bluuebunny/crossref_metadata_2025 huggingface dataset:
The Sedan Chair vs the Steamboat: The Sichuan Route and the Maritime Route in the making of modern Sino-Tibetan relations
Authors: ZHANG HUASHA
Published: March 2021

This article tells the intertwined tales of two historical routes that testify to the extensive geographical distance and profound political connections between Tibet and China throughout the modern era. In much of the eighteenth and nineteenth centuries, the Sichuan Route operated as the transportation artery upon which the Qing empire depended to maintain authority in Kham and Tibet. It was also the site of a rite of passage for frontier functionaries and a meeting ground between imperial agents and the indigenous population. Despite its destruction after the implosion of the Qing in 1911, the histories and memories of the Sichuan Route continued to influence decision-makers in both China and Tibet in the following decades. The Maritime Route, which emerged in the late nineteenth century with the proliferation of steam transportation in Asia, revolutionized the way in which Tibet connected to China and the rest of the world. It also competed with the Sichuan Route and encouraged the Qing to reconfigure its presence in its non-Chinese territories in the southwest. After the empire fell, political tensions continued to evolve around the Maritime Route, which functioned simultaneously as the reluctant choice of Chinese emissaries and a strategic tool that the Lhasa government wielded to curtail China's influence. Through an exploration of the Sichuan Route and the Maritime Route on the levels of experience and representation, this article sketches the two routes’ troubled interconnections with each other and with every twist and turn in Sino-Tibetan relations from the eighteenth to the twentieth centuries.
Cognitive decline among European retirees: impact of early retirement, nation-related and personal characteristics
Authors: Carmel Sara , Tur-Sinai Aviad
Published: March 2021

Our study aimed to enhance understanding of memory decline (MD) in old age by evaluating longitudinal effects of personal and national contributing factors. We used data collected by the Survey of Health, Ageing and Retirement in Europe (SHARE) from 12 European countries and Israel. Our sample included 11,930 retirees aged 50+, interviewed at baseline and four years later. MD was evaluated by the change in the number of recalled words from first to second interview. Except for gender, all of our explanatory variables had a significant unique effect on MD – age, education, type of occupation, European geographical region, early retirement, time elapsed from retirement, reason for retirement, active lifestyle, re-employment, health/function status, depressive symptoms, and decline in physical and mental health – over the four years of the study. Our findings indicate that MD can be postponed by national policies such as those which prolong years of education and participation in the workforce, and by social interventions directed to promote active lifestyles in late life, especially in Mediterranean and Eastern European nations.
Leaf and root attributes as growth and phosphorus uptake determinants in two grass species from South America’s natural grasslands
Authors: Marques Anderson Cesar Ramos , Quadros Fernando Luiz Ferreira de , Brunetto Gustavo , Ferigolo Leticia Frizzo , Schwalbert Raissa , Del Frari Bianca Knebel , Fernandes Gíllian Santos , Nicoloso Fernando Teixeira
Published: March 2021

Phosphorus uptake by grass species from natural South American grasslands can change depending on root and leaf attributes capable of determining higher, or lower, relative growth rate. The aim of the current study is to investigate whether leaf and root attributes capable of determining leaf and root area production in native C4 grass species Axonopus affinis and Andropogon lateralis are related to higher relative growth rate (RGR), P uptake capacity (maximum P influx; Imax) and concentration. Species grown in 2-litre pots with added nutrition solution were subjected to two treatments, namely 5 μM P l−1 and 30 μM P l−1. Solution aliquots (10 ml) were collected for 30 hours at the end of the study to determine P concentrations. RGR was 3.6 and 2.8 times higher in A. affinis than in A. lateralis in treatments with 5 μM P and 30 μM P. Axonopus affinis recorded the highest P concentration in leaf tissue. This outcome was associated with Imax 85% higher in A. affinis. High RGR was associated with larger leaf and root surface area per dry mass unit, as well as with high P influx capacity and with higher affinity transporters. These species often prevail in areas accounting for greater natural fertility and are more responsive to phosphate fertilization.
The Role of the European Education Area in European Union Integration in Times of Crises
Authors: Kushnir Iryna
Published: March 2021

The European Union has faced many crises, such as populism, xenophobia, economic and political challenges, to name a few. This has resulted in some questioning whether the EU will survive. Herein, the neo-institutionalist perspective on crises in EU integration frames an original and timely inquiry into the role of a new EU initiative – the European Education Area – in supporting EU integration in these challenging times. This inquiry relies on a thematic analysis of relevant key policy materials. The findings highlight that while it is not surprising that the EEA is an example of an education convergence project in the EU, the novelty of other findings is striking. It appears that the crises in the EU inspired the authors of the EEA to utilize its education as a tool for EU deepening, which is an aspect of EU integration related to the strengthening of the relationships amongst its Member States. Specifically, the EEA has been a driver in the development of a common European identity and European economy, the EU as a socially-just society and the continent of progress. These findings address important gaps of our knowledge about the role of education in driving EU integration.
Uncertainty and dispute resolution for blockchain and smart contract institutions
Authors: Howell Bronwyn E. , Potgieter Petrus H.
Published: March 2021

