bluuebunny/crossref_metadata_2025 huggingface dataset:
A Buddhist reconfiguration of John Hick's pluralistic hypothesis: a Madhyamaka perspective
Authors: ZHAO XUAN
Published: July 2020

In presenting his theory of religious pluralism, John Hick discussed the Buddhist concept ofśūnyatā, emptiness, which he regarded as functionally equivalent to his postulated noumenal Real. This article introduces Hick's pluralistic hypothesis and reviews the major criticisms of his theory. It then investigates Hick's understanding ofśūnyatā, before arguing that a Madhyamaka interpretation ofśūnyatā, within the context of the Buddhist theory of ‘two truths’, differs considerably from Hick's understanding. The article suggests that the Madhyamaka interpretation ofśūnyatācan be used to reconfigure Hick's pluralistic hypothesis, thereby avoiding the major criticisms Hickian pluralism faces, for it provides a new way of thinking about the relation between ultimate reality and the reality that we experience.
The Yiddish Art Theatre in Paris after the Holocaust, 1944–1950
Authors: Underwood Nick
Published: July 2020

Almost as soon as Paris was liberated from Nazi Occupation on 25 August 1944, Yiddish actors took back the stages on which they had once performed. In fact, on 20 December 1944, while war and the Holocaust still raged, a small cohort of actors produced what they advertised in theNaye preseas the “first grand performance by the‘Yiddish folks-bine.’” This performance was to take place at the four-hundred-seat Théâtre Lancry, a performance space located in Paris's 10th arrondissement, not far from the Place de la République and the Marais. “Lancry,” as it was known, had played host to Yiddish theatre as early as 1903 and, during the interwar years, it was the center of Parisian Yiddish cultural activity: dozens of theatre performances occurred there and it was where the Kultur-lige pariz was based, among other institutions. During the postwar years, it also went by the name Théâtre de la République after 1947 and Théâtre du Nouveau-Lancry after 1951, but many still referred to it simply as “Lancry.”
The trends and developments of L2 Japanese research in the 2010s
Authors: Mori Yoshiko , Hasegawa Atsushi , Mori Junko
Published: July 2020

This article updates the trends and developments of Japanese as a second language (JSL) research since Mori and Mori (2011) by reviewing nearly 200 selected empirical studies published in English or Japanese between 2010 and early 2019. The first section of this review examines the cognitive aspects of second language (L2) Japanese development, focusing on vocabulary and kanji (i.e., Chinese characters transferred into Japanese) learning, syntactic development, and the issues surrounding reading and writing. The second part investigates sociocultural issues in L2 Japanese development and use, including pragmatic development, multilingual/translingual perspectives, and multilingual youth. The third section explores the role of affective variables (primarily learner motivation) in L2 Japanese development. The last section considers various pedagogical issues, including corpus-based studies and the development of materials and resources, instructional designs and classroom studies, technology-enhanced language learning and new instructional models, critical approaches to teaching Japanese and content-based instruction. The review of these themes illuminates trends and emerging areas of interest in post-2010 L2 Japanese research inspired by current developments in applied linguistics and second language acquisition (SLA) research, as well as unique features of Japanese language and sociocultural contexts.
Application of evidence-informed deliberative processes in health technology assessment in low- and middle-income countries
Authors: Oortwijn Wija , van Oosterhout Sanne , Kapiriri Lydia
Published: July 2020

Objectives

Evidence-informed deliberative processes (EDPs) were introduced to guide health technology assessment (HTA) agencies to improve their processes toward more legitimate decision making. A survey among members of the International Network of Agencies for HTA (INAHTA) showed that EDPs can also be relevant for countries that have not (yet) established such an agency. Therefore, we explored to what extent low- and middle-income countries (LMIC) applied the steps and elements stipulated in the EDP framework and their need for guidance.

Methods

The survey among INAHTA members was slightly adapted to address LMIC context and sent to 416 experts identified through several HTA sources. The questions focused on contextual factors and the EDP steps (installation of an appraisal committee, selecting technologies and criteria, assessment, appraisal, communication and appeal). Data collection took place between 21 May and 1 September 2019. Descriptive statistics and qualitative analyses were used to summarize the findings.

Results

We received sixty-six meaningful responses from experts in thirty-two LMIC. We found that contextual factors to support HTA development are overall not present or only present to some extent. Respondents indicated that guidance was needed for specific elements related to selecting technologies and criteria, assessment, appraisal, as well as communication and appeal.

Conclusions

EDPs have the potential to provide steps for improving HTA processes. The results of this study can serve as a baseline measurement for future monitoring and evaluation of EDP application in the responding LMIC. This could support the countries in improving their processes and enhancing legitimate decision making when using HTA.
Prevention and control mechanism for coronavirus disease 2019 epidemic at the primary level: perspective from China
Authors: Zhang Xiaoyan , Wang Yuxuan
Published: July 2020

After the 2003 SARS epidemic, China started constructing a primary-level emergency response system and focused on strengthening and implementation of policies, resource allocation. After 17 years of restructuring, China's primary-level response capabilities towards public health emergencies have greatly improved. During the coronavirus disease 2019 epidemic, primary-level administrative and medical personnel, social organisations, volunteers, etc. have played a significant role in providing professional services utilising the primary-level emergency response system of 17 years. However, China's organisations did not learn their lesson from the SARS epidemic, and certain problems are exposed in the system. By analysing the experience and shortcomings of China's disease prevention and control system at the primary level, we can focus on the development of disease control systems for major epidemics in the future.
Contribution of acute-phase reaction proteins to the diagnosis and treatment of 2019 novel coronavirus disease (COVID-19)
Authors: Li Lu , Chen Changzheng
Published: July 2020

