both groups in the morning (P = 0.635) and throughout the day (P = 0.681), even after adjusting for confounders. It can be concluded that diurnal changes of the IVDs occurred in the entire (including cervical and thoracic) spine. WL and NWL showed similar morning baseline T2-values and diurnal changes. Weightlifting may not negatively affect IVDs chronically or acutely.
The prognostic significance of VISTA and CD33-positive myeloid cells in cutaneous melanoma and their relationship with PD-1 expression
Authors: Choi Jae Won , Kim Young Jae , Yun Kyung A. , Won Chong Hyun , Lee Mi Woo , Choi Jee Ho , Chang Sung Eun , Lee Woo Jin
Published: September 2020

V-domain Ig suppressor of T-cell activation (VISTA), which mediates immune evasion in cancer, is mainly expressed on hematopoietic cells and myeloid cells in the tumor. We evaluated correlations among the expression of VISTA, the myeloid-derived suppressor cell marker CD33, and programmed death-1 (PD-1), and determined their relationships with clinicopathological characteristics and disease outcomes in melanoma. Diagnostic tissue from 136 cases of melanoma was evaluated by immunohistochemistry for CD33, VISTA, and PD-1 expression. Dual immunofluorescence using CD33 and VISTA antibodies was performed. VISTA expression positively correlated with CD33 expression in melanoma tissue. Dual immunofluorescence staining revealed that VISTA was expressed by CD33-positive myeloid cells. PD-1 expression correlated with CD33 and VISTA expression. CD33 and VISTA expression were significantly associated with negative prognostic factors, including a deeper Breslow thickness and an advanced stage of disease. High expression of either CD33 or VISTA was associated with worse survival. Positivity for both VISTA and PD-1 predicted worse survival. Multivariate analysis showed that both CD33 and VISTA expression were independent prognostic factors in cutaneous melanoma. VISTA and CD33 expression are independent unfavourable prognostic factors in melanoma, which suggests their potential as therapeutic targets.
Auditory cognition and perception of action video game players
Authors: Stewart Hannah J. , Martinez Jasmin L. , Perdew Audrey , Green C. Shawn , Moore David R.
Published: September 2020

A training method to improve speech hearing in noise has proven elusive, with most methods failing to transfer to untrained tasks. One common approach to identify potentially viable training paradigms is to make use of cross-sectional designs. For instance, the consistent finding that people who chose to avidly engage with action video games as part of their normal life also show enhanced performance on non-game visual tasks has been used as a foundation to test the causal impact of such game play via true experiments (e.g., in more translational designs). However, little work has examined the association between action video game play and untrained auditory tasks, which would speak to the possible utility of using such games to improve speech hearing in noise. To examine this possibility, 80 participants with mixed action video game experience were tested on a visual reaction time task that has reliably shown superior performance in action video game players (AVGPs) compared to non-players (≤ 5 h/week across game categories) and multi-genre video game players (> 5 h/week across game categories). Auditory cognition and perception were tested using auditory reaction time and two speech-in-noise tasks. Performance of AVGPs on the visual task replicated previous positive findings. However, no significant benefit of action video game play was found on the auditory tasks. We suggest that, while AVGPs interact meaningfully with a rich visual environment during play, they may not interact with the games’ auditory environment. These results suggest that far transfer learning during action video game play is modality-specific and that an acoustically relevant auditory environment may be needed to improve auditory probabilistic thinking.
Post-transcriptional modulation of cytochrome P450s, Cyp6g1 and Cyp6g2, by miR-310s cluster is associated with DDT-resistant Drosophila melanogaster strain 91-R
Authors: Seong Keon Mook , Coates Brad S. , Pittendrigh Barry R.
Published: September 2020

The role of miRNAs in mediating insecticide resistance remains largely unknown, even for the model species Drosophila melanogaster. Building on prior research, this study used microinjection of synthetic miR-310s mimics into DDT-resistant 91-R flies and observed both a significant transcriptional repression of computationally-predicted endogenous target P450 detoxification genes, Cyp6g1 and Cyp6g2, and also a concomitant increase in DDT susceptibility. Additionally, co-transfection of D. melanogaster S2 cells with dual luciferase reporter constructs validated predictions that miR-310s bind to target binding sites in the 3ʹ untranslated regions (3ʹ-UTR) of both Cyp6g1 and Cyp6g2 in vitro. Findings in the current study provide empirical evidence for a link between reduced miRNA expression and an insecticidal resistance phenotype through reduced targeted post-transcriptional suppression of transcripts encoding proteins involved in xenobiotic detoxification. These insights are important for understanding the breadth of adaptive molecular changes that have contributed to the evolution of DDT resistance in D. melanogaster.
Substitution of Thr572 to Ala in mouse c-Myb attenuates progression of early erythroid differentiation
Authors: Kitagawa Kyoko , Uchida Chiharu , Horiguchi Ryo , Ohhata Tatsuya , Sakai Satoshi , Niida Hiroyuki , Yasumoto Shuhei , Handa Yukino , Suzuki Moena , Hashimoto Masako , Tazawa Toshiyasu , Yokochi Yuta , Tsuji Mayumi , Kitagawa Masatoshi
Published: September 2020