Smart contracts have been proposed as a means of revolutionizing transacting between human actors and contributing to blockchain platforms substituting for many current institutions. However, the technical nature of blockchain platforms and smart contracts requires levels of certainty and foresight sufficient for contracts to be complete. We examine the technical and economic characteristics of blockchains and smart contracts to identify sources of uncertainty that may pose challenges to the ability of these technologies to displace existing institutional arrangements, in particular, the courts and other arbitration arrangements. Despite the development of alternative automated blockchain institutions such as the Kleros dispute resolution system, the case for smart contracts and blockchain applications to supplant real-world institutions remains weak. Inherent incompleteness due to limits to information availability, human cognition, and communication means that traditional contract governance institutions will continue to complement blockchain smart contract governance arrangements. The more complex and unique the transaction, the higher the value at risk, the harder to anticipate and precisely specify contingencies and measure and observe outcomes. Furthermore, the longer the time frame between agreement and execution, the less likely it is that smart contracting will be more efficient than traditional contracting.
Signal distortions in circular dielectric waveguides at mm-wave frequencies
Authors: Meyer Andre , Schneider Martin
Published: March 2021

Despite the great progress in data transmission systems using dielectric waveguides (DWGs) in the millimeter-wave (mm-wave) frequency band (30–300 GHz), the signal distortions caused by DWGs have not yet been fully understood. However, such investigations would help to optimize DWGs as a transmission channel in order to further increase data rate and transmission distance of such systems without the need for more complex transceivers. Therefore, this paper presents a detailed study of the expected signal distortions caused by frequency-dependent attenuation and frequency-dependent group delay of circular DWGs at mm-wave frequencies. Based on a low-complexity digital transmission system, the effects of DWGs on the signal-to-noise ratio and the intersymbol interference at the receiver are evaluated. The figures and equations given in this paper allow the reader to easily calculate the channel properties and signal distortions for a wide range of circular DWGs without the need of finite element method solver or other time-consuming numerical simulations. Finally, design recommendations are given to minimize signal distortions for transmitting signals along DWGs.
Prevalence of psychiatric disorders for Indigenous Australians: a population-based birth cohort study
Authors: Ogilvie James M. , Tzoumakis Stacy , Allard Troy , Thompson Carleen , Kisely Steve , Stewart Anna
Published: March 2021

Aims

Limited information exists about the prevalence of psychiatric illness for Indigenous Australians. This study examines the prevalence of diagnosed psychiatric disorders in Indigenous Australians and compares this to non-Indigenous Australians. The aims were to: (1) determine prevalence rates for psychiatric diagnoses for Indigenous Australians admitted to hospital; and (2) examine whether the profile of psychiatric diagnoses for Indigenous Australians was different compared with non-Indigenous Australians.

Methods

A birth cohort design was adopted, with the population consisting of 45 141 individuals born in the Australian State of Queensland in 1990 (6.3% Indigenous). Linked administrative data from Queensland Health hospital admissions were used to identify psychiatric diagnoses from age 4/5 to 23/24 years. Crude lifetime prevalence rates of psychiatric diagnoses for Indigenous and non-Indigenous individuals were derived from the hospital admissions data. The cumulative incidence of psychiatric diagnoses was modelled separately for Indigenous and non-Indigenous individuals. Logistic regression was used to model differences between Indigenous and non-Indigenous psychiatric presentations while controlling for sociodemographic characteristics.

Results

There were 2783 (6.2%) individuals in the cohort with a diagnosed psychiatric disorder from a hospital admission. The prevalence of any psychiatric diagnosis at age 23/24 years was 17.2% (491) for Indigenous Australians compared with 5.4% (2292) for non-Indigenous Australians. Indigenous individuals were diagnosed earlier, with overrepresentation in psychiatric illness becoming more pronounced with age. Indigenous individuals were overrepresented in almost all categories of psychiatric disorder and this was most pronounced for substance use disorders (SUDs) (12.2 v. 2.6% of Indigenous and non-Indigenous individuals, respectively). Differences between Indigenous and non-Indigenous Australians in the likelihood of psychiatric disorders were not statistically significant after controlling for sociodemographic characteristics, except for SUDs.

Conclusions

There is significant inequality in psychiatric morbidity between Indigenous and non-Indigenous Australians across most forms of psychiatric illness that is evident from an early age and becomes more pronounced with age. SUDs are particularly prevalent, highlighting the importance of appropriate interventions to prevent and address these problems. Inequalities in mental health may be driven by socioeconomic disadvantage experienced by Indigenous individuals.
Quantifying Errors in Observationally Based Estimates of Ocean Carbon Sink Variability
Authors: Gloege Lucas , McKinley Galen A. , Landschützer Peter , Fay Amanda R. , Frölicher Thomas L. , Fyfe John C. , Ilyina Tatiana , Jones Steve , Lovenduski Nicole S. , Rodgers Keith B. , Schlunegger Sarah , Takano Yohei
Published: March 2021