The emergence of 2019 novel coronavirus disease (COVID-19) is currently a global concern. In this study, our goal was to explore the changing expression levels of acute-phase reaction proteins (APRPs) in the serum of COVID-19 patients and to elucidate the immunological characteristics of COVID-19. In the study design, we recruited 72 COVID-19 patients, including 22 cases of mild degree, 38 cases of moderate degree and 12 cases of severe degree. We also recruited 20 patients with community-acquired pneumonia (CAP) and 20 normal control subjects as a comparison. Fasting venous blood was taken to detect the content of complement 3 (C3), complement 4 (C4), C-reactive protein (CRP), serum amyloid A (SAA) and prealbumin (PA). When compared the COVID-19 group with the CAP and normal control groups, respectively, the mean value of CRP and SAA in the COVID-19 group (including mild, moderate and severe patients) had increased significantly (P < 0.01), whereas the mean values of C3, C4 and PA decreased (P < 0.01). For the asymptomatic or mild symptomatic patients with COVID-19, the actual aggravation of disease may be more advanced than the clinical appearances. Meanwhile, the statistical analyses indicated that the development of COVID-19 brought about a significant increase in the content of CRP and SAA (P < 0.01), and a decline in the content of C3, C4 and PA (P < 0.01). These findings suggested that the changes in the level of APRPs could be used as indicators to identify the degree and progression of COVID-19, and the significant changes might demonstrate the aggravation of disease. This study provided a new approach to improve the clinical management plan and prognosis of COVID-19.
Geographical variation in case fatality rate and doubling time during the COVID-19 pandemic
Authors: Mazumder A. , Arora M. , Sra M. S. , Gupta A. , Behera P. , Gupta M. , Agarwal M. , Rao A. , Mohanta R. , Parameswaran G. G. , Lohiya A. , Shewade H. D.
Published: July 2020

Case fatality rate (CFR) and doubling time are important characteristics of any epidemic. For coronavirus disease 2019 (COVID-19), wide variations in the CFR and doubling time have been noted among various countries. Early in the epidemic, CFR calculations involving all patients as denominator do not account for the hospitalised patients who are ill and will die in the future. Hence, we calculated cumulative CFR (cCFR) using only patients whose final clinical outcomes were known at a certain time point. We also estimated the daily average doubling time. Calculating CFR using this method leads to temporal stability in the fatality rates, the cCFR stabilises at different values for different countries. The possible reasons for this are an improved outcome rate by the end of the epidemic and a wider testing strategy. The United States, France, Turkey and China had high cCFR at the start due to low outcome rate. By 22 April, Germany, China and South Korea had a low cCFR. China and South Korea controlled the epidemic and achieved high doubling times. The doubling time in Russia did not cross 10 days during the study period.
Voice quality and coda /r/ in Glasgow English in the early 20th century
Authors: Sóskuthy Márton , Stuart-Smith Jane
Published: July 2020

We present acoustic and auditory analyses of changes to coda /r/ and voice quality in Glasgow English in the early twentieth century. Our initial acoustic analysis suggests that /r/ was weakening across the board based on an increase in F3. However, an auditory analysis of the same data finds no significant changes. An acoustic analysis of the same speakers’ vowels reveals that the shift in F3 is not unique to /r/. It reflects a change in voice quality, which we link to velarization using Vocal Profile Analysis. We then reanalyze the acoustic /r/ data, controlling for voice quality, and find only moderate changes that are restricted to females. These findings provide new evidence for diachronic changes in voice quality, contribute to our understanding of the development of /r/ in Glasgow English, and highlight the importance of investigating speech sounds in their broader context using multiple methodologies.
Effects of metformin on epicardial adipose tissue and atrial electromechanical delay of obese children with insulin resistance
Authors: Güneş Hatice , Güneş Hakan , Özmen Şebnem , Çelik Enes , Temiz Fatih
Published: July 2020

Introduction:

Obesity is usually related to insulin resistance and glucose metabolism disorders. The relationship between insulin resistance and epicardial adipose tissue and atrial electromechanical delay has been described in previous studies.

Aim:

This study aims to demonstrate the effects of metformin on epicardial adipose tissue and electromechanical delay in patients using metformin for insulin resistance.

Materials and methods:

A total of 30 patients using metformin for insulin resistance were included in the study. Pre-treatment and post-treatment epicardial adipose tissue and electromechanical delay were evaluated.

Results:

There was a statistically significant decrease in epicardial adipose tissue thickness after 3 months of metformin therapy (6.4 ± 2.1 versus 4.7 ± 2.0; p = 0.008). Furthermore, the inter-atrial and intra-atrial electromechanical delay also significantly decreased after 3 months of metformin monotherapy (23.6 ± 8.2 versus 18.1 ± 5.8; p < 0.001, 9.1 ± 2.9 versus 6.3 ± 3.6; p = 0.003, respectively).

Conclusion:

In this study, we show that metformin monotherapy significantly decreases epicardial adipose tissue thickness and electromechanical delay in obese children.
A case of double-outlet left ventricle, malposition of the great arteries, and superior–inferior ventricular arrangement
Authors: Palma Andreia , Henriques Cláudio , Silva Patrícia V. , Francisco Andreia , Pires António
Published: July 2020

Superior–inferior ventricular arrangement with double-outlet left ventricle and malposition of the great arteries is an extremely rare congenital cardiac anomaly. The authors present the case of an infant who presented with cyanosis and respiratory distress. To the best of our knowledge, this is the first case reported.
Spatial Distribution and Impacts of Aerosols on Clouds Under Meiyu Frontal Weather Background Over Central China Based on Aircraft Observations
Authors: Yang Junmei , Li Junxia , Li Peiren , Sun Guode , Cai Zhaoxin , Yang Xiao , Cui Chunguang , Dong Xiquan , Xi Baike , Wan Rong , Wang Bin , Zhou Zhimin
Published: July 2020