The expression level of transcription factor c-Myb oscillates during hematopoiesis. Fbw7 promotes ubiquitin-mediated degradation of c-Myb, which is dependent on phosphorylation of Thr572. To investigate the physiological relevance of Fbw7-mediated c-Myb degradation, we generated mutant mice carrying c-Myb-T572A (TA). Homozygous mutant (TA/TA) mice exhibited a reduction in the number of peripheral red blood cells and diminished erythroblasts in bone marrow, presumably as a result of failure during erythroblast differentiation. We found that c-Myb high-expressing cells converged in the Lin−CD71+ fraction, and the expression of c-Myb was higher in TA/TA mice than in wild-type mice. Moreover, TA/TA mice had an increased proportion of the CD71+ subset in Lin− cells. The c-Myb level in the Lin−CD71+ subset showed three peaks, and the individual c-Myb level was positively correlated with that of c-Kit, a marker of undifferentiated cells. Ultimately, the proportion of c-Mybhi subgroup was significantly increased in TA/TA mice compared with wild-type mice. These results indicate that a delay in reduction of c-Myb protein during an early stage of erythroid differentiation creates its obstacle in TA/TA mice. In this study, we showed the T572-dependent downregulation of c-Myb protein is required for proper differentiation in early-stage erythroblasts, suggesting the in vivo significance of Fbw7-mediated c-Myb degradation.
Toward a nanopaper-based and solid phase immunoassay using FRET for the rapid detection of bacteria
Authors: Heli Bentolhoda , Ajji Abdellah
Published: September 2020

In this study, we propose a novel sensitive solid-based immunosensor developed on a plasmonic nanopaper platform for the detection of Escherichia coli (E. coli) bacteria. This plasmonic nanopaper that comprises of carboxylated bacterial cellulose (CBC) impregnated with gold nanoparticles (AuNP-CBC), employed as a quencher and a sustainable functionalized platform to be conjugated with protein A. Thus, the conjugated protein A allows the aligned linkage of EAb-QD (anti-E. coli conjugated quantum dot) and EAb-AF (anti-E. coli conjugated Alexa Fluor 488). Interestingly, once E. coli was captured by the AuNP-CBC/EAb-QD or AuNP-CBC/EAb-AF, the energy transfer from the QD or Alexa Fluor fluorophores is triggered due to the conformational change in the antibody structure and this, in turn, causes a decrease in the distance between fluorophores and the quencher nanopaper and, therefore diminishing their photoluminescence. The immunosensors performed successfully to recognize E. coli at concentrations as low as 50 CFU mL−1 in the standard buffer. The examined functionality of the immunosensors in a real matrix such as chicken extract and lettuce juice demonstrated a highly efficient response while QD is the main fluorophore with a limit of detection around 100 CFU mL−1.
3-T T2 mapping magnetic resonance imaging for biochemical assessment of normal and damaged glenoid cartilage: a prospective arthroscopy-controlled study
Authors: Wuennemann Felix , Kintzelé Laurent , Braun Alexander , Zeifang Felix , Maier Michael W. , Burkholder Iris , Weber Marc-André , Kauczor Hans-Ulrich , Rehnitz Christoph
Published: September 2020

This study evaluated the ability of T2 mapping to assess the glenoid cartilage using arthroscopy as the gold standard. Eighteen consecutive patients (mean age: 52.4 ± 14.72 years, including 12 men) with shoulder pain underwent T2 mapping at 3-T with subsequent shoulder arthroscopy. With correlation to cartilage-sensitive morphologic sequences regions-of-interest were placed in the corresponding T2 maps both in normal-appearing cartilage and focal cartilage lesions using a quadrant-wise approach. Inter-reader and intra-reader correlation coefficients (ICCs) between two independent radiologists as well as cut-off values with their sensitivities/specificities for the detection of cartilage damage were calculated. The mean T2 value for healthy cartilage was 23.0 ± 3 ms with significantly higher values in the superior quadrants compared to the inferior quadrants (p < 0.0001). In 5 patients with focal cartilage damage significantly higher T2 values of 44.7 ± 3.7 ms (P < 0.01) were observed. The maximum T2 value in normal cartilage (27.3 ms) was lower than the minimum value in damaged cartilage (40.8 ms) resulting in perfect sensitivities/specificities of 100% (95% confidence-interval 47.8–100.0) for all cut-off values between 27.3–40.8 ms. ICCs ranged between 0.63 and 0.99. In conclusion, T2 mapping can evaluate biochemical cartilage integrity and discriminates arthroscopy-proven healthy and damaged glenoid cartilage with high diagnostic performance.
Adipose-derived exosomal miR-210/92a cluster inhibits adipose browning via the FGFR-1 signaling pathway in high-altitude hypoxia
Authors: Zhang Yifan , Song Kang , Qi Gang , Yan Ranran , Yang Yanqing , Li Yan , Wang Shunjuan , Bai Zhenzhong , Ge Ri-li
Published: September 2020

Cold and hypoxia are critical drivers of adaptation to high altitudes. Organisms at high altitudes have adapted to maximize the efficiency of oxygen utilization and are less prone to obesity and diabetes than those at low altitudes. Brown adipose tissue (BAT) dissipates energy in the form of heat in both humans and rodents; it also serves to regulate metabolism to curb obesity. However, the role of BAT in high-altitude populations is poorly understood. Serum exosomes can be easily obtained, enabling the study of BAT functions and identification of biomarkers in serum exosomes, both of which contribute to understanding the role of BAT in high-altitude populations. 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography integrated with computed tomography (PET/CT) is the gold standard for studying BAT in human adults. Here, we studied BAT in healthy high-altitude populations via PET/CT and serum exosomal microRNAs (miRNAs). The observations were validated in mouse tissues and demonstrated that high-altitude hypoxia activated BAT through attenuated white adipose tissue (WAT) secreted exosomal miR-210/92a, which enhanced the FGFR-1 expression in BAT.