Reducing uncertainty in the global carbon budget requires better quantification of ocean CO2 uptake and its temporal variability. Several methodologies for reconstructing air‐sea CO2 exchange from pCO2 observations indicate larger decadal variability than estimated using ocean models. We develop a new application of multiple Large Ensemble Earth system models to assess these reconstructions' ability to estimate spatiotemporal variability. With our Large Ensemble Testbed, pCO2 fields from 25 ensemble members each of four independent Earth system models are subsampled as the observations and the reconstruction is performed as it would be with real‐world observations. The power of a testbed is that the perfect reconstruction is known for each of the original model fields; thus, reconstruction skill can be comprehensively assessed. We find that a neural‐network approach can skillfully reconstruct air‐sea CO2 fluxes when it is trained with sufficient data. Flux bias is low for the global mean and Northern Hemisphere, but can be regionally high in the Southern Hemisphere. The phase and amplitude of the seasonal cycle are accurately reconstructed outside of the tropics, but longer‐term variations are reconstructed with only moderate skill. For Southern Ocean decadal variability, insufficient sampling leads to a 31% (15%:58%, interquartile range) overestimation of amplitude, and phasing is only moderately correlated with known truth (r = 0.54 [0.46:0.63]). Globally, the amplitude of decadal variability is overestimated by 21% (3%:34%). Machine learning, when supplied with sufficient data, can skillfully reconstruct ocean properties. However, data sparsity remains a fundamental limitation to quantification of decadal variability in the ocean carbon sink.
Influencing Indicators and Spatial Variation of Diabetes Mellitus Prevalence in Shandong, China: A Framework for Using Data‐Driven and Spatial Methods
Authors: Li Yizhuo , Fei Teng , Wang Jian , Nicholas Stephen , Li Jun , Xu Lizheng , Huang Yanran , Li Hanqi
Published: March 2021

To control and prevent the risk of diabetes, diabetes studies have identified the need to better understand and evaluate the associations between influencing indicators and the prevalence of diabetes. One constraint has been that influencing indicators have been selected mainly based on subjective judgment and tested using traditional statistical modeling methods. We proposed a framework new to diabetes studies using data‐driven and spatial methods to identify the most significant influential determinants of diabetes automatically and estimated their relationships. We used data from diabetes mellitus patients' health insurance records in Shandong province, China, and collected influencing indicators of diabetes prevalence at the county level in the sociodemographic, economic, education, and geographical environment domains. We specified a framework to identify automatically the most influential determinants of diabetes, and then established the relationship between these selected influencing indicators and diabetes prevalence. Our autocorrelation results showed that the diabetes prevalence in 12 Shandong cities was significantly clustered (Moran'sI = 0.328,p < 0.01). In total, 17 significant influencing indicators were selected by executing binary linear regressions and lasso regressions. The spatial error regressions in different subgroups were subject to different diabetes indicators. Some positive indicators existed significantly like per capita fruit production and other indicators correlated with diabetes prevalence negatively like the proportion of green space. Diabetes prevalence was mainly subjected to the joint effects of influencing indicators. This framework can help public health officials to inform the implementation of improved treatment and policies to attenuate diabetes diseases.
Configuration of the Earth’s Magnetotail Current Sheet
Authors: Artemyev Anton , Lu San , El‐Alaoui Mostafa , Lin Yu , Angelopoulos Vassilis , Zhang Xiao‐Jia , Runov Andrei , Vasko Ivan , Zelenyi Lev , Russell Christopher
Published: March 2021

The spatial scale and intensity of Earth’s magnetotail current sheet determine the magnetotail configuration, which is critical to one of the most energetically powerful phenomena in the Earth’s magnetosphere, substorms. In the absence of statistical information about plasma currents, theories of the magnetotail current sheets were mostly based on the isotropic stress balance. Such models suggest that thin current sheets cannot be long and should have strong plasma pressure gradients along the magnetotail. Using Magnetospheric Multiscale and THEMIS observations and global simulations, we explore realistic configuration of the magnetotail current sheet. We find that the magnetotail current sheet is thinner than expected from theories that assume isotropic stress balance. Observed plasma pressure gradients in thin current sheets are insufficiently strong (i.e., current sheets are too long) to balance the magnetic field line tension force. Therefore, pressure anisotropy is essential in the configuration of thin current sheets where instability precedes substorm onset.
Grain Size Variations Record Segregation of Residual Melts in Slow‐Spreading Oceanic Crust (Atlantis Bank, 57°E Southwest Indian Ridge)
Authors: Ferrando C. , France L. , Basch V. , Sanfilippo A. , Tribuzio R. , Boulanger M.
Published: March 2021

Beneath slow‐spreading ridges, melt bodies are generally considered to represent ephemeral magma reservoirs filled with crystal mushes. Formation of the oceanic crust requires at least partial extraction of melts from these crystal mushes. However, melts collection and extraction are processes yet to be fully constrained. We investigate olivine gabbros from the plutonic section recovered at the IODP Hole U1473A, in the Atlantis Bank Oceanic Core Complex (Southwest Indian Ridge), to unravel (i) the process of melt migration through lower crustal crystal mushes, and (ii) the collection and segregation of melts forming discrete microgabbro intervals. Throughout the Hole, fine‐ to coarse‐grained intervals are widespread in olivine gabbros. Along the contacts, coarse‐grained minerals display resorbed grain boundaries against the fine‐grained minerals, suggesting partial dissolution by the melt crystallizing the fine‐grained material. Coarse‐grained plagioclase and clinopyroxene are zoned, showing progressive chemical evolution from more primitive crystal cores to more evolved crystal rims. Fine‐grained minerals are unzoned and chemically similar to rims of coarse‐grained minerals, indicating a genetic relationship. We attribute significant enrichments in the most incompatible elements of plagioclase and clinopyroxene to a magma evolution process associated with reactive melt migration. As temperature decreased, melts residual from the reactive processes were segregated in magma pockets that ultimately crystallize the fine‐grained intervals (microgabbros). We document, for the first time, that these microgabbros are crystallization products of melts modified by reactive melt migration; the melts were extracted from the crystal mush and accumulated into discrete melt‐rich zones. This process could have promoted partial extraction of those melts that in turn potentially contribute to Mid Ocean Ridge Basalts erupted at the seafloor.
The Horizontal Slab Beneath East Asia and Its Subdued Surface Dynamic Response
Authors: Liu Shaofeng , Ma Pengfei , Zhang Bo , Gurnis Michael
Published: March 2021