An airborne field campaign was conducted from 10 June to 10 July 2018 in Hubei Province over central China as a part of the State Key Natural Science Foundation Project referred to as Integrative Monsoon Frontal Rainfall Experiment (IMFRE). Comprehensive observations of atmospheric aerosols and cloud characteristics in this region were collected and analyzed. In this study, data from six flights on nonprecipitating days were selected to investigate the spatial distribution of aerosols and microphysical properties of clouds. The profiles of aerosol number concentrations (Na) were 1 order of magnitude lower than those over the North Plain of China, due to the different atmospheric backgrounds, local emission, and long‐range transport. The highest Na occurred at the altitude of the temperature inversion layer (TIL), indicating that Na profiles were significantly affected by the TIL structure. Relative humidity (RH) had an effect on the aerosol size distribution where high RH values corresponded well with large values of particle mean diameter (MD). Compared with the vertical distributions of Na and MD, their horizontal directions had minor changes, except for the MD at 4,000 m in one case. Of the three flights that penetrated through the stratiform clouds, the probability distribution functions of cloud droplet number concentration (Nc), effective radius (re), and liquid water content (LWC), showed the same features with a single peak mode. Since the nucleation of aerosol in‐cloud caused the decrease of aerosol concentration, the maximum aerosol activation ratio almost reached 74%. The average spectrum of cloud droplets showed a multimodal distribution and their microphysical properties were analyzed in this study.
The ECCO‐Darwin Data‐Assimilative Global Ocean Biogeochemistry Model: Estimates of Seasonal to Multidecadal Surface Ocean pCO2 and Air‐Sea CO2 Flux
Authors: Carroll D. , Menemenlis D. , Adkins J. F. , Bowman K. W. , Brix H. , Dutkiewicz S. , Fenty I. , Gierach M. M. , Hill C. , Jahn O. , Landschützer P. , Lauderdale J. M. , Liu J. , Manizza M. , Naviaux J. D. , Rödenbeck C. , Schimel D. S. , Van der Stocken T. , Zhang H.
Published: July 2020

Quantifying variability in the ocean carbon sink remains problematic due to sparse observations and spatiotemporal variability in surface ocean pCO2. To address this challenge, we have updated and improved ECCO‐Darwin, a global ocean biogeochemistry model that assimilates both physical and biogeochemical observations. The model consists of an adjoint‐based ocean circulation estimate from the Estimating the Circulation and Climate of the Ocean (ECCO) consortium and an ecosystem model developed by the Massachusetts Institute of Technology Darwin Project. In addition to the data‐constrained ECCO physics, a Green's function approach is used to optimize the biogeochemistry by adjusting initial conditions and six biogeochemical parameters. Over seasonal to multidecadal timescales (1995–2017), ECCO‐Darwin exhibits broad‐scale consistency with observed surface ocean pCO2 and air‐sea CO2 flux reconstructions in most biomes, particularly in the subtropical and equatorial regions. The largest differences between CO2 uptake occur in subpolar seasonally stratified biomes, where ECCO‐Darwin results in stronger winter uptake. Compared to the Global Carbon Project OBMs, ECCO‐Darwin has a time‐mean global ocean CO2 sink (2.47 ± 0.50 Pg C year−1) and interannual variability that are more consistent with interpolation‐based products. Compared to interpolation‐based methods, ECCO‐Darwin is less sensitive to sparse and irregularly sampled observations. Thus, ECCO‐Darwin provides a basis for identifying and predicting the consequences of natural and anthropogenic perturbations to the ocean carbon cycle, as well as the climate‐related sensitivity of marine ecosystems. Our study further highlights the importance of physically consistent, property‐conserving reconstructions, as are provided by ECCO, for ocean biogeochemistry studies.
Upper Mantle Shear Wave Velocity Structure of Southeastern China: Seismic Evidence for Magma Activities in the Late Mesozoic to the Cenozoic
Authors: Zhang Yayun , Yao Huajian , Xu Min , Liu Bin
Published: July 2020

The Fujian‐Taiwan Strait‐Taiwan region, as the active eastern margin of Eurasia since the Mesozoic, has experienced the subduction and retreat of the Paleo‐Pacific plate from the Middle Mesozoic, the breakup of the continental margin in the early Cenozoic, and then the collision with the Philippine Sea plate in the late Cenozoic. To better understand the tectonic evolution process, a high‐resolution 3‐D shear wave velocity model of the crust and upper mantle was obtained from surface wave tomography through a direct inversion method. Intermediate‐ to long‐period Rayleigh wave dispersion curves, extracted from teleseismic surface wave with the traditional two‐station method, were combined with the short‐period dispersion curves obtained from ambient noise cross correlation to obtain broader band surface wave data. Two groups of large‐scale low‐velocity bodies are found to be located in the upper mantle of Fujian and the Taiwan Strait and are inferred to be closely related to the magmatic activities caused by the Mesozoic subduction and Cenozoic extension, respectively. The low‐velocity anomalies in Fujian are concentrated in the west Cathaysia block in deep regions and split into small bodies in the uppermost mantle, while the low‐velocity body in the strait is divided into northern and southern parts, corresponding to the two‐stage Cenozoic extension. The velocity gradient was also calculated to estimate the lithospheric thickness, which is only 60–80 km, and the lithosphere‐asthenosphere boundary also features strongly horizontal variations and discontinuities. Our results provide important seismological constraints to investigate the geological and tectonic processes of this region.
Assessing the Effects of the Hong Kong‐Zhuhai‐Macau Bridge on the Total Suspended Solids in the Pearl River Estuary Based on Landsat Time Series
Authors: Guo Jin , Ma Chunlei , Ai Bin , Xu Xiaoping , Huang Wei , Zhao Jun
Published: July 2020

Total suspended solids (TSSs) can affect primary production through influencing light penetration and nutrient availability in aquatic environments. In this study, novel algorithms were developed for TSS in the Pearl River estuary using Landsat‐derived reflectance corrected for Rayleigh scattering (Rrc). Comparisons between in situ and estimated TSS using the calibration and validation data sets resulted in R2s > 0.8 and mean absolute percentage errors < 35%. Landsat‐derived annual TSS between 1987 and 2018 in the Pearl River estuary ranged from 16.5 to 41 mg L−1. It indicated a statistically significant decreasing trend with an annual rate of 0.26 mg L−1 and decreased by 58.5% from 1987 to 2018. It showed a higher decreasing rate after than before the construction of the Hong Kong‐Zhuhai‐Macau Bridge. Nonetheless, TSS 2 km upstream from the Hong Kong‐Zhuhai‐Macau Bridge on the western side increased after the construction of the bridge related to the change of flow influenced by piers and artificial islands.
Satellite Retrieval of Cloud Condensation Nuclei Concentrations in Marine Stratocumulus by Using Clouds as CCN Chambers
Authors: Efraim Avichay , Rosenfeld Daniel , Schmale Julia , Zhu Yannian
Published: July 2020

A new methodology for the satellite retrieval of cloud condensation nuclei (CCN) in shallow marine boundary layer clouds is developed and validated in this study. The methodology is based on retrieving cloud base drop concentrations (Nd) and updrafts (Wb), which are used for calculating the supersaturation (S). The Nd is then defined as the CCN at that S. The accuracy of the satellite retrievals was validated against ship‐borne measurements of CCN done in recent campaigns in the Southern Oceans (ACE‐SPACE, MARCUS, & PEGASO [2015–2018]) and in the subtropics (MAGIC [2012–2013]). The satellite‐retrieved Nd and S at cloud base were validated against the measured CCN at sea surface. The main findings show that (a) coupled clouds have good agreement between satellite retrievals and ship measurements of CCN; (b) the best agreement is achieved when using the brightest 10% of the clouds and accounting for their adiabatic fraction; (c) most of the decoupled clouds had much lower CCN than were present at the underlying surface. This means that most CCN in the coupled clouds originate from the surface and not from the free troposphere. This study validates the satellite retrievals of CCN and allows us to further quantify the relationships between CCN and cloud microphysical properties.
First Lidar Observations of Quasi‐Biennial Oscillation‐Induced Interannual Variations of Gravity Wave Potential Energy Density at McMurdo via a Modulation of the Antarctic Polar Vortex
Authors: Li Zimu , Chu Xinzhao , Harvey V. Lynn , Jandreau Jackson , Lu Xian , Yu Zhibin , Zhao Jian , Fong Weichun
Published: July 2020

This work presents the first lidar observations of a Quasi‐Biennial Oscillation (QBO) in the interannual variations of stratospheric gravity wave potential energy density (Epm in 30–50 km) at McMurdo (77.84°S, 166.67°E), Antarctica. This paper also reports the first identification of QBO signals in the distance between McMurdo and the polar vortex edge. Midwinter stratospheric gravity wave activity is stronger during the QBO easterly phase when the June polar vortex expands and the polar night jet shifts equatorward. During the QBO westerly phase, gravity wave activity is weaker when the polar vortex contracts and the polar night jet moves poleward. Nine years of lidar data (2011–2019) exhibit the mean Epm winter maxima being ~43% higher during QBO easterly than westerly. The June polar vortex edge at 45 km altitude moves equatorward/poleward during QBO easterly/westerly phases with ~8° latitude differences (39.7°S vs. 47.7°S) as revealed in 21 years of MERRA‐2 data (1999–2019). We hypothesize that an equatorward shifted polar vortex corresponds to less critical level filtering of gravity waves and thus higher Epm at McMurdo. The critical level filtering is characterized by wind rotation angle (WRA), and we find a linear correlation between the WRA and Epm interannual variations. The results suggest that the QBO is likely controlling the interannual variations of the Epm winter maxima over McMurdo via the critical level filtering. This observationally based study lays the groundwork for a rigorous numerical study that will provide robust statistics to better understand the mechanisms that link the tropical QBO to extratropical waves.
Longitudinal monitoring of circulating tumour DNA improves prognostication and relapse detection in gastroesophageal adenocarcinoma
Authors: Openshaw Mark R. , Suwaidan Ali Abdulnabi , Ottolini Barbara , Fernandez-Garcia Daniel , Richards Cathy J. , Page Karen , Guttery David S. , Thomas Anne L. , Shaw Jacqui A.
Published: July 2020

Background

Gastroesophageal adenocarcinoma (GOA) has poor clinical outcomes and lacks reliable blood markers. Here we present circulating tumour DNA (ctDNA) as an emerging biomarker.

Methods

Forty patients (17 palliative and 23 curative) were followed by serial plasma monitoring. Primary tumour DNA was analysed by targeted next-generation sequencing to identify somatic single-nucleotide variants (SNVs), and Nanostring nCounter® to detect copy number alterations (CNAs). Patient-specific SNVs and CNA amplifications (CNAamp) were analysed in plasma using digital droplet PCR and quantitative PCR, respectively.