The kinematics of plate tectonics, deformation, and dynamic topography are strong indicators of coupling between plates and the mantle. East Asia is characterized by the presence of an unusually large horizontal slab that lies within the mantle transition zone. How this feature evolved and is linked to plate tectonics, deformation, and topography is poorly understood. Here, we show four‐dimensional geodynamic modeling results constrained by a new deforming plate reconstruction that fits mantle architecture inferred from seismic tomography. We find that the subducted western Pacific slab was progressively torn by the Philippine Sea plate rotating clockwise during the Miocene and that northwestward mantle flow contributed to shaping the horizontal slab during subduction, leading to dynamic subsidence along the East Asia margin. The rather subdued change in dynamic topography, predicted from those models that fit the horizontal slab in the mantle, is consistent with the variation in residual topography, recorded in the stratigraphy, within only about ±200 m over the last 50 Myr during a period of no large marine inundation or retreat. The tectonics and topography of East Asia strongly contrast with those of Southeast Asia and are reflective of slabs ephemerally stagnating in the mantle below East Asia while avalanching into the lower mantle below Southeast Asia.
New Uppermost Mantle Pn Velocity and Anisotropy Model of the Eastern Caribbean
Authors: Lü Yan , Liu Jiaqi , He Yuhui , Guan Yurui
Published: March 2021

Using the Pn tomography method and new ISC‐EHB data, we obtained a new Pn velocity and anisotropy model of the uppermost mantle in eastern Caribbean. The consistency between the Pn fast directions and SKS splitting fast wave directions indicates that the anisotropic structure of the uppermost mantle in the area of the collisional plate boundary is the main cause of shear‐wave splitting. The results show that the seismic velocity of uppermost mantle beneath the Aves Ridge is not anomalous, implying that this area is no longer affected by the upwelling of mantle material. We observe high Pn velocities in the uppermost mantle beneath eastern Caribbean Sea, which are higher than in the deeper parts (100–200 km in depth) of the upper mantle; comparing these results with similar findings in the Japan Sea at the northwestern Pacific subduction zone, we believe the uppermost mantle beneath the back‐arc region is not or little affected by hot material from the deeper mantle.
Eddy‐Driven Transport of Particulate Organic Carbon‐Rich Coastal Water Off the West Antarctic Peninsula
Authors: Castelao Renato M. , Dinniman Michael S. , Amos Caitlin M. , Klinck John M. , Medeiros Patricia M.
Published: March 2021

The Southern Ocean is characterized by high eddy activity and high particulate organic carbon (POC) content during summer, especially near Antarctica. Because it encircles the globe, it provides a pathway for inter‐basin exchange. Here, we use satellite observations and a high‐resolution ocean model to quantify offshore transport of coastal water rich in POC off the West Antarctic Peninsula. We show that nonlinear cyclonic eddies generated near the coast often trap coastal water rich in POC during formation before propagating offshore. As a result, cyclones found offshore that were generated near the coast have on average higher POC content in their interior than cyclones generated locally offshore. This results in a POC enrichment of 5.7 ± 3.0 Gg C year−1 in offshore waters off the Peninsula. Actual POC enrichment is likely substantially larger, since about half of the volume transport of coastal water is driven by small eddies that are missed by observations.
Surface Ozone in the Yangtze River Delta, China: A Synthesis of Basic Features, Meteorological Driving Factors, and Health Impacts
Authors: Zhan Chenchao , Xie Min , Liu Jane , Wang Tijian , Xu Meng , Chen Bing , Li Shu , Zhuang Bingliang , Li Mengmeng
Published: March 2021

Ozone (O3) is of great importance to air quality in the Yangtze River Delta (YRD) region, China. Focusing on surface O3 in the YRD, its spatiotemporal characteristics, meteorological driving factors, and health impacts are investigated based on surface O3 observations in this study. We find that from 2015 to 2019, most cities failed to meet the national standards and O3 pollution mainly occurred in warm seasons (April‐September). Surface O3 in the YRD increased in the recent years, so did tropospheric column O3. Spatially, surface shows a significant positive autocorrelation over the YRD except for 2019, and high O3 values mainly gather in the central of the YRD. The first two empirical orthogonal functions (EOFs) of O3 accounted for 37.4% and 20.0% of the total variance in O3, respectively, with their spatial patterns characterized by the same phase and west and east contrast, respectively. The EOF1 is related to the change in radiation and the EOF2 is attributed to regional transport by prevailing westerly wind. Downward UV radiation, temperature and u wind are crucial factors. The premature mortality caused by O3 for respiratory disease in the YRD is estimated to be 5,889 cases per year. Furthermore, we find that premature mortality is more sensitive to O3 concentration than population, suggesting that controlling peak O3 concentration can bring great health benefits.
Reply to the Comment by Bábek et al. on Hypogenic Versus Epigenic Origin of Deep Underwater Caves Illustrated by the Hranice Abyss (Czech Republic)—The World’s Deepest Freshwater Cave: Can the Hranice Abyss, the Deepest Underwater Cave in the World, Really Reach 1 km Depth?
Authors: Kadlec Jaroslav , Klanica Radek , Tábořík Petr , Mrlina Jan , Valenta Jan , Kováčiková Světlana , Hill Graham J.
Published: March 2021