Results

Thirty-five patients (13 palliative, 22 curative) had ≥1 SNVs and/or CNAamp detected in primary tumour DNA suitable for tracking in plasma. Eighteen of 35 patients (nine palliative, nine curative) had ≥1 ctDNA-positive plasma sample. Detection of postoperative ctDNA predicted short RFS (190 vs 934 days, HR = 3.7, p = 0.028) and subsequent relapse (PPV for relapse 0.83). High ctDNA levels (>60.5 copies/ml) at diagnosis of metastatic disease predicted poor OS (90 vs 372 days, HR = 11.7 p < 0.001).

Conclusion

Sensitive ctDNA detection allows disease monitoring and prediction of short OS in metastatic patients. Presence of ctDNA postoperatively predicts relapse and defines a ‘molecular relapse’ before overt clinical disease. This lead time defines a potential therapeutic window for additional anticancer therapy.
A simple method for detecting oncofetal chondroitin sulfate glycosaminoglycans in bladder cancer urine
Authors: Clausen Thomas Mandel , Kumar Gunjan , Ibsen Emilie K. , Ørum-Madsen Maj S. , Hurtado-Coll Antonio , Gustavsson Tobias , Agerbæk Mette Ø. , Gatto Francesco , Todenhöfer Tilman , Basso Umberto , Knowles Margaret A. , Sanchez-Carbayo Marta , Salanti Ali , Black Peter C. , Daugaard Mads
Published: July 2020

Proteoglycans in bladder tumors are modified with a distinct oncofetal chondroitin sulfate (ofCS) glycosaminoglycan that is normally restricted to placental trophoblast cells. This ofCS-modification can be detected in bladder tumors by the malarial VAR2CSA protein, which in malaria pathogenesis mediates adherence of parasite-infected erythrocytes within the placenta. In bladder cancer, proteoglycans are constantly shed into the urine, and therefore have the potential to be used for detection of disease. In this study we investigated whether recombinant VAR2CSA (rVAR2) protein could be used to detect ofCS-modified proteoglycans (ofCSPGs) in the urine of bladder cancer patients as an indication of disease presence. We show that ofCSPGs in bladder cancer urine can be immobilized on cationic nitrocellulose membranes and subsequently probed for ofCS content by rVAR2 protein in a custom-made dot-blot assay. Patients with high-grade bladder tumors displayed a marked increase in urinary ofCSPGs as compared to healthy individuals. Urine ofCSPGs decreased significantly after complete tumor resection compared to matched urine collected preoperatively from patients with bladder cancer. Moreover, ofCSPGs in urine correlated with tumor size of bladder cancer patients. These findings demonstrate that rVAR2 can be utilized in a simple biochemical assay to detect cancer-specific ofCS-modifications in the urine of bladder cancer patients, which may be further developed as a noninvasive approach to detect and monitor the disease.
Molecular subtyping and genomic profiling expand precision medicine in refractory metastatic triple-negative breast cancer: the FUTURE trial
Authors: Jiang Yi-Zhou , Liu Yin , Xiao Yi , Hu Xin , Jiang Lin , Zuo Wen-Jia , Ma Ding , Ding Jiahan , Zhu Xiaoyu , Zou Jianjun , Verschraegen Claire , Stover Daniel G. , Kaklamani Virginia , Wang Zhong-Hua , Shao Zhi-Ming
Published: July 2020

Triple-negative breast cancer (TNBC) is a highly heterogeneous disease, and molecular subtyping may result in improved diagnostic precision and targeted therapies. Our previous study classified TNBCs into four subtypes with putative therapeutic targets. Here, we conducted the FUTURE trial (ClinicalTrials.gov identifier: NCT03805399), a phase Ib/II subtyping-based and genomic biomarker-guided umbrella trial, to evaluate the efficacy of these targets. Patients with refractory metastatic TNBC were enrolled and stratified by TNBC subtypes and genomic biomarkers, and assigned to one of these seven arms: (A) pyrotinib with capecitabine, (B) androgen receptor inhibitor with CDK4/6 inhibitor, (C) anti PD-1 with nab-paclitaxel, (D) PARP inhibitor included, (E) and (F) anti-VEGFR included, or (G) mTOR inhibitor with nab-paclitaxel. The primary end point was the objective response rate (ORR). We enrolled 69 refractory metastatic TNBC patients with a median of three previous lines of therapy (range, 1–8). Objective response was achieved in 20 (29.0%, 95% confidence interval (CI): 18.7%–41.2%) of the 69 intention-to-treat (ITT) patients. Our results showed that immunotherapy (arm C), in particular, achieved the highest ORR (52.6%, 95% CI: 28.9%–75.6%) in the ITT population. Arm E demonstrated favorable ORR (26.1%, 95% CI: 10.2%–48.4% in the ITT population) but with more high grade (≥ 3) adverse events. Somatic mutations of TOP2A and CD8 immunohistochemical score may have the potential to predict immunotherapy response in the immunomodulatory subtype of TNBC. In conclusion, the phase Ib/II FUTURE trial suggested a new concept for TNBC treatment, demonstrating the clinical benefit of subtyping-based targeted therapy for refractory metastatic TNBC.
Prior vaccination with rVSV-ZEBOV does not interfere with but improves efficacy of postexposure antibody treatment
Authors: Cross Robert W. , Bornholdt Zachary A. , Prasad Abhishek N. , Geisbert Joan B. , Borisevich Viktoriya , Agans Krystle N. , Deer Daniel J. , Melody Kevin , Fenton Karla A. , Feldmann Heinz , Sprecher Armand , Zeitlin Larry , Geisbert Thomas W.
Published: July 2020