Comment by Bábek et al. (2020, https://doi.org/10.1029/2020JF005916) is concerning the interpretation of realized geophysical measurements. Since, to our knowledge, Klanica et al. (2020, https://doi.org/10.1029/2020JF005663) conducted the deepest geophysical surveys in the area, a scale of work was probably misunderstood within the interpretation of our results. Second, a large number of objections arise from the comment about the post‐Badenian geological development at the eastern margin of the Bohemian Massif. However, evidence for the time when particular geological processes took place is not definite and our conclusions of our study can be related to early Badenian age.
Extreme Precipitation Across Adjacent Burned and Unburned Watersheds Reveals Impacts of Low Severity Wildfire on Debris‐Flow Processes
Authors: McGuire Luke A. , Youberg Ann M. , Rengers Francis K. , Abramson Nathan S. , Ganesh Indujaa , Gorr Alexander N. , Hoch Olivia , Johnson Justin C. , Lamom Patt , Prescott Alexander B. , Zanetell Jessica , Fenerty Brendan
Published: March 2021

In steep landscapes, wildfire‐induced changes to soil and vegetation can lead to extreme and hazardous geomorphic responses, including debris flows. The wildfire‐induced mechanisms that lead to heightened geomorphic responses, however, depend on many site‐specific factors including regional climate, vegetation, soil texture, and soil burn severity. As climate and land use change drive changes in fire regime, there is an increasing need to understand how fire alters geomorphic responses, particularly in areas where fire has been historically infrequent. Here, we examine differences in the initiation, magnitude, and particle‐size distribution of debris flows that initiated within the area burned by the 2019 Woodbury Fire in central Arizona, USA, and those that initiated in a nearby unburned area. Despite similar rainfall intensities, unburned watersheds were less likely to produce debris flows. Debris flows in unburned areas initiated from both runoff and shallow landslides, while debris flows only initiated from runoff‐related processes in the burned area. The grain‐size distribution making up the matrix of debris‐flow deposits within the burned area generally had a lower ratio of sand to silt relative to debris flows that initiated in the unburned area, though there were no systematic differences in the coarse fraction of debris‐flow sediment between burned and unburned areas. Results help expand our ability to predict postwildfire debris‐flow activity in a wider range of settings, specifically the Sonoran Desert ecoregion, and provide general insight into the impact of wildfire on geomorphic processes in steep terrain.
Not all Icequakes are Created Equal: Basal Icequakes Suggest Diverse Bed Deformation Mechanisms at Rutford Ice Stream, West Antarctica
Authors: Kufner Sofia‐Katerina , Brisbourne Alex M. , Smith Andrew M. , Hudson Thomas S. , Murray Tavi , Schlegel Rebecca , Kendall John M. , Anandakrishnan Sridhar , Lee Ian
Published: March 2021

Microseismicity, induced by the sliding of a glacier over its bed, can be used to characterize frictional properties of the ice‐bed interface, which are a key parameter controlling ice stream flow. We use naturally occurring seismicity to monitor spatiotemporally varying bed properties at Rutford Ice Stream, West Antarctica. We locate 230,000 micro‐earthquakes with local magnitudes from −2.0 to −0.3 using 90 days of recordings from a 35‐station seismic network located ∼40 km upstream of the grounding line. Events exclusively occur near the ice‐bed interface and indicate predominantly flow‐parallel stick‐slip. They mostly lie within a region of interpreted stiff till and along the likely stiffer part of mega‐scale glacial lineations. Within these regions, micro‐earthquakes occur in spatially (<100 m radius) and temporally (mostly 1–5 days activity) restricted event‐clusters (up to 4,000 events), which exhibit an increase, followed by a decrease, in event magnitude with time. This may indicate event triggering once activity is initiated. Although ocean tides modulate the surface ice flow velocity, we observe little periodic variation in overall event frequency over time and conclude that water content, bed topography and stiffness are the major factors controlling microseismicity. Based on variable rupture mechanisms and spatiotemporal characteristics, we suggest the event‐clusters relate to three end‐member types of bed deformation: (1) continuous creation and seismogenic destruction of small‐scale bed‐roughness, (2) ploughed clasts, and (3) flow‐oblique deformation during landform formation or along bedrock outcrops. This indicates that multiple processes, simultaneously active during glacial sliding, can accommodate stick‐slip behavior and that the bed continuously reorganizes.
Inherent Dissipation of Upwind‐Biased Potential Temperature Advection and its Feedback on Model Dynamics
Authors: Gassmann A.
Published: March 2021