A replication-competent vesicular stomatitis virus vaccine expressing the Ebola virus (EBOV) glycoprotein (GP) (rVSV-ZEBOV) was successfully used during the 2013-16 EBOV epidemic. Additionally, chimeric and human monoclonal antibodies (mAb) against the EBOV GP have shown promise in animals and humans when administered therapeutically. Uncertainty exists regarding the efficacy of postexposure antibody treatments in the event of a known exposure of a recent rVSV-ZEBOV vaccinee. Here, we model a worst-case scenario using rhesus monkeys vaccinated or unvaccinated with the rVSV-ZEBOV vaccine. We demonstrate that animals challenged with a uniformly lethal dose of EBOV one day following vaccination, and then treated with the anti-EBOV GP mAb MIL77 starting 3 days postexposure show no evidence of clinical illness and survive challenge. In contrast, animals receiving only vaccination or only mAb-based therapy become ill, with decreased survival compared to animals vaccinated and subsequently treated with MIL77. These results suggest that rVSV-ZEBOV augments immunotherapy.
Preferential inhibition of adaptive immune system dynamics by glucocorticoids in patients after acute surgical trauma
Authors: Ganio Edward A. , Stanley Natalie , Lindberg-Larsen Viktoria , Einhaus Jakob , Tsai Amy S. , Verdonk Franck , Culos Anthony , Ghaemi Sajjad , Rumer Kristen K. , Stelzer Ina A. , Gaudilliere Dyani , Tsai Eileen , Fallahzadeh Ramin , Choisy Benjamin , Kehlet Henrik , Aghaeepour Nima , Angst Martin S. , Gaudilliere Brice
Published: July 2020

Glucocorticoids (GC) are a controversial yet commonly used intervention in the clinical management of acute inflammatory conditions, including sepsis or traumatic injury. In the context of major trauma such as surgery, concerns have been raised regarding adverse effects from GC, thereby necessitating a better understanding of how GCs modulate the immune response. Here we report the results of a randomized controlled trial (NCT02542592) in which we employ a high-dimensional mass cytometry approach to characterize innate and adaptive cell signaling dynamics after a major surgery (primary outcome) in patients treated with placebo or methylprednisolone (MP). A robust, unsupervised bootstrap clustering of immune cell subsets coupled with random forest analysis shows profound (AUC = 0.92, p-value = 3.16E-8) MP-induced alterations of immune cell signaling trajectories, particularly in the adaptive compartments. By contrast, key innate signaling responses previously associated with pain and functional recovery after surgery, including STAT3 and CREB phosphorylation, are not affected by MP. These results imply cell-specific and pathway-specific effects of GCs, and also prompt future studies to examine GCs’ effects on clinical outcomes likely dependent on functional adaptive immune responses.
Evaluation of the immunogenicity of prime-boost vaccination with the replication-deficient viral vectored COVID-19 vaccine candidate ChAdOx1 nCoV-19
Authors: Graham Simon P. , McLean Rebecca K. , Spencer Alexandra J. , Belij-Rammerstorfer Sandra , Wright Daniel , Ulaszewska Marta , Edwards Jane C. , Hayes Jack W. P. , Martini Veronica , Thakur Nazia , Conceicao Carina , Dietrich Isabelle , Shelton Holly , Waters Ryan , Ludi Anna , Wilsden Ginette , Browning Clare , Bialy Dagmara , Bhat Sushant , Stevenson-Leggett Phoebe , Hollinghurst Philippa , Gilbride Ciaran , Pulido David , Moffat Katy , Sharpe Hannah , Allen Elizabeth , Mioulet Valerie , Chiu Chris , Newman Joseph , Asfor Amin S. , Burman Alison , Crossley Sylvia , Huo Jiandong , Owens Raymond J. , Carroll Miles , Hammond John A. , Tchilian Elma , Bailey Dalan , Charleston Bryan , Gilbert Sarah C. , Tuthill Tobias J. , Lambe Teresa
Published: July 2020

Clinical development of the COVID-19 vaccine candidate ChAdOx1 nCoV-19, a replication-deficient simian adenoviral vector expressing the full-length SARS-CoV-2 spike (S) protein was initiated in April 2020 following non-human primate studies using a single immunisation. Here, we compared the immunogenicity of one or two doses of ChAdOx1 nCoV-19 in both mice and pigs. Whilst a single dose induced antigen-specific antibody and T cells responses, a booster immunisation enhanced antibody responses, particularly in pigs, with a significant increase in SARS-CoV-2 neutralising titres.
Methane emission from high latitude lakes: methane-centric lake classification and satellite-driven annual cycle of emissions
Authors: Matthews E. , Johnson Matthew S. , Genovese V. , Du J. , Bastviken D.
Published: July 2020

Methane (CH4) is emitted from lakes by several processes: bubbles released from bottom sediments that reach the atmosphere (ebullition); spring release of CH4 trapped in bubbles in and under the ice during fall freeze (bubble release), and diffusion of CH4 from sediments to the surface. Each of these emission routes is highly variable over space and time, and episodic in the extreme, making reliable measurements difficult to carry out. However, lakes are receiving increasing interest for their important contribution to global CH4 emissions. Their area, distribution and emissions respond to interannual and longer-term climate fluctuations and close to half the world’s lake area is in high northern latitudes that are experiencing rapidly-warming temperatures and lengthening thaw periods. We report on a new spatially-explicit data set of lakes > 50°N, classified with methane-relevant criteria. The seasonality of daily CH4 fluxes is driven with satellite observations of thaw timing and duration. We found that observed thaw seasons are 10–30% shorter than those assumed in previous studies. The area of lakes is 1,095 × 103 km2 and total CH4 emission is 13.8–17.7 Tg CH4 year−1: 11.2–14.4 Tg via diffusion and ebullition and 2.6–3.3 Tg from spring release of CH4 stored in bubbles in winter lake ice. This novel suite of data and methodologies provides a unique framework to model CH4 emission from lakes under current, past and future climates.
Hybrid predictor for ground-motion intensity with machine learning and conventional ground motion prediction equation
Authors: Kubo Hisahiko , Kunugi Takashi , Suzuki Wataru , Suzuki Shingo , Aoi Shin
Published: July 2020