Higher order upwind‐biased advection schemes are often used for potential temperature advection in dynamical cores of atmospheric models. The inherent diffusive and antidiffusive fluxes are interpreted here as the effect of irreversible sub‐gridscale dynamics. For those, total energy conservation and positive internal entropy production must be guaranteed. As a consequence of energy conservation, the pressure gradient term should be formulated in Exner pressure form. The presence of local antidiffusive fluxes in potential temperature advection schemes foils the validity of the second law of thermodynamics. Due to this failure, a spurious wind acceleration into the wrong direction is locally induced via the pressure gradient term. When correcting the advection scheme to be more entropically consistent, the spurious acceleration is avoided, but two side effects come to the fore: (i) the overall accuracy of the advection scheme decreases and (ii) the now purely diffusive fluxes become more discontinuous compared to the original ones, which leads to more sudden body forces in the momentum equation. Therefore, the amplitudes of excited gravity waves from jets and fronts increase compared to the original formulation with inherent local antidiffusive fluxes. The means used for supporting the argumentation line are theoretical arguments concerning total energy conservation and internal entropy production, pure advection tests, one‐dimensional advection‐dynamics interaction tests and evaluation of runs with a global atmospheric dry dynamical core.
Bentho‐Pelagic Decoupling: The Marine Biological Carbon Pump During Eocene Hyperthermals
Authors: Griffith Elizabeth M. , Thomas Ellen , Lewis Angela R. , Penman Donald E. , Westerhold Thomas , Winguth Arne M. E.
Published: March 2021

Future environmental change may profoundly affect oceanic ecosystems in a complex way, due to the synergy between rising temperatures, reduction in mixing and upwelling due to enhanced stratification, ocean acidification, and associated biogeochemical dynamics. Changes in primary productivity, in export of organic carbon from the surface ocean, and in remineralization deeper in the water column in the so‐called “twilight zone” may substantially alter the marine biological carbon pump, thus carbon storage in the oceans. We present different proxy records commonly used for reconstructing paleoproductivity, and re‐evaluate their use for understanding dynamic change within and between different constituents of the marine biological pump during transient global warming episodes in the past. Marine pelagic barite records are a proxy for carbon export from the photic and/or mesopelagic zone, and are not positively correlated with benthic foraminiferal proxies for arrival of organic matter to the seafloor over three early Eocene periods of global warming (Ocean Drilling Program Site 1263, SE Atlantic). These two proxies reflect processes in different parts of the water column, thus different components of the biological pump. An increase in temperature‐dependent organic carbon remineralization in the water column would have caused decreased arrival of food at the seafloor, starving the benthic biota and explaining the differences between the proxies, and may have led to ocean deoxygenation. Carbon cycle modeling demonstrates the feasibility of enhanced water‐column remineralization to explain both Site 1263 records, suggesting that this mechanism amplifies pCO2 increase, representing a positive feedback during hyperthermal warming.
PKD3 promotes metastasis and growth of oral squamous cell carcinoma through positive feedback regulation with PD-L1 and activation of ERK-STAT1/3-EMT signalling
Authors: Cui Bomiao , Chen Jiao , Luo Min , Liu Yiying , Chen Hongli , Lü Die , Wang Liwei , Kang Yingzhu , Feng Yun , Huang Libin , Zhang Ping
Published: March 2021

Oral squamous cell carcinoma (OSCC) has a high incidence of metastasis. Tumour immunotherapy targeting PD-L1 or PD-1 has been revolutionary; however, only a few patients with OSCC respond to this treatment. Therefore, it is essential to gain insights into the molecular mechanisms underlying the growth and metastasis of OSCC. In this study, we analysed the expression levels of protein kinase D3 (PKD3) and PD-L1 and their correlation with the expression of mesenchymal and epithelial markers. We found that the expression of PKD3 and PD-L1 in OSCC cells and tissues was significantly increased, which correlated positively with that of mesenchymal markers but negatively with that of epithelial markers. Silencing PKD3 significantly inhibited the growth, metastasis and invasion of OSCC cells, while its overexpression promoted these processes. Our further analyses revealed that there was positive feedback regulation between PKD3 and PD-L1, which could drive EMT of OSCC cells via the ERK/STAT1/3 pathway, thereby promoting tumour growth and metastasis. Furthermore, silencing PKD3 significantly inhibited the expression of PD-L1, and lymph node metastasis of OSCC was investigated with a mouse footpad xenograft model. Thus, our findings provide a theoretical basis for targeting PKD3 as an alternative method to block EMT for regulating PD-L1 expression and inhibiting OSCC growth and metastasis.
Non-antibiotic pharmaceuticals promote the transmission of multidrug resistance plasmids through intra- and intergenera conjugation
Authors: Wang Yue , Lu Ji , Zhang Shuai , Li Jie , Mao Likai , Yuan Zhiguo , Bond Philip L , Guo Jianhua
Published: March 2021