The use of strongly biased data generally leads to large distortions in a trained machine learning model. We face this problem when constructing a predictor for earthquake-generated ground-motion intensity with machine learning. The machine learning predictor constructed in this study has an underestimation problem for strong motions, although the data fit on relatively weak ground motions is good. This underestimation problem is caused by the strong bias in available ground-motion records; there are few records of strong motions in the dataset. Therefore, we propose a hybrid approach of machine learning and conventional ground-motion prediction equation. This study demonstrates that this hybrid approach machine learning technology and physical model reduces the underestimation of strong motions and leads to better prediction than either of the individual approaches applied alone.
Comparative efficacy of antitumor necrosis factor agents and tacrolimus in naïve steroid-refractory ulcerative colitis patients
Authors: Kitayama Moto , Akazawa Yuko , Yoshikawa Daisuke , Higashi Shuntaro , Morisaki Tomohito , Oda Hidetoshi , Ikeda Maho , Nakashima Yujiro , Tabuchi Maiko , Hashiguchi Keiichi , Matsushima Kayoko , Yamaguchi Naoyuki , Kondo Hisayoshi , Nakao Kazuhiko , Takeshima Fuminao
Published: July 2020

While retrospective studies have compared the efficacy of anti–tumour necrosis factor (TNF) agents and tacrolimus (TAC) in ulcerative colitis (UC), information regarding first-time use of these agents is limited. The aim of our study was to investigate the short- and long-term efficacy of anti-TNF agents [adalimumab (ADA) and infliximab (IFX)] and TAC in anti-TNF agent- and TAC-naïve steroid-refractory UC patients. We evaluated 150 steroid-refractory UC patients receiving anti-TNF agents (IFX: n = 30, ADA: n = 41) or TAC (n = 79) at eight institutions in Japan. Clinical response rates at 8 weeks were 73.2% and 75.9% while remission rates were 30.1% and 25.3% in the anti-TNF and TAC groups, respectively. Logistic regression analysis showed the male sex and higher C-reactive protein to be independent factors for response to anti-TNF agents and TAC, respectively. Use of TAC was an independent factor for relapse. No differences in response to the treatment or relapse were observed between IFX and ADA. In conclusion, TAC and anti-TNF agents promoted similar short-term effects, but anti-TNF agents ensured better long-term outcomes at first-time treatment of steroid-refractory UC patients.
Molecular evidence for the involvement of cotton GhGLP2, in enhanced resistance to Verticillium and Fusarium Wilts and oxidative stress
Authors: Pei Yakun , Zhu Yutao , Jia Yujiao , Ge Xiaoyang , Li Xiancai , Li Fuguang , Hou Yuxia
Published: July 2020

Germin-like proteins (GLPs) are a diverse and ubiquitous family of plant glycoproteins belonging to the cupin super family; they play considerable roles in plant responses against various abiotic and biotic stresses. Here, we provide evidence that GLP2 protein from cotton (Gossypium hirsutum) functions in plant defense responses against Verticillium dahliae, Fusarium oxysporum and oxidative stress. Purified recombinant GhGLP2 exhibits superoxide dismutase (SOD) activity and inhibits spore germination of pathogens. Virus-induced silencing of GhGLP2 in cotton results in increased susceptibility to pathogens, plants exhibited severe wilt on leaves, enhanced vascular browning and suppressed callose deposition. Transgenic Arabidopsis (Arabidopsis thaliana) plants overexpressing GhGLP2 showed significant resistance to V. dahliae and F. oxysporum, with reduced mycelia growth, increased callose deposition and cell wall lignification at infection sites on leaves. The enhanced tolerance of GhGLP2-transgenic Arabidopsis to oxidative stress was investigated by methyl viologen and ammonium persulfate treatments, along with increased H2O2 production. Further, the expression of several defense-related genes (PDF1.2, LOX2, and VSP1) or oxidative stress-related genes (RbohD, RbohF) was triggered by GhGLP2. Thus, our results confirmed the involvement of GhGLP2 in plant defense response against Verticillium and Fusarium wilt pathogens and stress conditions.
A novel method for identifying and distinguishing Cryptococcus neoformans and Cryptococcus gattii by surface-enhanced Raman scattering using positively charged silver nanoparticles
Authors: Hu Shan , Gu Feng , Chen Min , Wang Chongwen , Li Jia , Yang Jian , Wang Guangyu , Zhou Zhe , Yang Ying
Published: July 2020

There are approximately 1 million cryptococcal infections per year among HIV+ individuals, resulting in nearly 625,000 deaths. Cryptococcus neoformans and Cryptococcus gattii are the two most common species that cause human cryptococcosis. These two species of Cryptococcus have differences in pathogenicity, diagnosis, and treatment. Cryptococcal infections are usually difficult to identify because of their slow growth in vitro. In addition, the long detection cycle of Cryptococcus in clinical specimens makes the diagnosis of Cryptococcal infections difficult. Here, we used positively charged silver nanoparticles (AgNPs+) as a substrate to distinguish between C. neoformans and C. gattii in clinical specimens directly via surface-enhanced Raman scattering (SERS) and spectral analysis. The AgNPs+ self-assembled on the surface of the fungal cell wall via electrostatic aggregation, leading to enhanced SERS signals that were better than the standard substrate negatively charged silver nanoparticles (AgNPs). The SERS spectra could also be used as a sample database in the multivariate analysis via orthogonal partial least-squares discriminant analysis. This novel SERS detection method can clearly distinguish between the two Cryptococcus species using principal component analysis. The accuracy of the training data and test data was 100% after a tenfold crossover validation.
STAGdb: a 30K SNP genotyping array and Science Gateway for Acropora corals and their dinoflagellate symbionts
Authors: Kitchen S. A. , Von Kuster G. , Kuntz K. L. Vasquez , Reich H. G. , Miller W. , Griffin S. , Fogarty Nicole D. , Baums I. B.
Published: July 2020