Antibiotic resistance is a global threat to public health. The use of antibiotics at sub-inhibitory concentrations has been recognized as an important factor in disseminating antibiotic resistance via horizontal gene transfer. Although non-antibiotic, human-targeted pharmaceuticals are widely used by society (95% of the pharmaceuticals market), the potential contribution to the spread of antibiotic resistance is not clear. Here, we report that commonly consumed, non-antibiotic pharmaceuticals, including nonsteroidal anti-inflammatories (ibuprofen, naproxen, diclofenac), a lipid-lowering drug (gemfibrozil), and a β-blocker (propranolol), at clinically and environmentally relevant concentrations, significantly accelerated the dissemination of antibiotic resistance via plasmid-borne bacterial conjugation. Various indicators were used to study the bacterial response to these drugs, including monitoring reactive oxygen species (ROS) and cell membrane permeability by flow cytometry, cell arrangement, and whole-genome RNA and protein sequencing. Enhanced conjugation correlated well with increased production of ROS and cell membrane permeability. Additionally, these non-antibiotic pharmaceuticals induced responses similar to those detected when bacteria are exposed to antibiotics, such as inducing the SOS response and enhancing efflux pumps. The findings advance understanding of the transfer of antibiotic resistance genes, emphasizing the concern that non-antibiotic, human-targeted pharmaceuticals enhance the spread of antibiotic resistance among bacterial populations.
Correction: Phosphatase, pseudo-phosphatase, or both? Understanding PRL oncogenicity
Authors: Gehring Kalle , Miki Hiroaki
Published: March 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41416-021-01311-2
CTRP12 ameliorates atherosclerosis by promoting cholesterol efflux and inhibiting inflammatory response via the miR-155-5p/LXRα pathway
Authors: Wang Gang , Chen Jiao-Jiao , Deng Wen-Yi , Ren Kun , Yin Shan-Hui , Yu Xiao-Hua
Published: March 2021

C1q tumor necrosis factor-related protein 12 (CTRP12), a conserved paralog of adiponectin, is closely associated with cardiovascular disease. However, little is known about its role in atherogenesis. The aim of this study was to examine the influence of CTRP12 on atherosclerosis and explore the underlying mechanisms. Our results showed that lentivirus-mediated CTRP12 overexpression inhibited lipid accumulation and inflammatory response in lipid-laden macrophages. Mechanistically, CTRP12 decreased miR-155-5p levels and then increased its target gene liver X receptor α (LXRα) expression, which increased ATP binding cassette transporter A1 (ABCA1)- and ABCG1-dependent cholesterol efflux and promoted macrophage polarization to the M2 phenotype. Injection of lentiviral vector expressing CTRP12 decreased atherosclerotic lesion area, elevated plasma high-density lipoprotein cholesterol levels, promoted reverse cholesterol transport (RCT), and alleviated inflammatory response in apolipoprotein E-deficient (apoE−/−) mice fed a Western diet. Similar to the findings of in vitro experiments, CTRP12 overexpression diminished miR-155-5p levels but increased LXRα, ABCA1, and ABCG1 expression in the aortas of apoE−/− mice. Taken together, these results suggest that CTRP12 protects against atherosclerosis by enhancing RCT efficiency and mitigating vascular inflammation via the miR-155-5p/LXRα pathway. Stimulating CTRP12 production could be a novel approach for reducing atherosclerosis.
Single-cell analysis reveals the origins and intrahepatic development of liver-resident IFN-γ-producing γδ T cells
Authors: Hu Yuan , Fang Keke , Wang Yanan , Lu Nan , Sun Haoyu , Zhang Cai
Published: March 2021

γδ T cells are heterogeneous lymphocytes located in various tissues. However, a systematic and comprehensive understanding of the origins of γδ T cell heterogeneity and the extrathymic developmental pathway associated with liver γδ T cells remain largely unsolved. In this study, we performed single-cell RNA sequencing (scRNA-seq) to comprehensively catalog the heterogeneity of γδ T cells derived from murine liver and thymus samples. We revealed the developmental trajectory of γδ T cells and found that the liver contains γδ T cell precursors (pre-γδ T cells). The developmental potential of hepatic γδ T precursor cells was confirmed through in vitro coculture experiments and in vivo adoptive transfer experiments. The adoptive transfer of hematopoietic progenitor Lin−Sca-1+Mac-1+ (LSM) cells from fetal or adult liver samples to sublethally irradiated recipients resulted in the differentiation of liver LSM cells into pre-γδ T cells and interferon-gamma+ (IFN-γ+) but not interleukin-17a+ (IL-17a+) γδ T cells in the liver. Importantly, thymectomized mouse models showed that IFN-γ-producing γδ T cells could originate from liver LSM cells in a thymus-independent manner. These results suggested that liver hematopoietic progenitor LSM cells were able to differentiate into pre-γδ T cells and functionally mature γδ T cells, which implied that these cells are involved in a distinct developmental pathway independent of thymus-derived γδ T cells.
Epidemiology of moderately severe and severe non-proliferative diabetic retinopathy in South West England
Authors: Nevill Clareece R. , Stratton Irene M. , Maruti Sonia S. , Massó-González Elvira L. , Sivaprasad Sobha , Bailey Clare , Ehrlich Michael , Chong Victor , Scanlon Peter H.
Published: March 2021

Aims

To estimate the incidence of early treatment diabetic retinopathy study (ETDRS) level 47 and 53 and progression to treatment with panretinal photocoagulation (PRP) for proliferative DR (PDR).

Methods

Log-linear regression was used to estimate the incidence of level 47–53 or worse for 33,009 people with diabetes (PWD) in Gloucestershire during 2013–2016 by calendar year and diabetes type, based on the first recording. Progression was analysed in Gloucestershire and Bristol with a parametric survival analysis examining the association of baseline and time-varying demographic and clinical factors on time to PRP after the first recording of level 47–53.