Standardized identification of genotypes is necessary in animals that reproduce asexually and form large clonal populations such as coral. We developed a high-resolution hybridization-based genotype array coupled with an analysis workflow and database for the most speciose genus of coral,Acropora, and their symbionts. We designed the array to co-analyze host and symbionts based on bi-allelic single nucleotide polymorphisms (SNP) markers identified from genomic data of the two CaribbeanAcroporaspecies as well as their dominant dinoflagellate symbiont,Symbiodinium ‘fitti’.SNPs were selected to resolve multi-locus genotypes of host (called genets) and symbionts (called strains), distinguish host populations and determine ancestry of coral hybrids between Caribbean acroporids. Pacific acroporids can also be genotyped using a subset of the SNP loci and additional markers enable the detection of symbionts belonging to the generaBreviolum, Cladocopium, andDurusdinium. Analytic tools to produce multi-locus genotypes of hosts based on these SNP markers were combined in a workflow called theStandardTools forAcroporidGenotyping (STAG). The STAG workflow and database are contained within a customized Galaxy environment (https://coralsnp.science.psu.edu/galaxy/), which allows for consistent identification of host genet and symbiont strains and serves as a template for the development of arrays for additional coral genera. STAG data can be used to track temporal and spatial changes of sampled genets necessary for restoration planning and can be applied to downstream genomic analyses. Using STAG, we uncover bi-directional hybridization between and population structure within Caribbean acroporids and detect a cryptic Acroporid species in the Pacific.
Molecular characterization of megaplasmids encoding the type VI secretion system in Campylobacter jejuni isolated from chicken livers and gizzards
Authors: Marasini Daya , Karki Anand B. , Bryant John M. , Sheaff Robert J. , Fakhr Mohamed K.
Published: July 2020

Megaplasmids in Campylobacter spp. likely play important roles in antibiotic resistance, virulence, and horizontal gene transfer. In this study, megaplasmids pCJDM202 (119 kb) and pCJDM67L (116 kb) from C. jejuni strains WP2-202 and OD2-67, respectively, were sequenced and characterized. These megaplasmids contained genes for tetracycline resistance [tet(O)], the Type IV secretion system, conjugative transfer and the Type VI secretion system (T6SS). The T6SS genes in Campylobacter plasmids encoded genes and proteins that were similar to those identified in Campylobacter chromosomal DNA. When the megaplasmid pCJDM202 from C. jejuni WP2-202 was transferred via conjugation to C. jejuni NCTC11168 Nal+, transconconjugants acquired tetracycline resistance and enhanced cytotoxicity towards red blood cells. A T6SS mutant of strain WP2-202 was generated and designated Δhcp3; the mutant was significantly impaired in its ability to lyse red blood cells and survive in defibrinated blood. The cytotoxicity of Campylobacter strains towards the human embryonic kidney cell line HEK 293 was not impacted by the T6SS. In summary, the T6SS encoded by Campylobacter megaplasmids mediates lysis of RBCs and likely contributes to survival on retail meats where blood cells are abundant.
A multilevel statistical toolkit to study animal social networks: the Animal Network Toolkit Software (ANTs) R package
Authors: Sosa Sebastian , Puga-Gonzalez Ivan , Hu Fenghe , Pansanel Jérôme , Xie Xiaohua , Sueur Cédric
Published: July 2020

The possible role played by individual attributes, sociodemographic characteristics and/or ecological pressures in the interaction between animals and the development of social relationships between them is of great interest in animal ecology and evolutionary biology. Social Network Analysis is an ideal tool to study these types of questions. The Animal Network Toolkit Software (ANTs) R package was specifically developed to provide all the different social network analysis techniques currently used in the study of animal social networks. This global package enables users to (1) compute global, polyadic and nodal network measures; (2) perform data randomisation: data stream and network (node and link) permutations; (3) perform statistical permutation tests for static or temporal network analyses, and (4) visualise networks. ANTs allows researchers to perform multilevel network analyses ranging from individual network measures to interaction patterns and the analysis of the overall network structure, and carry out static or temporal network analyses without switching between different R packages, thus making a substantial contribution to advances in the study of animal behaviour. ANTs outperforms existing R packages for the computation speed of network measures and permutations.
Rapid isolation of rare targets from large fluid volumes
Authors: Hedde Per Niklas , Bouzin Margaux , Abram Timothy J. , Chen Xiaoming , Toosky Melody N. , Vu Tam , Li Yiyan , Zhao Weian , Gratton Enrico
Published: July 2020

Rapidly isolating rare targets from larger, clinically relevant fluid volumes remains an unresolved problem in biomedicine and diagnosis. Here, we describe how 3D particle sorting can enrich targets at ultralow concentrations over 100-fold within minutes not possible with conventional approaches. Current clinical devices based on biochemical extraction and microfluidic solutions typically require high concentrations and/or can only process sub-milliliter volumes in time. In a proof-of-concept application, we isolated bacteria from whole blood as demanded for rapid sepsis diagnosis where minimal numbers of bacteria need to be found in a 1–10 mL blood sample. After sample encapsulation in droplets and target enrichment with the 3D particle sorter within a few minutes, downstream analyses were able to identify bacteria and test for antibiotic susceptibility, information which is critical for successful treatment of bloodstream infections.