Results

Incidence decreased from 0.57 (95% confidence intervals (CI) 0.48–0.67) per 100 PWD in 2013 to 0.35 (95% CI 0.29–0.43) in 2016 (p < 0.001). For progression, 338 eligible PWD from Gloucestershire and 418 from Bristol were followed for a median of 1.4 years; 78 and 83% had Type 2 diabetes and a median (interquartile range) of 15 (10–22) and 17 (11–25) years duration of diagnosed diabetes respectively. Three years from the incident ETDRS 47–53, 18.9% and 17.2% had received PRP respectively. For Gloucestershire, severe IRMA and updated mean HbA1c were associated with an increase in the risk of initiating PRP (hazard ratio 3.14 (95% CI: 1.60–6.15) and 1.21 (95% CI: 1.06–1.38 per 10 mmol/mol) respectively).

Conclusion

This study provides additional understanding of this population and shows that a high proportion of patients with ETDRS levels 47–53 need to be monitored as they are at high risk of progressing to PDR.
Functional expression of complement factor I following AAV-mediated gene delivery in the retina of mice and human cells
Authors: Dreismann Anna K. , McClements Michelle E. , Barnard Alun R. , Orhan Elise , Hughes Jane P. , Lachmann Peter J. , MacLaren Robert E.
Published: March 2021

Dry age-related macular degeneration (AMD) is characterised by loss of central vision and currently has no approved medical treatment. Dysregulation of the complement system is thought to play an important role in disease pathology and supplementation of Complement Factor I (CFI), a key regulator of the complement system, has the potential to provide a treatment option for AMD. In this study, we demonstrate the generation of AAV constructs carrying the human CFI sequence and expression of CFI in cell lines and in the retina of C57BL/6 J mice. Four codon optimised constructs were compared to the most common human CFI sequence. All constructs expressed CFI protein; however, most codon optimised sequences resulted in significantly reduced CFI secretion compared to the non-optimised CFI sequence. In vivo expression analysis showed that CFI was predominantly expressed in the RPE and photoreceptors. Secreted protein in vitreous humour was demonstrated to be functionally active. The findings presented here have led to the formulation of an AAV-vectored gene therapy product currently being tested in a first-in-human clinical trial in subjects with geographic atrophy secondary to dry AMD (NCT03846193).
Overexpression of angiotensin-converting enzyme 2 by renin-angiotensin system inhibitors. Truth or myth? A systematic review of animal studies
Authors: Kai Hisashi , Kai Mamiko , Niiyama Hiroshi , Okina Norihito , Sasaki Motoki , Maeda Takanobu , Katoh Atsushi
Published: March 2021

Angiotensin-converting enzyme 2 (ACE2) protects against organ damage in hypertension and cardiovascular diseases by counter regulating the renin-angiotensin system (RAS). ACE2 is also the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on the claim that RAS inhibitors (RASIs) cause ACE2 overexpression in some animal experiments, concerns have arisen that RASIs may aggravate SARS-CoV-2 infection and coronavirus disease-2019 severity in RASI-treated patients. To achieve a comprehensive review, a systematic search of MEDLINE/PubMed was conducted regarding the effects of RASIs on tissue ACE2 mRNA/protein expression in healthy animals and animal models of human diseases. We identified 88 eligible articles involving 168 experiments in the heart, kidneys, lungs, and other organs. Three of 38 experiments involving healthy animals showed ACE2 expression greater than twice that of the control (overexpression). Among 102 disease models (130 experiments), baseline ACE2 was overexpressed in 16 models (18 experiments) and less than half the control level (repression) in 28 models (40 experiments). In 72 experiments, RASIs did not change ACE2 levels from the baseline levels of disease models. RASIs caused ACE2 overexpression compared to control levels in seven experiments, some of which were unsupported by other experiments under similar conditions. In 36 experiments, RASIs reversed or prevented disease-induced ACE2 repression, yielding no or marginal changes. Therefore, ACE2 overexpression appears to be a rare rather than common consequence of RASI treatment in healthy animals and disease models. Future studies should clarify the pathophysiological significance of RASI-induced reversal or prevention of ACE2 repression in disease models.
Missense mutation of Fmr1 results in impaired AMPAR-mediated plasticity and socio-cognitive deficits in mice
Authors: Prieto Marta , Folci Alessandra , Poupon Gwénola , Schiavi Sara , Buzzelli Valeria , Pronot Marie , François Urielle , Pousinha Paula , Lattuada Norma , Abelanet Sophie , Castagnola Sara , Chafai Magda , Khayachi Anouar , Gwizdek Carole , Brau Frédéric , Deval Emmanuel , Francolini Maura , Bardoni Barbara , Humeau Yann , Trezza Viviana , Martin Stéphane
Published: March 2021

Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and the best-described monogenic cause of autism. CGG-repeat expansion in the FMR1 gene leads to FMR1 silencing, loss-of-expression of the Fragile X Mental Retardation Protein (FMRP), and is a common cause of FXS. Missense mutations in the FMR1 gene were also identified in FXS patients, including the recurrent FMRP-R138Q mutation. To investigate the mechanisms underlying FXS caused by this mutation, we generated a knock-in mouse model (Fmr1R138Q) expressing the FMRP-R138Q protein. We demonstrate that, in the hippocampus of the Fmr1R138Q mice, neurons show an increased spine density associated with synaptic ultrastructural defects and increased AMPA receptor-surface expression. Combining biochemical assays, high-resolution imaging, electrophysiological recordings, and behavioural testing, we also show that the R138Q mutation results in impaired hippocampal long-term potentiation and socio-cognitive deficits in mice. These findings reveal the functional impact of the FMRP-R138Q mutation in a mouse model of FXS.